WO2011038155A2 - Analyse génétique - Google Patents

Analyse génétique Download PDF

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Publication number
WO2011038155A2
WO2011038155A2 PCT/US2010/050054 US2010050054W WO2011038155A2 WO 2011038155 A2 WO2011038155 A2 WO 2011038155A2 US 2010050054 W US2010050054 W US 2010050054W WO 2011038155 A2 WO2011038155 A2 WO 2011038155A2
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WO
WIPO (PCT)
Prior art keywords
panel
phenotype
genetic
specialist
dog
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PCT/US2010/050054
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English (en)
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WO2011038155A3 (fr
Inventor
Brandon Colby
Andrew Norman
Bethany Slater
Melvyn Colby
Bryon Colby
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Existence Genetics Llc
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Application filed by Existence Genetics Llc filed Critical Existence Genetics Llc
Priority to EP10819485A priority Critical patent/EP2480690A2/fr
Priority to CA2775345A priority patent/CA2775345A1/fr
Publication of WO2011038155A2 publication Critical patent/WO2011038155A2/fr
Publication of WO2011038155A3 publication Critical patent/WO2011038155A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B10/00—ICT specially adapted for evolutionary bioinformatics, e.g. phylogenetic tree construction or analysis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention generally relates to biology and genetics. More specifically, the invention relates to methods and compositions for genetic analysis of an organism.
  • the genomes of organisms contain a vast amount of information that can be mined in order to predict, identify, or describe phenotypes of an organism, such as diseases, conditions, disorders, traits, characteristics, morphology, biochemical properties, or physiologic properties. Phenotypes can also be affected, determined, or predicted from non-genetic factors, or from some combination of genetic and non-genetic factors. There is an unmet need for an intelligent approach to using genetic and non- genetic information to predict, identify, analyze or describe phenotypes in an organism.
  • a first aspect provided herein is a method of determining an organ system score of an organism comprising: identifying a set of genetic variants in an organism, wherein said genetic variants relate to an organ system phenotype; calculating the predisposition or carrier status of said organism for at least two phenotypes wherein said predisposition or carrier status is based on said set of genetic variants; combining the results of the previous step to obtain an organ system score; and, reporting said organ system score to said organism, a health care provider of said organism, or a third party.
  • reporting an organ system score may comprise reporting to an organism's veterinarian, a herder, a rancher, a company that owns the organism, an individual who owns the organism, and/or an organism's caretaker.
  • a second aspect provided herein is a method of determining an overall genetic health score of an organism comprising: identifying a set of genetic variants in an organism; calculating two or more organ system scores according to the first 3 steps of the first aspect; combining said two or more organ system scores to obtain an overall genetic health score; and, reporting said overall genetic health score in a report to said organism, a health care provider of said organism, or third party.
  • reporting an overall genetic health score may comprise reporting to an organism's veterinarian, a herder, a rancher, a company that owns the organism, an individual who owns the organism, and/or an organism's caretaker.
  • said organ system is selected from the group consisting of: cardiovascular; heart; lung; dermatology; development and learning; ear, nose, and throat; dental; endocrinology; pancreas; thyroid; gastroenterology; hepatology; liver; gall bladder; gynecology; hematology and oncology; immunology; allergy; lactation system, central nervous system, psychological system including but not limited to temperament, infectious diseases; men's health; metabolic diseases; rare diseases; male health; musculoskeletal; neonatology; neurology; obstetrics; ophthalmology; pharmacology, toxicology; anesthesiology; psychiatry; reproductive health, rheumatology; sexuality; fertility; sleep medicine; surgery; syndromes; temperament, laryngology; traits and special abilities; obstetrics, otology; urology and nephrology; and vascular; geriatric health; and female health.
  • said organ system score in said report is divided into two or more specific phenotypes.
  • at least one of said phenotypes is a rare disease.
  • at least one of said phenotypes follows monogenic inheritance.
  • at least one of said phenotypes follows multifactorial or polygenic inheritance.
  • at least one of said phenotypes follows monogenic inheritance; and at least one of said phenotypes follows multifactorial or polygenic inheritance.
  • said reporting is by e-mail, a website, paper, a telephone call, on a CD-ROM, on an electornic storage device, a text message, or in person.
  • said reporting is by transmission over a network.
  • the methods further comprise providing a pedigree analysis of said organism to said organism's owner, organism's potential owner, organism's caretaker, a veterinarian or other healthcare provider of said organism, a herder, a rancher, a government agency, an entity, or third party.
  • the methods further comprise providing a medical recommendation based on said score by a veterinarian, biologist, physician, or other qualified person to said organism's owner, organism's potential owner, organism's caretaker, a veterinarian or other healthcare provider of said organism, a government agency, an entity, or third party.
  • said veterinarian is a generalist.
  • said veterinarian, biologist, breeder, specialist in the field, or researcher is selected from the group consisting of: artificial insemination specialist, anesthesiologist, bacteriologist, cattle specialist, cat specialist, cardiologist, chicken specialist, cloning specialist, dermatologist, dog specialist, endocrinologist, gastroenterologist, geneticist, goat specialist, governmental agency representative, cultivator, hematologist, horse specialist, infectious disease specialist, immunologist, fertility specialist, mouse specialist, nutrition and obesity specialist, neurologist, obstetrician, gynecologist, oncologist, ophthalmologist, pig specialist, pharmacologist, primate specialist, psychiatrist, pulmonologist, rancher, rat specialist, reproduction specialist, rheumatologist, surgeon, transgenic specialist, urologist, virologist.
  • said set of genetic variants comprises genetic variants for at least five genes. In other embodiments of the methods of the first two aspects, said set of genetic variants comprises at least two genetic variants, each of which is correlated to the same phenotype. In some embodiments of the methods of the first two aspects, said set of genetic variants comprises at least 10 single nucleotide polymorphisms. In some embodiments of the methods of the first two aspects, said set of genetic variants comprises at least 50 single nucleotide polymorphisms, wherein each SNP is correlated to a phenotype. In some embodiments of the methods of the first two aspects, said set of genetic variants comprises at least one SNP sequence not listed in a public database, wherein said at least one SNP sequence is correlated to a phenotype.
  • calculating of said score includes the gender, breed, strain, age, weight, purpose of organism (including but not limited to companion to humans, work-related, production-related, transgenic related, food-related, environment-related, aesthetic -related), where organism will be born and live (including but not limited to a country farm, a city farm, a farm with less than 100 animals, a farm with more than 100 animals, a farm with more than 1,000 animals, a farm with more than 10,000 animals, an urban household with children, an urban household without children, a fishery, a stable, a mill, a ranch, a field, a greenhouse, a valley, a mountain, and/or free-range).
  • purpose of organism including but not limited to companion to humans, work-related, production-related, transgenic related, food-related, environment-related, aesthetic -related
  • organism will be born and live (including but not limited to a country farm, a city farm, a farm with less than 100 animals, a farm with more than 100 animals, a farm with more than 1,000 animals
  • said reporting is performed within one week of the first step. In some embodiments of the methods of the first two aspects, said reporting is performed only when a decreased predisposition for said phenotype is determined. In some embodiments of the methods of the first two aspects, said reporting is performed only when an increased predisposition for said phenotype is determined. In some embodiments of the methods of the first two aspects, said at least two phenotypes are selected.
  • said calculating is performed by consulting a database comprising at least one scientific article about a study that shows a correlation or association between at least one genetic variant and at least one phenotype.
  • said scientific article is ranked against other scientific articles based on one or more of the following factors: the number of organisms in the phenotype cohort of said study, the number of organisms in control cohort of said study, the total number of organisms in said study, the caliber of the institution that conducted said study, the place said study was conducted, the year said study was published, the reputation of any of the authors of said study, and the rating of the journal where said scientific article appeared.
  • rating of said journal is based on one or more of the following factors: the Impact Factor of said journal, the Immediacy Index of said journal, the cited half-life of said journal, and the Page Rank of said journal.
  • calculating is performed by consulting a database comprising a ranking system that rates genetic variants based on the relative strength of the data reported from studies.
  • calculating excludes a genetic variant in linkage disequilibrium with a genetic variant with a higher rating as determined by said ranking system.
  • said ranking system is based on one or more of the following factors: the number of studies reporting a correlation or association between said at least one genetic variant and said at least one phenotype; the number of studies showing contradictory results regarding said correlation or association; the aggregate number of organisms included in said studies; the type of study conducted; the degree to which the study has been replicated; and the year the study was conducted.
  • said calculating is performed by consulting a database comprising a ranking system that rates genetic variants based on the relative clinical value of the association between the genetic variant and the phenotype.
  • relative clinical value is determined by one or more medical specialists.
  • relative clinical value is determined by one or more: veterinarian, biologist, breeder, specialist in the field, or researcher is selected from the group consisting of: artificial insemination specialist, anesthesiologist, bacteriologist, cattle specialist, cat specialist, cardiologist, chicken specialist, cloning specialist, dermatologist, dog specialist, endocrinologist, gastroenterologist, geneticist, goat specialist, cultivator, hematologist, horse specialist, infectious disease specialist, immunologist, fertility specialist, mouse specialist, nutrition and obesity specialist, neurologist, obstetrician, gynecologist, oncologist, ophthalmologist, pig specialist, pharmacologist, primate specialist, psychiatrist, pulmonologist, rancher, rat specialist, reproduction specialist, rheumatologist, surgeon, transgenic specialist, urologist, virologist.
  • said methods are performed at a ranch, farm, veterinarian's office, in the field, in the wild, at the owner's home, at a government facility, at a supermarket, at a food testing facility, at a corporation.
  • said set of genetic variants is generated using at least one panel from FIGS. 15-20.
  • a third aspect provided herein is a method of determining and reporting the predisposition or carrier status of an organism for a reflex phenotype comprising: a) identifying a set of genetic variants in an organism, wherein each of said genetic variants is correlated with a phenotype; b) determining the predisposition or carrier status of said organism to an initial phenotype and to a reflex phenotype, wherein said predisposition or carrier status is based on said set of genetic variants; and c) reporting said predisposition or carrier status to said organism, to a owner, veterinarian, biologist, breeder, specialist in the field, or researcher, government agencies, of or in-charge of said organism, or to a third party, wherein the reporting of the predisposition or carrier status to the reflex phenotype depends on the outcome of said determination of predisposition or carrier status to the first phenotype.
  • said reflex phenotype is reported when said organism is predisposed to, at risk of, or a carrier of said initial phenotype and/or has already been known to have said initial phenotype. In some embodiments, said reflex phenotype is reported when said organism is not predisposed to, at risk of, or a carrier of said initial phenotype. In some embodiments, said reflex phenotype is reported concurrently with said initial phenotype. In other embodiments, said reflex phenotype is reported subsequently to said initial phenotype. In further embodiments, said reflex phenotype is not reported when said organism is not predisposed to, at risk of, or a carrier of said initial phenotype. In another embodiment, said reflex phenotype is a phenotype that is not the initial phenotype.
  • said determining of the predisposition or carrier status of the organism to said reflex phenotype is determined subsequently to the determining of the predisposition or carrier status of the organism for said initial phenotype.
  • said reflex phenotype is a disease that is positively correlated with said initial phenotype.
  • said initial phenotype is a disease and said reflex phenotype is a symptom or sequela of said disease.
  • said reflex phenotype is a trait that is positively correlated with said initial phenotype.
  • said initial phenotype is a trait and said reflex phenotype is a symptom or sequela of said trait.
  • said initial phenotype is a disease or disorder and said reflex phenotype is a side effect of, or response to, a treatment for said initial phenotype.
  • said predisposition or carrier status is determined from at least two genetic variants. In further embodiments, at least two genetic variants are correlated with the same phenotype.
  • a fourth aspect provided is a method of predicting a genetic predisposition or carrier status of a potential offspring comprising: a) identifying one or more genetic variants in the genome of the potential mother of a potential offspring, or obtaining one or more previously-identified genetic variants in the genome of the potential mother, wherein each of the genetic variants is associated with a phenotype; b) identifying one or more genetic variants in the genome of the potential father of a potential offspring, or obtaining one or more previously-identified genetic variants in the genome of the potential father, wherein each of the genetic variants is associated with a phenotype; c) based on the set of genetic variants, calculating the predisposition or carrier status of the potential offspring's mother for the phenotype; d) calculating the predisposition or carrier status of the potential offspring's father for the phenotype wherein the predisposition or carrier status is based on the set of genetic variants; e) calculating the potential
  • the predisposition is the highest potential risk. In an embodiment, the predisposition is the lowest potential risk. [0018] In an embodiment of the fourth aspect, the method further comprises identifying or obtaining the genetic location of the genetic variants of step a) and step b), wherein said genetic location is an autosomal chromosome, a non-autosomal chromosome, a mitochondrial chromosome, a cytoplasmic chromosome, a plasmid chromosome, or a chloroplast chromosome.
  • the method further comprises the steps of adjusting the result of step c) in light of the results obtained in the previous embodiment and adjusting the result of step d) in light of the results obtained in the previous embodiment.
  • said identifying is by nucleic acid array or sequencing apparatus.
  • Certain embodiments of the fourth aspect comprise reporting a predicted genetic predisposition or carrier status of a potential offspring in a report to a company that owns the potential mother or father, an individual who owns the potential mother or father, a company or individual that would own the potential offspring or a third party. For instance, reporting may comprise reporting to a veterinarian, a herder, a rancher or a caretaker.
  • the potential mother in step f) is the same as the potential mother in step a) and the potential father in step f) is different from the potential father in step b) and the method further comprising the step of comparing the result from step e) with the result from step f).
  • the method further comprises the step of identifying the potential father of a potential offspring with the highest risk or predisposition for a phenotype and/or the lowest risk or predisposition for a phenotype.
  • steps a) through e) are repeated with a plurality of potential mothers and/or a plurality of potential fathers and the results are combined to predict the probability of a genetic predisposition or carrier status of a potential offspring from a population of potential mothers and/or fathers.
  • the plurality of potential mothers and/or father may constitute a breeding population, such as a herd, and repeating analysis with a plurality of potential mother and/or fathers can be used to predict a predisposition or carrier status of a potential offspring from the breeding population or to select potential mother and/or fathers from the population to be used for breeding.
  • the potential father in step f) is the same as the potential father in step b) and the potential mother in step f) is different from the potential mother in step a) and the method further comprising the step of comparing the result from step e) with the result from step f).
  • the method further comprises the step of repeating step f) one or more times.
  • the method further comprises the step of identifying the potential mother of a potential offspring with the highest risk or predisposition for a phenotype and/or the lowest risk or predisposition for a phenotype.
  • the potential mother in step a) and the potential father in step b) are both members of the same species.
  • the potential mother in step a) and the potential father in step b) are both cows.
  • the potential mother in step a) and the potential father in step b) are both cattle.
  • the potential mother in step a) and the potential father in step b) are both cats.
  • the potential mother in step a) and the potential father in step b) are both mice.
  • the potential mother in step a) and the potential father in step b) are both rats.
  • the potential mother in step a) and the potential father in step b) are both horses. In further embodiments of the fourth aspect, the potential mother in step a) and the potential father in step b) are both pigs. In another embodiment of the fourth aspect, the potential mother in step a) and the potential father in step b) are both dogs. In another embodiment of the fourth aspect, the potential mother in step a) and the potential father in step b) are both cats. In another embodiment of the fourth aspect, the potential mother in step a) and the potential father in step b) are both chickens. In another embodiment of the fourth aspect, the potential mother in step a) and the potential father in step b) are both primates.
  • the potential mother in step a) and the potential father in step b) are both goats. In another embodiment of the fourth aspect, the potential mother in step a) and the potential father in step b) are both turkeys. In yet another embodiment of the fourth aspect, the potential mother in step a) and the potential father in step b) are both sheep. In some embodiments of the fourth aspect, the potential mother in step a) and the potential father in step b) are both mammals. In other embodiments of the fourth aspect, the potential mother in step a) and the potential father in step b) are both plants. In other embodiments of the fourth aspect, the potential mother in step a) and the potential father in step b) are both fish. In another embodiment of the fourth aspect, the potential mother in step a) and the potential father in step b) are members of different species.
  • the method further comprises identifying or obtaining the genetic location of the genetic variants of step a) and step b), wherein said genetic location is an autosomal chromosome, a non-autosomal chromosome, or mitochondrial chromosome, a cytoplasmic chromosome, a plasmid chromosome, or a chloroplast chromosome
  • said method also further comprises the step of identifying the potential father of a potential offspring with the highest risk or predisposition for a phenotype.
  • a fifth aspect provided herein is an array comprising at least 25 oligonucleotide sequences attached to a support, wherein each of said sequences is associated with a genetic variant, and the majority of said genetic variants are linked to at least one citation for a scientific article correlating said genetic variant to a phenotype.
  • each of said genetic variants is correlated to a phenotype.
  • a sixth aspect provided herein is an array comprising at least 25 oligonucleotide sequences attached to a support, wherein at least 5% of said sequences are not listed in a public database, and each of said sequences is associated with a genetic variant correlated to a phenotype.
  • a seventh aspect provided herein is an array comprising at least 25 oligonucleotide sequences attached to a support, wherein each of said sequence is used to determine an organ system score for an organism.
  • said organ system is selected from the group consisting of: cardiovascular; heart; lung; dermatology; development and learning; ear, nose, and throat; dental; endocrinology; pancreas; thyroid; gastroenterology; hepatology; liver; gall bladder; gynecology; hematology and oncology; immunology; immunology and allergy; infectious diseases; men's health; metabolic diseases; rare diseases; male health; musculoskeletal; neonatology; neurology; obstetrics; ophthalmology; pharmacology, toxicology; anesthesiology; psychiatry; reproductive health, rheumatology; sexuality; fertility; sleep medicine; surgery; syndromes; temperament, laryngology; traits and special abilities; otology; urology and
  • An eighth aspect provided herein is an array comprising at least 25 oligonucleotide sequences attached to a support, wherein each of said sequences is linked to at least one recommendation by a veterinarian, trainer, rancher, herder, scientist, biologist, physician, or other qualified person, owner, caretaker, other healthcare provider of said organism, a government agency, specialist, or third party.
  • said specialist is selected from the group consisting of: artificial insemination specialist, anesthesiologist, bacteriologist, cattle specialist, cat specialist, cardiologist, chicken specialist, cloning specialist, dermatologist, dog specialist, endocrinologist, gastroenterologist, geneticist, goat specialist, governmental agency representative, cultivator, hematologist, horse specialist, infectious disease specialist, immunologist, fertility specialist, mouse specialist, nutrition and obesity specialist, neurologist, obstetrician, gynecologist, oncologist, ophthalmologist, pig specialist, pharmacologist, primate specialist, psychiatrist, pulmonologist, rancher, rat specialist, reproduction specialist, rheumatologist, surgeon, transgenic specialist, urologist, virologist.
  • a ninth aspect provided herein is a system comprising: a database comprising at least 25 oligonucleotide sequences attached to a support, wherein each of said sequences are associated with a genetic variant; code for linking each of said sequences to at least one recommendation by a a veterinarian, biologist, physician, or other qualified person, owner, caretaker, other healthcare provider of said organism, a government agency, specialist, or third party; and, code for generating a report comprising said recommendation.
  • a tenth aspect provided herein is a system comprising: a database comprising at least 25 oligonucleotide sequences attached to a support, wherein each of said sequences are associated with a genetic variant; code for calculating one or more organ system scores based on said sequences; and, code for generating a report comprising said score.
  • each of said genetic variants is correlated to a phenotype.
  • at least one of said phenotypes is a rare disease.
  • at least one of said phenotypes is a monogenic phenotype.
  • at least one of said phenotypes is a multifactorial phenotype.
  • said specialist is selected from the group consisting of: artificial insemination specialist, anesthesiologist, bacteriologist, cattle specialist, cat specialist, cardiologist, chicken specialist, cloning specialist, dermatologist, dog specialist, endocrinologist, gastroenterologist, geneticist, goat specialist, governmental agency representative, cultivator, hematologist, horse specialist, infectious disease specialist, immunologist, fertility specialist, mouse specialist, nutrition and obesity specialist, neurologist, obstetrician, gynecologist, oncologist, ophthalmologist, pig specialist, pharmacologist, primate specialist, psychiatrist, pulmonologist, rancher, rat specialist, reproduction specialist, rheumatologist, surgeon, transgenic specialist, urologist, virologist..
  • said organ system is selected from the group consisting of: cardiovascular; heart; lung; dermatology; development and learning; ear, nose, and throat; dental; endocrinology; pancreas; thyroid; gastroenterology; hepatology; liver; gall bladder; gynecology; hematology and oncology; immunology; immunology and allergy; infectious diseases; men's health; metabolic diseases; rare diseases; male health; musculoskeletal; neonatology; neurology; obstetrics; ophthalmology; pharmacology, toxicology; anesthesiology; psychiatry; reproductive health, rheumatology; sexuality; fertility; sleep medicine; surgery; syndromes; temperament, laryngology; traits and special abilities; otology; urology and nephrology; and vascular; geriatric health; and female health.
  • An eleventh aspect provided herein is a computer readable medium, comprising a set of instructions to cause a computer to perform the steps of comparing input data comprising genetic variant information from an organism's genome against a set of data comprising association data correlating genetic variants with phenotypes and generating an output comprising an evaluation of the predisposition, or carrier status, of said organism for at least two phenotypes.
  • a twelfth aspect provided herein is a computer program product comprising a computer readable medium having computer program logic recorded therein for enabling a processor to determine the genetic predisposition or carrier status of an organism, said computer logic comprising: a) a storing procedure that enables the processor to store a set of information comprising a set of correlations, wherein each correlation comprises a correlation between a genetic variant and a phenotype; b) a receiving procedure that enables the processor to receive a set of information comprising one or more genetic variants within the genome of a subject; c) a comparing procedure to compare input data from the genome of said subject against the set of information in step a); d) a calculating procedure to calculate one or more scores based on said genetic variants within the genome of said subject; and e) an output procedure to provide a report of said comparison.
  • the computer program product further comprising: a linking procedure linking each of said genetic variants to at least one citation for a scientific article or association study correlating said genetic variant to a phenotype.
  • a linking procedure linking each of said genetic variants to at least one citation for a scientific article or association study correlating said genetic variant to a phenotype.
  • at least one of said phenotypes follows monogenic inheritance and at least one of said phenotypes follows multifactorial or polygenic inheritance.
  • a thirteenth aspect provided herein is a method of selecting a haploid genome containing cell comprising: applying a sample from said cell to an array; and, determining a set of genetic variants of said cell.
  • said cell is of male origin.
  • said cell is of female origin.
  • said cell is an oocyte.
  • said cell is a sperm cell.
  • the method further comprises selecting said haploid genome containing cell to produce a diploid embryo.
  • the method further comprises incorporating one or more factors chosen from the gender, breed, strain, age, weight, purpose of organism (including but not limited to companion to humans, work-related, production-related, transgenic related, food- related, environment-related, aesthetic-related), where organism will be born and live (including but not limited to a country farm, a city farm, a farm with less than 100 animals, a farm with more than 100 animals, a farm with more than 1,000 animals, a farm with more than 10,000 animals, an urban household with children, an urban household without children, a research facility, in a cage, free range, , in the wild, a fishery, a stable, a mill, a ranch, a field, a greenhouse, a valley, a mountain, and/or free-range), family history of phenotype, and organism history of phenotype of the donor of said haploid genome containing cell.
  • factors chosen from the gender, breed, strain, age, weight, purpose of organism including but not limited to companion to humans, work-related, production-related
  • a fourteenth aspect provided herein is an array comprising at least one oligonucleotide for detecting a degree of risk to an initial phenotype and a second oligonucleotide for detecting a degree of risk to a reflex phenotype.
  • said initial phenotype is a disease or disorder and said reflex phenotype is the response to or effectiveness of a drug for treating said disease or disorder, a drug or treatment that modifies a phenotype.
  • said initial phenotype is cancer and said reflex phenotype is the response to a cancer drug.
  • said initial phenotype is milk production and said reflex phenotype is the response to a drug that increases milk production.
  • said initial phenotype is a disease and said reflex phenotype is the response to a drug that prevents or treats said disease.
  • said initial phenotype is a fertility rate and said reflex phenotype is the response to a drug that increases fertility rates.
  • said initial phenotype is racing speed and said reflex phenotype is the response to a drug that increases racing speed.
  • said initial phenotype is temperament and said reflex phenotype is the response to a drug that makes temperament more docile and/or prevents acts of aggression.
  • said initial phenotype is food allergy and said reflex phenotype is the response to a specific food.
  • the genetic variants are present in nucleic acids provided from the organism as a sample, which sample may have been previously obtained, i.e. prior to performance of the methods provided herein. In some embodiments, the genetic variants are present in an organism's genome or nucleic acids provided by the organism or a third party as a sample, which sample may have been previously obtained, i.e. prior to performance of the methods provided herein.
  • One aspect provides a nucleic acid sample from an organism for use in a method of determining the risk, predisposition, or carrier status of that organism for one or more phenotypes, the method comprising: identifying by nucleic acid array or sequencing apparatus one or more genetic variants in an organism or a set of genetic variants in an organism, wherein each of said genetic variants is correlated with a phenotype; using a computer to determine the predisposition of said organism for a phenotype wherein said predisposition is based on said set of genetic variants or said one or more genetic variants; and, optionally, providing a report of said predisposition to said organism.
  • Another aspect provided herein is related to gender specific health phenotypes and is a method of determining the predisposition or carrier status of an organism for two or more gender specific health phenotypes comprising: identifying by nucleic acid array, sequencing apparatus, or nanopore sequencer a set of genetic variants in an organism, wherein each of said genetic variants is correlated with a gender- specific health phenotype; using a computer to determine the predisposition or carrier status of said organism for at least two phenotypes, wherein said predisposition or carrier status is based on said set of genetic variants; providing a report of said predisposition or carrier status to said organism, to a health care provider of said organism, or to a third party; and optionally combining the predisposition or carrier status of said organism for said at least two phenotypes into a gender- specific health score, wherein said score is reported to said organism, to a health care provider, or to a third party.
  • At least two phenotypes comprise an initial phenotype and a reflex phenotype, wherein said reflex phenotype is a phenotype that is not the initial phenotype, and wherein the reporting of the predisposition or carrier status of said organism for the reflex phenotype depends on the outcome of said determination of predisposition or carrier status of said organism for the first phenotype.
  • at least two phenotypes are at least two phenotypes listed in any of the panels in FIGS. 15-20.
  • at least two phenotypes comprise at least five phenotypes.
  • At least two phenotypes comprise: at least one phenotype that follows monogenic inheritance; and at least one phenotype that follows multifactorial or polygenic inheritance. In further embodiments, at least two phenotypes comprise: at least one phenotype that is a trait; and at least one phenotype that is a disease.
  • At least two phenotypes comprises at least two of the following phenotypes: female fertility, infertility, spontaneous abortion, miscarriages, or reproduction system abnormalities; osteoporosis or osteoporotic fracture; obesity or leanness; heart disease; thrombophilia or thromboembolic disease; cancer of female reproductive organs; skin cancer or sensitivity to ultraviolet light; lung cancer; colorectal cancer; hypertension or blood pressure level; polycystic ovary syndrome; or stroke.
  • At least two phenotypes comprises at least two of the following phenotypes: myocardial infarction; breast cancer; osteoporosis or osteoporotic fracture; Alzheimer's disease; thrombophilia or thromboembolic disease; cardiac arrhythmia or cardiac conduction abnormality, cardiomyopathy; obesity or leanness; skin cancer or sensitivity to ultraviolet light; or lung cancer.
  • At least two phenotypes comprises at least two of the following phenotypes: female fertility, infertility, spontaneous abortion or miscarriages; ovulatory defects, premature ovarian failure or ovarian dysgenesis; thrombophilia or thromboembolic disease; fetal viability; bleeding diathesis, coagulation disorders or hemophilia; primary or secondary sex characterisitics, sex reversal or hypogonadism; or hypogonadism.
  • At least two phenotypes comprises at least two of the following phenotypes: breast cancer; thrombophilia or thromboembolic disease; infectious disease susceptibility; ovarian abnormalities or failure; or ovarian cancer.
  • At least two phenotypes comprises at least two of the following phenotypes: male fertility or infertility; heart disease; thrombophilia or thromboembolic disease; cardiac arrhythmia or cardiac conduction abnormality; cardiomyopathy, cancer of male reproductive organs; skin cancer or sensitivity to ultraviolet light; lung cancer; colorectal cancer; hypertension or blood pressure level; or stroke.
  • At least two phenotypes comprises at least two of the following phenotypes: myocardial infarction; skin cancer; colorectal cancer; prostate cancer; alopecia; thrombophila or thromboembolic disease; cardiac arrcardiomyopathy.
  • at least two phenotypes comprises at least two of the following phenotypes: male fertility or infertility; erectile dysfunction medication treatment, effectiveness or sensitivity; peripheral arterial disease; fetal viability; primary or secondary sex characteristics, sex reversal or hypogonadism; or hypogonadism.
  • At least two phenotypes comprises at least two of the following phenotypes: male fertility or infertility; erectile dysfunction medication treatment, effectiveness or sensitivity; prostathythmia or cardiac conduction abnormality; cancer; nephrolithiasis or urolithiasis; bladder cancer, kidney cancer, or adrenal cancer; IgA nephropathy; diabetic nephropathy; polycystic kidney disease.
  • at least two phenotypes comprises at least two of the following phenotypes: sexual attraction; pair bonding; personality traits; degree of relationship commitment or divorce potential; or pheromone perception.
  • said reflex phenotype is reported when said organism has an increased predisposition or carrier status for said initial phenotype. In further embodiments, said reflex phenotype is reported when said organism has a decreased predisposition or carrier status for said initial phenotype. In another embodiment, said reflex phenotype is not reported if the organism has neither a decreased or increased predisposition or carrier status for said initial phenotype. In yet another embodiment, said reflex phenotype is reported concurrently with said initial phenotype. In an embodiment, said reflex phenotype is reported subsequently to said initial phenotype.
  • the determination of the predisposition or carrier status of the organism for said reflex phenotype is determined subsequently to the determination of the predisposition or carrier status of the organism for said initial phenotype.
  • said reflex phenotype is a disease that is positively correlated with said initial phenotype.
  • said initial phenotype is a disease and said reflex phenotype is a symptom of said disease.
  • said initial phenotype is a disease or disorder and reflex phenotype is a side effect of, or response to, a treatment for said initial phenotype.
  • said initial phenotype is osteoporosis or osteoporotic fracture
  • said reflex phenotype is one or more selected from the group consisting of: effects of specific diets on bone mineral density or osteoporosis; and effect of caffeine consumption on bone mineral density or osteoporosis.
  • said initial phenotype is obesity or leanness
  • said reflex phenotype is one or more selected from the group consisting of: amount of feed needed to gain weight; change in body fat with age or diet; exercise intolerance, or optimal exercise regimen.
  • said initial phenotype is a trait
  • said reflex phenotype is an associated trait or disease.
  • two or more phenotypes are selected.
  • said set of genetic variants is identified using a high density DNA microarray.
  • said set of genetic variants is identified by sequencing genomic DNA from said organism.
  • said organism is of the female gender.
  • said organism is of the male gender.
  • gender specific health set of probes comprising probes, wherein each of said probes is specifically selected to detect a genetic variant correlated with a gender- specific health phenotype.
  • said set detects at least two phenotypes listed in FIGS.15-20.
  • the gender-specific health set of probes said set comprises at least two probes, and each of said at least two probes detects a different genetic variant, and wherein each of said different genetic variants is correlated to the same phenotype.
  • Another aspect provided herein is related to Medical Care phenotypes and is a method of determining the predisposition or carrier status of an organism for two or more Medical Care phenotypes comprising: identifying by nucleic acid array, sequencing apparatus, or nanopore sequencer a set of genetic variants in an organism, wherein each of said genetic variants is correlated with a medical care phenotype; using a computer to determine the predisposition or carrier status of said organism for at least two phenotypes, wherein said predisposition or carrier status is based on said set of genetic variants; providing a report of said predisposition or carrier status to said organism, to a health care provider of said organism, or to a third party; and, optionally, (d)combining the predisposition or carrier status of said organism for said at least two phenotypes into a Medical Care score, wherein said score is reported to said organism, to a health care provider of said organism, or to a third party.
  • At least two phenotypes comprise an initial phenotype and a reflex phenotype, wherein said reflex phenotype is a phenotype that is not the initial phenotype, and wherein the reporting of the predisposition or carrier status of said organism for the reflex phenotype depends on the outcome of said determination of predisposition or carrier status of said organism for the first phenotype.
  • at least two phenotypes are at least two phenotypes listed in one or more of FIGS. 15-20 .
  • at least two phenotypes comprise: at least one phenotype that follows monogenic inheritance; and at least one phenotype that follows multifactorial or polygenic inheritance.
  • said reflex phenotype is reported when said organism has an increased predisposition or carrier status for said initial phenotype.
  • said reflex phenotype is reported when said organism has a decreased predisposition or carrier status for said initial phenotype.
  • said reflex phenotype is not reported if the organism has neither a decreased or increased predisposition or carrier status for said initial phenotype.
  • said reflex phenotype is reported concurrently with said initial phenotype.
  • said reflex phenotype is reported subsequently to said initial phenotype.
  • phenotypes comprise an initial phenotype and a reflex phenotype
  • said reflex phenotype is a phenotype that is not the initial phenotype
  • the reporting of the predisposition or carrier status of said organism for the reflex phenotype depends on the outcome of said determination of predisposition or carrier status of said organism for the first phenotype, wherein the determination of the predisposition or carrier status of the organism for said reflex phenotype is determined subsequently to the determination of the predisposition or carrier status of the organism for said initial phenotype.
  • said reflex phenotype is a disease that is positively correlated with said initial phenotype.
  • said initial phenotype is a disease and said reflex phenotype is a symptom of said disease.
  • said initial phenotype is a disease or disorder and reflex phenotype is a side effect of, or response to, a treatment for said initial phenotype.
  • a method of determining the predisposition or carrier status of an organism for two or more phenotypes related to Medical Care is provided, wherein said two or more phenotypes are selected.
  • said set of genetic variants is identified using a high density DNA microarray.
  • said set of genetic variants is identified by sequencing genomic DNA from said organism.
  • said organism is a subject of one or more genetic panels of the invention.
  • said organism is a suffering from an unknown disease or condition.
  • said organism is an organ, cell, or tissue transplant candidate.
  • said organism has died of unknown causes.
  • a medical care set of probes comprising probes, wherein each of said probes is specifically selected to detect a genetic variant correlated with a medical care phenotype.
  • said set detects at least two phenotypes listed in FIGS. 15-20.
  • said set comprises at least two probes, and each of said at least two probes detects a different genetic variant, and wherein each of said different genetic variants is correlated to the same phenotype.
  • a method comprising: obtaining by nucleic acid array, sequencing apparatus, or nanopore sequencer a set of genetic variants for one or more subjects, wherein said one or more subjects have been or are contemplated to be in a clinical drug efficacy or safety trial, and wherein each member of said set of genetic variants is identified with each of said one or more subjects and wherein each member of said set of genetic variants is also correlated with a phenotype; obtaining clinical trial results data for said one or more subjects, or providing clinical trial results data previously obtained for said one or more subjects, wherein each of said clinical trial results are identified with each of said one or more subjects; and using a computer to correlate the clinical trial results identified with each subject with the set of genetic variants identified with each subject; wherein the step of correlating identifies one or more of said genetic variants that are predictive for one or more of said clinical trial results.
  • the method further comprises identifying one or more subsets of subjects that have a set of genetic variants that provide an increased chance of a positive or negative clinical trial result.
  • said clinical trial results indicate the level of safety of said clinical drug.
  • said clinical trial results indicate the level of effectiveness of said clinical drug.
  • said clinical trial results indicate the degree of adverse effects of said clinical drug.
  • said set of genetic variants comprises one or more genetic variants correlated with a phenotype listed in the Research & Clinical Trial Panels.
  • Another aspect provided herein is related to longevity or lifecycle phenotypes and is a method of determining the predisposition or carrier status of an organism for two or more longevity or lifecycle phenotypes comprising: identifying by nucleic acid array, sequencing apparatus, or nanopore sequencer a set of genetic variants in an organism, wherein each of said genetic variants is correlated with a longevity phenotype; using a computer to determine the predisposition or carrier status of said organism for at least two phenotypes, wherein said predisposition or carrier status is based on said set of genetic variants; providing a report of said predisposition or carrier status to said organism, to a health care provider or owner of said organism, or to a third party; and optionally combining the predisposition or carrier status of said organism for said at least two phenotypes into a longevity score, wherein said score is reported to said organism, to a health care provider, or owner, or to a third party.
  • At least two phenotypes comprise an initial phenotype and a reflex phenotype, wherein said reflex phenotype is a phenotype that is not the initial phenotype, and wherein the reporting of the predisposition or carrier status of said organism for the reflex phenotype depends on the outcome of said determination of predisposition or carrier status of said organism for the initial phenotype.
  • at least two phenotypes comprise: at least one phenotype that follows monogenic inheritance; and at least one phenotype that follows multifactorial or polygenic inheritance.
  • said reflex phenotype is reported when said organism has an increased predisposition or carrier status for said initial phenotype. In another embodiment, said reflex phenotype is reported when said organism has a decreased predisposition or carrier status for said initial phenotype. In yet another embodiment, said reflex phenotype is not reported if the organism has neither a decreased or increased predisposition or carrier status for said initial phenotype. In some embodiments, said reflex phenotype is reported concurrently with said initial phenotype. In other embodiments, said reflex phenotype is reported subsequently to said initial phenotype.
  • the determination of the predisposition or carrier status of the organism for said reflex phenotype is determined subsequently to the determination of the predisposition or carrier status of the organism for said initial phenotype.
  • said reflex phenotype is a disease that is positively correlated with said initial phenotype.
  • said initial phenotype is a disease and said reflex phenotype is a symptom of said disease.
  • said initial phenotype is a disease or disorder and reflex phenotype is a side effect of, or response to, a treatment for said initial phenotype.
  • said two or more phenotypes are selected.
  • said set of genetic variants is identified using a high density DNA microarray.
  • said set of genetic variants is identified by sequencing genomic DNA from said organism.
  • a Research and Clinical trial aspect is a method of determining the predisposition or carrier status of an organism for two or more Research and Clinical Trial phenotypes comprising: identifying by nucleic acid array, sequencing apparatus, or nanopore sequencer a set of genetic variants in an organism, wherein each of said genetic variants is correlated with a Research and Clinical Trial phenotype; using a computer to determine the predisposition or carrier status of said organism for at least two phenotypes, wherein said predisposition or carrier status is based on said set of genetic variants; providing a report of said predisposition or carrier status to said organism, to a health care provider of said organism, researcher, company, or to a third party; and, optionally, combining the predisposition or carrier status of said organism for said at least two phenotypes into a Research and Clinical Trial score, wherein said score is reported to said organism, to a health care provider of said organism, a researcher, or a company, or
  • At least two phenotypes comprise an initial phenotype and a reflex phenotype, wherein said reflex phenotype is a phenotype that is not the initial phenotype, and wherein the reporting of the predisposition or carrier status of said organism for the reflex phenotype depends on the outcome of said determination of predisposition or carrier status of said organism for the first phenotype.
  • at least two phenotypes comprise at least five phenotypes.
  • at least two phenotypes comprise: at least one phenotype that follows monogenic inheritance; and at least one phenotype that follows multifactorial or polygenic inheritance.
  • said organism is a research subject.
  • said organism is a suffering from an unknown disease or condition.
  • said organism is an organ, cell, or tissue transplant candidate.
  • said organism has died of unknown causes.
  • a second Research and Clinical trial aspect provided herein is a research and clinical trial set of probes, wherein said set comprises probes, wherein each of said probes is specifically selected to detect a genetic variant correlated with a Research and Clinical Trial phenotype.
  • said set comprises at least two probes, and each of said at least two probes detects a different genetic variant, and wherein each of said different genetic variants is correlated to the same phenotype.
  • a third Research and Clinical trial aspect provided herein is a method comprising: obtaining by nucleic acid array, sequencing apparatus, or nanopore sequencer a set of genetic variants for one or more subjects, wherein said one or more subjects have been or are contemplated to be in a clinical drug efficacy or safety trial, and wherein each member of said set of genetic variants is identified with each of said one or more subjects and wherein each member of said set of genetic variants is also correlated with a phenotype; obtaining clinical trial results data for said one or more subjects, or providing clinical trial results data previously obtained for said one or more subjects, wherein each of said clinical trial results are identified with each of said one or more subjects; and using a computer to correlate the clinical trial results identified with each subject with the set of genetic variants identified with each subject; wherein the step of correlating identifies one or more of said genetic variants that are predictive for one or more of said clinical trial results.
  • the method further comprises identifying one or more subsets of subjects that have a set of genetic variants that provide an increased chance of a positive or negative clinical trial result.
  • said clinical trial results indicate the level of safety of said clinical drug.
  • said clinical trial results indicate the level of effectiveness of said clinical drug.
  • said clinical trial results indicate the degree of adverse effects of said clinical drug.
  • FIG. 1 illustrates an overview of some methods or business methods of providing genetic testing, profiles, and/or analysis.
  • FIG. 2 depicts a diagram of a sample genetic pedigree, illustrated herein for a human organism.
  • a male organism proband
  • the organism's maternal grandfather died from unknown cancer at age 55 and an uncle, on his maternal side, died from prostate cancer at age 58.
  • His paternal grandparents both died in their 50' s from unknown illnesses, a paternal uncle died of heart disease around the age of 60, and his father died recently of a heart attack at the age of 72.
  • His mother has glaucoma and arthritis but is otherwise healthy and his sister and her two children are also healthy. No other family history is given. Genetic Pedigree Analysis may be utilized for genetic counseling.
  • the same genetic pedigree analysis can be applied to nonhuman organisms as well.
  • the pedigree may enable veterinary healthcare professionals, , to follow disease trends and identify possible at-risk organisms. Additionally, such information may be of use by animal husbandry specialists for breeding purposes.
  • males are represented by squares, females as circles, and a line connecting a square and a circle from two different lineages represents a mating.
  • FIG. 3 illustrates a Punnett Square where both parents are carriers of a monogenic disease.
  • Normal Allele refers to the allele that is not associated with the phenotype (such as a disease).
  • Disease Allele refers to the allele that is associated with the phenotype (such as a disease).
  • Carrier means the organism possesses one phenotype-associated allele but does not have the phenotype. The organism may pass on a phenotype-associated allele to future generations.
  • Diseased means the organism is 'Affected' or 'Likely to be Affected' by the phenotype. The organism may pass on a phenotype- associated allele to future generations.
  • 'Carrier status' may refer to either being a 'carrier' or being 'affected or likely to be affected' by a phenotype.
  • FIG. 4 depicts an information chart for a subject organism with A) limited information about the subject and B-C) with more information about the subject.
  • FIGS. 5A and 5B depict a sample report of genotypic data. "Rs" numbers are used when the genetic variant and it's surrounding sequence has been included in the public United States' National Center for Biotechnology Information's (NCBI) dbSNP database (accessible at www.ncbi.nlm.nih.gov/SNP/) and assigned an "rs number”. If that specific genetic variant is not included in this public dbSNP database, then the genetic variant and its flanking sequence is assigned an "eg" number, which serves as an internal identification number.
  • NCBI National Center for Biotechnology Information's
  • the genotype column denotes the diploid genotype for that variant (e.g. a genotype of "GA” denotes a heterozygous sequence of guanine and adenine at the position identified by the given variant), DEL denotes a deletion, and INS denotes an insertion.
  • the data shown represents genetic variants for human organisms. The sample reports for non-human organisms may be generated in a similar manner.
  • FIGS. 6 A-G illustrate sample internal data reports as well as examples by which these reports can be filtered, such as for A) all conditions or traits, B) GVP > 1.5, C) monogenic, D) replicated or monogenic conditions, or E-G) phenotypes
  • CSR refers to Clinical Significance Rating
  • PIR refers to Phenotype Impact Rating
  • the particular phenotypes, conditions or traits described may be illustrative of human disease or may be illustrative of non-human organism disease. If the phenotype, condition or traitis illustrative for human disease only, it is described herein to demonstrate the methods of analysis to be applied to non-human organism disease states. For FIG.
  • Column 3 Gene or Locus identifies the gene where the genetic variant (from column 1) occurs within or bordering. If the genetic variant occurs within an intergenic region, then the loci where the genetic variant exists is identified.
  • Phenotype identifies the phenotype associated with the genetic variant (column 1) and its genotype (column 2). This association is ascertained from scientific literature.
  • Column 6 Population Match? identifies whether or not the organism's population (such as gender, variety, breed, etc.) matches the population from scientific studies in which the genotype- phenotype association is deduced.
  • Column 7 Monogenic? identifies whether the genotype-phenotype association is monogenic or not. This information is ascertained from scientific literature.
  • Monogenic Status identifies the status (affected or carrier) of monogenic phenotypes.
  • Risk The risk value associated with the allele or genotype for the genotype- phenotype association. This is ascertained from scientific literature.
  • Absolute Value this is either an absolute or cumulative value for this genetic variant's specific genotype-phenotype association, as reported in the scientific literature.
  • An example of an absolute value is the new lifetime risk for that organism based on that genotype or an absolute amount associated with the phenotype (as opposed to an odds ratio, relative risk, or hazard ratio), such as a specific genetic variant's genotype being associated with an average systolic blood pressure of 140 mmHg + 5 mmHg.
  • blood pressure if the blood pressure value is in the hypertensive range, then this would contribute to the CGR and PMR for hypertension as described herein.
  • the genetic variant's genotype-phenotype association is not found to be statistically significant in subsequent studies after a study has found it to be statistically significant, then it is assigned "Failed”. If there are three or more studies, where one or more contains data that is contradictory to the other studies (such as if two studies find a statistically significant association between a genetic variant's allele or genotype and a phenotype but a third does not) for the same population, then the studies with the highest power (number of organisms in the study cohort) are considered most relevant.
  • GVP Score the GVP Score means the 'Genetic Variant-Phenotype Score', which is a value for the degree to which that genetic variant has been replicated in the scientific literature. The description for GVP score appears in FIG. 7.
  • GVP Triage the GVP Triage means the 'Genetic Variant-Phenotype Triage', which is a value that discerns its clinical significance. The descriptions for GVP Triage appearin FIG. 8.
  • GVP Rank the GVP Rank is the order in which that genetic variant should be utilized in case two or more genetic variants within tight linkage disequilibrium are both detected during genetic testing. If these genetic variants are associated with the same signal, they may give the same risk information about the phenotype association and only one should be included in the calculations and algorithm. The genetic variant designated with a GVP Rank of "1" will always be utilized first, over any other rank.
  • genetic variant Y may still also be tested for and/or analyzed because it may give other information about another phenotype, it may be part of a haplotype, it may be part of a panel of variants that are tested and/or analyzed, or the data may be obtained as a consequence of obtaining the data for genetic variant X. If only genetic variant Y is detected but genetic variant X is not, then that means genetic variant Y, with a GVP Rank of 2, will then be used in the calculations and algorithm.
  • FIG. 7 illustrates a sample of a Genetic Variant-Phenotype (GVP) scoring scheme.
  • FIG. 8 illustrates a sample of a Genetic Variant-Phenotype (GVP) Triage scoring scheme.
  • FIG. 9 is a CGR Multiplier and PMR (Predictive Medicine Risk) or NRV (No Risk Value) Multiplier chart.
  • FIG. 10 is an example of a chart for scores by organ system and an overall genetic health score.
  • the Cumulative Action Score (CAS) can be filled in for more than one organ system and determined for an organ system.
  • the organ system score or Indicator of Genetic Health of an Organ System can be indicated by a color.
  • Red can be used for scores less than -10, indicating high importance for discussion with the subject's caretaker and may be highly important for the caretaker to follow-up with a veterinary health professional or animal husbandry specialist based on this information, pink can be used for scores between -1 to -10 to indicate moderately important risk, green can be used for scores of 0 to indicate no pertinent deleterious or protective information discovered although organ system is accessed, blue can be used for scores between +1 to +10, to indicate moderately important protection, gold can be used for scores >+10 indicating very beneficial protection, and no color can be used for an Organ System or Medical Specialty if it is not accessed.
  • FIGS. 11A and 11B depict a schematic of a computer system useful in the methods of the present invention.
  • FIG. 11A is a schematic of a non-limiting example of a computer system that can be used for storing, receiving and analyzing data from genetic results or testing.
  • FIG. 11B is a schematic of a non-limiting example of the general steps for obtaining a genetic analysis of a subject sample from a computer system that can be used for receiving and analyzing genetic data.
  • FIGS. 12A to 12G depict reports that are generated from a subjec that ist tested with a full genome analysis panel, illustrated herein for a human.
  • the exemplary reports include A-B) Risk Assessment reports for Alzheimer's Disease(A) and Macular Degeneration, Age-Related (B),C-D) Carrier Assessment reports for Malignant Hyperthermia (C), and Cystic Fibrosis (D), E) Healthcare Professional Summary and F-G) References.
  • A-B Risk Assessment reports for Alzheimer's Disease(A) and Macular Degeneration
  • E Healthcare Professional Summary and F-G) References.
  • the Healthcare Professional Summary may be directed to either a veterinary professional or an animal husbandry specialist.
  • the references may refer specifically to the disease state in a specific non-human organism or may include references concerning human disease wherein the results may be extended to a non-human organism.
  • FIG. 13 D depicts a general matrix reflex testing schematic;
  • FIGS. 14A and 14B depict schematics for the 2 part analysis for Offspring Projection through the Combined Analyses of Different Individuals (OP-CADI).
  • FIGS. 15A to 15DD depict panels relevant to cattle, including General Cattle Panel (15 A to 15D); Cattle Dairy Panel (15D to 15G); Cattle Disease Panel (15H); Cattle Growth Panel (15H to 151); Cattle Lifecycle and Economic Productivity Panel (151 to 15L); and Cattle Meat Panel (15M to 15BB).
  • FIGS. 16A to 161 depict panels relevant to chickens, including General Chicken Panel (16A to 16B); Chicken Disease Panel (16B to 16C); Chicken Egg Panel (16C); Chicken Growth Panel (16C to 16D); Chicken Immune System Panel (16D); ); Chicken Lifecycle and Economic Productivity Panel (16D to 16F); and Chicken Morphology Panel (16F to 16G); and Chicken Reproduction Panel (16G tol6H).
  • FIG 17A to 17J depict panels relevant to dogs, including General Dog Panel (17A); Companion Panel ( 17A to 17C); Dog Conformation Events Panel (17C to 17D); Dog Disease Panel (17D to 17E); Dog Herding and Hunting Panel (17E); Dog Law Enforcement Panel (17E to 17F);Dog Learning and Intelligence Panel (17F); Dog Morphology Panel (17F to 17G); Dog Racing Panel (17G); and Dog Research & Clinical Study Panel (17G to 17J).
  • FIGS. 18A to 18D depict panels relevant to horses, including General Horse Panel (18A); Horse Lifecycle and Economic Productivity Panel (18A-18B); Horse Morphology Panel (18B); Horse Racing/Sports Panel (18B); Horse Reproduction Panel (18B); and Horse Worker Panel (18C-18D).
  • FIGS. 19A to 191 depict panels relevant to pigs, including General Pig Panel (19A to 19C); Pig Meat Panel (19C to 19D); Pig Morphology Panel (19D to 19E); Pig Reproduction Panel (19E); Pig Disease Panel (19E to 19F); and Pig Lifecycle and Economic Productivity Panel (19F to 19H).
  • FIG. 20 depicts a General panel relevant to sheep.
  • FIG. 21 depicts various options for selection of phenotypes from panels, such as Offspring Projection through the Combined Analyses of Different Organisms (OP-CADI) Option, Only Decreased Risk Option, Only Increased Risk Option, or Specific Disease Exclusion Option.
  • OP-CADI Combined Analyses of Different Organisms
  • FIG. 22A to 22Q depicts significant genetic variants and their associated disease or trait.
  • FIG. 23A to 23C depict example indications that, if present, may suggest genetic testing using the specified panel.
  • FIG. 24 illustrates multifactorial phenotype risks which have, for example, both a genetic component and an non-genetic factor as compared to monogenic or polygenic phenotype risks.
  • Genotypes contribute to phenotypes, such as traits, diseases, disorders, conditions, or characteristics.
  • Genotypes comprising genetic variations can provide a method of correlating a genotype with one or more phenotypes for an organism.
  • clinically relevant polymorphisms can be used to determine clinically relevant phenotypes, including phenotypes such as the risk or predisposition an organism has for a specific disease, disorder, condition, or trait.
  • Phenotypes may also include the pharmacogenomic profile of an organism including medication metabolism, effectiveness, adverse reactions, dosing indications, and choice of medication.
  • phenotypes such as diseases, disorders, traits and conditions are multifactorial and may be interconnected with other phenotypes.
  • Monogenic disorders can also be interconnected with other phenotypes.
  • a comprehensive, dynamic analysis of an organism genome, combined with non-genetic factors, can be used to understand the organism's risk or predisposition, carrier status, diagnosis, determination and risk or predisposition to future generations of monogenic, polygenic and multifactorial phenotypes, as well as their interconnectedness with other relevelent phenotypes.
  • genetic profiles includes genetic analyses and/or genotype profiles.
  • the genetic profiles can provide comprehensive, dynamic genetic analysis for an organism. Genetic profiles can use genetic information from an organism to determine the carrier status of a phenotype or a predisposition or risk for a phenotype.
  • Organisms may be human as well as non-human, such as other mammals, including, but not limited to pets, such as dogs, cats, and birds; farm animals such as pigs, cattle or cows, goats, chickens, turkeys, ducks, turkey, fish, and sheep, as well as other animals, such as apes, bison, camels, , (for example, racehorses, such as Harness and Thoroughbred), whales and dolphins.
  • the disclosure applies to human organisms. In some cases, the disclosure applies to non-human organisms. In some cases, the disclosure applies to mammals or non-human mammals. Genetic profiles may also be generated for plants, including but not limited to cotton plants, olive trees, evergreen coniferous trees, banana trees, apple trees, orange trees, grapefruit trees, cherry trees, almond trees, wheat, corn, hemp, soybeans and rice. Genetic profiles can be generated for fish, including but not limited to salmon, tuna, sea bass, Alaska pollock, cod, eels, tilapia, flashlight fish, anglerfish or sharks. Genetic profiles can also be generated for invertebrates, such as lobsters, shrimp, scallops and insects; fungi; microorganisms, such as bacteria or viruses; and endangered species or extinct species from which genetic material can be obtained.
  • plants including but not limited to cotton plants, olive trees, evergreen coniferous trees, banana trees, apple trees, orange trees, grapefruit trees, cherry trees, almond trees, wheat, corn, hemp, soybeans and rice. Genetic profiles can be
  • a phenotype is any observable, detectable or measurable characteristic of an organism, such as a condition, disease, disorder, trait, behavior, biochemical property, metabolic property or physiological property.
  • the genetic information can also be used to determine the pharmacogenomic profile for an organism.
  • the genetic information can also be used to determine the likelihood or predisposition of an organism or a couple in passing on genes and genetic variants that may contribute to specific phenotypes in their offspring or the likelihood of specific phenotypes occurring in potential offspring through the genetic analysis of different organisms as potential parents.
  • the information may also be used in a second analysis or determination of an organism's carrier status of a phenotype or their risk or predisposition to a phenotype.
  • Risks or predispositions can be reflected by scores or other numerical values. For example, the score or numerical value may be scaled to express the level of risk or predisposition to a phenotype, such as a medical condition or a non-medical condition.
  • FIG. 1 illustrates some general and non-limiting steps involved in genetic analysis.
  • Samples or specimens such as any biologic specimen or biologic material, may be taken at the central location (104) and after or before payment, submitted for processing (112 or 116) at a sample processing facility (108) such as a laboratory (158) that may processes the sample, conduct the genetic testing and/or generate the results (such as raw genotypic data or genetic analysis) (120, 156, 144).
  • the laboratory (158) may or may not adhere to appropriate governmental agency guidelines and requirements, for example, in the United States, a processing laboratory may be regulated by one or more federal agencies such as the Food and Drug Administration (FDA) or the Centers for Medicare and Medicaid Services (CMS), and/or one or more state agencies.
  • FDA Food and Drug Administration
  • CMS Centers for Medicare and Medicaid Services
  • Samples may also be obtained from organisms at other locations such as health care facilities (110) or directly from the organisms themselves (102, 134). Samples may also be obtained from other channels or facilities (114), e.g., DNA storage bank, blood bank, tissue bank, tissue repository, crime scene, pathology laboratory, morgue, archeological site, or other location. For example, ' ancient DNA' may be found at an archeological dig site. Thus, at times, the actual 'organism', such as a person or animal or other organism, may not actually be present when the sample is collected.
  • the nucleic acid may be provided from the organism, or third party, as a sample, which sample may have been previously obtained, i.e. prior to performance of the method of the invention (102).
  • Other channels or facilities (114) also may include facilities such as spas, medical spas, gyms, fitness centers, weight loss centers, clinics, kiosks, nurses offices, schools, governmental agencies or offices, programs, crime scenes, prisons, jails, military locations, ambulances, hospitals, medical centers, doctor's office, clinics, fertility centers, assisted reproductive technologies centers, sperm banks or donation centers, egg donation centers or programs or companies, prenatal testing companies, business locations, corporate locations, bench research centers, clinical research centers, pharmaceutical companies, places of military, police, or clandestine operations, an organism's house, wellness centers, in the wild, at an owner's home, at an owner's place of business, at a corporation, at a governmental facility, at a supermarket, at a food processing center, at a food quality control center, longevity centers, space centers, executive health programs, funeral homes, veterinarian's offices, veterinary clinics, veterinary hospitals, farms, ranches, natural habitats, archeological digs, archeological centers, museums, cemetaries, or
  • Such facilities may themselves collect samples or specimens (112, 116) from organisms or animals or any organism or from the sample's place of occupancy as stated herein and submit to a central (104) location after or before payment, where the samples are then submitted to a laboratory (158), such as a CLIA laboratory or a non-CLIA laboratory, for processing.
  • a laboratory such as a CLIA laboratory or a non-CLIA laboratory
  • the sample may be sent directly from the place of sample collection (104, 110, 114, 134) to a laboratory (158) (either CLIA or non-CLIA certified laboratory) where the genetic testing and/or genetic analysis then occurs or the sample may undergo genetic testing and/or genetic analysis at the sample collection site (104, 110, 114, 134) itself.
  • an organism's owener may receive "pre-test" genetic counseling (106). Following such counseling, the specimen may be sent to a CLIA or NON-CLIA laboratory (108). In some cases, an organism's owner, caretaker, or representative of organism may send the organism's genetic testing results directly to the Central Location (146), where such results may be further analyzed, compiled into a report, and sent or transmitted back to the organism (148). Results may refer to genotypic data ascertained at any time point, such as concurrently or anytime in the past, and may refer to genotypes at one or more genetic variants. [00116] As also illustrated in FIG.
  • a physician, veterinarian, or other healthcare professional may obtain a biological specimen from a subject organism, third party or animal (150, 152) and may send it to either a central location (112, 104) or to a laboratory (154, 158) for genetic testing and/or analysis in order to ascertain the genotype of one or more genetic variants throughout the genome and, optionally, in order to correlate the genotype with one or more phenotypes.
  • the central location or laboratory may also be a site where methylation status, epigenetic factors at one or more genetic variants throughout the genome, karyotype and/or cytogenetic properties are evaluated.
  • the results of the genetic testing or the genetic analysis may then be sent and/or transmitted to the veterinarian, health care professional, animal husbandry specialist, and/or the caretaker of the organism (110).
  • the genetic testing may have already been completed, either at the time or in the past, and the results of the genetic testing, such as genotypic results may then be sent or transmitted to a central location or analytical IT system (112) where genetic analysis may be performed.
  • the genetic analysis (such as a genetic report) may then be sent or transmitted (124) to the veterinarian, health care professional, animal husbandry specialist, and/or the caretaker of the organism (110) or to another location (114).
  • a consumer, caretaker of an organisim, or third-party may collect a biological specimen from the organism on his or her own as described herein and send the specimen (138) to the laboratory (158).
  • the laboratory may then perform genetic testing on genetic material isolated from the biological specimen (or the biological specimen may already be genetic material, such as isolated DNA) in order to determine one or more genetic variants throughout the genome and will send and/or transmit the results and/or the analysis (such as a genetic report, if the laboratory also conducts the analysis) back to the consumer, caretaker of the organism or third party (140).
  • the laboratory may send the genetic testing results (120) to a central location and/or analytical IT system (104) that then may conduct the genetic analysis and may send the analysis either back to the laboratory (118) that may then return the analysis (140) to the consumer, caretaker of the organism, or third party (134) or the central location and/or analytical system may send or transmit the analysis (148) (such as a genetic report) to the consumer, caretaker of the organism, entity, or patient (134).
  • a central location and/or analytical IT system 104 that then may conduct the genetic analysis and may send the analysis either back to the laboratory (118) that may then return the analysis (140) to the consumer, caretaker of the organism, or third party (134) or the central location and/or analytical system may send or transmit the analysis (148) (such as a genetic report) to the consumer, caretaker of the organism, entity, or patient (134).
  • the consumer, caretaker of the organism, or third party (134) may already have results from genetic testing (such as from current or recent genetic testing or genetic testing done anytime in the past) and may send the results of this genetic testing (146) to a central location and/or Analytical IT System (104) that then may analyze the results and send or transmit or both the analysis (such as a genetic report) (148) to the consumer, caretaker of the organism, or third party (134).
  • results from genetic testing such as from current or recent genetic testing or genetic testing done anytime in the past
  • Analytical IT System (104) that then may analyze the results and send or transmit or both the analysis (such as a genetic report) (148) to the consumer, caretaker of the organism, or third party (134).
  • a genetic report describing genetic analysis or genetic tests and containing other information described herein may then be sent or transmitted to the caretaker of the organism, or to another third party, such as the veterinarian or animal husbandry specialist of the organism (132).
  • a consumer, caretaker of the organism, third party and/or non -human species may either visit, or be taken to, a location that extracts a biological specimen (as described herein) or leave a biological specimenfrom the organism (136) at a location (114), either willingly (such as donating sperm to a sperm bank or donating a tissue sample to a tissue bank) or unwillingly (such as being a victim of a crime that leaves blood or other bodily fluid at the scene of a crime or a biological sample discovered at a place of archeological excavation and/or investigation) and this biological specimen may then be sent (142) to a laboratory (158) or the specimen may be sent (116) from the location (114) to a central location and/or analytical IT system (104) where it may undergo genetic testing (such as with a lab on a chip handheld device) or stored or the specimen may be sent (118) to a laboratory (158) to be stored or for testing. The results of the genetic testing may then be sent or transmitted (120) to
  • the results may be analyzed at the central location and/or analytical IT system (104) and then the analysis (such as a genetic report) is sent and/or transmitted (126), back to the location (114), which may be the same location (such as a forensics laboratory) or a different location (such as a government building or a police station).
  • the analysis such as a genetic report
  • the location which may be the same location (such as a forensics laboratory) or a different location (such as a government building or a police station).
  • the location (114) may also already have the results from current or previous genetic testing and may send or transmit the results (116) to a central location and/or analytical system (104) where the results are analyzed and then the analysis is sent or transmitted (126) back to the location (114), which can be the same location that sent the results or a different location (for example, the results may have been sent or transmitted (116) by a governmental agency (114) and the analysis (such as a genetic report) is sent or transmitted the Department of Agriculture (114), or the analysis can be sent or transmitted or both to more than one location, such as to the governmental agency (114), the Department of Agriculture (114), the Food and Drug Administration (114), a farm or ranch (114) and/or a vertinarian's office (110).
  • Genetic testing results or analysis may be sent or transmitted or both back to the same location that sent the specimen or to a different location or they may be sent or transmitted to multiple locations at once or at different times.
  • the genetic specimen may also be stored at various locations (104, 110, 114, 158, 134) for a defined amount of time (such as one year) or indefinitely.
  • the results or the analysis or both may also be stored at various locations (104, 110, 114, 158, 134) for a defined amount of time (such as one year or five years or ten years or 20 years or 50 years or 100 years) or indefinitely.
  • the laboratory may refer to a desktop device or machine that exists within the field or an office or home setting, or other location, such as within the office where the biologic sample is taken or received or both (102, 104, 110, 114, 134, 150, 158).
  • the laboratory may also refer to a handheld device that analyzes either the purified DNA sample or the unprocessed biologic specimen or both, as is currently being developed, such as "lab on a chip” technology (see for example, Karlinsey and Landers, Lab Chip, 8: 1285 (2008)) .
  • the genetic testing to ascertain specific alleles or genotypes or both of specific genetic variants or for partial exome, full exome, or full genome sequencing may occur on this desktop or hand-held device or the analysis itself of the genetic variants, their genotypes, and their association with phenotypes, or both, may either in part or in whole occur on the device, and the desktop or handheld device may display or print out all the results or a subset of the results of the genetic testing, such as specific phenotypes, such as the diagnosis or carrier status of specific diseases or traits or the risk of specific diseases or traits.
  • Conducting genetic testing utilizing a desktop or handheld device may allow for rapid genotype or associated phenotypes to be analyzed and elucidated or both genotyping (genetic testing) and phenotyping (analysis), results to be reported, analyzed, understood, or conveyed to the healthcare provider or any person operating the device or requesting the testing or analysis or both.
  • the laboratory processes the sample to isolate the genetic material needed for genetic testing and runs the genetic testing to generate a raw genetic genotype profile (that provides the genotypes or specific alleles at one or more places within the genome).
  • the biological sample can be any sample from the organism in which genetic material may be isolated. Such biological samples include, but are not limited to, blood, hair, skin, saliva, semen, urine, fecal material, sweat, tears, buccal tissue, tongue cells, epithelial cells, and various bodily tissues (e.g., a buccal swab, hair follicle, saliva sample, semen sample, skin sample, epithelial cells, genetic material, DNA, or blood).
  • bodily tissues e.g., a buccal swab, hair follicle, saliva sample, semen sample, skin sample, epithelial cells, genetic material, DNA, or blood.
  • the tissue or DNA sample may be directly collected by the organism (134), for example, a buccal or cheek sample may be obtained by the organism taking a swab against the inside of their cheek. Other samples such as a hair follicle, saliva, semen, skin, urine, fecal material, or sweat, may also be supplied by the organism's owner or representative themselves (134). Other biological samples may be taken by a physician, veterinarian, or health care specialist, such as a phlebotomist, genetic counselor, nurse or physician, physician assistant, nurse practitioner, or other healthcare provider or specialist providing access to the genetic testing and analysis service (110, 104). For example, blood samples may be withdrawn from an organism by a nurse.
  • Biological samples may also be taken by other organisms, such as, for example, a medical examiner, a police officer, a crime scene investigator, an archeologist, a medic, or a government official (114).
  • Tissue biopsies may be performed by a physician, veterinarian, or health care specialist (110) , and kits may also be available to health care specialists to efficiently obtain samples.
  • a small cylinder of skin or tissue may be removed or a needle or scalpel or swab or adhesive may be used to remove a small sample of tissue or fluids.
  • Blood or other bodily fluid may be collected from a crime scene by swab or field kit or other collection apparatus by, for example, a detective, officer of the law, forensic investigator, or medical examiner (114).
  • the sample may be obtained at any time either at one of the locations described herein or at any other location not described herein. While the genetic testing of the sample (to obtain genotypic data) may have also occurred, either at a CLIA or non-CLIA laboratory or at any other location, such as the sample collection site (104, 110, 114, 134), in the past (so that some or all of the genotypic data may be already known) or may occur at the present time, such as at a CLIA or non-CLIA laboratory (158) or other facility or at the sample collection site itself, the genetic analysis of the genotypic data to ascertain phenotypic data may occur either at a separate time or at the same time as the genetic testing.
  • the genetic analysis may occur at the same or different location from where the sample is obtained and the genetic analysis may occur at the same or different location from where the genetic testing occurred or is occurring and the.
  • the sample collection, genetic testing and analysis may all both occur at the health care professional's office (110) or the sample collection may occur at the health health care professional's office (110), the genetic testing may occur at a CLIA or non-CLIA laboratory (158), and the genetic analysis may then occur at a central location (104) or at the via interaction with a physician, veterinarian or healthcare professional, such as at a physician's or veterinarian's office (110).
  • the sample collection such as blood
  • the genetic testing may then occur at the present time at a central location (104), and the genetic analysis may occur immediately following the genetic testing, also at a centeral location (104) and then the results of either the genetic testing or the genetic analysis or both, such as contained within a genetic report, may then be conveyed to the organism or company or agency or governmental body that ordered the genetic testing (104) or the genetic analysis or both either immediately following the genetic testing and/or analysis or at a later time.
  • the genetic testing or the genetic analysis or both may have occurred at a laboratory (158), such as a CLIA or non-CLIA laboratory.
  • specimen collection may occur at time A, with genetic testing occurring instantaneously or seconds, minutes, hours, days, weeks, months, years, decades, centuries, millennia later at time B and genetic analysis may then occur instantaneously as well or may occur seconds, minutes, hours, days, weeks, months, years, decades, centuries, millennia later at time C.
  • a biological sample detected in permafrost or a mummy from an archeological site may provide a sample of DNA that may be very old, referred to as ' ancient DNA', and this biological sample may then be sent to a laboratory (158) where genetic testing occurs with some initial preliminary analysis.
  • the genetic testing results may then be stored for a numbr of years or decades and either the biological sample may undergo genetic testing again and then analyzed or the original genetic testing genotypic data may be reanalyzed at this later time point.
  • the results of the genetic testing or genetic analysis or both may be stored or conveyed or both to the organism or agency or government who ordered or paid for the test, or both.
  • Reflex testing, OP-CADI (both of which are terms that are described further herein), and/or testing for specific phenotypes by utilizing specific genetic variants or panels may also apply to one or more of the following: desktop or handheld genetic testing and/or analysis and/or reporting.
  • This type of laboratory (158) and/or handheld device may or may not fall under certain regulations, such as governmental regulations, or have to satisfy certain quality control, or governmental, requirements.
  • Phenotype include all subcategories of that phenotype.
  • the phenotype Fat Content of Milk in Cattle refers to the percentage fat content of milk, the fat yield of the milk, the fat yield over the duration lactation period, and/or the total fat content of the milk. Any possible way to measure the phenotype and/or convey the phenotype is contained within the phenotype name.
  • An organism's risk or prediposition for a phenotype may include his or her risk for a monogenic phenotype.
  • an organism's risk or predisposition for a phenotype includes his or her risk or predisposition for polygenic or multifactorial phenotypes.
  • the likelihood of developing a phenotype can be calculated based on an organism's alleles or genotypes for one or more genetic variants associated with polygenic or multifactorial phenotypes, and may also include analysis of non-genetic factors such as environment (non-genetic) factors.
  • Risk may also be referred to as a predisposition. Risks may also be expressed as a percentage for an indication of the likeliness of the chance event, such as a medically defined phenotype, such as a condition or a non-phenotype, such as a trait, to occur. Risks scores can also be provided with a confidence interval, a statistical value such as a p-value, Z-score, correlation (e.g. R or R 2 ), chi- square, f-value, t-value or both a confidence interval and a statistical value, indicating the strength of correlation between the score and the condition or trait thereof. Scores can be generated for an organism's risks or predispositions for medical conditions based on an organism's genetic profile.
  • Scores can be determined for a specific phenotype (e.g., disease, disorder, condition or trait), for an organ system, for a specific organ, for a combination of phenotypes, for a combination of phenotype(s) and organ(s) or organ system(s), for overall health, or for overall genetic predisposition to or risk of specific phenotypes.
  • the phenotype may be a medical condition, for example, scores can be generated for an organism's risks or predispositions for medical conditions based on an organism's genetic profile. Alternatively, scores can be for non-medical conditions, or for both medical and nonmedical conditions.
  • Scores may be generated by methods known in the arts, such as described in PCT Publication WO2008/067551 and US Publication No. 20080131887(each of which is incorporated by reference in its entirety) methods such as described herein, or variations and combinations thereof.
  • the risks may be determined using a machine such as a general purpose computer or a special purpose computer using instructions provided on computer readable medium.
  • Inclusion of the specific algorithms described herein to analyze the genetic information and calculate scores representing risks, predisposition to a phenotype and/or overall health profiles for example, transform a general purpose computer into a special purpose computer for analyzing the genetic variants identified.
  • Such algorithms can be provided in any combination to execute those functions desired by a client.
  • the computer system may include some or all of the computer executable logic encoded on computer readable medium to instruct the computer system to complete the analysis, evaluations, scoring of the identified genetic variants, recommendations and reports for the client as desired.
  • the calculated or determined risk or predisposition of one or more specific phenotypes from an organism's genetic profile provides a measure of the relative risk or predisposition of that organism for one or more phenotypes, as further described herein.
  • the relative risk may be determined as compared to the general population or as compared to a control (e.g. a different organism) lacking one or more of the genetic variants identified in the organism's genetic profile. Additional examples and further description of risk and risk scores are provided herein.
  • an organism with an increased relative risk or predisposition for a specific phenotype may be an organism with an odds ratio of greater than 1 for the specific phenotype, for example an organism with an odds ratio of about 1.01, 1.05, 1.1, 1.2, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or 100 or more for developing a phenotype relative to the general population or a control organism.
  • an organism with an increased risk or predisposition may be an organism with a greater than 0% increased probability of a phenotype, for example an organism may have a 0.001% greater probability of a phenotype based on their genetic profile, a 0.01% greater probability, a 1% greater probability, a 5% greater probability, a 10% greater probability, a 20% greater probability, a 30% greater probability, a 50% greater probability, a 75% greater probability, a 100% greater probability, a 200%, 300%, 400%, 500% or more greater probability of a phenotype relative to the general population or a control organism.
  • an organism with an increased risk or predisposition may be an organism with a greater than 1 fold increased probability of a phenotype relative to a control organism or the general population such as for example about a 1.01 fold, 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 3 fold, 5 fold, 10 fold, 100 fold or more increased probability of a phenotype relative to a control organism or the general population.
  • Increased risk or increased predisposition may also be determined using other epidemiological methods such as for example calculation of a hazard ratio or a relative risk.
  • an organism with a decreased risk or decreased predisposition for a specific phenotype is an organism with an odds ratio of less than 1, for example 0.99, 0.9, 0.8, 0.7, 0.5, 0.4, 0.2, 0.1, 0.01 or lower odds ratio relative to a control organism or relative to the general population.
  • An organism with a decreased risk or predisposition for a specific phenotype may be an organism with a lower percentage probability than a control organism or the general population for a phenotype.
  • the organism may have a 0.1% lower risk, 1% lower risk, 5% lower risk, 10% lower risk, 15% lower risk, 25% lower risk, 30% lower risk, 40% lower risk, 50% lower risk, 75% lower risk, or 100% lower risk than a control organism or the general population for a phenotype.
  • An organism's decreased risk or predisposition may also be determined as a hazard ratio or a relative risk.
  • An organism's genetic profile and scores can be used by third parties such as for example, genetic counselors (GCs) and medical professionals such as, for example, physicians, physician assistant, nurse practitioner and medical specialists, or veterinarians (if the genetic testing is conducted on animals) in providing recommendations based on an organism's genetic profile.
  • GCs genetic counselors
  • the genetic profiles and scores can also be used by ranchers, herders, corporations, veterinarians, animal reproduction specialists, trainers, owners, potential owners, fitness instructors, athletic coachs, therapists, chiropractors, acupunturists, weight loss specialists, nutritionists, and the like in providing recommendations to an organism.
  • the genetic profile for an organism can have information on one or more specific phenotypes. Examples of other numbers of phenotypes included in a genetic profile are described herein.
  • a genetic profile can have a "score" that indicates a general risk or predisposition to the specific phenotype or to a group of phenotypes.
  • the specific phenotype can be monogenic or multigenic (polygenic).
  • the phenotype can also be multifactorial.
  • the phenotypes/conditions analyzed may include clinical and non-clinical phenotypes.
  • Phenotypes/conditions can include medical conditions such as diseases and disorders, e.g., described herein.
  • Phenotypes can also include specific traits. Specific traits may include physical traits, physiological traits, mental traits, personality and emotional traits, breed, lineage (e.g., an organism's place of origin and organism's ancestor's place of origin), age (e.g., age expectancy, or age of onset, of different phenotypes, such as conditions and traits), and any other phenotype, such as diseases, disorders, or traits.
  • Some phenotypes concern an age of onset. "Age of Onset" may refer to the age that the phenotype is most likely to manifest or the age at which symptoms will first become noticeable and therefore the disease may be diagnosed.
  • the genetic profile includes a score that indicates a risk or predisposition of an organism for one or more multifactorial phenotypes.
  • the multifactorial inheritance of a phenotype is based on the interaction between genes and the environment.
  • the genetic factors may be a number of genes; a number of genetic variants within the same or different genes or elsewhere within the genome that is not within a gene; the non-genetic factors may be environmental exposures; habits; or specific traits.
  • Other factors that may also be included in the risk analysis of multifactorial phenotypes include abnormal or suggestive results from a medical examination or test; physical or mental symptoms; specific medical condition or medical history; family history or other genetic or non-genetic factor.
  • phenotypes may be monogenic, polygenic or multifactorial .
  • FIG.24 shows that for a multifactorial phenotype, the total risk is composed of genetic and non-genetic factors, also refered to as environmental factors. The amount that genetics or the environment contributes to this risk differs by phenotype. For example, one phenotype may be determined by approximately 70% genetics and approximately 30% environment while another phenotype may be determined by approximately 40% genetics and approximately 60% environment. The amount that genetics contributes to a phenotype is called the phenotype' s heritability. Heritability for a specific phenotype may be determined from various scientific studies, such as twin studies or parent-offspring regression, and the heritability of specific phenotypes can be found in published scientific literature, such as journal articles.
  • An organism's risk or predisposition for polygenic or multifactorial phenotypes can be calculated based on the allele or genotypes for one or more genetic variants associated with polygenic or multifactorial phenotype(s).
  • genetic risk or predisposition for multifactorial phenotypes By determining genetic risk or predisposition for multifactorial phenotypes, one can identify those organisms at higher risk due to their genetics and then proactively adjust their modifiable risk due to one or more non-genetic factors, for example, by modifying , modifying medications, conducting screening exams, and instituting other or living changes.
  • This approach can empower organisms, physicians, and health-care providers and enable them to identify non-genetic factors that can be modified and that will be of the most value.
  • genetic risk may remain unchanged, decreasing risk due to non-genetic factors risk may have the effect of decreasing risk overall, thereby decreasing the incidence of that phenotype, delaying its onset, or decreasing its morbidity or mortality.
  • the caretakers of organisms are informed of the monogenic diseases that they carry and may pass on to future generations.
  • a genetic profile is determined by obtaining the genetic information of an organism and correlating the genetic information to a specific phenotype.
  • a specific phenotype may be correlated to one or more genetic variants and their allele or genotype.
  • Genetic markers and variants may include different numbers of nucleotide repeats, nucleotide insertions, nucleotide deletions, single nucleotide polymorphisms, multiple nucleotide length polymorphisms, chromosomal translocations, chromosomal duplications, length of telomeres, copy number variations, or any combination thereof.
  • Copy number variation may include organism or multiple exons or other parts of a gene, an entire gene, multiple genes, microsatellite repeats, nucleotide repeats, centromeric repeats, or telomeric repeats.
  • Genetic markers and variants may also include epigenetic factors, such as methylation status. Genetic variants may also be changes to a single nucleotide, referred to as point mutations or polymorphisms or mutations or variants, such as single nucleotide polymorphisms, or SNPs. Genetic variants may also be changes to multiple nucleotides, such as changes to two or more nucleotides that are located next to each other or are not located next to each other. Genetic variants may also be the deletion or insertion of one or more nucleotides anywhere within an organism's genetic code, referred to as a deletion or insertion, or deletion insertion polymorphisms, or DIPs (also referred to as indels).
  • Genetic markers and variants may include changes to nuclear DNA, mitochondrial DNA, chloroplast DNA, cytoplasmic DNA, plasmid DNA, or combinations thereof. Genetic markers and variants may also occur in genetic sequences that are not contained within a cell, such as from lysed cells at a crime scene or if genetic sequences are detectable in the blood or plasma, such as when fetal oligonucleotides exist within maternal blood.
  • genetic sequences such as DNA or RNA or cells containing DNA or RNA, from one organism may occur within another organism and be able to be isolated or analyzed, such as when fetal cells can be detected and isolated from maternal blood during pregnancy, or such as with hematophagy when one organism, such as an insect, contains blood from another organism, such as within its stomach, and genetic analysis and a genetic profile can be determined from this source of genetic information as well.
  • the genetic profile may be determined by obtaining genetic information from any source of genetic information, such as DNA or RNA, which may exist anywhere within the organism, such as within the cytoplasm of bacteria, within the nucleus and mitochondria of cells from mammals, within the capsid of viruses or within the nucleus and chloroplast of plants and eukaryotic algae.
  • any source of genetic information such as DNA or RNA, which may exist anywhere within the organism, such as within the cytoplasm of bacteria, within the nucleus and mitochondria of cells from mammals, within the capsid of viruses or within the nucleus and chloroplast of plants and eukaryotic algae.
  • Genetic variants may also be in linkage disequilibrium with other genetic variants that are detected or determined for an organism's genomic profile. Each new allele is typically initially associated with the other alleles that happened to be present on the particular chromosomal background on which it arose. The specific set of alleles observed on a single chromosome, or part of a chromosome, is called a haplotype. New haplotypes can be formed by additional mutations or by recombination, such as between maternal and paternal chromosomes, resulting in a mosaic of the two parental haplotypes.
  • Linkage disequilibrium can be applicable to all types of genetic variants, including SNPs, DIPs, nucleotide repeats, translocations, methylation status, and CNVs, and is also applicable to all species, including humans and non-humans.
  • the genetic variants described herein may be used to determine specific haplotypes or diplotypes.
  • genetic markers or variants such as SNPs, nucleotide repeats, insertions, deletions and other as described herein, may be in linkage disequilibrium with genetic markers that have been shown to be associated with specific phenotypes.
  • a nucleotide insertion is correlated with a phenotype and a SNP is in linkage disequilibrium with the nucleotide insertion.
  • a disease predisposing allele cosegregates with a particular allele of a SNP or a combination of particular alleles of SNPs.
  • haplotype A particular combination of SNP alleles along a chromosome is termed a haplotype, and the DNA region in which they occur in combination can be referred to as a haplotype block. While a haplotype block can consist of one SNP, typically a haplotype block represents a contiguous series of 2 or more SNPs exhibiting low haplotype diversity across organisms and with generally low recombination frequencies. An identification of a haplotype can be made by identification of one or more SNPs that lie in a haplotype block.
  • Linkage disequilibrium can be measured by the variables D and r 2 , such as described by Hill and Robertson (TAG Theoretical and Applied Genetics 38: 226-231 (1968)).
  • the International HapMap provides these measures of LD for genetic variants.
  • r 2 is a measure of the LD between two genetic variants and the range of r 2 is from zero to one.
  • the specific genetic variant is the cause of that phenotype (that genetic variant is the causal genetic variant).
  • that genetic variant is the causal genetic variant.
  • chromosome 1 in the coagulation factor V gene (F5) there exists a genetic variation (an adenine base appears instead of a guanine, IUPAC nucleotide code R (see Table 1)) that changes amino acid position 506 from an Arginine (Arg) to a Glutamine (Gin) (see Table 2 for IUPAC amino acid codes used herein), which appear in dbSNP as rs6025 (Bertina et al., Nature 369:64-67 (1994)).
  • Factor V Leiden This genetic variant was found to be one of the direct causes of activated protein C resistance, which causes the thrombophilia phenotype. Without being bound by theory, it is thought that any genetic variant that is in tight LD (has a high r 2 value) with the Factor V Leiden genetic variant may also be associated with thrombophilia.
  • the sequence for a genetic variant may be from any available database, public or private.
  • the sequence data may be from the March 2006 human reference sequence (NCBI Build 36.1), produced by the International Human Genome Sequencing Consortium and the mitochondrial sequence may be from NCBI Genebank #AC_000021.2.
  • the sequence data may be from the October 2007 Bos Taurus draft assembly (Baylor release Btau_4.0), produced by the Baylor College of Medicine Human Genome Sequencing Center.
  • the sequence data may be from the May 2006 chicken (Gallus gallus) v2.1 draft assembly, produced by the Genome Sequencing Center at the Washington University School of Medicine in St. Louis, MO, USA (WUSTL).
  • sequence data may be from the May 2005 dog (Canis familiaris) whole genome shotgun (WGS) assembly v2.0, sequenced and assembled by the Broad Institute of MIT/Harvard and Agencourt Bioscience.
  • WGS whole genome shotgun
  • the sequence data may be from the Sep. 2007 Equus caballus draft assembly EquCab2 (UCSC version equCab2), produced by The Broad Institute.
  • UCSC version equCab2 EquCab2
  • the sequence data may be from journal articles that discuss a specific genetic variant and/or the genetic sequence surrounding and/or including the genetic variant.
  • the sequence data may be from the March 2006 Felis catus draft assembly (Broad Release 3), produced by the Broad Institute of MIT/Harvard and Agencourt Bioscience.
  • the sequence data may be from the March 2006 chimpanzee (Pan troglodytes) browser displays data from the 6X whole genome shotgun draft assembly (Build 2 Version 1, Oct. 2005), produced by the Chimpanzee Sequencing and Analysis Consortium.
  • the sequence data may be from the July 2007 mouse (Mus musculus) genome data, obtained from the Build 37 assembly by NCBI and the Mouse Genome Sequencing Consortium.
  • the sequence data may be from the November 2004 rat (Rattus norvegicus) genome assembly, based on version 3.4 produced by the Atlas group at Baylor Human Genome Sequencing Center (HGSC) as part of the Rat Genome Sequencing Consortium.
  • the sequence data may be from the v5.0.1 Ornithorhynchus anatinus draft assembly, produced by the Genome Sequencing Center at Washington University, St. Louis.
  • the sequence data may be from the Feb. 2008 Cavia porcellus draft assembly (Broad Institute cavPor3), produced by the Broad Institute at MIT and Harvard.
  • the sequence data may be from the January 2006 rhesus macaque (Macaca mulatta) draft assembly v.1.0, Mmul_051212, obtained from the Baylor College of Medicine Human Genome Sequencing Center (BCM HGSC).
  • the sequence data may be from the Jul. 2007 Pongo pygmaeus abelii draft assembly (WUSTL version Pongo_albelii-2.0.2), produced by the Genome Sequencing Center at Washington University School of Medicine in St. Louis (WUSTL).
  • the sequence data may be from the Feb. 2007 Anolis carolinensis draft assembly (Broad Institute AnoCar (1.0)), produced by the Broad Institute at MIT and Harvard.
  • a human genetic variant for the F5 gene may be referenced as "F5 Chr. 1 : 167785673 R", meaning that the genetic variant exists within or boardering the F5 gene on chromosome 1, at position 167785673 on chromosome 1, and that the base is either an adenine or a guanine.
  • the sequence numbering can be relative to the coordinate systems for each chromosome from NCBI Build 36.1. All coding and abbreviations are based on IUPAC nomenclature.
  • the genomic sequence surrounding this genetic variant on the reverse strand is as follows, with R (A or G) appearing at position 167785673: TGTAAGAGCAGATCCCTGGACAGGC(R)AGGAATACAGGTATTTTGTCCTTGA
  • Some associations between genetic variants and risk of disease are based upon a 'signal' of risk in the vicinity of that genetic variant.
  • the genetic variant may not be the causal genetic variant (ie. it may not be the exact cause of the phenotype) but because it is in LD with the causal variant, the non-causal genetic variant shows an association with the phenotype.
  • These signals can be used clinically as they can allow for the ascertainment of risk from signals (genetic variants in LD with the causal genetic variant) without the exact causal variant being specifically known at that moment. For example, as described in Zeggini et al. (Nat. Genet. 40: 638-645 (2008)), Zeggini et al.
  • DMII Diabetes Mellitus
  • McCarroll et al. conducted research on the cause of the association (the cause of the signal) that had previously been detected (Partes et al. Nat Genet 39:830-832 (2007); The Wellcome Trust Case Control Consortium Nature 447:661-678 (2007); Franke et al. Nat Genet 40:713-715 (2008)) between region 5q33.1 (containing the IRGM gene) and Crohn's disease (CD). McCarroll et al.
  • a specific genetic variant in LD with previously reported genetic variants (rsl3361189 and rs4958847) in the region may be the actual causal genetic variant in that region associated with a predisposition for Crohn disease.
  • They found a common, 20-kb deletion polymorphism upstream of IRGM and in perfect linkage disequilibrium (r 2 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences.
  • r 2 1.0
  • any one of these genetic variants in tight LD with each other can be used to ascertain a specific predisposition to Crohn's disease in relation to the signal at 5q33.1.
  • any one of the genetic variants can be tested for, and used to discern whether an organism has a predisposition for Crohn disease based on the specific signal in this region (5q33.1, IRGM gene) of the genome.
  • genetic variants detected for an organism may be in LD with a causal genetic variant.
  • the genetic variants detected may have an r 2 value of at least 0.2, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92. 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or 1 with a causal genetic variant.
  • the genetic variants detected may have an r 2 value of at least 0.2, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or 1 with published genetic variants that are correlated or associated with a phenotype.
  • oligonucleotides that specifically detect a genetic variant, either a genetic variant directly correlated with a condition, or a genetic variant in linkage disequilibrium with a genetic variant that is correlated to a phenotype.
  • the genetic variant detected by such an oligonucleotide is associated with a phenotype, such as a medical condition.
  • the association of a genetic variant with a phenotype may be from a scientific publication.
  • the genetic variant that is detected can also be correlated to a non-phenotype.
  • genetic variants such as described herein, may be detected by oligonucleotides specifically selected to detect such genetic variants, wherein the genetic variants are correlated to a phenotype, such as medical conditions, non-medical conditions, or a combination thereof.
  • sequences to detect genetic variants may be unique sequences (e.g., those not listed in public databases, such as NCBI's dbSNP Builds 126 - 129 for example) upstream or downstream (flanking) of a genetic variant.
  • sequence may contain sequence information that encompasses about 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 150, or 200 bps or more immediately upstream or downstream of a genetic variant.
  • the genetic profiles can be determined from oligonucleotide sequences wherein at least 5, 10, 25, 50, 65, 70, or 75% of the sequences corresponding to a genetic variant are sequences not listed in a public database, for example sequences about 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 150, or 200 bps or more (upstream or downstream) of the genetic variant.
  • the sequences to detect genetic variants, or the sequence of a genetic variant, such as the deleted sequence of a deletion polymorphism may be stored in a private database, such as, but not limited to, the Predictive Medicine Database further described below, and illustrated in Example 9.
  • the private database may be contracted to comprise both publicly available genetic variants, such as sequences containing these genetic variants from public databases as well as sequences not available in public databases.
  • the private database may have at least about 50, 100, 1000, 5000, 6,000, 6,500, 7,000, 8,000, 10,000, 15,000, 20,000, 25,000, 30,000, 45,000, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 350,000, 400,000, 450,000, 500,000, 750,000, 1,000,000, 1,500,000, 2,000,000, 2,500,000, 3,000,000, 3,500,000, 4,000,000, 4,500,000, 5,000,000, 5,500,000, 6,000,000, 6,500,000, 7,000,000, 7,500,000, 8,000,000, 8,500,000, 9,000,000, 9,500,000, 10,000,000 or more genetic variants, such as SNPs, that are associated with specific phenotypes, such as diseases or traits.
  • the private database may contain genetic variants associated with specific phenotypes, such as diseases or traits, present in at least 100, 250, 500, 750, 1000, 1250, 1500, 2000, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11000, 11500, 12000, 12500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18500, 19000, 19500, or 20,000 genes.
  • specific phenotypes such as diseases or traits
  • the database may contain genetic variants present in non-coding regions.
  • the genetic variants may be medically related or non-medically related.
  • the genetic variants, such as SNPs may include only clinically relevant genetic variants, or genetic variants in genes or in linkage disequilibrium with other genetic variants correlated with clinical phenotypes.
  • the SNPs, or other genetic variants may be organized by medical specialty, organ system, gene, chromosome, location on a chromosome, or phenotype.
  • the SNPs, or other genetic variants can be organized by clinical severity or by how well that genetic variant is thought to correlate with a specific phenotype or by the degree or status of replication of that genetic variant with its associated phenotype.
  • the private database can also have precise information for each genetic variant, such as a SNP. For example, information such as odds ratio, relative risk, hazard ratio, absolute risk value, applicable populations and ethnicities/species, inheritance patterns, journal references, journal links, genetic variant synopsis, phenotype information, phenotype prevalence, phenotype incidence, genetic variant allele frequencies, and recommendations or interventions, such as those that have been associated with decreasing the incidence or impact of that phenotype.
  • information such as odds ratio, relative risk, hazard ratio, absolute risk value, applicable populations and ethnicities/species, inheritance patterns, journal references, journal links, genetic variant synopsis, phenotype information, phenotype prevalence, phenotype incidence, genetic variant allele frequencies, and recommendations or interventions, such as those that have been associated with decreasing the incidence or impact of that phenotype.
  • the database is a Predictive Medicine Database (PMD), which can be constructed from, or through a review of some, many, or all published studies throughout some, many, or all worldwide journal articles relating to specific genetic variants associated with a phenotype (disease, condition, trait, process, modifier of other phenotype, and others).
  • PMD can allow for a an analysis, a comprehensive analysis, or a complete analysis of some, many or all known phenotype-associated genetic variants throughout the partial or entire genome of an organism of any species.
  • the PMD may or may not be part of an Analytical IT System (FIG 1).
  • An Analytical IT System can process genetic data from genetic testing and/or may analyze genetic information from genetic testing.
  • An Analytical IT System may also process non-genetic factors (such as medical history and/or primary location an animal may be raised, such as free-range or caged) and may include that non-genetic information in the analysis of the genetic data and/or genetic information.
  • An Analytical IT System may associate the genetic information or data with one or more phenotypes.
  • the Analytical IT System may, or may not, include, be part of, or be able to access one or more phenotype matrices, gene matrices, and/or genetic variant matrices (described herein).
  • the Analytical IT System may enable and make possible comprehensive, integrated and/or actionable genetic analysis and/or clinical genetic analysis and/or may enable partial genome analysis, full genome analysis (e.g., whole genome analysis), partial genome clinical analysis and/or full genome clinical analysis (e.g., whole genome clinical analysis).
  • full genome analysis e.g., whole genome analysis
  • partial genome clinical analysis e.g., whole genome clinical analysis
  • One or more Analytical IT System(s) may be capable of analyzing genetic data and/or information, such as allele or genotype data for one or more genetic variants within a genome and may be capable of generating an analysis, such as a genetic report (described herein).
  • a number of PMDs are generated, wherein each PMD is specific for a particular species. For example, a PMD may be provided for humans, and another PMD for canines.
  • the PMD can also be agnostic, in that the data in the PDM can be utilized on any genetic testing platform (such as those provided by Illumina, Sequenom, General Electric, Agilent, 454 Life Sciences, Pacific Biosciences, Complete Genomics, Helicos Biosciences, Intelligent Bio-Systems, IBM, ION Torrent Systems, Halcyon Molecular, GE Global, Stratos Genomics, Genome Corp., Genome Diagnostics, Agencourt Bioscience, Microchip Biotechnologies, or Affymetrix) and with any genetic testing methodology (such as arrays, massarrays, beadarrays, microarrays, genechips, PCR, partial or full exome sequencing, and partial or full genome sequencing, such as with pyrosequencing, nanopore, fluorophores, nanopore sequencing, nanoballs, sequencing by synthesis, sequencing by expansion, single molecule real time technology (SMRT)TM, true single molecule sequencing technology (tSMS)TM, or sequencing by ligation, microfluidics, infrared
  • the PMD can also be used only for one or more specific platforms.
  • all specific genetic variants associated with any discernible phenotype are included within the PMD, including single nucleotide polymorphisms (SNPs), deletion and insertion polymorphisms (DIPs), mutations, repeats, inversions, duplications, copy number variations (CNV), rearrangements, telomere size, and epigenetic factors such as methylation status.
  • the genetic variants may be throughout the entire genome, including those that may exist within or near binding sites, such as transcription binding sites, translation binding sites, or microRNA (miRNA) binding sites, as well as genetic variants that may exist in DNA or RNA within the nucleus, mitochondria, freely within blood or plasma or in the cytoplasm. Genetic veriants may also be detected in genetic material that exists in any location in different species, such as contained within the capsid of a virus or within the nucleus or chloroplast of a plant.
  • the database may be constructed to contain variety of fields dependent upon the particular desired use, the genetic variants being analyzed or the types of scores being provided in the report to the client. Fields of the database are first created and all ascertainable data from each and every journal article is then entered into each of the fields. Nomenclature used in the database can follow the recommendations of The Ad Hoc Committee on Mutation Nomenclature (Human Mutation 8(3): 197-202); Beutler et al. (V. A. M. A. G. M. C. R. S. F. H Human Mutation 8(3): 203-206 (1996)); Stylianos and Antonarakis (Human Mutation 11(1): 1-3 (1998)); and den Dunnen, S. E. A. (Human Mutation 15(1): 7-12 (2000)).
  • Journal articles can be divided by diseases and genetic variants that are monogenic or deterministic versus those that are polygenic or multifactorial and risk-associated.
  • the PMD fields may include: Full Gene Name or Locus (if the genetic variant is not located within or bordering a gene), Gene Symbol, Gene Locus, and Exact Genetic Variant Identification.
  • Journal articles can be from any journal from around the world that contains published studies of genetic variant-phenotype associations, and may be found through such resources as print version of the journal, libraries, and various internet resources such as through Entrez Pubmed (see for example, www.ncbi.nlm.nih. gov/ site s/entrez) .
  • the Exact Genetic Variant Identification can be the exact genomic sequence surrounding the genetic variant.
  • it can be the 25, 50, 100, or 200 bp of sequence upstream (5' flank) of the variant or 25, 50, 100, or 200 of sequence downstream (3'flank) of the variant or both.
  • the Exact Genetic Variant Identification can be about 4, 5, 8, 10, 15, 20, 25, 30, 35, 40, 45, or 50 bp of sequence upstream and downstream of the variant.
  • Sources of sequence information can be any available in the arts, such as, but not limited to the Human Genome Project's Reference Sequence, Celera's Sequence, the European Molecular Biology Laboratory- European Bioinformatics Institute-Sanger Institute's Ensembl database (such as from www.ensembl.org/Homo_sapiens/index.html)and the National Center for Biotechnology Information database (www.ncbi.nlm.nih.gov/gene).
  • the genomic sequence surrounding the genetic variant can be identified according to International Union of Pure and Applied Chemistry (IUPAC) nucleotide ambiguity codes,as described by Cornish-Bowden ("IUPAC-IUB SYMBOLS FOR NUCLEOTIDE NOMENCLATURE" Nucl Acids Res.
  • PMD fields may include location of the genetic variant in or near the gene, such as Intergenic, Intron, Exon, Promoter, Regulatory, Enhancer, 3 'untranslated region, 5 'untranslated region, Intron Splice Site, Exon Splice Site, or miRNA Binding Site.
  • other PMD fields can include position within gene relative to start codon, amino acid number that the genetic variant occurs within, amino acid change that occurs due to genetic variant according to IUPAC nomenclature (Nomenclature, I. -I. C. o. B. (1966). J. Biol. Chem.
  • PMD fields may be Allele 1 (specific nucleotide if it is a SNP or nucleotide sequence if it is a DIP or repeat, or copy number if it is a CNV), Allele 2 (specific nucleotide if it is a SNP or nucleotide sequence if it is a DIP or repeat, or copy number if it is a CNV), Phenotype-associated Allele (Specific nucleotide if it is a SNP or nucleotide sequence if it is a DIP or repeat, or copy number if it is a CNV), or Phenotype-associated haplotype or diplotype for two or more genetic variants (if applicable), and Phenotype-associated Genotype (Specific genotype if it is a SNP or nucleotide sequence if it is a DIP or repeat, or copy number if it is a CNV).
  • the haplotype for two or more genetic variants may have all genetic variants and
  • F FANS (fans.ngc. sinica.edu. tw/fans/input.do), which is typically used for unique sequences, i.e. those without dbSNP rs numbers.
  • FANS fans.ngc. sinica.edu. tw/fans/input.do
  • dbSNP rs numbers i.e. those without dbSNP rs numbers.
  • PMD fields may include one or more of the following: Risk Value, Risk Type (Odds Ratio, Relative Risk, or Hazard Ratio), Confidence Interval for risk value, p-value of risk value or cumulative or absolute value, Cumulative or Absolute Value (such as an Absolute Value, Absolute Risk or Lifetime Risk); Cumulative or Absolute Value Descriptor; Minor Allele Frequency (MAF) or Haplotype Frequency; Specific Population(s) that the risk and risk-allele (or risk-genotype or risk- haplotype) applies to, incidence of non-phenotype associated allele or genotype in disease cohort, incidence of phenotype associated allele or genotype in control cohort; total number of that specific population within the disease cohort(s); total number of that specific population within the control cohort(s); inheritance (such as Autosomal Recessive, Autosomal Dominant, Multi
  • PMD fields may include one or more of the following: Inheritance (such as Autosomal Recessive, Autosomal Dominant, Codominance, Incomplete Dominance, X-linked Recessive, X-linked Dominant, etc.), Replication Status, Genetic Variant-Phenotype Score Rating (GVP Score), Genetic Variant-Phenotype Triage (GVP Triage) also referred to as the Genetic Variant-Phenotype's Clinical Significance Rating (CSR), and/or Study Type (such as: Prospective, Retrospective, Genome -wide Association Study, etc.).
  • Inheritance such as Autosomal Recessive, Autosomal Dominant, Codominance, Incomplete Dominance, X-linked Recessive, X-linked Dominant, etc.
  • Replication Status Genetic Variant-Phenotype Score Rating (GVP Score)
  • GVP Triage Genetic Variant-Phenotype Triage
  • CSR Clinical Significance Rating
  • Study Type
  • PMD fields may include, but not be limited to, Journal Article Author's Name(s), Journal Article's Date of Publication, Name of Journal, Primary Journal Article Reference, World Wide Web (www) address of the pubmed listing of the journal article, World Wide Web (www) address of the actual journal article, and/or References of any other published study on that specific genetic variant-phenotype association.
  • Haplotypes may also be included in the PMD, and each haplotype -phenotype -risk value association may receive its own unique haplotype identifier number. All genetic variants that compose the haplotype may be listed in the PMD, as shown in the fields below.
  • the specific haplotype under its unique identified number can list the genetic variants that compose the haplotype along with the genetic variant's alleles or genotypes that compose the haplotype and are associated with the risk-value for that specific phenotype in that specific population. Selected PMD fields are shown in Table 3.
  • the information for PMD fields may be publicly available, such as through published journal articles, published studies, websites, or from databases such as the aforementioned Entrez Gene database or other Entrez databases, the Ensembl database, the National Center for Biotechnology Information dbSNP database, or the International HapMap Project.
  • the risks can represent an estimate for an organism to be at risk for, to have, to be a carrier of, or be predisposed to have, a phenotype (e.g., condition, disorder, disease, trait, and the like).
  • the risks or predispositions may be indicated by a numerical value, such as a risk value.
  • the risk value can be an odds ratio (OR), relative risk (RR), hazard ratio (Z), cumulative risk (CR), absolute risk (AR), or lifetime risk (LR).
  • the risk value, or degree of risk can be expressed in numbers, words, colors, graphs, charts, pictures, or other means, for example, the risk value can be described as high, medium, low, or none.
  • the risk value, or degree of risk can also be expressed as a range, such as a range of numbers, for example, from -5 to +5, wherein -5 indicates a highly unlikely occurrence of a condition in an organism to +5, wherein there is a highly likely occurrence of a condition in an organism.
  • the risk value, or degree of risk can also be expressed in a range of colors, for example, red indicating a high risk of having a condition, yellow for no risk, and blue for a decreased risk (protection against) having a phenotype, such as a condition.
  • the number or color ranges can also include numbers or ranges that indicate an organism's genetic profile shows a protective effect for the phenotype, such as a condition.
  • the risk value, or degree of risk can also be an absolute value (e.g., amount of milk production per day in kilograms). Further methods of calculating the risk of, carrier status of, or predisposition of an organism for a phenotype are provided herein. Such risks, predispositions and carrier statuses are also further described herein.
  • the score for a disease or condition can be determined by one or more genetic variants, such as polymorphisms, as well as other factors, such as non-genetic factors, including non-genetic factors or previously known diseases, conditions or traits.
  • One or more scores can be generated for a genetic profile of an organism.
  • An organism's genetic profile can include values or scores for one or more phenotypes, such as diseases or traits.
  • a genetic profile can also include information for selected phenotypes, such as traits or conditions, such as only clinical conditions.
  • a genetic profile can contain information for non-clinical phenotypes only, or a combination of clinical and non-clinical phenotypes.
  • an organism has a clinical genetic profile that includes at least 2, 3, 5, 10, 20, 50, 100, 150, 200, 500, or 1000 clinically-relevant phenotypes, such as conditions, diseases or disorders. In some cases, an organism has a clinical genetic profile that includes other numbers of phenotypes, as described herein.
  • a non-limiting example of representative genes and loci included in the present invention is shown in Table 4.
  • melanocortin 1 receptor alpha melanocyte dog MC1R stimulating hormone receptor
  • solute carrier family 36 proton/amino acid horse SLC36A1 symporter
  • ADN APM1 ;
  • Pig IGFBP-3 insulin-like growth factor binding protein 3 ig MAN2B2 mannosidase, alpha, class 2B, member 2 ig MMP-2 matrix metalloproteinase-2
  • the genetic profile (e.g., analysis) can be determined from detecting at least approximately 2, 3, 4, 5, 10, 25, 50, 100, 1000, 2,000, 5000, 6,000, 6,500, 7,000, 8,000, 10,000, 12,000, or 15,000 genetic variants. In some cases, genetic profiles can be determined from at least approximately 20,000, 25,000, 30,000, 45,000, or 50,000 genetic variants. The genetic variants may be correlated to a phenotype, such as medically relevant or non-medically relevant phenotypes or conditions.
  • a number of genetic variants may cause, be associated with, or be correlated to a single phenotype, or a single genetic variant can be correlated to a single phenotype.
  • a number of genetic variants may also be correlated to a number of phenotypes.
  • a single genetic variant may be associated with a number of phenotypes.
  • Each genetic variant can be correlated or associated with at least one phenotype and each phenotype is correlated or associated with at least one genetic variant.
  • a genetic profile may be used to detect (or calculate the risk of , carrier status of , or predisposition for) at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, at least 60, at least 70, at least 100, at least 200, or at least 500 phenotypes (e.g., phenotypes described herein).
  • phenotypes e.g., phenotypes described herein.
  • a genetic profile is used to detect at least 2 phenotypes, but no more than 10 phenotypes, no more than 15 phenotypes, no more than 20 phenotypes, no more than 25 phenotypes, no more than 30 phenotypes, no more than 35 phenotypes, no more than 40 phenotypes, no more than 45 phenotypes, no more than 50 phenotypes, no more than 100 phenotypes, no more than 200 phenotypes, no more than 300 phenotypes, no more than 500 phenotypes, no more than 1000 phenotypes, or no more than about 10, about 20, about 50, about 100, about 200, about 300, about 500, or about 1000 phenotypes (e.g., phenotypes described herein).
  • a genetic profile is used to detect at least 3 phenotypes, but no more than 10 phenotypes, no more than 20 phenotypes, no more than 50 phenotypes, no more than 100 phenotypes, no more than 200 phenotypes, no more than 300 phenotypes, no more than 500 phenotypes, no more than 1000 phenotypes, or no more than about 10, about 20, about 50, about 100, about 200, about 300, about 500, or about 1000 phenotypes (e.g., phenotypes described herein).
  • a genetic profile is used to detect at least 4 phenotypes, but no more than 10 phenotypes, no more than 20 phenotypes, no more than 50 phenotypes, no more than 100 phenotypes, no more than 200 phenotypes, no more than 300 phenotypes, no more than 500 phenotypes, no more than 1000 phenotypes, or no more than about 10, about 20, about 50, about 100, about 200, about 300, about 500, or about 1000 phenotypes (e.g., phenotypes described herein).
  • a genetic profile is used to detect at least 5 phenotypes, but no more than 10 phenotypes, no more than 20 phenotypes, no more than 50 phenotypes, no more than 100 phenotypes, no more than 200 phenotypes, no more than 300 phenotypes, no more than 500 phenotypes, no more than 1000 phenotypes, or no more than about 10, about 20, about 50, about 100, about 200, about 300, about 500, or about 1000 phenotypes (e.g., phenotypes described herein).
  • a genetic profile is used to detect at least 6 phenotypes, but no more than 10 phenotypes, no more than 20 phenotypes, no more than 50 phenotypes, no more than 100 phenotypes, no more than 200 phenotypes, no more than 300 phenotypes, no more than 500 phenotypes, no more than 1000 phenotypes, or no more than about 10, about 20, about 50, about 100, about 200, about 300, about 500, or about 1000 phenotypes (e.g., phenotypes described herein).
  • a genetic profile is used to detect at least 7 phenotypes, but no more than 10 phenotypes, no more than 20 phenotypes, no more than 50 phenotypes, no more than 100 phenotypes, no more than 200 phenotypes, no more than 300 phenotypes, no more than 500 phenotypes, no more than 1000 phenotypes, or no more than about 10, about 20, about 50, about 100, about 200, about 300, about 500, or about 1000 phenotypes (e.g., phenotypes described herein).
  • the genetic profiles can also be determined from detecting genetic variants in at least approximately 2, 5, 10, 25, 50, 100, 250, 500, 750, 1000, 1250, 1500, 2000, 2500, 3000, 3500, 4000, 5000, 6000, or genes or loci. In some embodiments, at least approximately 1000, 1500, 2000, 2500, 3000, 4000, 5000 genetic variants are detected in an organism's genetic profile. In some embodiments, approximately 50 or more , 100 or more , 200 or more , 500 or more , 1000 or more, 1500 or more, 2000 or more, 2500 or more, 3000 or more, 4000 or more, 5000 or more, or 6000 or more genetic variants are detected in an organism's genetic profile.
  • At least approximately 6000 genetic variants or at least approximately 6500 genetic variants are detected in an organism's genetic profile.
  • the genetic profile can include genetic variant identification in at least 2, 5, 10, 25, 50, 100, 200, 500, 1000, 1200, 1500, 2000, 3000, 4000, 5000, or 6000 genes.
  • each of the genetic variants in the genes or loci are associated with one or more phenotypes.
  • each of the genetic variants in the genes or loci is medically relevant.
  • each of the sequences is linked to a journal reference or a preventive intervention/recommendation or both.
  • each of the genetic variants is for a specific disease or for a specific type of genetic testing, such as for children, for a adults, for newborns, for a fetus, for organisms that participate in sports or gambling activities, for carrier information, for research, for governmental agency purpose.
  • the genetic variants can also be used to determine the pharmacogenomic profile of an organism and be utilized in assessing clinical trials to stratify the pospulation and further identify genetic variants associated with improved or decreased efficacy or adverse effects.
  • the genetic variants can be used to determine the suitability of a particular medication, drug or treatment for a given disease, condition or phenotype.
  • suitability may include determining whether an organism has a risk of reacting adversely to a drug or treatment, whether a drug may have little effect on the organism's condition (or phenotype), whether a drug is likely to be beneficial to the organism, whether one drug or treatment may be more effective or beneficial than another drug or treatment, whether the drug is likely to be effective in treating a condition, or the timeframe (such as described by a certain number of seconds, minutes, hours, days, weeks, months, years, or decades) in which a response, such as therapeutic response,is likely to be observed with a specific medication or class of medications.
  • Suitability or pharmacogenomics results may include but are not limited to drug resistance, sensitivity, effectiveness, metabolism, absorption, or excretion of a specific drug or class of drugs such as for example aminoglycosides, anti-cancer drugs, sulfonamides, opiates or NSAIDs.
  • Other pharmacogenomic results may include information on a suitable drug dosage for an organism, such as the most appropriate dose of a drug to start at in order to obtain effectiveness or increased effectiveness or to limit potential adverse effects, including but not limited to addiction, toxicity, allergic reaction, abuse potential, treatment-emergent suicidality, hypersensitivity, induced parkinsonim, resistance and intolerance.
  • genetic variants are "indicators of or may be an indicator of which indicates that genetic testing and/or analysis can ascertain one of three possible phenotypes: an increased phenotype, a normal phenotype, or a decreased phenotype.
  • genetic variants may provide enhanced protection against an adverse phenotype given a specific intervention.
  • variants that indicate hormone therapy may be particularly advantageous for protection against breast cancer.
  • Non limiting examples of pharmacogenomic genetic variants include variants in cytochrome P450 genes and any other genes involved in the pharmacodynamics, pharmacokinetics, metabolism, processing, excretion, and/or absorption of any injested, injected, absorbed, or inhaled substance.
  • the evaluation of the genetic variants and their relationship to phenotype and the significance to the client may be further analyzed to produce one of a variety of scores that combine two or more of the variants identified and in some embodiments also include non-genetic information about the client to provide a score as described herein.
  • the particular profile or score provided in the report to the client to third party may be based on a request from the client, doctor or another third party as described herein.
  • the risk for a phenotype e.g., specific disease, disorder, characteristic, trait or condition
  • responses to drug treatments such as efficacy of a drug
  • a score or action score for a specific disease or trait can be determined by multiplying the phenotype' s Clinical Significance Rating (CSR), Phenotype Impact Rating (PIR) and Notice Me Factor (NMF).
  • CSR Clinical Significance Rating
  • PIR Phenotype Impact Rating
  • NMF Notice Me Factor
  • an Action Score may be determined by using a subset of the aforementioned factors, additional factors, or a combination thereof, as further described below.
  • Other scores or measures may also be determined (See for example, FIG. 6, Table 8, Table 9A-9B and Example 7).
  • the Generic Lifetime Risk is the gender-specific or gender matched lifetime risk of a specific phenotype for a population and this can be obtained from published literature and various resources such as from the United States Department of Health and Human Services' Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH).
  • the GLR may also be age-matched and/or gender-matched for a population.
  • the Cumulative Genetic Risk is the organism's risk of a phenotype based on their genetic profile, containing one or more genetic variants associated with risk for that phenotype, and is determined by taking into account all relevant genetic variants associated with that phenotype.
  • the Predictive Medicine Risk is the organisms new lifetime risk for a phenotype based on the phenotype' s GLR and the organism's CGR.
  • the PIR (also known as the DIR), or Phenotype Impact Rating, indicates the clinical severity of a phenotype.
  • the PIR ranges from -3 to +3, where -3 causes sudden death or debilitating phenotype, such as a disease, -2 indicates a serious phenotype, such as a disease, a phenotype, such as a disease or condition, that is difficult to cure, may cause death, or has significant negative life consequences, -1 indicates a phenotype, such as a disease or condition, that is usually manageable, 0 is a neutral phenotype, such as a condition or trait, +1 indicates a slightly positive phenotype, such as a condition or trait; +2 indicates that the phenotype is a helpful trait or protection against (lower risk of) a harmful phenotype, such as a condition, and +3 indicates a significant advantage or significant protection against a harmful phenotype, such as a condition.
  • the Genetic Variant- Phenotype Score may be used as a measure or rating system for genetic variant-phenotype correlations, or the association or strength of association between a genetic variant's allele or genotype and a phenotype, such as a disease or condition.
  • a GVP score can be determined for a disease or trait, such as milk production, based on studies correlating a genetic variant with a phenotype.
  • an organism's genetic profile may be reported with different sections divided by the level of replication, substantiation, validationand confirmation (e.g., the level the associations have been replicated, substantiated, validated or confirmed).
  • the report may have a first section that contains genetic variant-phenotype associations that are only highly replicated and substantiated while the second section contains phenotype information assessed from genetic variant- phenotype associations that are highly replicated and substantiated and also moderately replicated and substantiated, and so forth.
  • a kidney transplant physician or researcher such as a clinical trial researcher, may find this information useful in watching adverse reactions or in determining the starting dose of the medication even if the association is not substantiated by replicated studies.
  • Factors that can be used in a system for rating genetic variant alleles or genotypes and their correlations with one or more phenotypes may include, but are not be limited to, the aggregate number of organisms in the disease cohort(s), or cohort(s) exhibiting a certain condition or trait, across all studies for the population (such as a population with the same ethnicity/species, gender, age, habits, past medical history, suspected medical condition, surgical history, family history, prior genetic testing or analysis results, prior laboratory results, medications currently taking, medications previously taking, medications that may be given in the future, or any combination thereof), the aggregate number of organisms in the control cohort(s) across all studies (such as for a population with the same species, gender, age, , habits, , past medical history, suspected medical condition, surgical history, family history, prior genetic testing or analysis results, prior laboratory results, medications currently taking, medications previously taking, medications that may be given in the future, or any combination thereof), the aggregate number of total organisms in the studies (such as a population with the same species
  • the GVP Score is an example of a system used for rating a genetic variant-phenotype correlation (see for example, FIG. 7). It may be the only system used or combined with other systems, as further described below. Thus in the embodiments described herein, other rating systems (such as those described below) may be used instead of the GVP score, or in combination with the GVP score.
  • the GVP score may be population specific or it may not be population specific.
  • the GVP score is designated as 0 when there are 2 or more contradictory studies pertaining to the genetic variant and the phenotype, such as a disease or condition or, if there are three or more more studies pertaining to the same genetic variant-phenotype association in the same population then the score is a 0 when there is contradiction in one or more of the top three studies (including meta- analysis studies) with the highest power (the largest number of organisms in the study cohort); 0.25 for a single study with single disease cohort study population containing under 250 organisms; 0.50 for a single study with a single disease cohort study population containing over 250 organisms; 0.75 for a single study with two or more disease cohort study populations (each disease cohort population can be the same or different species or gender), with each containing under 250 organisms; 1 for a single study with two or more disease cohort study populations (each disease cohort population can be the same or different species or gender), each containing 250-999 organisms and each giving similar results; 1.25 for a single study with two or more disease cohort study
  • Contradictory studies may also exist when a study finds an opposite direction of association between the same allele or genotype of the same genetic variant and the same phenotype, such as if one study of a genetic variant finds increased risk of a phenotype while another study of the same genetic variant's allele or genotype or a genetic variant's allele in tight linkage disequilibrim with the original genetic variant's allele finds decreased risk of the same phenotype.
  • the GVP score is 1.50 since there are two studies with similar results.
  • the rating system being used can be entered into the database along with the genetic variant (for example, the rs number from the dbSNP database, the chromosome that contains the genetic variant, the location of the genetic variant within a specific gene or chromosome such as its amino acid number and amino acid change (eg.
  • the rating system may also include Replication Status rating, such as whether an association between a genetic variant with a phenotype has been replicated in two or more studies (Yes), has not been replicated yet (No), has been replicated only in two or more disease cohorts within the same study (Within), or has failed replication in comparing two or more studies (Failed).
  • the rating scales, including the Replication Status rating are applicable to all types of genetic variant-phenotype associations, including multigenic, multifactorial, and monogenic. In some cases, such as for example for monogenic phenotypes, reported results can be considered very reliable even without replication of the results. Accordingly, in some embodiments of the present invention, a Replication Status of "Mono" can be assigned for monogenic phenotypes.
  • the replication status of "Mono" can be assigned for reported monogenic phenotypes that have not been replicated, indicating that they are nevertheless more reliable than non-replicated polygenic or multifactorial phenotypes, and a replication status of "Yes” or “Failed” can be assigned for monogenic phenotypes that have been replicated. In other cases, all monogenic phenotypes may be given a replication status of "Mono.”
  • the Replication Status rating can be in addition to the GVP score or in-place of the GVP score.
  • the studies with the highest power are considered most relevent. If the top three studies (including meta-analysis studies) with the highest power (the number of organisms in the study cohort) confirm the same genetic variant's genotype -phenotype association (or if they confirm the phenotype association with two or more genetic variants' that are in linkeage disequilibrium with each other), then the genetic variant's genotype-phenotype association is assigned a "Yes".
  • This rating system may be utilized to make the genetic analysis and final genetic report for an organism's genomic profile either more or less substantiated, or to include the genetic variant in some panels (further described below) or some genetic analysis (including, but not limited to, one or more of the following: analysis to calculate the risksuch as predictive medicine risk, the calculation of organ risk, calculation of genetic health, and inclusion or exclusion of the genetic variant and its associated data within the genetic report) and not others.
  • the genetic report may contain genotype information, genotype-phenotype associations, preventive medicine recomendations or interventions.
  • an organism or their health care provider or manager or other third party may request, order, obtain, or have an organism's genomic profile that provides only genetic variants associated with phenotypes that have a specific threshold value for one or more of the rating systems utilized.
  • the threshold value can be a specific value, such as above or below a specific value or it can be a range.
  • the threshold value for the GVP score can be above 1, below 1, or a range of values, such as any value between 0.25-1.25, any value not between 0.25-1.25.
  • the threshold value can be a single numerical value such as 2.
  • FIG. 6B shows a genetic data analysis with a threshold GVP Score equal to or greater than 1.5
  • FIG. 6C which shows a genetic data analysis with a threshold of only monogenic phenotypes
  • FIG. 6D which shows the threshold as being either Replicated associations or Monogenic phenotypes.
  • GVP score also known as GVDC
  • GVDC GVP score of 0.25 or above that are associated with a specific phenotype, such as a disease, trait, condition or process, or that is included in a panel or an organ system
  • a GVP score also known as GVDC
  • GVDC GVDC
  • all genetic variants with a GVP score (also known as GVDC) of 0.25 or above that are associated with a specific phenotype, such as a disease, trait, condition or process, or that is included in a panel or an organ system, can or will be utilized in the analysis of predisposition and risk and may also be utilized to determine the Predictive Medicine Risk, organ score, genetic health score, or one or more of the above, and included within the genetic report.
  • the threshold value selected may be selected by the organism's whose genomic profile is being used, a health care manager of the organism, a medical professional, a medical entity such as a hospital, a laboratory director, or another third party.
  • the threshold value may be determined by the party or entity, such as a company or laboratory generating the genetic data, as that party or entity may have one or more preset threshold values.
  • the threshold values may be determined by an organism in consultation with the party or entity generating the genetic data, their health care manager or provider, or another third party.
  • the report for an organism's genomic profile may also contain all known associations, but the associations are divided into sections by the level of association.
  • the report may have section 1 that contains only genetic variant-phenotype (disease/trait/condition) score associations with a cut off of 1.75 or above, section 2 may contain genetic variant-phenotype (disease/trait/condition) score associations with a cut off of 1.5, section 3 may have a cut-off of 0.75-1.25, and section 4 may have a cut-off of 0.25-0.50.
  • the reported GVP score may be changed at a later date. For example, an initial report for only highly substantiated associates can be generated for an organism, and a later report with all associations (i.e.
  • a lower GVP score threshold value is provided in a subsequent report.
  • This rating system may also be updated, for example, by incorporation of new journal articles and data on an on-going basis. For instance, a genetic variant associated with a phenotype is assigned a GVP of 0.25 and another study is discovered or published that shows the same phenotype associated with the same genetic variant in the same population and the study and results are statistically significant. The GVP is then raised to 1.5. As a result, new reports can be generated based on incorporation of new journal articles and new studies and as a result new GVP score values for genetic-variant-phenotype associations.
  • the new or updated reports may be produced from the initial data obtained from analyzing the genetic variants of an organism, the initial genetic sample obtained from an organism, or from a new sample. The new or updated reports may be provided for an additional fee.
  • two or more different versions of the genetic report may be created utilizing this rating system.
  • a panel may be ordered for an organism through its cardiologist.
  • the report produced for the cardiologist may only contain information on genetic variants and their phenotypes that have GVP score (coefficients) of 1.5 or greater while the report produced for the organism may contain information on genetic variants and their phenotypes with a GVP score of 0.75 or greater.
  • the report produced for the cardiologist may only contain information on genetic variants and their phenotypes that have a GVP score of 0.75 or greater, while the report produced for the organism may contain information on genetic variants and their phenotypes with a GVP score of 0.75 or greater.
  • a physician ordering the genetic testing and/or analysis may request a GVP score of 1.5 or greater but a medical researcher who is also working with the same subject may request a GVP score of 0.25 or greater.
  • a physician may order the genetic testing and/or analysis with two different GVP scores, such that one report or one section of the report contains analysis and information pertaining to only GVP scores of 1.75 or greater while the second report or another section of the same report contains GVP scores of 0.5 or greater, thereby allowing the physician to assess not only the subject's risk or predisposition or affected status or carrier status for the phenotypes contained in the genetic testing and/or analysis panel ordered based on replicated research but to also receive information on genetic variants and phenotypes that are not replicated yet but may still provide useful information for the physician or the patient or both. Genetic analysis or genetic reports or both ordered with more than one GVP score threshold value may be provided for an additional fee.
  • a specific genetic variant may have more than one GVP score, such as if it is associated with more than one phenotype.
  • the same genetic variant's genotype may be associated with increased risk for prostate cancer as well as a decreased risk for diabetes mellitus, type II.
  • the GVP score for genotype -phenotype association with prostate cancer may be 1.5 while the GVP score for the genotype-phenotype association with diabetes mellitus, type II, may be 2.
  • this genetic variant and its data for diabetes mellitus, type II would be utilized in the analysis for diabetes mellitus, type II, in order to determine risk for diabetes mellitus, type II, including risk analysis, PMR, AS, organ score, or genetic health score, but this genetic variant would not be utilized in the analysis for prostate cancer as the GVP score threshold value is above the GVP score for the prostate cancer phenotype for that genetic variant.
  • the aggregate number of organisms with the phenotype such as a disease or condition, cohort(s) (also referred to as the disease cohort(s) or the study cohort(s)) such as described above for the GVP score, may be the sole factor or in combination with other systems described herein, for rating a genetic variant or genotypes and their correlations with one or more phenotypes.
  • the rating system for the GVP score can include information pertaining to the number of studies (such as journal articles) that have shown an association between that exact genetic variant (or a genetic variant in linkage disequilibrium with that genetic variant, such as an r 2 >0.3), as well as whether or not one or more of those studies is a Genome-Wide Association Study.
  • journal articles pertaining to genetic variants and their allele or genotype-phenotype association may be included automatically for computing a GVP score.
  • specific journal articles such as those decided to be added to the database or added to the genetic analysis or both, may be used.
  • the journal articles or publications may be analyzed before incorporating and storing both the article and its corresponding data and information within a database.
  • a journal article relating to one or more genetic variants and their association with any phenotype may be read and analyzed, by a human or automated to be fully accomplished or partially accomplished by a computer or other information technology system or software.
  • a scaling system (such as numbers, letters, colors, symbols or combinations thereof) is then applied to the journal article based on numerous factors of that journal article.
  • the factors of the journal article that are taken into account may contain the number of organisms in the disease (study) cohort, the number of organisms in the control cohort, the total number of organisms in the study, the institution that conducted the study, the place the study was conducted (such as state or country or region or continent), a rating for the journal itself (ratings may include, but not be limited to, an internal rating or the Impact-Factor of the journal, such as the system created by Eugene Garfield at this Institute for Scientific Information, the Immediacy Index of the journal (such as published in the Journal Citation Reports), the Cited Half-life of the journal, the Page Rank of the journal, or any other measure), the year the study was published, the type of study that was conducted (for example, Genome Wide Association Study (GWAS), Case-Control Study, Prospective Study, Retrospective Study, Meta- Analysis Study) the name of the journal, the name or reputation of any or all of the authors involved in the study, or any and all combinations of the factors thereof, such as shown in Table 5.
  • GWAS
  • the rating scale categories for a journal article may be used organismly, or in various combinations, in determining a ranking system for the journal article, or in identifying a threshold value (such as described for GVP score herein), for including or excluding, the information in determining predisposition values, risk values, a genotype, a phenotype, or any such association between a genetic variant and a phenotype, such as a disease, trait, condition, or process.
  • the rating or value given to a journal article may indicate that the journal article should be read or not read, that the journal article or its data should be included in the database or not included in the database, that the journal article or its data should be included in the genetic analysis of a person or not included in the genetic analysis, or that the journal article or its data should be included in the genetic report or not included in the genetic report.
  • the threshold may be: below 5 do not include in database, 5-6 include in database but not in genetic analysis, and 7 or greater to include in database and include in genetic analysis.
  • Replication Status Another rating system that may be used in combination with other systems described herein, or alone, is a rating system that determines whether or not the genetic variant's genotype -phenotype association for a specific genetic variant existing anywhere in the genome has been replicated, called the Replication Status.
  • Replication can either mean two or more studies have shown the same direction (increased risk or decreased risk) for that genetic variant in the same or similar populations.
  • An alternative system requires that at least 3 or more, 4 or more, 5 or more, etc. studies have arrived at similar results as stated above.
  • Status of replication for each genetic variant can be designated either a simple Yes/No.
  • status of replication can be a scale, such as Definitively Replicated, Moderately Replicated, Not Replicated Yet, or Failed Replication (if there are contradictory studies, such as a study that one or more studies that meet the threshold for the journal article factor(s) have shown no statistically significant genotype -phenotype association with that specific genetic variant or a genetic variant in linkage disequilibrium with that genetic variant). If a single study contains two or more separate disease cohorts and the genetic variant-phenotype association is similar in each cohort, then a separate rating of "Within” may be applied to the Replication Status for that genetic variant-phenotype association.
  • Monogenic phenotypes can be also be represented according to replication status, being assigned a replication status of "Mono" if the genetic variant is shown to segregate with the phenotype, if it occurs in a gene previously implicated with the phenotype, if it occurs in a gene suspected of being implicated with the phenotype, or if biochemical, molecular, phylogenetic, computational, or bioinformatic analysis shows that the genetic variant is most likely deleterious or harmful or likely to be associated with a disease or phenotype.
  • This rating system may be utilized as described with the Replication Status, the GVP score or journal ranking system, in genetic analysis and generating genomic profiles and the genetic report by having more or less substantiated genetic variant-phenotype associations included or to include the genetic variant in some panels or genetic analysis (including one or more of the following: analysis to calculate the risk, the calculation of organ risk, calculation of genetic health, calculation of Predictive Medicine Risk, calculation of Notice Me Factor, calculation of action score, calculation of cumulative action score, and inclusion of the genetic variant and its data in the genetic report) and not others. For example, only replicated genetic variants may be included in the analysis of an organism's genomic information. If so, only the genetic variants that are designated as replicated (i.e.
  • a Replication Status of "Yes" within the database such as the Predictive Medicine Database, or a linked database may be included in the analysis and in the genetic report.
  • the person who orders the genetic test and/or analysis may want to know all possible associations and to have all genetic variants found associated with a specific disease or a panel or a organ system regardless of replication status and therefore both genetic variants that are designated as replicated and those that are designated as not replicated may be included in the analysis.
  • All genetic variants with a chosen Replication Rating can be utilized in the analysis of predisposition and risk and may also be utilized in determining the Predictive Medicine Risk, Notice Me Factor, Action Score, Cumulative Action Score, organ score or genetic health score.
  • GVP Triage Genetic Variant-Phenotype Triage
  • GVP-CSR GVP-Clinical Significance Rating
  • a GVP Triage can be ranked numerically, where 0 would indicate no clinical use, 1 would indicate limited clinical significance, value, or use, 2 would indicate moderate clinical significance, 3 would indicate very useful in a clinical setting, where a medical professional would likely find the result valuable, and 4 would indicate extreme clinical significance, such as a life-threatening condition.
  • the GVP Triage may be used also to determine whether genetic variants are included or excluded in genetic analysis or a report of the analysis. For example, genetic variants that have a GVP Triage of 2 or higher can be selected to be the only ones included in the analysis or report or both for an organism's genomic profile. Thus, similar to the aforementioned rating systems, GVP Triage values may serve as threshold values.
  • Each phenotype can have a separate GVP Triage rating assigned to it (for example, assigned by a licensed physician) for an increased risk of that phenotype and for a decreased risk of that phenotype.
  • GVP Triage rating assigned to it for the carrier state and for the affected state. The designation of carrier or affected is based on whether or not the genetic variant(s) associated with that phenotype are recessive or dominant in terms of Mendelian inheritance.
  • both alleles are considered dominant and the heterozygous genotype or diplotype may be associated with its own phenotype (such as Blood Type AB for the ABO blood group system in Homo sapiens sapiens) and for incomplete dominance, the heterozygous genotype may be associated with its own phenotype (such as with the Merle coat color trait in Canis lupus familiaris or with Sickle Cell Trait in Homo sapiens sapiens).
  • the GVP Triage rating is "0" because hair color does not have clinical significance.
  • the Long QT Syndrome phenotype is assigned a GVP Triage of "4" if the person is most likely affected with the syndrome because this information most likely requires immediate attention by a healthcare professional.
  • this has less clinical significance and is assigned a rating of "2" because it is moderately useful (a healthcare professional may find this information useful in terms of educating their patient about the risk their children or future children may have in regards to Long QT Syndrome and also in educating their patient that a relative may carry or be affected by this syndrome and therefore may want to undergo genetic testing and/or analysis and health care professional consultation as well).
  • the GVP Triage rating can occur at the genetic variant-phenotype level, so there is a GVP Triage rating (number) assigned to each genetic variant-phenotype association, meaning that there is at least one GVP Triage number assigned to each genetic variant.
  • the rating systems described herein may also be applied not to specific genetic variants but instead at the phenotypelevel, such as a disease, condition, or trait level. When this occurs, the rating system is no longer called GVP Triage but instead is called Clinical Significance Rating (CSR). The CSR is discussed below.
  • GVP Rank also referred to as the SNP Ranking system
  • SNP Ranking system may be used to discern between genetic variants that are in linkage disequilibrium with each other (usually located within the same locus or within nearby loci) and that have been found to be, or can assumed to be, associated with the same signal or risk of the same phenotype.
  • a GVP Rank may be provided for any two or more genetic variants and their alleles that are in linkage disequilibrium with each other and that are associated with the same or similar phenotype and the same direction of risk (either increased risk or decreased risk or no risk).
  • the genetic variant, such as an SNP, with the most significant statistical association with the phenotype is indicated by a special designation, such as the number 1, and is therefore the highest ranking genetic variant, such as an SNP.
  • the genetic variant, such as an SNP, with the second most statistically significant association with the phenotype is then assigned 2.
  • the genetic variant, such as an SNP, with the third most significant statistical association with the phenotype is then assigned 3, and so forth.
  • genetic variant A is the most statistically significant genetic variant associated with early-onset heart attack out of A, B, and C and is therefore assigned the GVP Rank of 1
  • genetic variant B is the second most significantly associated with that phenotype and is assigned GVP Rank of 2
  • genetic variant C is the third most significantly associated and is assigned GVP Rank of 3.
  • the Cardiovascular Genetic Testing Panel may be chosen by the organism and genetic testing and/or analysis may find that the organism's genotypes for genetic variant A, B, and C are all associated with increased risk for early-onset heart attack.
  • genetic variant A which has the highest GVP Rank (1) is the only genetic variant that is utilized within the analysis while the other genetic variants (B and C) are not further analyzed. Only genetic variant A's risk value information and data is therefore utilized to ascertain the risk GCR and PMR for early-onset heart attack.
  • Genetic variant A's risk and data can be entered into an algorithm or computation that takes into account other genetic variants (not in linkage disequilibrium with genetic variant A) or genetic variant A may be analyzed on its own. If the genotype associated with early-onset myocardial infarction for genetic variant A is not detected, but genetic variants B and C are both detected, then the next highest GVP Rank genetic variant is B, so B is utilized in the analysis and in any calculations to ascertain risk for early-onset heart attack while C is not utilized in the calculations.
  • haplotype X that contains genetic variants A, B, and C
  • haplotype X is designated the GVP Rank of 1
  • genetic variant A is designated SNP Ranking of 2
  • genetic variant B is designated SNP Ranking of 3
  • genetic variant C is designated SNP Ranking of 4.
  • haplotype X has the highest GVP Rank (1).
  • haplotype X does not exist and therefore the methodology looks at the next highest GVP Rank, 2, which is genetic variant A, and so forth until either an allele or genotype associated with early-onset heart attack is found and that genetic variant's risk value is the only one (out of those that are in linkage disequilibrium with it and have assigned GVP Rankings) utilized in the analysis and calculation of risk.
  • GVP Rankings the number of genetic variants within the same haplotype block as opposed to linkage disequilibrium, or both haplotype block data and linkage disequilibrium data can be utilized together.
  • This methodology can also be applied to any genetic variants that have been shown in published literature to be associated with the same signal for a phenotype or for a risk or predisposition to a phenotype.
  • the rating systems and analytical methodology described herein such as the journal ranking, GVP score, GVP Triage, Replication Status and GVP Rank can all be utilized independently of each other, or in any combination of two or more, and can be included as categories in a database described herein.
  • the various rating systems may also be used to sort the results from genetic testing or analysis prior to any further analysis, processing, or the generation of the PMR, AS, CAS, or the genetic report.
  • the various rating systems may also be used to choose and sort the genetic variants that will be tested for during the actual laboratory genetic testing and/or analysis process or the genetic variants that the laboratory will provide allele or genotypic information on.
  • CSR Clinical Significance Rating
  • Each phenotype can have a separate CSR rating assigned to it (for example, by a licensed physician or veterinarian) for an increased risk of that phenotype and for a decreased risk of that phenotype.
  • each phenotype has a separate CSR rating assigned to it for the carrier state and for the affected or likely affected state (monogenic phenotypes with variable or low penetrance or expressivity may be designated as 'likely-affected' instead of affected, because the manifestation of the phenotype and the degree of phenotype severity may have variability).
  • the designation of carrier or affected is based on whether or not the genetic variant(s) associated with that phenotype are recessive or dominant in terms of Mendelian inheritance.
  • Co-dominance and incomplete dominance may both be associated with unique phenotypes in the heterozygous state and those phenotypes will have their own CSR.
  • a sample of phenotypes and their associated CSR ratings can be seen in FIG. 6E-G.
  • the CSR rating is "0" because hair color does not have clinical significance.
  • this phenotype is assigned a CAR rating of "4" if the person is most likely affected with the syndrome because this information may require immediate attention by a healthcare professional.
  • the person is a carrier of a genetic variant associated with Long QT Syndrome but is not affected by the syndrome, then this has less clinical significance and is assigned a rating of "2" because it is moderately useful (a healthcare professional may find this information useful in terms of educating their patient about the risk their children (or future generations) may have in regards to Long QT Syndrome and also in educating the patient that a family relative may carry or be affected by this syndrome and therefore they may want to disucss this with them and have the family talk with their physicians about this, as the family members may want to undergo genetic testing and/or analysis as well).
  • Clinical significance and relevancy takes into account multiple factors (for example, by a licensed physician), such as whether or not a healthcare professional will find the information about a risk or predisposition or carrier status (including carrier, affected, or likely affected) for a specific phenotype useful.
  • a healthcare professional will find the information about a risk or predisposition or carrier status (including carrier, affected, or likely affected) for a specific phenotype useful.
  • the phenotype Amyotrophic Lateral Sclerosis (ALS) has very scarce preventive measures available and only limited treatment options.
  • a speedier and more efficient diagnosis may also limit the stress and psychological turmoil to the patient's family as well as the financial impact to the patient and the overall medical system, such as due to decreased physician visits or decreased number of tests or medications or both that are not specficially targeted at the true causative phenotype (the accurate diagnosis).
  • ARVC Arrhythmogenic Right Ventricular Cardiomyopathy
  • carrier status affected or likely affected
  • preventive measures that can be implemented to limit or avoid the sequela from the phenotype (such as sudden death). If an organism is known to have an ARVC associated genetic variant (and is found to be affected or likely affected), this information may be tremendously empowering to a healthcare professional and may possibly lead to life-saving interventions and preventive measures.
  • the CSR is similar to the GVP Triage but occurs at the phenotype level, while GVP Triage occurs at the genetic variant- phenotype level. This allows for the sorting and filtering of data at multiple levels, as well as threshold values to be implemented throughout the analytical process at multiple levels and augments operator control through providing multiple data filtering levels.
  • PIR Phenotype Impact Rating
  • Table 7 Other rating systems may include the Phenotype Impact Rating (PIR), such as shown inTable 7.
  • the PIR is a rating scale that assigns an integer (such as an integer ranging from -3 to +3) to each phenotype based on the impact that phenotype may have upon the person.
  • the PIR allows phenotypes beneficial to survival to be discerned efficiently from phenotypes that are detrimental to survival, and also phenotypes that are more beneficial or those that are more detrimental to be discerned efficiently from those that are less beneficial or detrimental.
  • a separate PIR is assigned to monogenic carrier, monogenic affected, multifactorial decreased risk, and multifactorial increased risk. Polygenic phenotypes are assumed to follow a multifactorial model throughout the analytical process.
  • Each phenotype can have a separate PIR rating assigned to it (for example, by a licensed physician or veterinarian) for an increased risk of that phenotype and for a decreased risk of that phenotype.
  • each phenotype can have a separate PIR rating assigned to it for the carrier state and for the affected state.
  • the designation of carrier or affected is typically based on whether or not the genetic variant(s) associated with that phenotype are recessive or dominant in terms of Mendelian inheritance. As an example, the phenotype of 'Increased Longevity' is assigned a "+3" if there is an increased risk of that phenotype.
  • the PIR is "-2" because it is a very serious chronic disease but is usually not life-threatening. If there is a decreased risk of Crohn's disease, however, the assigned PIR is because it is slightly beneficial to be protected against this disease but since most organisms don't have Crohn's disease and since protection against Crohn's disease won't significantly augment or prolong life (or decrease the morbidity or mortality of any other diseases), decreased risk of this disease has less of an impact upon a person than an increased risk of the disease (which is why increased risk for Crohn's disease is assigned a "-2" while decreased risk is assigned a
  • the PIR is one of the components of the Action Score; because of this, one of the ways the Action Score is weighted is by how beneficial or how harmful that specific phenotype is. Table 7: Phenotype Impact Rating (PIR)
  • the aforementioned rating systems can be used in ranking genetic variants and phenotypes. For example, based on the ratings or rankings, genetic variants associated with phenotypes can be selected for analysis to generate a genetic profile and/or a genetic report tailored to a specific organism.
  • Analysis may include determining the Cumulative Genetic Risk (CGR) and the Predictive Medicine Lifetime Risk (PMR) for polygenic or multifactorial phenotypes by analyzing all (one or more) relevant (based on information known and rating systems applied, such as GVP Score and GVP Triage) genetic variants that are associated with that phenotype.
  • CGR Cumulative Genetic Risk
  • GCR Genetic Cumulative Risk
  • Relevant genetic variant(s) can be selected based on those that make the cut-off threshold for analysis, as previously described.
  • the first step in calculating the CGR is to convert the odds ratios associated with the alleles or genotypes of all the relevant genetic variants associated with that specific phenotype into relative risks.
  • odds ratios are converted into relative risks as described by Zhang and Yu (JAMA 280:1690-1691 (1998)).
  • the genotype frequency, from sources available in the arts, such as The International HapMap Project (www.hapmap.org)) for each of the three possible genotypes for each of the genetic variants is then multipled by the relative risks for each of the three genotypes for each relevant genetic variant associated with that phenotype.
  • the HapMap population used to ascertain these values is matched as closely as possible with the population of the organism who is currently undergoing genetic analysis (for example, if the organism is an European American, then the 'CEU' HapMap frequencies are utilized in the calculation).
  • the resulting three values (genotype frequencies multiplied by relative risks for all three possible genotypes) for the genetic variant are then added together and produce a single number for each genetic variant. This value is then multipled together for all relevant genetic variants detected during genetic testing and the resulting value is referred to as the Generic Population Risk Load (GPL).
  • GPL Generic Population Risk Load
  • the organism's genotype is considered at each of the relevant genetic variants and the relative risks associated with each of those relevant genetic variants (based on that genetic variant's genotype for that organism) are multiplied together to create a single value, known as the Proband Risk Load (PRL).
  • PRL Proband Risk Load
  • the Predictive Medicine Lifetime Risk is the new lifetime risk for an organism for polygenic or multifactorial phenotypes based on their gender-matached population specific Generic Lifetime Risk (GLR) and their own CGR.
  • the PMR (GLR)x(CGR).
  • Monogenic phenotypes are typically reported as a 'carrier status', which is analyzed and reported as non-carrier and non-affected, carrier but not affected, or affected. The degree to which the organism may be affected may also be reported, such as the potential age of onset, severity, penetrance or expressivity.
  • An exemplary embodiment describing a method for determining a Predictive Medicine Lifetime Risk for an organism is provided herein as Example 5.
  • the genetic report may contain a comprehensive analysis of both risk, predisposition and carrier status for the organism.
  • Some phenotypes are associated with both monogenic and multifactorial inheritance.
  • monogenic genetic variants may be analyzed as monogenic variants that may be deterministic of a phenotype, while multifactorial variants that predispose to the phenotype may be analyzed separately, as described herein for multifactorial phenotypes, and the results of the monogenic analysis and the multifactorial analysis may either be reported together or separately in the genetic report.
  • a genetic report may contain information concerning an organism's risk of, predisposition for, or carrier status for two or more multifactorial phenotypes and two or more monogenic phenotypes. In some cases, a genetic report may contain information concerning an organism's risk of, predisposition for, or carrier status for: two or more multifactorial phenotypes; and one or more monogenic phenotypes, two or more monogenic phenotypes, three or more monogenic phenotypes, five or more monogenic phenotypes, ten or more monogenic phenotypes, twenty or more monogenic phenotypes, or fifty or more monogenic phenotypes.
  • a genetic report may contain information concerning an organism's risk of, predisposition for, or carrier status for: two or more monogenic phenotypes; and one or more multifactorial phenotypes, two or more multifactorial phenotypes, three or more multifactorial phenotypes, five or more multifactorial phenotypes, ten or more multifactorial phenotypes, twenty or more multifactorial phenotypes, or fifty or more multifactorial phenotypes.
  • the number of multifactorial or monogenic phenotypes reported is "no more than” a certain number, e.g, no more than ten, no more than fifteen, no more than twenty, no more than thirty, no more than fifty, no more than one hundred, no more than two hundred, or no more than five hundred phenotypes.
  • Select genetic variants of clinical significance may be independently reported on or discussed in the genetic report.
  • the genetic variants reported or discussed may be associated with monogenic or polygenic phenotypes or risk for multifactorial phenotypes.
  • Some genetic variants may be included in the report, even if the predictive medicine risk or action score for that multifactorial phenotype is not included in the genetic report, such as if it does not make a certain threshold or cut-off value.
  • a single nucleotide polymorphism in the ITGB3 gene on is associated with premature coronary events and other phenotypes associated with premature heart disease and treatment effectivness for heart disease.
  • the genetic report may still specifically mention this genetic variant and its phenotype associations, as this SNP has been shown to be responsible for considerable morbidity and mortality and has clinical utility on its own.
  • the determination of what multifactorial risk genetic variants are of special clinical utility and significance or the designation of genetic variants as having special clinical significance may be made by a licensed medical physician or veterinarian and can be automatically reported on (included) in the genetic report.
  • genetic variants -phenotype associations with a specific GVP Triage level or phenotypes with a specific CSR may be chosen for inclusion within the genetic report regardless of the phenotypes ultimate AS or PMR.
  • Specific genetic variant(s) that are tested for whose allele(s) or genotype(s) deduced are found to not be associated with risk for a phenotype may also be included within the genetic report, so that the organism who for which the genetic report was ordered, or their physician or veterinarian or other third party, is aware that the specific genetic variant or phenotype or both is tested for but the phenotype associated allele(s) or genotype(s) isn't detected or no increased or decreased risk is ascertained based on the allele(s) or genotype(s) that are detected through the genetic testing and analysis. For example, if the organism is found to not have the major cystic fibrosis related deletion, referred to as the delta-F508 mutation (CFTR Chr.
  • the delta-F508 mutation CFTR Chr.
  • the genetic report may specifically indicate that this clinically significant genetic variant is not detected.
  • a list of some or all genes or genetic variants or both tested for, regardless of whether or not their alleles or genotypes are associated with increased or decreased risk or no change in risk of a multifactorial phenotype or a carrier or affected of a polygenic or monogenic phenotype, as well as a list of some or all of the phenotypes that are tested for, may or may not be included in the genetic report and may or may not appear in a separate section of the genetic report.
  • the genetic variants with the greatest significance such as those that are more frequently the cause of, or are associated with, the phenotype, (such as those with higher overall phenotype-associated allele or phenotype- associated genotype frequencies or those associated with a higher population attributable risk) may be listed first or in a separate section compared to those genetic variants that appear less frequently (such as those with lower overall phenotype-associated allele or phenotype-associated genotype frequencies or those associated with a lower population attributable risk) as the cause of, or associated with, the phenotype in a single population, throughout multiple populations, or throughout all populations.
  • the Generic Lifetime Risk is the gender-specific population lifetime risk for a specific phenotype prior to any genetic analysis, which may be represented as a percentage or be able to be converted to a percentage.
  • This data can be obtained from published literature and from sources available in the arts including, but not limited to, published journal articles, national governmental health and disease services agencies or departments (such as the Health and Human Services in the United States or the National Health Service in the United Kingdom), including all of the agencies and divisions of the primary governmental health agency such as the United States Department of Health and Human Services (HHS) and all of its agencies and divisions including the United States' Centers of Disease Control and Prevention (CDC) and the United States' National Institutes of Health (NIH) as well as all its divisions, such as the National Cancer Institute (NCI).
  • HHS United States Department of Health and Human Services
  • CDC United States' Centers of Disease Control and Prevention
  • NAI National Institutes of Health
  • the Generic Lifetime Risk at birth for Diabetes Mellitus is 0.312 for females and 0.267 for males, for African Americans it is 0.490 for females and 0.402 for males, and for Hispanic Americans it is 0.525 for females and 0.454 for males (Narayan et al. JAMA 290(14).
  • the Generic Lifetime Risk for Melanoma at birth for European American's is 0.0173 for females and 0.0256 for males
  • for African American's is 0.0009 for females and 0.0007 for males
  • for Hispanic American's is 0.0058 for females and 0.0052 for males
  • for Asian American's is 0.0016 for females and 0.0017 for males
  • for Native American's is 0.0024 for females and 0.0034 for males.
  • the Generic Lifetime Risk can be dependent on the age of an organism.
  • the GLR for Lung Cancer for Hispanic Americans is 0.0363 for females and 0.0526 for males at birth and 0.0369 for females and 0.0548 for males at age 40
  • African Americans the GLR for Lung Cancer is 0.0545 for females and 0.0775 for males at birth and 0.0569 for females and 0.0847 for males at age 40
  • Asian Americans the GLR for Lung Cancer is 0.0428 for females and 0.0703 for males at birth and 0.0432 and 0.0719 for males at age 40
  • Native Americans the GLR for Lung Cancer is 0.0487 for females and 0.0527 for males at birth and 0.0510 for females and 0.0575 for males at age 40
  • the GLR for Lung Cancer for European Americans is 0.0652 for females and 0.0786 for males at birth and 0.0665 for females and 0.0819 for males at age 40.
  • Generic Lifetime Risk can be determined for gender- specific populations for each phenotype both from birth and at different ages.
  • phenotypes are described as a "susceptibility to", or an "increased risk of, this susceptibility or risk may refer to genetic variants that provide for an increased risk as compared to the species and/or gender and/or age matched population generic lifetime risk values. Protection against may refer to a decreased risk or no risk as compared to the ethnicity and /or gender and/or age matched population generic risk values.
  • Prevalence rates, incidence rates, and heritability for phenotypes can be obtained through sources available in the arts, such as, but not limited to published literature and various public resources, such as previously described, including the HHS and its CDC or the NCI. If exact gender- specific population statistics (incidence rates or prevalence rates or both for a phenotype) do not exist, then comparable statistics may be utilized, such as determined by a geneticist, an epidemiologist or a licensed physician or veterinarian. For example, incidence rates of phenotype A may not be known for African American males but it is known for African Americans in-general (females + males), this value would be used until a value specific for African American males is reported or obtained. In other embodiments, prevalence rates of phenotype B is not currently known for European American females but it is known for Western European Caucasian females, and this value is used until a value specific for European American females is reported or obtained.
  • the GLR and PMR can be used to calculate the Percent Change in Lifetime Risk.
  • the Percent Change in Lifetime Risk calculates the percent change between the GLR for a phenotype (for example, ascertained from journal articles or published records, such as from the CDC or NCI, as previously described) and the calculated PMR.
  • NMF Notice Me Factor
  • This NMF is one component of the Action Score; because of this, one of the ways the Action Score is weighted is by the NMF which is, in turn, determined by the Percent Change in Lifetime Risk. This is used because while some phenotypes may have high clinical significance (and therefore have a high CSR) and also be very detrimental to a person's health (and therefore have a negative PIR), the genetic variants, when analyzed together, may not increase or decrease the lifetime risk of that disease significantly.
  • the Action Score is a combination of the Clinical Significance Rating (CSR), the Phenotype Impact Rating (PIR), and the Notice Me Factor (NMF). These three numbers allow for the action score to be weighted by clinical significance, phenotype benefit or harm, and also the degree to which a person's genetic profile affects their risk for that phenotype.
  • CSR Clinical Significance Rating
  • PIR Phenotype Impact Rating
  • NMF Notice Me Factor
  • the Action Score can allow both the healthcare provider and the organism to efficiently discern which phenotypes they need to focus on in terms of understanding, education, surveillance, treatment and/or preventive measures.
  • the more negative the Action Score the more significant the harmful risk is for a specific phenotype based on the person's genetic profile.
  • the more positive the Action Score the more significant the beneficial value is for a specific phenotype based on the person's genetic profile.
  • a color-coding system may be used in an organism's genetic profile. For example, a shade of a red color may be used to to depict a significantly harmful phenotype, whereas a shade of a blue color may be used to depict a significantly beneficial phenotype.
  • Table 9 illustrates some embodiments, however, other colors may be correlated with different AS ranges, and other AS ranges may be used.
  • the risks for phenotypes can also be used to determine scores for one or more specific organ systems, or specialties, such as, but not limited to those shown in FIG. 10 and listed in Table 10.
  • a cardiovascular score which indicates the genetic health for an organism's cardiovascular system, can be determined by integrating the risk factors for each of the specific conditions and diseases affecting the cardiovascular system of an organism. Scores for organ systems or medical specialties can include the risk factors determined from the genetic profile and can further include information obtained from the organism.
  • Organ systems or medical specialties can include cardiovascular; heart; lung; laryngology and dental; laryngology; dental; nutrition, exercise, and weight; otology; pediatrics and/or neonatology; pulmonology; anesthesiology and critical care; dermatology; development and learning; ear, nose, and throat; endocrinology; gastroenterology and hepatology; gastroenterology; hepatology; gall bladder; liver; thyroid; pancreas; gynecology; hematology; oncology; hematology and oncology; immuunology; immunology and allergy; infectious diseases; metabolic diseases; metabolic diseases and rare diseases; rare diseases; men's health, musculoskeletal; neonatology; neurology; obstetrics; obstetrics and fetology; ophthalmology; pharmacology, toxicology and anesthesiology; pharmacology; tocicology; anesthesiology; psychiatry; psychiatry and
  • FIGS. 15-20 disclose specific panels.
  • the panels of genetic variants provide a profile of the health and risks that detail not only one or more diseases or conditions but also the genetic variants associated with the efficacy of drugs that may be utilized to treat the diseases or conditions or the genetic variants linked to habits that are linked to the disease. For example, there are genetic variants involving habits, such as eating particular foods, which increase or decrease one's risk of a disease based on another genetic variant.
  • identifying these genetic variants and the related phenotype may allow one to alter his or her life and impact the ultimate result of one's genes.
  • the panels are chosen to combine those genetic variants that will provide composite information about the genetic profile along with additional variants beneficial to the subject's assessment and/or use of the information. These panels are newly created and offer beneficial advantages that allow one to identify the optimal medical intervention, medication, dosage of a drug, or adverse impacts of a drug at an earlier stage and thus avoid serious delays in crucial treatment.
  • the panels serve a variety of functions for analyzing a group of genetic variants of an organism and in some embodiments allow one to evaluate the suitability of an organism for therapuetics, suitability for medical interventions such as surgery, transplantations (donor or recipient), psychiatric treatment, or treatment associated with other medical specialties described herein; or identify the best candidates for career recruitment or training such as for military or police work.
  • the panels in some cases, aggregate diverse genetic variants to provide a valuable profile of organisms that allows significant benefits in their overall treatment or management of life choices to improve health and, in some instances, longevity.
  • the panels of genetic variants may be performed on an organism simultaneously or over periods of time depending on the outcome of some of the tests completed.
  • some panels may include variants considered to be reflex phenotypes that may be follow -on evaluations depending upon the outcome of a first phenotype.
  • reflex phenotypes provide useful additional screening of the genome to determine the presence of valuable variants that will contribute to earlier intervention and reduce wasted treatments or eliminate dead ends in therapy. Reflex testing and reflex phenotypes are further discussed herein.
  • the different organ systems or medical specialties can be represented by different panels,
  • the panels comprise groups of phenotypes, including conditions, traits, diseases, and disorders, and corresponding genes and loci that can be tested.
  • the panels may comprise arrays, probes, primers or sequences that may be used to determine an organism's carrier status or risk of, or predisposition for, a phenotype, such as a condition, disease, disorder or trait.
  • the panel may also be a Custom Panel where an organism's owner or third party can choose any phenotype from any of the panels described herein.
  • An organism's owner or third party can choose different sets of any phenotypes from any of the panels or from a complete list of all phenotypes available, such as a Custom 10 Panel, which tests for 10 phenotypes or a Custom 20 Panel, which tests for 20 phenotypes.
  • Custom panels can range from two phenotypes to over 1,000 phenotypes.
  • an organism may choose any panel or set of panels for various other options (FIG. 21).
  • any panel or specific phenotype may be used for the Offspring Projection through the Combined Analyses of Different Organisms (OP-CADI)Option (which is further described herein).
  • OP-CADI Combined Analyses of Different Organisms
  • any panel or specific phenotype may be designated as "Protection Only” at the request of an organism or healthcare provider. This designation means that only phenotypes that show a lower risk value (protection against the phenotype) are utilized for the organ system color or are included in the Genetic Report or both. Those phenotypes that the organism is found to be at increased risk for may then not appear in the Genetic Report.
  • any panel or phenotype may be designated as "Increased Risk Only" at the request of an organism.
  • This designation means that only phenotypes that show a higher risk value (higher risk for the phenotype) are utilized for the organ system color or are included in the Genetic Report or both. Those phenotypes that the organism is found to be at decreased risk for may then not appear in the Genetic Report.
  • any phenotype(s) may be chosen to be excluded from being included in the analysis, and in the calculation of the organ system score and color, the genetic health score and color, and in the Genetic Report. If the raw genotypic data is saved and identifiable, then the organism may choose to have this Exclusion Option revoked at a later time so that all phenotypes that were excluded are analyzed (which may incur an additional fee). If the organism's raw genotypic data is not identifiable, then new genetic material may have to be obtained and the genetic testing rerun at the laboratory (which may incur an additional fee).
  • the panels also describe various genes and loci that may be used to detect the risk of the various phenotypes, such as diseases or traits, but it should be clear that other genetic variations in other genes and loci that are correlated with the various phenotypes, such as diseases or traits, can also be used.
  • variants that are thought to be significant in determining a phenotype may include, but not be limited to, those described in FIGS. 22A-22P.
  • the phenotypes, such as diseases or traits, listed may also be a general disease category, such as cancer, which may include a variety of types.
  • Each phenotype, such as a condition, that is found to have either an increased risk or decreased risk may be factored into a genetic algorithm under one or more organ system / medical specialty categories. This links the results from the panel to a genetic analysis algorithm, which then computes the genetic health score for each organ system / medical specialty tested for within that panel and then an overall genetic health score. This information is then utilized to produce one or more genetic reports, which contains information including, but not limited to, preventive recommendations and/or interventions based upon the results of the comprehensive genetic testing results and analysis.
  • An organ system score, or medical specialty score can be determined from at least 2 specific phenotypes, such as conditions, diseases or traits, of an organ system or medical specialty. Other organ system scores may be determined from at least 3, 4, 5, 6, 7, 8, 9, or 10 specific phenotypes, including conditions, diseases, disorders, or traits.
  • An organism or third party such as for example a medical professional, may choose to have carrier status or risks or both for a subset of phenotypes (also referred to herein as conditions, diseases or traits) listed in a panel to be determined.
  • an organism or third party may choose to have one or more of carrier status or risks or predispositions for a subset of phenotypes, such as conditions, listed in a panel to not be determined or reported to them.
  • phenotypes such as conditions, listed in a panel to not be determined or reported to them.
  • an organism may choose at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or all of the conditions of a panel to be analyzed or determined for their genetic profile.
  • an organism may choose at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25 of the conditions of a panel to not be analyzed or determined for their genetic profile.
  • An organ system score may be determined from a subset of the phenotypes, such as conditions, chosen or from all of the phenotypes, such as conditions. If a subset is chosen, the organism or third party may further choose to have carrier status or risks or both for other phenotypes, such as conditions, listed in a panel be determined after the initial risk or carrier status or both determination of a subset of phenotypes, such as conditions, listed on a panel, and the subsequent results can be added to the initial organ system score.
  • Each phenotype, such as a trait, condition or disease, tested may be assigned to one or more of categories of organ systems or medical specialties (such as by a licensed physician or veterinarian) and such assignment can be factored into a genetic health score for each organ system/medical specialty.
  • An overall genetic health score, described further below, can be determined using an algorithm that takes into account all of this information.
  • An organism can be notified directly, or through a third party, on a recurring basis, such as for example every 3 to 6 months, or 6 months to yearly, or when the phenotype may become relevant (such as when the organism turns a specific age or when a specific milestone or event is met, such as for example if through genetic testing and analysis an organism is found to be at increased or decreased risk for West Nile Virus susceptibility and an increase in regional West Nile Virus infection cases occurs or an epidemic or pandemic occurs), about any updates, such as to changes in their predictive medicine score or their genetic health scores.
  • the disclosure provides for monitoring of local, state, national, and/or international trends (e.g., rates of infection, increases in infection, decreases in infection, or outbreaks) of diseases, disorders or conditions or any infectious or transmittable disease or condition.
  • Significant changes in local, state, national, and/or international trends may be associated with organisms who fit certain geographic criteria e.g., they reside or travel, or plan to reside or travel, in the local, state, or international area identified with the changing trend).
  • Identified organisms who are found to be at increased or decreased risk for the infectious or transmittable disease, disorder or condition may then be notified of this change.
  • the notification service may be offered for an additional fee, such as for example a subscription fee.
  • the notification may include an updated genetic report, or updated predictive medicine score(s) or genetic health score(s).
  • the predisposition, risk and/or carrier status of an organism may be determined for a subset of phenotypes, e.g., a subset of phenotypes listed in the Cattle Lifecycle & Economic Productivity Panel (FIGS. 15I-15J) or any other panel provided herein.
  • a cardiovascular system score may be determined from this subset.
  • the organism may further choose to have his or her predisposition, risk, and/or carrier status for other phenotypes, listed in a panel to be determined after the initial risk and/or carrier status determination of the first subset of phenotypes (e.g., diseases, disorders, traits or conditions) is determined.
  • the second set of results can be integrated into the initial cardiovascular system score to obtain a new score.
  • a "subset" may refer to any number of phenotypes (e.g., diseases, disorders, traits or conditions) less than the entire list of phenotypes, (e.g., diseases, disorders, traits or conditions) for a panel.
  • the subset of phenotypes e.g., diseases, disorders, traits or conditions
  • a single sample may be tested for an initial subset of phenotypes, (e.g., diseases, disorders, traits or conditions) and a subsequent sample may be tested for subsequent phenotypes (e.g., diseases, disorders, traits or conditions).
  • a single sample can be used to determine the carrier status, predisposition or risk of an organism for of all the phenotypes of a single panel, but only a subset of the results are reported to the organism initially.
  • a single sample may also be used to generate results from more than 1 panel.
  • a single sample may be used to generate results from 2 or more, 3 or more, 4 or more, 5 or more, or all of the panels.
  • Results from a subset of the panels may be reported.
  • all the phenotypes, such as conditions, of a subset of the panels can be reported.
  • a subset of the phenotypes e.g., uneven diseases, disorders, conditions or traits
  • Results from all the panels can also be reported to the organism.
  • all the phenotypes from all the panels, or a subset of phenotypes from all the panels can be used to generate a report.
  • Phenotypes e.g., diseases, disorders, traits or conditions
  • Phenotypes not reported initially can be subsequently reported, for example, after an organism consults with his or her physician, genetic counselor, physician assistant, nurse practitioner, other healthcare professional or other third party.
  • a single panel or combinations of the different panels may be used to generate a single organ system score.
  • the genetic profiles can have one or more organ system scores. For example, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 organ system scores may be determined from a genetic profile.
  • the organ system score can be selected by an organism or their health care provider or other third party. Selection can be based on an organism's consultation with one or more of the following: his or her genetic counselor, a managing doctor, a nurse practitioner, a physician assistant, a healthcare provider, a parent or legal guardian such as if the organism is a minor, a health care proxy, an advisor, or another third party.
  • the score can be indicated numerically or by color, as described above.
  • the score, or color can be a Cumulative Action Score (CAS) or an Indicator of Genetic Health of Organ System.
  • CAS Cumulative Action Score
  • the color red would be used for scores less than -10 for an organism's genetic profile, indicating highly important to discuss with organism and may be highly important for organism to follow-up with their physician or specialist based on this information.
  • Pink can be used for scores between -1 to -10 to indicate moderately important risk.
  • Green can be used for scores of 0 to indicate no pertinent deleterious or protective information discovered although organ system was accessed.
  • Blue can be used for scores between +1 to +10, to indicate moderately important protection.
  • Gold can be used for scores >+10 indicating very beneficial protection, and no color can be used for an Organ System or Medical Specialty that is not accessed, for example, if an organism chose a genetic testing panel or package that did not contain information about this system or specialty.
  • Each Action Score can be calculated such that each AS has a CSR, a PIR, and a NMF integrated into it, and as a result, the score is weighted in terms of clinical significance, degree of phenotype benefit or harm, and significance of the change in risk. Therefore, each organism Action Score may be added together and divided by the total number of Action Scores available that are applicable for that specific medical specialty or organ system. A single action score can be applicable to one or more medical specialties or organ systems.
  • the CAS is also known as the System Score because it gives a score to each organ system and medical specialties that apply to the body.
  • the System Score can be used in determining the organ system of greatest and least concern in terms of significant harmful risk for an organism and in terms of significant decreased risk for an organism.
  • a System Score may be calculated for each organ system (that can also be defined in terms of a medical specialty) and a System Color can be assigned to that organ system.
  • Other coloring schemes can also be used, as well as other system score ranges may also be used.
  • the coloring system can efficiently convey the organ systems and medical specialties of greater concern and those that are of lesser concern.
  • the System Score and the System Color can also be altered or changed with a change in non-genetic factors, such as decreasing red meat consumption and this change or potential change may conveyed in the genetic report.
  • non-genetic factors such as decreasing red meat consumption
  • Even information surrounding non-genetic factors, such as red meat consumption can be genetically tailored to the individual as specific genetic variants are known to increase the risk of colorectal cancer with red meat consumption to a greater degree in people with a specific variant - therefore, people with this variant can be specifically advised of their increased risk and that decreasing red meat consumption may decrease their risk of the disease.
  • the coloring can appear throughout a report for an organism's genetic profile, such as on tabs for each organ system and medical specialty, on a face or cover of the genetic report or one of the initial pages that displays a picture of the entire human body, with each organ system shaded by its System color and its score may also be indicated, or the coloring may appear in other locations throughout the report.
  • the System Color can represent an indicator of the health of each medical specialty or organ system based on the person's genetic profile. For organ systems and medical specialties that are not accessed in that panel, no coloring appears for the System Color.
  • Table 11 Color Scheme for System Score
  • genetic variants and polymorphisms including but not limited to, single nucleotide polymorphisms (SNPs), mutations, insertion/deletion polymorphisms (in/dels or DIPs), copy number variations (CNVs), repeats, translocations, inversions, gene expression levels and methylation status, can be detected at a single time.
  • Variants that increase risk and those that decrease risk can be evaluated, as well as variants that are associated with either being a carrier of a phenotype or having or likely having a phenotype can be evaluated, providing a more complete view of a person's overall genetic health.
  • the thousands of genetic variants, such as polymorphisms, and their associated phenotypes can be interconnected in a matrix, as previously discsussed (see for example, FIG. 13D, E) and the matrix can be assessed and analyzed for each organism based on reflex testing (see for example, FIG. 13A- C) (reflex testing is further described, herein).
  • the organ system scores, CAS, or results from the panels can also be used to generate a genetic health score.
  • the overall genetic health score can be generated from one or more phenotypes such as the phenotypes in a panel, a subset of the phenotypes in a panel, the phenotypes in a group of panels, a subset of phenotypes in a group of panels, or for a number of organ systems, medical specialties. All the Cumulative Action Scores that are calculated can be added together to obtain a Genetic Health Score, for all organ systems and medical specialties, which is an overall genetic health score, an indicator of genetic wellness.
  • the indicator can be a word, such as high, medium, or low, or ranging from extremely good, good, neutral, poor, extremely poor.
  • the genetic health score can be a number, for example, ranging from 0 to 5, wherein 0 indicates an extremely poor genetic wellness, which indicates a high risk to serious disease or condition and a 5 indicates an extremely high genetic wellness, indicating extremely low risk of medical conditions.
  • the genetic health score can also be a percentage, such as a high percentage indicating a high likelihood or risk of disease and a low percentage indicating a low likelihood or risk of disease.
  • Genetic health score or genetic wellness can also be expressed in a range of colors, for example, red indicating a high risk of having poor general health or predisposition to poor general health, yellow for average, and blue for an extremely high genetic wellness, with low risk of having diseases or conditions.
  • the Genetic Health Score is a single score that takes into account all System Scores that already have had all action scores factored into them. This provides for a single score that can be used to compare an organism's Genetic Health Score to others, as well as to see how an organism's Genetic Health Score changes over time with non-genetic factors, such as if an obese person institutes weight loss measures such as modifications, such as dieting and exercise, or by taking medications, such as sibutramine, or by having surgery, such as gastric bypass surgery or gastric banding, and is able to significantly decrease their body mass index.
  • each Genetic Health Score range can have a specific color associated with it (Table 12). Other colors and score ranges may also be used.
  • the formula used to calculate the Genetic Health Score for a N number of Cumulative Action Scores, with the minimum value that N can be is equal to 1, is: Genetic
  • Health Score (CASi + CAS 2 + CAS N) ) N.
  • the genetic analysis of the present invention may provide an aggregate score of the PMRs associated with a group of related phenotypes.
  • a set of phenotypes may be identified as related to gender specific health.
  • the aggregate score may be calculated in the same manner as a cumulative action score as described herein.
  • the aggregate score may be referred to as a gender specific health score.
  • a set of phenotypes may be identified as related to reproduction.
  • the aggregate score may be calculated in the same manner as a cumulative action score as described herein. In some cases, the aggregate score may be referred to as a pediatrics score, a reproduction score, or a reproduction/pediatrics score.
  • a set of phenotypes may be identified as related to the research. Such phenotypes may include but are not limited to one or more of the phenotypes, two or more of the phenotypes, or five or more phenotypes listed in Research-related panels.
  • the aggregate score may be calculated in the same manner as a cumulative action score as described herein. In some cases, the aggregate score may be referred to as a military score, military recruitment score, or military suitability score.
  • an organism's owner may view how the organism's Predictive Medicine Risk for each phenotype, his or her action scores, his or her cumulative actions acores, his or her longevity score, his or her gender specific health score, his or her pediatrics or reproduction score, his or her suitability-for-companions or service or sports or production, his or her medical care score, his or her reproductive health score, or gender- specific health score, changes based on cerain variables, such as if he or she follows preventive recommendations or interventions or the advice of his or her physician or other third party.
  • the change in risk values may be static, such as being printed in the genetic report, or dynamic, such as when the organism is meeting with a genetic counselor or nurse practitioner or physician assistant or other third party or if they are reviewing their results on the internet, such as on a webpage.
  • organisms may be able to see how risk values would change (which may be represented by changes in the number values of the PMR, the AS, the CAS, or the genetic health score, changes in their colors, or verbally conveyed by a healthcare professional or one or more of the above) by checking off boxes associated with specific preventive measures or verbally agreeing to follow or choosing certain preventive measures.
  • the organism's owner may be able to visualize these changes on a display, such as a computer screen, holographic image, monitor, or television. This may apply to any change in a non-genetic (environmental) factor (such as habits including eating habits and sexual habits, addictions, medications taken or not taken, compliance with medical advice, etc.) [00262]
  • an organism's owner may view how their Predictive Medicine Risk for each phenotype, their action scores, their cumulative actions acores, and their genetic health score changes based on cerain variables, such as if they change their habits or if they do not follow the treatment regimen.
  • the increase in risk may be separate values for each potential change in habits or preventive recommendation or intervention that they choose not to follow and the increase in risk may also be a different separate value when two or more preventive recommendations or interventions are combined).
  • This change in risk values may be static, such as being printed in the genetic report, or dynamic, such as when the organism is meeting with a genetic counselor or nurse practitioner or physician assistant or other third party or if they are reviewing their results on the internet, such as on a webpage.
  • organisms may be able to see how risk values would change (which may be represented by changes in the number values of the PMR, the AS, the CAS, or the genetic health score, changes in their colors, or verbally conveyed by a healthcare professional or one or more of the above) by checking off boxes associated with specific preventive measures or verbally agreeing to follow or choosing certain preventive measures.
  • the organism may be able to visualize these changes on a display, such as a computer screen, holographic image, monitor, or television. This may apply to any change in a non-genetic (environmental) factor (such as habits including eating habits and sexual habits, addictions, medications taken or not taken, compliance with medical advice, etc.)
  • an organism Prior to obtaining a genetic profile an organism may be "pre-tested", for example as shown in FIG. 1.
  • An organism's owner or representative or third party (102) can directly contact a central location (104), or a health care practitioner's office or other facility providing genetic testing and/or analysis, regarding genetic testing and/or analysis and obtain pre-testing consultation.
  • Pre-testing may include a confidential meeting between the organism and a physician, genetic counselor, nurse practitioner, physician assistant, nurse, other healthcare provider or other third party.
  • an organism's owener or representative or third party can consult with the healthcare provider, such as a genetic counselor, veterinarian or other third party who may suggest what type of genetic profile may be suitable for the organism based on the organism's owner or gardian's concerns or information from a questionnaire the organism's owner or gardian fills out.
  • the healthcare provider such as a genetic counselor, veterinarian or other third party who may suggest what type of genetic profile may be suitable for the organism based on the organism's owner or gardian's concerns or information from a questionnaire the organism's owner or gardian fills out.
  • the computer system and genetic analysis algorithm may take into account factors concerning the organism, including but not limited to: gender, age, weight, non- genetic (environmental) factors and habits, medications, alternative therapies, present medical symptoms, the organism's family history for a disease, disorder or condition (including confirmed, presumed, or suspected diagnoses), the organism's own medical history (including confirmed, presumed, or suspected diagnoses), results from a physical examination, results from a medical test, answers from a questionnaire filled out by the owner of the organism, or other phenotypes, such as a condition, disease, disorder, or trait, of an organism or other factor described herein.
  • factors concerning the organism including but not limited to: gender, age, weight, non- genetic (environmental) factors and habits, medications, alternative therapies, present medical symptoms, the organism's family history for a disease, disorder or condition (including confirmed, presumed, or suspected diagnoses), the organism's own medical history (including confirmed, presumed, or suspected diagnoses), results from a physical examination, results from a medical test, answers from a questionnaire
  • the questionnaire may be specific to an organism owner's concerns.
  • An organism's pedigree can be generated from the questionnaire (for example, as in FIG. 2).
  • the genetic pedigree can be analyzed by a physician, genetic counselor, physician assistant, nurse practitioner, or other othercare provider and used in combination with other information from the questionnaire in determining what genetic testing, analysis or level of services should be performed.
  • an organism can decide what type of genetic profile or services he or she wants.
  • the services can be customized to serve various cross sections of the society.
  • the phenotype, such as disease or condition, panels can be comprehensive, including many phenotypes, such as conditions, or limited, including one or two phenotypes, such as conditions.
  • the number of phenotypes, such as diseases or conditions, offered can be determined by socio-economic need of an organism agreeing to receive comprehnsive genetic analysis and a genetic profile.
  • Other levels of service with varying costs to the organism can include genetic profiles with more than one phenotype, such as a disease or trait, amount of pre-test or post-test (follow-up) interaction with a health care provider or both, type of panel chosen, number of panels chosen, if OP-CADI is chosen, if reflex testing is chosen as well as the degree and depth of reflex testing chosen, or phenotypes chosen.
  • Another level of service can be a comprehensive genetic profile or choice of panels. Other levels of service may depend on the type of panel chosen.
  • Other panels may be specific for testing the presence of various genetic variants for phenotypes, such as conditions, diseases or traits, of particular interest for a group of organisms.
  • the organisms interested in the panels may choose to have their genetic profile determined from a single panel, a number of panels, or a subset of phenotypes, such as conditions and traits, from a panel.
  • the organism's owner or representative or third party may also choose phenotypes, such as diseases or traits, to make a Custom Panel.
  • an organism may choose a Custom 10 Panel, which tests for 10 phenotypes, such as diseases, conditions or traits, the organism chooses, or a Custom 20 Panel, which tests for 20 phenotypes, such as diseases, conditions or traits.
  • the Custom Panel may have approximately 3, 5, 10, 15, 20, 25, 30, or more phenotypes, such as diseases, conditions or traits.
  • phenotypes such as diseases, conditions or traits.
  • an organism can choose different demoninations, such as a Custom 10 Panel, which tests for 10 phenotypes or a Custom 20 Panel, which tests for 20 phenotypes.
  • Custom panels can range from one phenotype to over 1,000 phenotypes.
  • An organism may make the choice after consultation with one or more of the following: GC, physician, nurse practitioner, physician assistant, or other healthcare provider or other third party.
  • Reflex testing refers to the process wherein the determination of the risk, predisposition, or carrier status of an organism for one or more phenotypes, leads to, triggeres, or causes another phenotype to be genotyped or not to be genotyped, to be analyzed or to not be analyzed, to be included in a report or not to be included in a report, to be included in a specific section of the report or not to be included in a specific section of the report, or any combination thereof.
  • the initial phenotype such as a condition, disease, disorder, trait or addiction, may receive a positive or a negative result
  • the reflex phenotype may be, but is not limited to, one or more of the following: a different phenotype, a phenotype related to the initial phenotype (e.g., indicator(s) of severity of initial phenotype, age of onset of initial phenotype, degree of penetrance or expressivity of initial phenotype (for example if the initial phenotype is coronary artery disease, the reflex testing may report on genetic variants that are indicators of the degree of severity of coronary atherosclerosis in coronary artery disease), a response to a type of treatment for the initial phenotype (e.g., adverse reaction to a medication used to treat or prevent the initial phenotype, ability to metabolize a medication used to treat the initial phenotype, indicators of what medications will or will not be most effective in treating or preventing the initial phenotype
  • the predicted phenotype Outcome of Surgery includes whether or not the surgical procedure is likely to be successful in treating a disease or a symptom of a disease, either in the short-term or long-term of both.
  • the initial phenotype may be a specific disease and the reflex phenotype may be a response to, or a sensitivity to, or effectiveness of, or adverse reaction to, a specific drug used to treat or prevent the disease.
  • an organism may be found to be at risk of breast cancer, and the reflex phenotype tested is the organism's response to, or sensitivity to, the drug tamoxifen.
  • the results of the reflex testing of an organism's response to, or sentivity to, tamoxifen may be reported simultaneously with the risk of breast cancer or may not be reported simultaneously but instead reported at a later time, such as if or when the organism is diagnosed with breast cancer.
  • an organism may be found to be at risk of an initial phenotype that is an addiction and the reflex phenotype, such as a condition, to be tested is a disease or disorder that can result from the addiction.
  • the reflex phenotype such as a condition
  • an organism may be found to be at risk for nicotine addiction, which reflexes to the condition of risk of developing lung cancer .
  • the reflex testing can be for risk of, predisposition to, or carrier status for more than one phenotype.
  • results from such testing may help guide decisions as to, for example, what preventive measures, such as genetically tailored prevention, the organism's oweners or representative or third party should follow, what medication the organism should take, whether the organism should follow a particular diet and/or exercise program, whether the organism should be fed a specific diet, whether a particular surgery should be performed or alternative surgeries or treatments considered, what kind of medical screenings the organism should have, and the like.
  • preventive measures such as genetically tailored prevention, the organism's oweners or representative or third party should follow
  • what medication the organism should take whether the organism should follow a particular diet and/or exercise program, whether the organism should be fed a specific diet, whether a particular surgery should be performed or alternative surgeries or treatments considered, what kind of medical screenings the organism should have, and the like.
  • reflex testing Other examples are disclosure herein, however, the present invention is not limited to those listed.
  • the indications for reflex testing may not rely on genotypes of genetic variants but instead may be due to a quality or action or diagnosis of the organism that the genetic sample is from.
  • the reflex takes into account the request not to be notified (known as the 'specific disease exclusion option') and these results do not appear in the report or in the analysis of the neurologic organ system or the overall genetic health score or appear elsewhere and the results may or may not be stored in person's raw genotypic data or the person's raw analytic data that is either saved by the company conducting the genetic testing and analysis or by the person or entity or third-party or by the organism that the genetic sample is from or who ordered the test.
  • the specific disease exclusion option may also be dependent upon the results of reflex testing. This applies to all phenotypes and all options available, such as specific disease exclusion option, only decreased-risk option, only increased-risk option, and OP-CADI.
  • Reflex testing may also be a level of service that is provided.
  • phenotypes such as conditions, disorder, traits and diseases, including monogenic, polygenic, and multifactorial phenotypes
  • reflex testing can be conducted in which a test result leads to operator- engagement or automatic engagement by an analysis system, such as a computer system, to examine other genetic variants of significance given those first results.
  • an analysis system such as a computer system
  • Reflex Testing can automatically or manually report the associated phenotypes (e.g., diseases, disorders, traits or conditions) such as those shown in FIGs. 15- 20.
  • a schematic of reflex testing is depicted in FIGs. 13A-C.
  • a positive or negative result for a first or an initial phenotype e.g., disease, disorder, trait or condition
  • a positive, or negative, result for the second phenotype may reflex again to testing a third phenotype (e.g., disease, disorder, trait or condition)such as depicted in FIGs. 13A-C.
  • the initial test result, phenotype, or genetic analysis may show either increased or decreased risk for a phenotype, such as a condition, or a carrier of a phenotype, or affected or likely affected by a phenotype.
  • Other intital results may include having, being suspected of having, or being diagnosed with a phenotype, or having a family member that has or is suspected of having or is diagnosed with a phenotype. In other cases,, or if an organism may be prescribed, or be taking, a certain medication or supplement.
  • an event that may trigger a reflex test may be that an organism reaches a certain milestone, such as a specific age or age range, or that an organism starts to go through puberty such as gonadarche, thelarche, or menarche, or weaning, or initiation of reproduction.
  • a positive result for a phenotype may reflex to testing for or analyzing a second or reflex phenotypes that is related to , or associated with, the first phenotype.
  • An initial phenotype may lead to testing, analyzing, and/or reporting a chain of 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 10 or more, 15 or more, or 20 or more reflex phenotypes.
  • an initial phenotype may lead to testing, analyzing or reporting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 50, 100, 200, or 500 reflex phenotypes.
  • a negative result may be obtained forthe initial phenotype (e.g., disease, disorder, trait or condition). The negative result may or may not be confirmed by repeating the test. The confirmation may or may not warrant any further reflex test.
  • Additional rounds of reflex testing may incur additional costs to an organism, or to his or her health care provider, or to a third party, such as an insurance provider. For instance, a low-cost service may be available whereas no reflex testing is available for any of the panel or phenotypes or both, a medium-cost service may be available where reflex testing goes only to round 2 and no further, and a high-cost service may be available where reflex testing goes through as many rounds as needed until no further reflex testing rounds exist. As another example, any additional reflex rounds beyond the initial first round may incur an additional fee, either all together or separately (each subsequent reflex round may represent another additional fee).
  • Reflex testing may be time independent or time dependent.
  • the updated reflex analysis and reporting may also take into account any new data, such as new genetic variant-phenotype association data, and updated information in regards to the initial round of testing, such as for coronary artery disease in the example above, so that both the updated initial round of testing and the reflex round of testing (which may also be updated with the most recent information) will be reported at time B, after the initial genetic testing and analysis is conducted at earlier time A.
  • the genetic testing analysis and reporting of results may be based on the initial DNA sample received from the organism, or a new DNA sample received at some later time, and may be based on the raw or already analyzed genetic testing data obtained from the initial genetic testing or from raw or already analyzed genetic testing data obtained from the organism since that initial time.
  • the organism's owner(s), representative ⁇ ), a healthcare provider or other third party may be able to request a partial or full reflex analysis at any time or if certain events occurs or milestones are reached, so that , for example, at an early age such as for example 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 17 ,18, 20, 21, 30 years or older, full reflex analysis can be analyzed and reported to the organism for phenotypes that may not affect that organism until they are older.
  • the genetic testing, analysis and reporting of results may be based on the initial DNA sample received from the organism, or a new DNA sample received at some later time, and may be based on the raw or already analyzed genetic testing data obtained from the initial genetic testing or from raw or already analyzed genetic testing data obtained from the organism since that initial time.
  • Reflex testing may automatically report relevant information to the organism, the organism's parents or legal guardians, the organism's health care proxy, the organism's physician or other healthcare provider, or a third-party, based on the age of the organism or other factors, such as if that organism is ever suspected of having or is diagnosed with a phenotype, such as a disease.
  • This reporting may occur by a written update to the genetic report, an email, a text message, an auditory alert, a manual or an automatic addition to the organism's medical record, a facsimile transmission, a verbal communication over the telephone, internet, or in person, or through an internet conference or website.
  • the organism or any third party receiving this reporting may be able to turn on or off automatic reporting as per their own preference.
  • the genetic testing analysis and reporting of results may be based on the initial DNA sample received from the organism, or a new DNA sample received at some later time, and may be based on the raw or already analyzed genetic testing data obtained from the initial genetic testing or from raw or already analyzed genetic testing data obtained from the organism since that initial time. This manual or automatic reporting of reflex testing analysis may incur an additional fee.
  • a patient or organism may choose to have only one level of reflex testing and/or analysis with his or her genetic analysis but, after reading the genetic report and, optionally, consulting with his or her healthcare provider, the patient or organism may decide to have further reflex testing and/or analysis or full reflex testing and/or analysis conducted that may then detect the carrier status, predisposition, or risk of said organism for one or more previously unreported phenotypes.
  • the genetic testing analysis and reporting of results may be based on the initial DNA sample received from the organism, or a new DNA sample received at some later time, and may be based on the raw or already analyzed genetic testing data obtained from the initial genetic testing or from raw or already analyzed genetic testing data obtained from the organism since that initial time.
  • Reflex testing may also be contingent upon actual diagnosis at earlier time A as the initial factor and then either genetic testing (the actual genotyping) or genetic analysis (of genotypic data) is conducted, or both, at later time B (which constitutes reflex testing because it is based off of the initial factor of a diagnosis) to ascertain one or more other phenotypes.
  • the analysis of genetic information and the reporting of phenotypes or panels or both or the reporting of genetic variants or genotypes or both or the analysis of genetic variants and their associated phenotype(s) is not dependent upon time.
  • a newborn may have his or her full genome sequenced and may have the raw data analyzed near or at that time when he or she is born, time A, or analyzed at a later time, time B, and reported at time B or reported at a later time, time C.
  • the raw genotypic data is ascertained at an earlier time and a panel is chosen and analyzed and reported on at a later time, either the original data concerning risk values of specific genetic variant-phenotype associations and carrier status may be used or updated data concerning risk values of specific genetic variant-phenotype associations and carrier status may be used.
  • the original algorithm that is being utilized when the raw genotypic data is ascertained e.g., from when the genetic testing was conducted
  • the genetic sample may also be obtained at a diferrent time or at the same time as when the genetic testing (to ascertain the raw genotypic data) is conducted. This manual or automatic reporting of initial analysis of results or reflex testing analysis either at the time of the actual genetic testing or at a later time or both may incur an additional fee.
  • Genetic testing that ascertains an organism's genotype at one or more places in the genetic code may be conducted at time A and the genetic analysis or the genetic reporting or both may be conducted at a later time, time B.
  • full genome sequencing may ascertain an embryo's or newborn's genetic code and this genetic code may be analyzed or reported on or both, in part or in full, immediately or not until a later time, such as seconds, minutes, hours, days, weeks, months, years, or even decades in the future after the initial testing and/or analysis occured.
  • the milestones that trigger the reporting of either the results of the initial round of genetic analysis and reporting or one or more reflex rounds of analysis and reporting or both at some time (either instantaneous or seconds to minutes to days to weeks to years to decades) after the initial genetic sample has been obtained (and either stored or genetic variants tested for or sequencing or full sequencing conducted so that raw genotypic data is obtained, such as genotypes at one or more positions within the genome) and preliminary analysis conducted (and either a report generated or no report generated or an abbreviated report generated with only some information) may be determined either by the service provider of the genetic analysis and genetic reporting or may be determined by the organism, the organism's parents or legal guardians, health care proxy, physician, genetic counselor, physician assistant, nurse practitioner, veterinarian, owner, representative, healthcare provider, or third party.
  • the genetic testing analysis and reporting of results may be based on the initial DNA sample received from the organism, or a new DNA sample received at some later time, and may be based on the raw or already analyzed genetic testing data obtained from the initial genetic testing or from raw or already analyzed genetic testing data obtained from the organism since that initial time.
  • This reporting can be either automatic, such as being notified automatically by e-mail, written report, in- person, telephone, facsimile, text message, webpage, or web conference or manual, such as if the organism must do something in order to access the analysis and results, such as accessing a specific website or calling a number, visiting an office, or contacting a third party in order to receive the analysis and results.
  • Milestones that trigger reporting of initial analysis results or reflex testing analysis results, or both, is applicable to all species, including humans and non-humans, such as livestock and pets.
  • Organisms may be human as well as other mammals (Mammalia) or Aves or Fish or Reptilia or other eukaryotes (such as Fungus or Protists) or prokaryotes (such as Bacteria and Archaea) or virus (including retroviruses and bacteriophage), including, but not limited to pets, such as dogs, cats, and birds; farm animals such as pigs, cattle or cows, goats, chickens, ducks, turkey, and sheep, as well as other animals, such as apes, bison, camels, horses (for example, racehorses, such as Harness and Thoroughbred), whales and dolphins.
  • mammals Mammalia
  • Aves or Fish or Reptilia or other eukaryotes such as Fungus or Protists
  • prokaryotes such as Bacteria and Archaea
  • virus including retroviruses and bacteriophage
  • pets such as dogs, cats, and birds
  • farm animals such as pigs
  • Genetic profiles may also be generated for plants, including but not limited to commercially important plants such as, for example, agricultural plants including but not limited to cotton plants, olive trees, evergreen coniferous trees, banana trees, apple trees, orange trees, grapefruit trees, cherry trees, almond trees, wheat, corn, hemp, soybeans and rice.
  • Genetic profiles can be generated for fish, including but not limited to salmon, tuna, sea bass, Alaska pollock, cod, eels, tilapia, flashlight fish, anglerfish, Kryptophanaron alfredi, or sharks.
  • Genetic profiles can also be generated for invertebrates, such as lobsters, shrimp, scallops, Tomopteris and insects; microorganisms, such as bacteria or viruses; and endangered species or extinct species from which genetic material can be obtained.
  • phenotypes that may be tested for in non-human animal's may be coat color(s), eye color, nose color, size, temperament, intelligence, agility, speed, racing performance, performance at conformation events, amount of shedding, amount of milk production, percentage of protein in milk, percentage of fat in milk, muscle strength, amount of lean meat, height, weight, eye color, longevity, reproductive capacity, and diseases and disease susceptibility, such as hip dysplasia, exercise-induced collapse or colic.
  • Initial and reflex phenotypes may be determined based on an agricultural company's, government's, farmer's, animal trainer's, veterinarian's, or pet owner's (or prospective pet owner's) preference.
  • a prospective pet owner may value a dog's coat color or performance at conformation events first, and thus have an initial phenotype for coat color, performance at conformation events, or both. If, for example, the predisposition for a puppy's grown size fits the prospective pet owner's size restriction, reflex testing to the prospective pet owner's second criteria, such as intelligence or exercise induced collapse, is performed. If the puppy does not fit the prospective owner's size restriction, no reflex testing may be performed. Additional rounds of reflex testing may be performed. [00292] Reflex testing can apply to both actual testing of the genotype (e.g., laboratory genetic test), r the analysis of the genotype, and/or the reporting of the genotype or phenotype or both.
  • reflex testing can apply to both actual testing of the genotype (e.g., laboratory genetic test), r the analysis of the genotype, and/or the reporting of the genotype or phenotype or both.
  • Reflex testing may also apply to only genotype testing and analysis or to only reporting of the genotype or phenotype or both.
  • reflex testing may mean that actual testing (genotyping) for those genetic variants is not conducted until a risk or predisposition or carrier status or diagnosis for the first phenotype, such as a disease or trait or process, is genotyped or before the risk or predisposition or carrier status or diagnosis for the first phenotype, such as a disease, is ascertained.
  • Reflex testing may also mean that genotyping for the reflex phenotype, such as a disease,condition, trait or process, occurs either before or after or at the same time of the genotyping for the first disease or trait or process but the results are not reported (such as not entered into any genetic analysis algorithms or analyzed or being shown anywhere in the report for an organism's genetic profile or conveyed in any manner to the organism or entity that ordered the genetic profile, or who views or has access to the results) unless there is an increased or decreased predisposition or carrier status identified for the first phenotype.
  • genotyping for the reflex phenotype such as a disease,condition, trait or process
  • Reflex testing also applies to the physical testing and genotyping process, the analysis of the genotypes and phenotypes as well as using or conveying the results (whether genotypes or phenotypes or predisposition or carrier status or diagnosis or any or all of the above) by electronic means, by paper, in-person, by verbal means, or any other means, to the entity, person, information technology system, or analytical program that is conducting the testing or analysis, or both, as well as the person that ordered the test, views or has access to the test, as well as using the genotypes or phenotypes or predispositions for or in any analysis or interpretation of the raw or analyzed genotype data or any other genotypes or phenotypes or predispositions.
  • reflex testing is not time dependent upon when the initial genetic testing (the actual genotyping) is conducted and is also not dependent upon when the initial phenotype or panel's first round (before any reflex testing) of analysis for risk or predisposition or carrier status is conducted.
  • Reflex testing may occur immediately following the diagnosis of a phenotype or the genetic testing (the actual genotyping), the initial analysis for the phenotype or panel or both (before any reflex testing is conducted), or at any other time point in the future, such as seconds, minutes, hours, days, weeks, months, years, or decades after either the initial genetic testing (the actual genotyping) or the initial analysis or both is conducted.
  • an organism may find that they are either genetically predisposed to coronary artery disease or have been diagnosed with coronary artery disease at earlier Time A, but then at a later time, Time B, either the organism, their healthcare provider, such as an Internist or Cardiologist or Pharmacist, or a third party, may want to analyze, deduce, investigate, ascertain or find out the organism's genetic risk or predisposition to adversereactions to HMG-CoA reductase inhibitors (Statins).
  • genetic testing actual genotyping
  • genetic analysis of genotypic data
  • both is then conducted to ascertain the organism's risk or predisposition to adverse reactions from HMG-CoA reducatase inhibitor medication at the later Time B, because it is known from earlier Time A that the person is predisposed to coronary artery disease or because the person is diagnosed with coronary artery disease, or both, then this also constitutes reflex testing.
  • reflex testing may occur immediately, or any time in the future, such as seconds, minutes, hours, days, weeks, months, years or decades after one or more of the following: the initial genetic testing (actual genotyping) is conducted or diagnosis of the phenotype is made or predisposition or risk or carrier status for the phenotype is ascertained (through genetic analysis of the genotypic data).
  • Reflex testing can also be accomplished either on the front end or back end of the analytical or reporting process or both. For example, if an organism has an increased predisposition for obesity, or has a high body mass index, then the reflex may analyze or show the person's predisposition to diabetes mellitus, type II (diabetes). Reflex testing may work by the analytical process identifying that an increased predisposition for obesity is present (predisposition can either be increased chance of getting the phenotype or decreased chance of getting the phenotype or being a carrier of the phenotype, which means that the person either carries or has or likely has the phenotype) and therefore reflexes to showing predisposition for diabetes.
  • Diabetes predisposition may only be shown if a person is found to be at increased or decreased predisposition or a carrier for obesity. If the person is not found to be at increased or decreased predisposition or a carrier for obesity, then diabetes predisposition may not appear in the report for the organism's genetic profile. This constitutes 'front-end' reflex.
  • reflex testing could occur by the analytical process identifying (i.e. calculating from the alleles or genotype(s) of one or more genetic variants) both predisposition for obesity (either increased or decreased predisposition or carrier status) and predisposition for diabetes (either increased or decreased predisposition).
  • the predisposition for diabetes is included in the analysis and is included in the genetic report. However, if no increased or decreased predisposition or carrier for obesity is found then the predisposition for diabetes is covered up (greyed out; blacked out; ignored; deleted; not shown, reported, or provided; made to appear less relevant or ireelevant; or such) and is either not displayed further in the analysis or the genetic report or both or is moved to the back of the genetic report, or otherwise made less relevant or irrelevant in the genetic reporting process, such as by putting it in a separate section of the report or conveying those results in a less relevant manner to the organism, such as by placing that information in a less relevant section of the genetic report, such as in a less relevant section of a webpage or website (for example, not placing the reflex phenotype information in the main or primary or same section where risk or predisposition or carrier status or diagnosis pertaining to the initial phenotype or the relevent phenotype
  • reflex testing is based on a predisposition or risk to a phenotype (e.g., disease, disorder, trait or condition).
  • reflex testing is not based on predisposition as some genetic variants are deterministic of disease, therefore reflex testing can be predicated upon an organism having a single genetic variant that is either deterministic for a phenotype (the organism either is a carrier but not affected by the phenotype or has or likely has the phenotype) or is associated with either increased or decreased predisposition for a phenotype.
  • an organism may be found to carry a genetic variant that causes (is deterministic for) cystic fibrosis. If this occurs, then reflex testing may occur that will look at other genetic variants in order to ascertain degree of lung disease with cystic fibrosis, severity of cystic fibrosis and prognosis with cystic fibrosis.
  • reflex testing is based on a phenotype that is not determined by genotyping or genetic anslysis.
  • a medical history, or a diagnosis may indicate a phenotype such as for example cancer, or obesity or any of the phenotypes provided herein.
  • the indicated phenotype may then cause another phenotype to be genotyped or not genotyped, to be analyzed or not to be analyzed, to be included in the report or not to be included in the report, to be included in a specific section of the report or not to be included in a specific section of the report, or any combination thereof.
  • the reflex phenotype may or may not be included in the raw data or as part of the preliminary analysis but its inclusion in the near-final and final report that is delivered to the organism, the healthcare provider, or any third-party who ordered the test is determined by whether or not there is a diagnosis, carrier status or an increased or decreased predisposition of the first phenotype, or whether a specific milestone event (trigger event) has occurred (as discussed previously).
  • reflex testing can go through multiple rounds and multiple layers deep (for example, first phenotype reflexes to second phenotype that reflexes to third phenotype that reflexes to fourth phenotype, etc.), this is applicable to each and every step.
  • reflex testing is indicated (either by one or more deterministic genetic variants (carrier) or by an increased or decreased predisposition for or a diagnosis of a phenotype) for the second phenotype, which is also found to be increased risk and this causes reflex testing for a third phenotype.
  • reflex testing may occur to round 2 to discern the person's predisposition for diabetes and if the person is predisposed to diabetes then reflex testing may continue on to round 3 to discern the age of onset of diabetes and if the person has a predisposition for greater or less effectiveness of or adverse reactions to any medications that are used to treat pre-diabetes or diabetes.
  • Reflex testing of the second phenotype may cause the analysis or reporting of the first phenotype to be modified. For instance, if a deterministic genetic variant for Hemochromatosis is found and reflex testing shows that other genetic variants indicate that Hemochromatosis may be severe, then the report may indicate this (that the person has a genetic variant that is associated with Hemochromatosis and that the disease presentation may be severe). The reflex testing may also cause both phenotypes to not be reported. An increased predisposition for a disease may be ascertained based on the allele or genotype of one or more genetic variants. This may cause reflex testing of an associated phenotype that negates the first phenotype.
  • the disease Hemochromatosis may be found initially but reflex testing may examine and analyze other genetic variants that may be associated with either very low or no penetrance or expressivity of Hemochromatosis for that organism. Therefore, neither Hemochromatosis nor the reflex testing results, or both, may be included anywhere in the analysis or Genetic Report or, alternatively, they may both be included in the report, such as in the main section or in a different section. Both pheno types also may both be included in the raw analytic data, one may be included in the raw analytic data, or neither of the phenotypes may be included in the raw analytic data.
  • Reflex testing may take into account many different factors besides the genotype of one or more genetic variants. These non-genotype factors may either occur at the first step or at a later step (such as where risk of uterine cancer is deduced but the reflex to medical history shows the organism had a hysterectomy and therefore the risk of uterine cancer is not included in the analysis of the organ system or in the analysis of the entire genetic health of the organism and may or may not be included in report).
  • the risk for the reflex phenotype may be tested at the same time as the initial phenotype; for example, a single sample may be used to test both the initial phenotype and the reflex phenotype.
  • the reflex phenotype may be tested after the initial phenotype, and another sample used, or perhaps an aliquot of the initial sample that was stored may be used.
  • the reflex phenotype and the initial phenotype may be tested at the same time, and the results for each test may be analyzed at the same time.
  • the reflex phenotype and the initial phenotype may be tested at the same time, and the results analyzed at different times.
  • the results for the reflex phenotype may be then analyzed.
  • the reflex phenotype can be reported concurrently with the initial phenotype, or subsequent to the initial phenotype.
  • the reflex phenotype can be initially requested by the organism, or third party, or after the organism receives the results of the initial phenotype, and optionally, after consultation with a genetic counselor, physician, nurse practitioner, physician assistant, other healthcare provider, or third party.
  • the reflex phenotype(s) may cost additional fees.
  • the panels described herein are used for determining the risk or predisposition of at least 2 phenotypes, which may include 2 phenotypes in the initial round of analysis or 1 phenotype in the initial round of analysis and 1 or more phenotypes deduced via reflex testing.
  • the phenotypes may be monogenic, multigenic, or multifactorial and each phenotype may be associated with one or more of the following: monogenic, polygenic, or multifactorial genetic variant(s).
  • the panels can be used for determining the risk or predisposition of 1, 2, 3, 4, 5 or more multifactorial phenotypes alone or 1, 2, 3, 4, 5 or more monogenic phenotypes alone or both 1, 2, 3, 4, 5 or more multifactorial and 1, 2, 3, 4, 5 or more monogenic phenotypes.
  • the multifactorial and monogenic phenotypes can be tested for and analyzed together, either at the time the initial genetic testing is conducted or at any other time based on genetic testing data (the detection of genetic variants via arrays, microarrays, massarrays, beadarrays, PCR, from partial or full exome or partial or full genome sequencing, such as with nanopore sequencing, or any other methodology that allows for the detection or identification of genetic variants throughout a genome).
  • a panel can be premade and presented to the organism, entity or third party ordering the genetic testing or genetic analysis or both, or the panel can be chosen at the time of consultation from a list of phenotypes that may be grouped according to organ system, disease process, age of onset, clinical relevancy, habits relevancy or any other grouping.
  • the list of phenotypes may appear on a laboratory requisition form.
  • the list may be in alphabetical order or grouped according to organ system, medical specialty, disease process, age of onset, clinical relevancy, habits relevancy or any other grouping.
  • An organism, entity, or third party ordering the genetic testing or genetic analysis or both may then choose a subset of these phenotypes such that a panel is constituted by a group of 2, 3, 4, 5, 6, 7, 8, 9, 10 or more phenotypes, or up to 10, 20, 25, 30, 35, 40, 45, 50, 100, 200, 300, 400, 500, or 1000 phenotypes.
  • Organisms may also choose other options. These phenotypes may then either be tested for or, if the raw genetic data already exists, then the genetic analysis may be conducted and all applicable reflex testing conducted for these phenotypes, taking into account each of the phenotypes selected both organismly and in-relation to each other, and a genetic report can be produced.
  • the panels can be defined as any group of two or more pehotypes reported together at any time, regardless of when the genetic testing (the actual genotyping) occured. For example, a fetus or newborn may undergo full genome sequencing so that in part or substantially the entire genetic code is obtained at that time.
  • the phenotype information that is then analyzed or conveyed in a report, or medical record, can constitute a panel.
  • the analysis, reporting or both, of the phenotypes in regards to being designated a panel is not time-dependent in relation to when the genetic testing (genotyping) occurred.
  • the analysis, reporting, or both can occur at any time, for example, during the initial genotyping (such as sequencing) or at any later date, such as seconds, minutes, hours, days, weeks, months, years or decades later, and the analysis, reporting or both of the phenotypes at any point of time still constitutes a panel.
  • the phenotype(s) may be determined initially, at approximately the same timeframe as the obtaining of genetic data, or may be determined later, or a combination thereof, such that some phenotypes are determined initially and some pheontypes are determined at a later time.
  • Panels and/or reflex testing and/or OP-CADI may also be ordered by and are applicable to patients, clinicians, veterinarian or veterinary surgeon, pet owners, animal owners, pharmacists, healthcare providers, insurance companies, hospitals, clinics, academic researchers, laboratory researchers, clinical researchers, pharmaceutical companies, agricultural companies, agricultural managers, ranchers, farmers, military personnel, governmental agencies, local, national and international agencies, such as the United States Food and Drug Administration (FDA), European Union (EU), United States Centers for Disease Control (CDC), United Nation's World Health Organization (WHO), World Organization for Animal Health (OIE), United Nation's Food and the Agriculture Organization (FAO), or any entity that may be interested in or able to utilize genetic information.
  • FDA United States Food and Drug Administration
  • EU European Union
  • CDC United States Centers for Disease Control
  • WHO World Health Organization
  • OIE World Organisation for Animal Health
  • FEO Food and the Agriculture Organization
  • the panels described herein, and subsets thereof, may be used for a variety of applications and in a wide range of settings. Similarly, a wide range of persons may request a genetic test.
  • the organism to be tested an organism seeking to confirm paternity, an organism's owner or representative or third party seeking information about potential sperm or egg donors or about the actual sperm or egg or embryo itself, or other governmental agency or subagencies or related agencies such as the Secret Service, the Department of Defense (DoD), the Defense Advanced Research Projects Agency (DARPA), Department of Homeland Security (DHS), Department of Agriculture (DoA), the White House, the Federal Bureau of Investigation (FBI), the National Security Agency (NSA), the Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF), the Central Intelligence Agency (CIA), the National Reconnaissance Office (NRO), the Joint Special Operations Command (JSOC), the Defense Intelligence Agency (DIA), the Bureau of Intelligence and Research (INR), the Office of Intelligence and Counterintelligence,
  • DoD Department
  • An organism's owner who has received certain results from a medical examination or medical test may also be tested with a specific panel, or subset thereof.
  • One or more panels, or subsets thereof may be selected based on the medications or supplements (e.g., vitamins, herbal supplements, minerals) an organism is taking or considering taking or may take in their future.
  • a panel, or subset thereof may also be used to test an organism that has a particular habit or possesses specific phenotypes, such as trait(s), or wants to find out if they or their current or future children have or may have specific phenotypes, such as traits.
  • breeding workers, ranchers, herders, owner's, and/or potential owners, that may be interested in the panels may be those interested in an organism's future offspring's genetic profile and phenotypes.
  • Such organisms can have a genetic profile determined from the combined analysis of the offspring's prospective parents.
  • the method is referred herein as "offspring projections from the combined analysis of different organisms", or OP-CADI (see FIG. 14 and FIG.21).
  • the genetic profile of each of the organism's parents is first organismly analyzed and then combined.
  • OP-CADI can be applicable to a single genetic variant, a single gene, a single locus, a single phenotype, part of the genome or the entire genome and may take into account monogenic, polygenic, and/or multifactorial phenotypes, as well as potential or suspected non-genetic factors that the offspring may be exposed to or interact with.
  • the female's genetic profile may be found to have genetic variants associated with Epidermolysis Bullosa Simplex, Cystic Fibrosis, Alzheimer's Disease, Macular Degeneration and being an Endurance Athlete while the male's genetic profile may be found to have genetic variants associated with Prostate Cancer, Cystic Fibrosis, Androgenic Alopecia, Alzheimer's Disease, and being an Endurance Athlete.
  • the future child's genetic profile and analysis may contain the following information: Epidermolysis Bullosa Simplex - 25% chance of being a carrier, 75% chance of being a non-carrier, Cystic Fibrosis - 25% chance of being affected, 50% chance of being a carrier, 25% chance of being a non-carrier (neither affected nor a carrier), Alzheimer's Disease - Predictive Medicine Lifetime Risk Range 23-45%. Macular Degeneration - Predictive Medicine Lifetime Risk Range 15-25%. Androgenic Alopecia - Predictive Medicine Lifetime Risk Range 5- 25%, Prostate Cancer - Predictive Medicine Lifetime Risk Range 14-22%, Endurance Athlete - Very high probability of having this trait, such as greater than 75% chance.
  • Couples interested in having children using their own genetic material, or by assisted reproductive technologies, such as by showing the potential genetic profile of offspring from an egg donor or sperm donor or both, may use OP-CADI. Breeders of lifestock and other animals, animal researchers, and organisms, researchers, or companies working with animals, mammals, fish, birds, reptiles or plants may also utilize OP-CADI in order to ascertain the projected phenotypes from different mate pairings, and they may base their mate selection on results that show either an increased likelihood of one or more phenotypes or a decreae likelihood of one or more phenotypes, or an increased likelihood of one or more genetic variants or genes or loci or a decreased likelihood of one or more genetic variants or genes or loci, and/or the carrier status of one or more phenotypes, from the OP-CADI results from one or more mate pairings analyzed.
  • OP-CADI may also allow for genetic information from genetic testing on a number (from 1 to over 1,000,000,000) of both potential male and female parents to be analyzed together and to create mate pairs that are more likely to produce one or more genotypes and/or phenotypes, or that are less likely to produce one or more genotypes and/or phenotypes, or a combination of the two (some genotypes and/or phenotypes are more likely while other genotypes and/or phenotypes are less likely, with one or more of the following: monogenic, polygenic, or multifactorial phenotypes).
  • OP-CADI is applicable to all species, including human and non-human, that produce offspring through the combination of genetic material from two parents. Also provided herein are methods for matchmakers and matchmaking services to use this method for matching organisms based on their genetic profiles or the genetic profiles of their potential children or both.
  • male children typically have a 100% chance of inheriting their y-chromosome from their father and females typically have a 100% of inheriting the one X-chromosome that the father has.
  • both male and female children typically have a 100% chance of inheriting the mitochondrial genetic code from their mother.
  • the chance of a child being affected with a phenotype, being a carrier of a phenotype, or being neither affected nor a carrier (a non-carrier), also known as their carrier status, as well as being at increased risk for a phenotype or decreased risk for a phenotype, can be deduced and this information can then be supplied to the organism interested in having the potential offspring or their physician or veterinarian or veterinary surgeon or agricultural manager or agricultural company or rancher or farmer or other third party.
  • Polygenic and multifactorial disease risk is determined by calculating the AS, CAS, CGR or PMR (as described herein), but OP-CADIcombines both the potential father and potential mother's genetic profile in order to project or predict the genotypes and phenotypes of their potential offspring.
  • the father most often contributes -50% of his autosomal genetic code, 100% of his y-chromosome code to any sons and 100% of his x-chromosome code to any daughters while the mother most often contributes -50% of her autosomal genetic code, one of her two X-chromosomes to any daughters, and 100% of her mitochondrial DNA to their offspring.
  • the first step in the analytical process is for a manual operator or the genetic analysis information technology system to perform multiple 'chops', with each chop taking into consideration approximately 50% of all the genetic variants that make the cut-off (such as GVDC > 1.5) for each phenotype being accessed (determined by the genetic variant(s), gene(s), locus, or phenotype(s) or panel(s) chosen for analysis) in order to determine the lowest possible lifetime risk and the highest possible lifetime risk for each polygenic or multifactorial phenotype. Therefore, OP-CADI analyzes all relevant genetic variants throughout the entire genome (that make the cut-off) in-relation to each phenotype.
  • the genetic profile chop for the female parent containing the genetic variants that constitute the lowest lifetime risk for each phenotype being assessed is designated "Mother - Low” and the genetic profile chop for the female parent containing the genetic variants that constitute the highest lifetime risk for each phenotype being assessed is designated "Mother - High”.
  • the genetic profile chop for the male parent containing the genetic variants that constitute the lowest lifetime risk for each phenotype being assessed is designated "Father - Low” and the genetic profile chop for the male parent containing the genetic variants that constitute the highest lifetime risk for each phenotype being assessed is designated "Father - High”.
  • Mongenic disorders generally follow monogenic Mendelian inheritance patterns for genes and genetic variants located on autosomes.
  • All genetic variants with a r 2 > 0.99 may be analyzed as being inherited together and may not be separated (separated meaning that the two genetic variants may be analyzed as potentially being separated during the inheritance process simulated by each chop, such as for example that one genetic variant is inherited while the other genetic variant is not) during the chop process.
  • it may be designated that all genetic variants with a r 2 > 0.95 or any operator-designated r 2 cut off value may be chosen so that any two or more genetic variants with an r 2 below that threshold may be separated during the chop process and any two or more genetic variants with r 2 above the designated threshold will be analyzed as being inherited together (meaning that they may not be separated during the chop process).
  • the sex chromosomes for example, the X- and Y-chromosomes in Homo sapiens sapiens
  • 50% of all the genetic variants from her X-chromosomes for each phenotype being assessed from her are analyzed within each chop.
  • the genetic variants that constitute the lowest lifetime risk for each polygenic or multifactorial phenotype is combined within "Mother - Low” genetic profile and the genetic variants from the chops that constitute the highest lifetime risk for each phenotype are combined within "Mother - High”. This is applicable to both the potential female and male offspring.
  • the mitochondrial genetic code For the mitochondrial genetic code, all offspring (e.g. children) are expected to inherit 100% of the mitochondrial genetic code from the female parent. Because of this, the analysis of the mitochondrial genetic code for "Child - Low” and “Child - High” (described below) utilizes 100% of the mitochondrial genetic code from the female parent. Sometimes genetic variants from the autosomes or sex chromosomes or both are analyzed together with mitochondrial genetic variants in the determination of carrier status or risk of certain phenotypes (for instance, in the analysis of the 'Exercise Intolerance' as well as the 'Deafness' phenotypes). In this case, the OP-CADI analysis takes into consideration all of the female parent's mitochondrial genetic variants for those phenotypes being assessed and ignores the male parent's mitochondrial genetic variants.
  • Part 1 involves taking the genetic variants that constitute the lowest lifetime risk for a phenotype from the female parent (Mother - Low) and combining them with the genetic variants that constitute the lowest lifetime risk for a phenotype from the male parent (Father - Low).
  • This new genetic profile is designated "Child - Low” and all the genetic variants (now a combination containing approximately 50% from the male parent and approximately 50% from the female parent) are run again through the genetic analysis system in order to arrive at the lowest lifetime risk value possibility for the possible offspring of these two parents.
  • Part 2 involves taking the genetic variants that constitute the highest lifetime risk for a phenotype from the female parent (Mother - High) and combining them with the genetic variants that constitute the highest lifetime risk for a phenotype from the male parent (Father - High).
  • This new genetic profile is designated "Child - High” and all the genetic variants (now a combination containing approximately 50% from the male parent and approximately 50% from the female parent) are run again through the genetic analysis system in order to arrive at the highest lifetime risk value possibility for the possible offspring of these two parents.
  • Combining the lifetime risk values ascertained for Child - Low and the Child - High gives a range, with the lowest value possibility being the value for Child -Low and the highest value possibility being the value for Child -High. This constitutes the lowest lifetime risk and carrier status and highest lifetime risk possibilities and carrier status (the "Child - Range”) for one or more phenotypes for any potential offspring.
  • the OP-CADI gives the range of possibilities.
  • the potential genetic profiles of mammalian female children (Child - Low and Child - High) primarily looks at a mosaicism pattern and therefore considers the two X-chromosomes (the one paternally derived X-chromosome and one of the X- chromosomes from the female parent, as well as repeating the steps of the analysis, this time with the same paternally derived X-chromosome but now with the other maternally derived X-chromosome) no different from the autosomes in the analysis in terms of finding the lowest range value and highest range value and the most likely outcome existing within this range.
  • this can be accomplished by assessing the phenotypes if the X-chromosome from their father is inactivated and then another assessment where the X-chromosome from their mother is inactivated.
  • the mosaicism pattern created due to lyonization is also taken into account by determining the carrier status and risks of phenotypes when one X-chromosome is inactivated versus when the other X- chromosome is inactived, and these different chops of examining and predicting lyonization results, may provide for a different, and potentially more accurate range for the potential female children.
  • the potential for crossing-over between the paternally derived X-chromosome and the maternally derived X-chromosomes' pseudoautosomal regions may be considered when assessing phenotypes associated with one or more genetic variants on one or more sex chromosomes.
  • Inheritance laws surrounding X-inactivation may be species specific and are known to persons of ordinary skill in the genetic analysis arts, and are integrated into the OP-CADI algorithm.
  • marsupial OP-CADI will analyze the potential offspring with the paternally derived X- chromosome inactivated (and the maternally derived X-chromosome will not be inactivated), meaning that the genetic variants and their associated phenotypes on the paternally derived X-chromosome may not affect the offspring and may not appear in the analysis and/or the report.
  • the OP-CADI can also give separate results for a potential female offspring (such as a child) and a potential male offspring (such as a child), and thus a separate OP-CADI Genetic Report can be generated for the potential female offspring (such as children) and the potential male offspring (such as children).
  • the primary difference occurs with whether the male parent's X-chromosome is considered in the analysis (for all female children) or whether the male parent's Y-chromosome is considered (for all male children).
  • the offspring are separated by gender, so that OP-CADI can give risk and carrier status information about the potential female offspring and about the potential male offspring.
  • the male offspring has a significantly higher risk or has an affected carrier status of a harmful phenotype, such as if it is an x-linked disease, and thus the male offspring and female offspring's OP-CADI report may be different.
  • mate pairing and possible sex selection methods can then be utilized, such as sperm sorting, pre- implantation genetic diagnosis and prenatal diagnosis , in order to choose or increase (or decrease) the likelihood of any phenotype(s), such as of gender, or of any genetic variant(s), gene(s), genetic sequence(s), or chromosome(s).
  • the above methodology can also be used for polygenic, multifactorial and/or monogenic phenotypes.
  • probabilities of a phenotype may be given. For instance, if humans if both parents are carriers of a genetic variant in the CFTR gene associated with the cystic fibrosis phenotype, then the probability of their child being affected with cystic fibrosis is 25%, the probability of the child being a carrier of a genetic variant associated with cystic fibrosis is 50%, and the probability of the child being neither affected nor a carrier (a non-carrier) is 25%.
  • This type of probability deduction follows the tenants of monogenic Mendelian inheritance (see for example FIG. 3).
  • Multifactorial phenotypes may be treated as polygenic.
  • the OP-CADI Genetic Report for the offspring such as children, may contain information relating to how non-genetic factors may influence the risk of certain phenotypes. By supplying this information to the parents, the parents can recognize how different non-genetic factors may influence their potential children.
  • the OP-CADI may take into account non-genetic factors, such as if it is known that the offspring will live in an urban environment or if it is known that the offspring will be farm-raised, or raised for a specific function, such as equine raised for Thoroughbred or Harness racing.
  • Genomic imprinting applies to certain phenotypes when the phenotypes only arise, or have a greater or lesser probability of arising, when the gene (containing the genetic variant(s)) is inherited from a specific parent (such if a phenotype only manifests if the genetic variant is inherited from the mother, while if it comes from the father than there is either a different phenotype or no discernable phenotype, and vice versa).
  • Genomic imprinting regarding phenotypes for which this is known to apply, is taken into account during the analysis process with the OP-CADI. For example, the diseases Prader-Willi Syndrome and Angelman Syndrome both are determined via parent-of-origin genomic imprinting.
  • Genomic imprinting relates not only to monogenic diseases but also to polygenic and multifactorial diseases. For example, atopy, atopic dermatitis and asthma have all been associated with genetic variants in the SPINK5 gene, but only when those genetic variants are maternally inherited. Walley et al. Nat Genet 29(2): 175-178 (2001)). Probabilities and risk-ranges of some phenotypes depend on which parent is contributing the genetic variants (as ascertained from published literature) and this is taken into account with the OP-CADI.
  • the OP-CADI may also be used for parent selection (mate selection) purposes, such as when choosing either a female egg donor or male sperm donor or both. For example, if a married couple is unable to have children because the female has fertility issues, the couple may choose to search for an egg donor while planning to utilize the husband's sperm in order to fertilize the egg.
  • the OP-CADI can be used as a scanning methodology that utilizes the husband's genetic profile and combines it with an egg donor's profile in order to assess the possible genotypes and phenotypes of the potential children.
  • This process can be run for all possible egg donors under consideration, either one at a time, in batches of egg donors, such as 2 or 5 or 10 at once, or by utilizing the genotypic information available from all egg donors at once. If the genetic profile (genotype, such as for example via genechip analysis, PCR analysis, or sequencing) of the egg donors has already been deduced, then this process may be run automatically back-to-back or simultaneously until a certain genotype or phenotype probability or risk-range or carrier status is deduced.
  • the couple may want to ensure that the potential child will have the lowest risk-range of breast cancer possible, then the OP- CADI can be utilized to scan the available egg donor's genetic profiles in-order to ascertain which egg donor(s) will provide the lowest risk-range for breast cancer both on its own and when combined with the male parent's genetic profile.
  • This approach can be utilized for any phenotype, and can be utilized for either just one phenotype or multiple phenotypes (for example in terms of humans, the lowest probability for all rare diseases and the lowest risk-range for breast cancer, Alzheimer's disease, and heart disease as well as the highest probability or highest risk-range for enhanced longevity, intelligence and blond hair).
  • the above process can be utilized for any parent selection purpose that wants to take into account the genetic profile of the potential children. For example, it may also be utilized by a woman who wants to discern who the best sperm donor(s) will be based on certain cutoffs that they impose upon the potential future children's genetic profile (for example, less than ( ⁇ ) 25% probability of any rare disease, metabolic disease, or syndrome).
  • a similar process may also be used by matchmakers or matchmaking services such that organisms submit their DNA or genetic profile and the matchmaker or service uses the OP-CADI to determine the potential genetic profiles for each match's potential children. Based on cut-off values supplied by either the matchmaking service for the organisms themselves (such as all matches must have less than ( ⁇ ) 25% probability of rare diseases), organisms can then be matched up. This information may also be combined with other analysis of each of the organisms own genetic profiles, for example to determine compatibility based on degree of sexual responsiveness.
  • the above process for the OP-CADI refers to genetic data ascertained through any method.
  • genetic data may be from array testing or nanopores or any other techniques that may not identify which specific chromosome that the genetic variant is from.
  • gene sequencing full exome sequencing and full genome sequencing, each organism chromosome may be seen as a discrete entity.
  • the information pertaining to which specific chromosome a genetic variant is contained on can be utilized within the analysis in order to identify a string (two or more) genetic variants that are likely to be inherited together as those genetic variants occur close to each other on the same chromosome.
  • a string of genetic variants may represent a haplotype or multiple haplotypes or it may just represent two genetic variants that are within physical proximity to each other on the same chromosome. Groups of genetic variants that exist closer together on the same chromosome may then move with more frequency together during each chop analysis. The effects of crossing-over may be taken into account and integrated into the OP-CADI by selecting a certain distance (such as in kilobases, or in centimorgans) that is more likely to segregate together. Genetic variants that exist on the same chromosome and within that certain distance from each other will then most likely segregate together and may not be separated during the chop process.
  • the OP-CADI can also be applied to non-humans, such as with the breeding of Felis catus, Bos taurus, Gallus gallus, Pan troglodytes, Canis lupus familiaris, Capra hircus, Equus caballus, Mus musculus, Sus scrofa, Rattus norvegicus, Ovis aries, Meleagris gallopavo, as well as other non-human mammals, aves or fish or plants.
  • the OP-CADI can be used to detect the pairs of canines (such as Canis lupus familiaris) that are most likely to produce offspring that are faster runners, have enhanced nighttime eyesight or have specific coat color.
  • bovine such as Bos Taurus
  • this novel approach can be used to detect the pairs that are most likely to have more offspring, or offspring that are greater in size or produce larger amounts of milk.
  • known species-specific inheritance patterns for each chromosome from each parent can be utilized in order to conduct the OP-CADI for any species where the genetic material of the offspring is from the combination of genetic material from two parent organisms.
  • the same process of genetic analysis applies to the OP-CADI as before, including applying the OP-CADI to any genetic variant(s), gene(s), locus, phenotype(s) or panel(s) and incorporating the option for reflex testing, which allows for a comprehensive, dynamic analysis of genetic information.
  • the OP-CADI can utilize and report on lifetime risk-ranges and probabilities of genotypes or phenotypes or both, it can also be utilized and report on action score risk-ranges and probabilities of phenotypes, and it can also utilize and report on cumulative action score -ranges or genetic health score ranges (such as existence score-ranges) and probabilities of phenotypes (such as for carrier status).
  • Any organism may be tested using one or more Full Genome Panel in order to determine his or her risk of, or predisposition for, one or more phenotypes.
  • a full genome analysis panel may aid the calculation of the general health of the organism or of a zygote, embryo or fetus.
  • An organism with a family history of a specific condition e.g., acute disease, chronic disease, degenerative disease, fatal disease
  • An organism on a particular diet may also be tested with such panel.
  • results from the Full Genome Panel(s) may help veterinarianor alternative professional make changes in the organism's habits (e.g., diet, exercise), or take actions to mitigate the organism's risk of developing an adverse condition.
  • a full genome analysis panel may also be run on a fetal genetic material (such as from a zygote, embryo or fetus) or on newborns or children in-order to analyze and assess their entire genetic genome including phenotypes that may negatively or positively affect their life.
  • a fetal genetic material such as from a zygote, embryo or fetus
  • newborns or children in-order to analyze and assess their entire genetic genome including phenotypes that may negatively or positively affect their life.
  • a panel may be used to determine an organism's Universal Identifier, which is a unique sequence of multiple genetic variants and the unique sequence at those variants when considered together is exactly specific to only one organism in the entire world.
  • a Universal Identifier Option may be available for all panels that allows for a Universal Identifier to be added on to any panel for any organism or the Universal Identifier Option may be run on its own for any organism as its own Panel so that only a Universal Identifier is ascertained for the organism. This is similar to a fingerprint but is detectable in any specimen from the organism (e.g. blood, urine, hair, semen, skin, saliva, tissue, etc) that contains genetic material.
  • identity e.g., if meat is found to be tainted with E. coli or salmonella then it's Universal Identifier can be used to trace the meat back's entire history from a person's household or market all the way back through the entire distribution process to the ranch where the contaminated meat originated from
  • an organism's unique genotype at the genetic variants that constitute the Universal Identifier can be used to identify or distinguish that organism from all other organisms in the world, with a probability of discrimination that may be greater than 90%, greater that about 95%, 99%, 99.9, or 99.99%.
  • the probability of discrimination may be greater than about 99.999, 99.9999, or 99.9999999999% or greater in all populations.
  • the Universal Identifier may be used on a variety of identification items such as on military identification tags (dog tags), on security cards, on documents, on medical records, on tissue specimens, on pathological specimens, on hair, blood, skin, saliva, semen or other bodily fluids, on stored genetic material, identification of organisms in government databases, in personal databases, in corporate databases, in military databases, in criminal databases, or any other use where personal identificiation with an extremely high degree of certainty and security are needed, wanted or required.
  • This Universal Identifier may represent a minimum set of genetic variants necessary to distinguish one organism from all other organisms in the world out of all populations and therefore genotyping of only these genetic variants may be necessary to confirm, or to rapidly confirm, an organism's identity.
  • This Universal Identifier may be composed of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 or more genetic variants throughout the organism's genome.
  • the panel may also test for the organism's blood group based on specific genetic variants in multiple genes and this can be utilized to further confirm identity and also by healthcare professionals to confirm the organisms' s exact blood group derived from other laboratory tests, such as another genetic way to further confirm indentity or a confirmatory or ancillary indicator of blood group prior to a blood transfusion.
  • the identifier can be used to identify an organism, such as from the time of birth, so that the organism can be tracked throughout its life and also after its death, such as by a government agency, private or public company, veterinarian, herder, rancher, caretaker, biologist, researcher, scientist, health care provider.
  • the internal identifier may be utilized after a cow is killed and its meat is distributed to supermarkets if there is an outbreak of a disease related to that specific meat, such as E. coli or spongiform encephalopathy, so that a government agency can trace the meat all the way back to where it was born and lived and was killed.
  • a biologist or researcher may also utilize this universal identifier to track migration patterns of organisms and a company that owns animals may utilize the animal's universal identifier to track the animal and claim ownership of a specific animal.
  • the number of panels or number of phenotypes or number of genetic variants, or number of genes or loci, or various combinations thereof, may be used to determine the level of service or price for determining an organism's risk or predisposition to or carrier status of various genetic variants or phenotypes or both. If a single panel is chosen, the sample for an organism that supplies the genetic material (such as buccal tissue, epithelial tissue, saliva, blood, hair, hair follicle, skin, etc.) may be used to test only that panel, or it may be used on a number of panels, but the results from only that panel is reported to the organism.
  • the genetic material such as buccal tissue, epithelial tissue, saliva, blood, hair, hair follicle, skin, etc.
  • the organism's sample may be tested for only the phenotypes, such as conditions, chosen by the organism, or their sample may be used for the entire panel or a number of panels, but only the results from the phenotypes, such as conditions, chosen by the organism are reported. Results from genetic variants, phenotypes, such as conditions, or panels not chosen by the organism initially may be released to the organism if the organism chooses so at a later date. The organism's owner, or representative, or third party may have to pay an additional cost. The organism may or may not submit another biologic sample.
  • the conditions selected can be selected not only by the organism who's risk or predisposition or carrier status is being tested for, but can also be selected by another party, such as a parent, guardian, relative, health care manager, medical professional, or third party with the authority to, or may be selected by the organism with consultation of the aforementioned parties, or selected by the aforementioned parties with the consultation of the organism being tested.
  • Different levels of service with varying costs can also be provided where the initial analysis is followed with a consultation with a specialist.
  • An organism's owner, or representative, or third party can choose a lower level of testing, for example, a single phenotype, such as a disease or condition, or a single genetic variant or single gene, and afterwards, decide to obtain a more comprehensive genetic profile or a full genetic profile.
  • An organism's owner, or representative, or third party may choose to have an initial consultation with a veterinarian or specialist, and decide to have a consultation with a specialist referred to by the managing doctor or genetic counselor or physician assistant or nurse practitioner or other healthcare professional. In some cases, non-medical specialists may be consulted as well, either in conjunction with a medical specialist or independently.
  • the organism may sign a waiver or other release or disclaimer and a biological sample is obtained from the organism for genetic testing.
  • the sample may be linked to a number, such as a "Confidential Client Number" or CCN, which is given to the organism or the organism's healthcare provider or the person who ordered the test or other third party with authority to order the test or have access to the CCN.
  • the organism's name and CCN can be encrypted and a single or multiple physical (non-electronic) copy or copies or electronic copy or copies of the information linking the organism's name to the CCN can be kept to maintain confidentiality.
  • kits provided to organisms with sample collection containers for the organism's biological sample.
  • the kit may also provide instructions for an organism to directly collect their own sample, such as how much hair, urine, sweat, buccal tissue, tongue cells, or saliva to provide.
  • the kit may also contain instructions for an organism to request tissue samples to be taken by a health care specialist, or instructions for how they can obtain their own biologic sample (as discussed above), to be stored indefinitely for the purpose of DNA banking (long- term storage of DNA for future use, such as analysis, or to pass on to future generations).
  • the kit may also provide return packaging for the sample to be sent to a sample processing facility, where the organism's genetic material is then isolated from the biological sample for either storage or for genetic testing or both.
  • a genetic sample of DNA or RNA may be isolated from a biological sample according to any of several well-known biochemical and molecular biological methods, see, e.g., Sambrook, et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, New York) (1989).
  • kits and reagents for isolating DNA or RNA from biological samples such as those available from DNA Genotek, Centra Systems, Qiagen, Ambion, and other suppliers.
  • Buccal sample kits are readily available commercially, such as the MasterAmpTM Buccal Swab DNA extraction kit from Epicentre Biotechnologies, as are kits for DNA extraction from blood samples such as Extract-N-AmpTM from Sigma Aldrich.
  • DNA from other tissues may be obtained by digesting the tissue with proteases and heat, centrifuging the sample, and using phenol- chloroform to extract the unwanted materials, leaving the DNA in the aqueous phase.
  • the DNA may then be further isolated by ethanol precipitation.
  • DNA may be collected using DNA self collection kit technology available, such as from DNA Genotek, an organism collects a specimen of saliva for clinical processing.
  • the sample conveniently may be stored and shipped at room temperature.
  • DNA is isolated by heat denaturing and protease digesting the sample, typically using reagents supplied by the collection kit supplier at 50°C for at least one hour.
  • the sample is next centrifuged, and the supernatant is ethanol precipitated.
  • the DNA pellet is suspended in a buffer appropriate for subsequent analysis.
  • the sample is obtained from a cheek swab.
  • a DNA sample may also be provided to the organism in a form visible to the human eye.
  • This visible DNA can be placed in a sealed container, tube, vial, locket, charm, watch, necklace, mantle-piece, show-piece or other display casing that may or may not be part of the genetic report or given to the organism at the same time as the genetic report or both.
  • the visible DNA may also be combined with a coloring or fluorescent agent in order to make it more visible against its background. This service may be at an additional cost.
  • the DNA may be made visible either using a laboratory kit, such as EPICENTRE® Biotechnologies' MasterPureTM Complete DNA and RNA Purification Kit, Axygen Biosciences' AxyPrepTM Multisource Genomic DNA Miniprep Kit, Whatman's GenSpinTM Genomic DNA Purification Kit, or any other commercially available kits, or by using methods known in the arts, such as by the following methodology: placing saliva or buccal tissue into 3-5 milliliters of water in a container (saliva can be obtained by swishing the 3-5ml of water around in the mouth and then spitting into a container), add approximately 1-2 teaspoons of salt, then add in 1-2 milliliters of household dish soap, sir for approximately five minutes, then add 4-5 milliliters of denatured alcohol and wait 10-20 minutes.
  • a laboratory kit such as EPICENTRE® Biotechnologies' MasterPureTM Complete DNA and RNA Purification Kit, Axygen Biosciences' AxyPrepTM Multisource Genomic DNA Miniprep Kit,
  • An organism may be interested in displaying their DNA.
  • This visible DNA can be shipped back to the organism directly or handed to them in person, either by their physician, healthcare provider, genetic counselor, nurse practitioner, physician assistant, or other person who ordered the test, either along with their genetic report or at a separate time.
  • This visible DNA may be ordered along with genetic analysis or on its own. This service may incur an additional fee.
  • DNA art may also be provided to the organism in the form of pictures or drawings that show either part of their genetic code or their entire genetic code.
  • the picture may be in the form of a black and white or color picture, photograph, image, or print out (such as of the data) of the array, microarray, massarray, beadarray, genechip, or sequencing (such as, for example, by utilizing shotgun sequencing, double-barrel shotgun sequencing, pyrosequencing, nanopores, fluorophores, or nanoballs) results from genetic testing that was conducted for that organism or for the organism's family, such as based on the panel they ordered, or may be a depiction or representation of part or the whole genome, such as their entire genetic code or a part of their genetic code, such as if sequencing or full genome sequencing is utilized.
  • the pictures, photographs, video images, computer images, drawings, sketches, or any other images depicting an organism's or a family's genetic code such as for a single genetic variant, multiple genetic variants, single gene, multiple genes, single locus, multiple loci, single chromosome, multiple chromosomes, partial genome, or full genome (such as sequence data, restriction fragment length polymorphisms, gel electrophoresis products, etc.) may be digital, printed, screened, via decalcomania, via holography, drawn, painted, woven, such as into rugs, carpets or tapestries, and blown, such as with glassblowing, and may range in size from very small, such as wallet-size, such as one inch by one inch, to extremely large, such as billboard size or building wall size, such as 100 feet by 100 feet.
  • DNA may be produced by the company that conducts the genetic testing or the genetic analysis, the laboratory (158) that processes the genetic sample and the genetic testing, or by another company, such as DNA 11 Inc. (Ottawa, Ontario, Canada).
  • the DNA art may be produced from the same genetic sample that is used for genetic testing and/or analysis or it may be from a different genetic sample.
  • the DNA art may appear within the genetic report, such as on the cover of the genetic report or within the genetic report, or be delivered with or around the same time as the genetic report, or at an earlier or later date, and may be ordered at the same time that the genetic testing, genetic analysis or genetic report is ordered or it may be ordered at a later time (utilizing either the same genetic material or new genetic material) or it may be ordered separately, on its own. This service may incur an additional fee.
  • RNA may also be used as the genetic sample.
  • genetic variations that are expressed can be identified from mRNA.
  • the term "messenger RNA” or “mRNA” includes, but is not limited to pre-mRNA transcript(s), transcript processing intermediates, mature mRNA(s) ready for translation and transcripts of the gene or genes, or nucleic acids derived from the mRNA transcript(s). Transcript processing may include splicing, editing and degradation.
  • a nucleic acid derived from an mRNA transcript refers to a nucleic acid for whose synthesis the mRNA transcript or a subsequence thereof has ultimately served as a template.
  • RNA reverse transcribed from an mRNA a DNA amplified from the cDNA, an RNA transcribed from the amplified DNA, etc.
  • RNA may be isolated from any of several bodily tissues using methods known in the art, such as isolation of RNA from unfractionated whole blood using the PAXgeneTM Blood RNA System available from PreAnalytiX.
  • mRNA may be used to reverse transcribe cDNA, which may then be used or amplified for gene variation analysis.
  • the methods described herein can be applied in the context of any platform capable of genotyping a sample, e.g., arrays, microarrays, massarrays, beadarrays, genechips, PCR-based techniques, exome sequencing, full (such as whole) exome sequencing, partial genome sequencing or full (such as whole) genome sequencing, such as with shotgun sequencing, double -barrel shotgun sequencing, pyrosequencing, nanopore sequencing (nanopores), fluorophore sequencing (fluorophores), DNA nanoball sequencing (nanoballs), or any other partial or full (such as whole) genome sequencing technologies.
  • any platform capable of genotyping a sample e.g., arrays, microarrays, massarrays, beadarrays, genechips, PCR-based techniques, exome sequencing, full (such as whole) exome sequencing, partial genome sequencing or full (such as whole) genome sequencing, such as with shotgun sequencing, double -barrel shotgun sequencing, pyrosequencing, nano
  • sequencing apparatus and “sequencing platform” include but are not limited to arrays, nanopores, nanoballs, pyrosequencing, shotgun sequencing, double-barrel shotgun sequencing, SMRTTM Sequencing Technology or any other method of genetic sequencing that identifies the allele or genotype of one or more genetic variants in a genome. Often, results or data from a sequencing apparatus or a sequencing platform are provided as part of sequencing services. Prior to identifying a genetic variant, such as a polymorphism, through testing or analysis or both, a genetic sample is typically amplified, either from DNA or cDNA reverse transcribed from RNA, although other genetic testing methodologies may exist that may not require DNA amplification.
  • DNA may be amplified by a number of methods, many of which employ PCR. See, for example, PCR Technology: Principles and Applications for DNA Amplification (Ed. H. A. Erlich, Freeman Press, NY, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications (Eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattila et al., Nucleic Acids Res. 19, 4967 (1991 ); Eckert et al, PCR Methods and Applications 1, 17 (1991); PCR (Eds. McPherson et al., IRL Press, Oxford); and U.S. Pat. Nos. 4,683,202, 4,683,195, 4,800,159 4,965,188, and 5,333,675, and each of which is incorporated herein by reference in their entireties for all purposes.
  • LCR ligase chain reaction
  • LCR ligase chain reaction
  • DNA for example, Wu and Wallace, Genomics 4, 560 (1989), Landegren et al., Science 241, 1077 (1988) and Barringer et al. Gene 89:117 (1990)
  • transcription amplification Kwoh et al., Proc. Natl. Acad. Sci. USA 86:1173-1177 (1989) and WO88/10315
  • self-sustained sequence replication (Guatelli et al, Proc. Nat. Acad. Sci. USA, 87:1874-1878 (1990) and WO90/06995)
  • selective amplification of target polynucleotide sequences U.S. Pat. No.
  • CP-PCR consensus sequence primed polymerase chain reaction
  • AP-PCR arbitrarily primed polymerase chain reaction
  • NABSA nucleic acid based sequence amplification
  • RCA rolling circle amplification
  • MDA multiple displacement amplification
  • C2CA circle-to-circle amplification
  • a low density or mid density or high density DNA array such as a microarray or massarray or bead array or genechip, can be used for genetic variant, such as SNP, identification, to generate a genotype(s) for one or more genetic variants (genetic testing that leads to a raw genotype profile for an organism) and profile generation.
  • genetic variant such as SNP
  • identification to generate a genotype(s) for one or more genetic variants (genetic testing that leads to a raw genotype profile for an organism) and profile generation.
  • Such arrays or microarrays or bead arrays are commercially available, for example, from Affymetrix and Illumina (see Affymetrix GeneChip® 500K Assay Manual, Affymetrix, Santa Clara, CA (incorporated by reference); Sentrix® humanHap650Y genotyping beadchip, Illumina, San Diego, CA).
  • a subset of the human genome can be amplified through a single primer amplification reaction using restriction enzyme digested, adaptor-ligated human genomic DNA.
  • the sample is denatured, labeled, and then hybridized to a microarray with small DNA probes at specific locations on a coated quartz surface.
  • the amount of label that hybridizes to each probe as a function of the amplified DNA sequence is monitored, thereby yielding sequence information and resultant SNP identification.
  • use of the Affymetrix GeneChip 500K Assay is carried out according to the manufacturer's directions. Briefly, isolated genomic DNA is first digested with either a Nspl or Styl restriction endonuclease.
  • the digested DNA is then ligated with a Nspl or Styl adaptor oligonucleotide that respectively anneals to either the Nspl or Styl restricted DNA.
  • the adaptor-containing DNA following ligation is then amplified by PCR to yield amplified DNA fragments between about 200 and 1100 base pairs, as confirmed by gel electrophoresis.
  • PCR products that meet the amplification standard are purified and quantified for fragmentation.
  • the PCR products are fragmented with DNase I for optimal DNA chip hybridization. Following fragmentation, DNA fragments should be less than 250 base pairs, and on average, about 180 base pairs, as confirmed by gel electrophoresis.
  • Samples that meet the fragmentation standard are then labeled with a biotin compound using terminal deoxynucleotidyl transferase.
  • the labeled fragments are next denatured and then hybridized into a GeneChip 250K array.
  • the array is stained prior to scanning in a three step process consisting of a streptavidin phycoerythin (SAPE) stain, followed by an antibody amplification step with a biotinylated, anti- streptavidin antibody (goat), and final stain with streptavidin phycoerythin (SAPE).
  • SAPE streptavidin phycoerythin
  • After labeling, the array is covered with an array holding buffer and then scanned with a scanner such as the Affymetrix GeneChip Scanner 3000. Analysis of data following scanning of an Affymetrix GeneChip Human Mapping 500K Array Set is performed according to the manufacturer's guidelines.
  • DNA sequencing may also be used to sequence a small portion (such as one full gene or a portion of one gene), a substantial portion (such as multiple genes or multiple chromosomes), or the entire genomic sequence of an organism.
  • DNA sequencing has been based the technique known as Sanger sequencing which uses polyacrylamide gel fractionation to resolve a population of chain-terminated fragments (Sanger et al., Proc. Natl. Acad. Sci. USA 74:5463-5467 (1977)).
  • Nanopore sequencing is one such method that may allow for high throughput DNA sequencing (Vercoutere, W. et al. Nature Biotechnology 19 , 248-252 (2001), Sauer- Budge, A.F. et al. Phys. Rev. Lett. 90, 238101-238101 - 238101-238104 (2003), Howorka, S. Nat Biotechnol. 2001 Jul;19(7):636-9). Nanopores may be used to sequence a small portion (such as one full gene or a portion of one gene), a substantial portion (such as multiple genes or multiple chromosomes), or the entire genomic sequence of an organism.
  • Nanopore sequencing technology may be commercially available or under development from Sequenom (San Diego, CA), Illumina (San Diego, CA), Oxford Nanopore Technologies LTD (Kidlington, United Kingdom), and Agilent Laboratories (Santa Clara, CA). Nanopore sequencing methods and apparatus are have been described in the art and for example are provided in US Patent No. 5,795,782, herein incorporated by reference in its entirety. Other sequencing technologies include nanoballs, fluorophores and Single Molecule Real Time DNA sequencing technology (SMRTTM) technology, and pyrosequencing, as described in US Patent Nos.
  • SMRTTM Single Molecule Real Time DNA sequencing technology
  • a low-, medium- or high-density array such as the commercially available platforms from Sequenom or Affymetrix or Illumina, is used for genetic variant identification and profile generation.
  • the massarray or microarray or beadarray can have at least 1000, 5000, 6,000, 6,500, 7,000, 8,000, 10,000, 15,000, 20,000, 25,000, 30,000, 45,000, or 50,000 unique oligonucleotide sequences.
  • Each oligonucleotide sequence may exist one or more times on the array, such as for redundancy or to increase accuracy, as the same (non-unique) oligonucleotide sequence may test for the same genetic variant and therefore these oligonucleotide sequences (which test for the same exact genetic variant) are not unique; only oligonucleotide sequences that test for or detect different genetic variants are considered herein unique oligonucleotide sequences.
  • a genetic variant may be unique if it exists in a different location within the genome, even if it is just one basepair away from another genetic variant, or it may also be unique if it occurs at the same exact location within the genome but encompasses a different type of variation, such as a different nucleotide change.
  • each of the unique oligonucleotide sequences corresponds to, or is associated with, a genetic variant, such as a genetic polymorphism, such as a SNP.
  • each sequence may be associated with a phenotype that is medically relevant or linked to at least one phenotype as reported in published literature.
  • an oligonucleotide sequence can comprise a genetic variant, be a sequence in linkage disequilibrium with a genetic variant, such as a SNP, or contain genetic sequence immediately flanking the genetic variant of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, or more bps upstream or downstream of a genetic variant.
  • the genetic variant may be medically related or non- medically related.
  • the genetic variant may be trait related or non-trait related.
  • each of the unique oligonucleotide sequences on an array is associated with a genetic variant, such as a polymorphism or mutation that is medically relevant or provides information about a trait, for example, each sequence on the array is associated with a SNP that is correlated with a disease or condition or trait.
  • the sequences on the array may be used to detect the genetic variants in the non-limiting examples of representative genes listed in Table 4.
  • Other non-limiting examples of representative genes may include those listed in FIGS. 15-20.
  • the array may comprise sequences that detect a genetic variation, such as a SNP, in each of the non-limiting examples of representative genes listed in Table 4, or those listed in FIG. 15-20, that is associated with a genetic condition or phenotype.
  • Some arrays may have oligonucleotide sequences, wherein at least 50, 70, 75, 80, 85, 90, or 95% of the sequences are associated with a genetic variant that is medically relevant. In some embodiments, at least 5, 10, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 250, 300, 400, 500, 1000 or more unique phenotypes are associated with the genetic variants on the array. In some embodiments, each of the oligonucleotides on the array is associated with a different genetic variant or a different phenotype, such as a disease or condition. In some arrays, different oligonucleotides may be associated with the same phenotype, such as a disease or condition.
  • Arrays can also have oligonucleotide sequences wherein at least 5, 10, 25, 50, 65, 70, or 75% of the sequences corresponding to a genetic variant, such as SNP, are unique sequences or sequences not listed in a public database, for example sequences immediately flanking the genetic variant that are about 5, 10, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 200, or more bps upstream or downstream of a genetic variant.
  • the oligonucleotides on an array may detect at least about 10, 20, 50, 75, 100, 1000, 5000, 6,000, 6,500, 7,000, 8,000, 10,000, 15,000, 20,000, 25,000, 30,000, 45,000, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 350,000, 400,000, 450,000, 500,000, 750,000, 1,000,000, 1,500,000, 2,000,000, 2,500,000, 3,000,000, 3,500,000, 4,000,000, 4,500,000, 5,000,000, 5,500,000, 6,000,000, 6,500,000, 7,000,000, 7,500,000, 8,000,000, 8,500,000, 9,000,000, 9,500,000, 10,000,000 or more genetic variants, such as SNPs.
  • the number of genetic variants may be present in at least approximately 2, 5, 10, 15, 20, 100, 250, 500, 750, 1000, 1250, 1500, 2000, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11000, 11500, 12000, 12500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18500, 19000, 19500, or 20,000 genes.
  • each sequence on an array is used to determine or calculate an organ system score.
  • each of the sequences is used to determine or calculate at least 2 or more organ system scores.
  • arrays contain sequences wherein each of the sequences is used to determine or calculate a score for a medical specialty. In yet other embodiments, each of the sequences are used to calculate or obtain an overall genetic health score. In some embodiments, the array comprises unique oligonucleotide sequences that detect at least 2, 5, 10, 50, 100, 200, 500, 1,000, 2,000, 5000 medically-relevant genetic variants or SNPs, at least 6000 medically-relevant genetic variants or SNPs, or at least 6500 medically-relevant genetic variants or SNPs.
  • Medically-relevant genetic variants or SNPs refer to a genetic variant that has been associated or linked in published literature, such as a published journal article, with either an increased or decreased risk or predisposition to disease or medical condition or associated with being a carrier or affected or likely-affected by a disease or medical condition .
  • the number of unique medically relevant phenotypes associated with genetic variants that the unique oligonucleotides may be able to test for or detect may include at least 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600 or more phenotypes.
  • the genetic variants detected by the array may be present in non-coding regions.
  • the genetic variants may be medically related or non-medically related.
  • the genetic variants may include only clinically relevant genetic variants, or genetic variants in genes or in linkage disequilibrium of other genetic variants, correlated with clinical phenotypes, such as diseases or medical conditions.
  • the genetic variants may be organized by medical specialty, gene, location on a chromosome, phenotype or disease.
  • the genetic variants may be organized by trait or with similar groups of traits.
  • the genetic variants can be organized by clinical severity or by how well that genetic variant is thought to correlate with a specific phenotype, such as a disease or condition.
  • the private database can also have precise information for each genetic variant.
  • information such as odds ratio or other risk value, applicable species/genus or populations, inheritance patterns, journal references, journal links, brief genetic variant synopsis, phenotype-associated allele or genotype, p-value of the association, confidence interval of the risk value, incidence or prevalence of the phenotype, frequencies of the alleles or genotypes, or both, of the genetic variant, different scoring systems for the genetic variant- phenotype association (as previously discussed), such as the GVP score, and recommendations.
  • each of the genetic variants detected by the array is medically relevant.
  • each of the sequences on the array is linked to a journal reference or a recommendation, directly or indirectly (for example, if the sequence is linked to a condition, wherein the condition is linked to a journal reference or recommendation or both).
  • each of the sequences on the array is for a specific phenotype, such as a disease, or for a specific genetic testing, such as for children, for carrier information, or for cancer patients.
  • the array can have sequences wherein each sequence, or a subset of the sequences, is used to determine the pharmacogenomic profile of an organism.
  • each sequence on an array, or a subset of sequences on the array may be used to determine the risk of phenotypes, such as conditions, or carrier status or both in the panels.
  • a single array may represent multiple panels (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more) or may represent a single panel.
  • the option is also available to choose different demoninations, such as a Custom 10 Panel, which tests for 10 phenotypes or a Custom 20 Panel, which tests for 20 phenotypes.
  • Custom panels can range from one phenotype to over 1,000 phenotypes.
  • the Custom Panel may have approximately, 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 100, 150, 200, 250, 300, 400, 500, 1000 or more phenotypes, such as diseases or traits.
  • a single array (meaing any type of genetic testing array, such as microarray, massarray, genechip or beadarray) may comprise sequences used to determine the degree of risk of phenotypes, such as diseases or traits, or carrier status, or both, on a number of panels, or all of the panels.
  • the degree of risk or predisposition to the phenotypes, such as diseases or traits, or carrier status, or both on one or more panels can be determined using any platform capable of genotyping a sample, e.g., microarrays, massarrays, bead arrays, PCR-based techniques, exome sequencing, or genome sequencing including partial or full genome sequencing, such as nanopore sequencing (herein refered to as nanopores).
  • Each panel can be used to detect all the phenotypes listed for each panel or a subset of the phenotypes listed.
  • the results (120), obtained from the genetic sample, for example, obtained by microarray analysis or sequencing analysis can be sent to the central location (104), and analysis of the isolated genetic sample and generation of a raw (unanalyzed in terms of associations with phenotypes) genetic genotype profile is performed.
  • the results and statistical analysis (such as p-values, accuracy, reproducibility, reliability or any other relevant values for each of the genetic variants detected) can be transmitted at step (122), (124), or (126) to a location, for example, where an organism submitted their sample.
  • the raw genotype results and statistical analysis may then be stored, partially analyzed or fully analyzed in order to generate a genetic report (report) to present to the organism (as described further below).
  • the report, results and analysis can be transmitted securely over a network.
  • the report may not be transmitted at all over a network, but is printed in hard copy and stored in hard copy only such that no electronic version is stored.
  • an electronic version is stored, but only with an identification number (such as the CCN).
  • Three different types of reports may be generated, one for a GC, one for the physician or the person or entity that ordered the genetic profile, and one for the organism, wherein each report is tailored to each person reading the report (who that specific report was sent or given to), respectively.
  • FIG. 11A is a block diagram showing a representative example logic device through which results can be received and analyzed to generate a report.
  • FIG. 11A shows a computer system (or digital device) 800 to receive and store results, analyze the results, and produce a report of the results and analysis.
  • the computer system 800 may be understood as a logical apparatus that can read instructions from media 811 and/or network port 805, which can optionally be connected to server 809 having fixed media 812.
  • the system shown in FIG. 11A includes CPU 801, disk drives 803, optional input devices such as keyboard 815 and/or mouse 816 and optional monitor 807. (Parts 800, 801, 803, 805, 807, 811, 815 and 816 are also depicted in FIG. 11B).
  • Data communication can be achieved through the indicated communication medium to a server 809 at a local or a remote location.
  • the communication medium can include any means of transmitting and/or receiving data.
  • the communication medium can be a network connection, a wireless connection or an internet connection. Such a connection can provide for communication over the World Wide Web. It is envisioned that data relating to the present invention can be transmitted over such networks or connections for reception and/or for review by a party 822.
  • the receiving party 822 can be but is not limited to an organism, a health care provider or a health care manager.
  • a computer-readable medium includes a medium suitable for transmission of a result of an analysis of a biological sample.
  • the medium can include a result regarding analysis of an organism's genetic profile, wherein such a result is derived using the methods described herein.
  • FIG. 1 IB is a schematic of a non-limiting example of the general steps for obtaining a genetic analysis of a sample obtained from an organism; the example includes a computer system that can be used for receiving, storing, and analyzing data from genotyping, genetic testing and/or genetic analysis.
  • a sample of genetic material 904 of an organism is obtained or isolated from a biological sample of an organism (e.g. blood, hair, skin, saliva, semen, buccal cells, epithelial tissue, and various bodily tissues).
  • the genetic sample 904 may be obtained by a variety of methods known in the art.
  • raw genetic data e.g. genomic sequence, SNP profiles, etc.
  • All or a portion of the data may be input by a user interface such as a mouse 816(also described in FIG. 11A) or a keyboard 815 (also described in FIG. 11A).
  • the computer may be connected to the geno typing or genome sequencing apparatus or platform via a network port 805 (also described in FIG. 11A), or the computer may be a part of the genotyping apparatus, or the data may be input by loading of removable media 811 (also described in FIG. 11A).
  • the genetic data may be stored on removable media such as a removable disk 811 or non-removable media such as a hard disk drive or a solid state disk drive 803 (also described in FIG. 11A).
  • the data and or results may be displayed at any time on a computer display 807(also described in FIG. 11 A) such as a monitor and may also be stored or printed at any time in the form of a genetic report.
  • step 908 genetic variants associated with phenotypes are obtained from scientific literature and sent to a computer system 800.
  • the alleles or genotypes of each genetic variation or polymorphism identified from the genetic sample are then reviewed to determine whether the presence or absence of a particular allele or genotype is associated with a phenotypeof interest.
  • the genotype variants and results from the biological samples are sent to, stored, and analyzed by a computer system (or digital device) 800, which produces a report of the results and analyses of the genomic data.
  • the results and analyses may be accessed online by subscribers or their health care managers via an online portal or website as in step 910.
  • the results and analyses can be viewed online, saved on a subscriber's computer, printed, or have mailed to the subscriber or health care manager 912.
  • the organism may obtain genetic counseling or present the reports to physicians and other health professionals for personalized health management 914.
  • Genetic data such as raw genotype code or data during the analysis process, such as during the analysis of the raw genotype code and during its correlation with phenotypes, or analyzed data, such as that which may appear or does appear within the genetic report, may also be displayable through virtual reality (VR) technology.
  • VR virtual reality
  • the user who is viewing the genetic data through VR may be able to manipulate and change the genetic data, the genetic analysis, or any of the analytical processes, while being within the VR environment, either through the use of keyboard, control pad, mouse, wand or other pointing device, input device, audio and/or phonetic device(s), eye sensor that tracks the movement of the user's eye(s), tactile glove(s), or tactile suit.
  • the VR environment may be viewable on a computer screen, or through the use of goggles, eye lenes or other optics, a helmet or other headpiece, or a VR room or other enclosed space, such as a VR machine that is large enough for one or more organisms to enter, either partially or fully.
  • a Predictive Medicine Database, or other database containing genomic information may also be viewable and/or modifiable via VR, as described above. Methods and apparatus for manipulating data with VR technology in general are known in the art and are described for example in US Patent Application Publication No. 20030033150, herein incorporated by reference in its entirety. [00357]
  • the computer system can also have a database of oligonucleotides sequences as described herein.
  • the computer system can have a database with at least 2, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 500, 1000, 5000, 10000, 15000, 20000, 30000, 40000 or more oligonucleotide sequences and each of the sequences are associated with a genetic variant, such as a polymorphism.
  • the database may have a variety of optional components that, for example, provide more information about the phenotypes.
  • a computer readable medium encoded with computer executable software that includes instructions for a computer to execute functions associated with the identified genetic variants.
  • Such computer system may include any combination of such codes or computer executable software, depending upon the types of evaluations desired to be completed.
  • the computer system may also have code for linking each of the sequences to at least one phenotype, such as a condition, for example, a medical condition.
  • a condition for example, a medical condition.
  • Each medical condition in turn can be linked to at least one recommendation by a medical specialistand code for generating a report comprising the recommendation.
  • the system can have code for calculating one or more scores for a phenotype, such as a condition or trait, for an organism, one or more action scores, one or more predictive medicine risk scores or carrier status or both, one or more organ system scores, or an overall genetic health score.
  • the system can further comprise code for linking each of the sequences to at least one citation for a published journal article, such as a peer-reviewed journal article, showing the correlation between the genetic variation associated with the sequence to a phenotype, such as a condition or trait.
  • the system can also have code for conducting genetic analysis based on specific panel(s) chosen.
  • the system can also have code for one or more of the following: conducting, analyzing, organizing or reporting the results of reflex testing, as described herein.
  • the system can also have code for generating a report. Different types of reports can be generated, for example, reports based on the level of detail an organism may want or have paid for.
  • an organism may have ordered analysis for a single phenotype, such as a condition, and thus a report maycomprise the results for that single phenotype, such as a condition.
  • Another organism may have requested a genetic profile for a panel or an organ system, or another organism may have requested a comprehensive genetic profile that includes analysis of all clinically relevant genetic variants with full reflex testing.
  • the reports for each of the organisms can represent each of their requests.
  • the analysis generated can be reviewed and further analyzed by a veterinarian or researcher or persona trained in genetic analysis, or other health care specialist, or other third party, in "Post- test", for example as shown in FIG. 1.
  • This person or group of people can meet with the organism's owners, or representative, or third party to discuss the results, analysis, and/or the genetic report (such as shown in FIG. 12A-G).
  • Discussions can include information about the genetic variant(s), such as the genetic variant(s) (for example, polymorphism(s)) that is or are detected, how they can be inherited or transmitted (for example using the pedigree generated from the questionnaire), the prevalence of the genetic variant, prevalence or incidence of the phenotype, and information about the phenotype (for example, specific conditions or traits, such as medically or clinically relevant conditions), such as how the phenotype may affect the organism, results of reflex testing (as described herein), and if adverse conditions, preventative measures are associated with the genetic variants identified and analyzed or the phenotype(s) identified and analyzed or both.
  • the genetic variant(s) for example, polymorphism(s)
  • the GC or medical professional may incorporate other information, such as other genetic information or information from questionnaires in their analysis and discussion with the organism.
  • Information about the phenotype, such as condition or trait can include recommendations, such as follow-up suggestions such as further genetic counseling (FIG. 1) or predictive medicine recommendations or preventive medicine recommendations for the organism's personal physician or other healthcare provider (132).
  • Screening information such as methods of breast cancer screening, may be discussed for example if an organism is found to be at a higher risk of breast cancer.
  • Other topics that may be discussed include habit modifications and medications. For example, habit modifications may be suggested such as dietary changes and specific diet plans may be recommended or an exercise regimen may be suggested and specific exercise facilities or trainers may be referred to the organism.
  • Medications that may prevent, limit the onset or delay the progression of a phenotype, such as a disease, the organism is predisposed to, or a medication with high efficacy and low side effects may be suggested for an organism, or medications or classes of medications that an organism should avoid due to possibility of adverse reaction(s).
  • the medical professional may make an assessment of the organism's likely drug response including metabolism, efficacy and/or safety.
  • the medical professional can also discuss therapeutic treatments, such as prophylactic treatments and monitoring (such as doctor visits and exams, radiologic exams, or laboratory tests) for potential need of treatment or effects of treatment based on information from the organism's genetic profile either alone or in combination with information about the organism's non- genetic factors (such as , habits, diagnosed medical conditions, current medications, and others).
  • Additional resources may also be listed, such as including information for the organism or the organism's physician or other healthcare professional to acquire additional information about the phenotype or the genetic variant(s) or both, such as links to websites that contain information on the phenotype, such as an internal website from the company that produces the genetic report or external websites, such as national organizations for the phenotype. Additional resources may also include reference to telephone numbers, books, or organisms that the organism may seek out to acquire more information about the phenotype or the genetic variant(s) or both. [00359]
  • a report with the results and analysis can include information such as shown in FIG. 6, and be given to the organism during the consultation. Alternatively, the report, or a genetic report is depicted in FIG. 12.
  • Reports may or may not typically also include a recommendation option by a physician or other licensed medical professional.
  • an organism may choose to further consult with a medical specialist or be referred to a medical specialist.
  • Another report specific for the organism's physician (such as a 'Healthcare Professional Summary') can also be generated and given to the organism or the organism's physician such as depicted in FIG. 12E.
  • the report can contain a patient summary, recommendations that may include follow-up recommendations, screening information, modifications, alternative therapies or interventions, common misconceptions, monitoring information, family planning information, references to additional resources, medications, organ system scores(s), overall genetic health score, and a clinician summary.
  • the recommendation options may be linked to a phenotype, such as a disease or trait, and can be presented in the report.
  • an organism may have a disease for which they have either an increased or decreased risk of based on their genetic profile, and that disease is linked to a specific recommendation which is presented within the report generated for the organism.
  • Reports may also contain other information, such as habits tailored to an organism, based on the organism's genetic profile, such as during the initial round of genetic testing or analysis or ascertained through reflex testing.
  • the report for an organism's genetic profile, or Genetic Report can contain information about an organism's genotypes or phenotypes or both, as well as information directly related to that genotype or phenotype concerning preventive medicine recommendation options or intervention options or both (for example, FIG. 12A-G).
  • the analysis of the genotypic and phenotypic data can include linked analysis and inclusion in the Genetic Report of all pertinent preventive medicine recommendation options or intervention options or both.
  • adjusting certain key non-genetic factors may help to decrease the risk and incidence of the phenotype, such as disease or condition, even in those organisms found to have a genetic predisposition for that phenotype, such as disease or condition (for example, FIG. 24).
  • the genetic analysis process and the Genetic Report may link a phenotype, such as disease, risk with preventive measure options.
  • GTP Genetically Tailored Prevention
  • PMs Preventive Measures based on Preventive Medicine Recommendations or Interventions
  • GTP Genetically Tailored Prevention
  • PMs based on PMRIs can be ascertained through a review of all current literature and both published and non-published studies concerning preventive measures that are shown to decrease the incidence or progression of the disease or both, or to delay time until disease onset (allow the organism to live longer without the disease or symptoms of the disease manifesting) or decrease the morbidity or mortality related to the disease, or both.
  • Some of the PMs based on PMRI's may also be linked to specific genetic variants that increase or decrease risk for a phenotype while others may be linked to the phenotype as a whole.
  • Two or more distinct Genetic Reports can be generated from the analysis of the same organism's genetic material. For example, one genetic report may be created for the patient and another genetic report may be created for the physician who ordered the test. Other targeted Genetic Reports may be created for other third parties, such as the Department of Agriculture or other governmental agency,
  • the generation of Genetic Reports, or the genetic profiles for generating them, may be subject to different levels of service, such as for the reflex testing for ordered panel(s) or phenotype(s) or both. For instance, a low-cost service may be available whereas no reflex testing is available for any of the panel or phenotypes or both, a medium-cost service may be available where reflex testing goes only to round 2 and no further, and a high-cost service may be available where reflex testing goes through as many rounds as needed until no further reflex testing rounds exist.
  • the panels themselves may also be differentiated by price, with certain panels that analyze a greater number of genetic variants or phenotypes, for both, incurring an additional or higher fee compared with other panels that analyze a lesser number of phenotypes.
  • OP-CADI also may be a different level of service that may have an additional or different fee associated with it.
  • the level of service may be changed or altered at any time, and may incur an additional fee.
  • an organism may originally have selected the low-cost service but after reviewing their Genetic Report, they order another analysis to be conducted and Genetic Report to be compiled utilizing the same exact genotype data, or by supplying new genetic material for genetic testing and new genotyping, but this time with a high-level of service that gives results about all possible reflex testing relating to the panel or phenotypes they ordered, or both.
  • An organism's owner, or representative, or third party with a pending genetic profile or genetic report to be generated for an organism may choose at any later date to have one or more of the following added to their analysis: reflex testing, additional panels, phenotypes, genes, specific genetic variant(s), or updated analysis based on updated or more recent research and genetic variant- phenotype association data. This additional genetic analysis and Genetic Report generation may require an additional fee.
  • This additional analysis and report generation may be accomplished by utilizing the organism's raw genotype data from the original analysis or by ascertaining new genotype data by running either a stored biologic specimen (such as saliva, blood, tissue, hair, buccal tissue, such as from a buccal swab, purified DNA, etc.) or a new biologic specimen from the same organism through the genetic testing process at the laboratory.
  • a stored biologic specimen such as saliva, blood, tissue, hair, buccal tissue, such as from a buccal swab, purified DNA, etc.
  • Example 1 Genetic Profile for a Human Male Individual
  • a healthy male organism fills out a short, five minute 'Presymptomatic Genetic Testing Questionnaire' in person.
  • the questionnaire includes questions on his current medical history, his family history including any known diseases, and any medications he is currently taking. There are also questions concerning his daily habits (such as tobacco, alcohol, caffeine, and drug use) along with his current exercise regimen.
  • the completed questionnaire is reviewed by the presymptomatic genetic counselor (GC) who also may construct a genetic pedigree based on the male organism's (proband's) family history (FIG. 2).
  • the GC briefly reviews his past medical and family history and gives the organism a copy of his genetic pedigree analysis that has already been conducted on his behalf.
  • the GC tells the organism more in-depth information regarding further genetic testing services, different genetic testing options and panels available and, based on the organism's background, the GC recommends the Platinum Executive Package, also known as the Executive Panel Alpha, which analyzes thousands of genes and possible disease predispositions.
  • the proband and the GC also briefly discuss the different cut-off and threshold values to be used during his genetic analysis, and the proband decides that he wants to be told about genetic variant-phenotype associations that may not be fully replicated yet, so the GVP score cut-off is set at greater than or equal to 0.75.
  • the organism agrees on the Platinum Executive Package and signs a legal waiver.
  • the GC takes a cheek swab sample and gives the organism a Confidential Client Number (CCN).
  • CCN Confidential Client Number
  • the GC explains that his genetic data is never linked with his name or any other identifiable information except for his Confidential Client Number (CCN), in order to ensure the highest level of confidentiality.
  • CCN Confidential Client Number
  • the GC gives the client's name and the corresponding CCN to the Managing Doctor who keeps a single copy of this encrypted information linking the CCN with the client's name in a fire-safe vault that is not kept online.
  • a follow-up appointment is scheduled with the same presymptomatic GC.
  • the sample is sent to the lab by overnight currier and after the processing time to conduct the genetic material purification and genetic testing, the lab electronically transmits back to the central location and the results and recommendations based on the client's complete genetic profile are generated.
  • the recommendations are included in an enhanced report, also known as the genetic report, is printed out and reviewed by the organism's GC.
  • a managing doctor may also review and sign the report and may also discuss the results with the GC.
  • the report includes information on the relevant genetic variants and their phenotypes that have been detected, including: ADORA2A, KALRN, 8q24, VKORC1, IRF5, and LRP6.
  • Organism has a genetic change that makes his body more sensitive to caffeine and that caffeine intake, even in the morning, may be affecting his sleep quality at night. Because of this, the organism may be advised to decrease or completely avoid products containing caffeine. He may also be advised that caffeine can be a difficult substance to stop using but that if he decreases his intake over a few weeks, he should be able to wean himself off it completely. Doing so may actually make him feel more awake and alert in the long run, since his sleep quality should improve. Based on the reflex testing conducting, he is also found to not be genetically predisposed to habitual caffeine use.
  • Organism has more than a 100 times greater likelihood of having early-onset coronary artery disease than the general population's risk of early-onset coronary artery disease. Due to this increased risk, the organism may consider instituting numerous modifications. His diet may be modified to limit his intake of trans-fats (such as hydrogenated oils that exist in fried foods, cakes, cookies, and margarine). The organism may also increase his exercise regimen, for example one option is that he exercises at least three times/week for at least 20 minutes per session.
  • trans-fats such as hydrogenated oils that exist in fried foods, cakes, cookies, and margarine.
  • the organism may also increase his exercise regimen, for example one option is that he exercises at least three times/week for at least 20 minutes per session.
  • the increased likelihood of early onset coronary artery disease also should be discussed with organism's primary care physician. Increased surveillance may help monitor disease onset and progression, such as yearly cholesterol blood tests. The organism is advised to discuss with his physician other possible methods to screen for plaque build-up in his coronary arteries, such as Echocardiograms and/or Nuclear Medicine Stress Testing (such as Adenosine-Thallium Scans).
  • the organism is also advised to discuss with his primary care physician the benefits and disadvantages of once a day low dose Aspirin therapy. Aspirin therapy may help decrease the risk of heart attacks and in the organism's future. (If the organism is interested in making an appointment with a local Cardiologist, the GC or report may provide him with a referral or list of cardiologists in his community.)
  • the organism may be genetically predisposed to prostate cancer. This result should be discussed with his primary care physician. The importance of yearly screening exams for prostate cancer are made clear to the organism and he is instructed that he should always make sure to go for his annual exam and to make sure his prostate is always checked for possible warning signs of cancer or precancer. With proper screening, the impact of prostate cancer may be limited in his future, if it should develop. [00379] Alternatively, the organism may also want to discuss this finding with an Urologist, who may advise for more radical screening modalities, such as yearly blood tests and possible radiological imaging of the prostate.
  • the organism is advised that now that he is aware of this predisposition, he can be empowered over it by making sure to stay connected with a healthcare professional that may screen him regularly for this disease so that they can take prompt action if it should ever manifest.
  • VKORC1 Polymorphism in VKORC1 detected (homozygous). This specific polymorphism has been shown to be associated with sensitivity for a frequently used blood-thinning medication called warfarin (Coumadin).
  • Warfarin is an oral medication frequently used in order to thin a person's blood to either avoid or treat a history of blood clots. The organism is advised that it is very important to discuss this with his primary care physician and that he should also consider adding this information to his official medical record. If he is given warfarin at the usual dosage, then he is at a much greater risk of bleeding complications. As long as this issue is known, however, then physicians may be able to take steps to avoid any potentially harmful effects of this medication if prescribing it to the proband ever becomes necessary. For example, his physician may start the medication at a lower dose and titrate up carefully, making sure to monitor him closely to make sure his blood does not become too thin. Recent studies have also shown that concomitant application of low dose vitamin K may also significantly reduce intra-organism warfarin dose variation and the organism's physician should also consider this as an option if the proband is ever required to take Coumadin.
  • the GC and the organism finish reviewing the rest of the findings.
  • the organism's GC and the managing physician then review these six findings discussed above, along with the other findings, with the organism and discuss some of the many genes that he did not have any polymorphisms in.
  • the organism is advised that his family members may also benefit from genetic testing because they may contain the same polymorphisms that were detected in the organism or they may contain different genetic variants or different combinations of variants that may put them at risk for different diseases.
  • These recommendations are handed to the organism in a confidential envelope as an Enhanced Client Report, also known at a Genetic Report, and an Enhanced Physician's Report, also known as the Healthcare Professional Summary, for the organism to give, at his discretion, to his physician(s).
  • Example 2 Determining Predispositions and Risks to Future Human Children
  • the couple fills out a Carrier Questionnaire.
  • the questionnaire has questions on the medical history as well as the family histories and any known genetic disorders.
  • the questionnaire also asks about any specific diseases that the couple is concerned about.
  • the Carrier GC reviews both of their completed questionnaires and writes a brief pre-meeting note, and may complete a genetic pedigree.
  • the GC discusses their medical history and reviews their genetic pedigrees, discusses what can and cannot be tested and discusses the limitations of genetic testing as well as the potential insights that may be learned.
  • the GC also talks about some of the most prevalent diseases that are screened for in the various panels, such as Cystic Fibrosis and Type II Diabetes, and some possible implications if the genetic testing is positive or negative for these diseases.
  • the GC explains tests for hundreds of rare genetic disorders are available all at once and provides information about these as well.
  • the GC also explains that even though the couple is primarily interested in diseases and traits that may affect their future children, they may also find out potentially important information about themselves since it is their genetic codes that are being analyzed.
  • the couple agrees to the service and chooses the 'Complete Carrier Package', also known as the Carrier Screening Panel, that investigates hundreds of diseases and traits that the couple could potentially pass on to their child.
  • the GC also explains and reiterates that, at times, carrier genetic testing may also detect disease predispositions that may affect the couple directly and that it is important that they understand this.
  • the couple agrees and may sign a legal waiver and the GC then takes three separate cheek swabs each from the male and female and gives them their respective Confidential Client Numbers, explaining how this is an added safeguard to protect their confidential genetic information so that not even the laboratory may have access to their names.
  • the couple also discusses the cut-off values and their meaning with the GC, and chooses to have all genetic variant-phenotype associations analyzed with a GVP score equal to or greater than 0.5.
  • the couple schedules a follow-up appointment in a few days with their same GC.
  • the cheek swab specimens are packaged and shipped overnight to the lab.
  • a few days later the couple's genotype results are transmitted back to the central location and the results are further processed and analyzed to produce a report for their GC, an enhanced report (the Genetic Report) for the couple, and another enhanced report for their physicians (the Healthcare Professional Summary).
  • the GC and the managing physician may review and discuss the reports.
  • the report includes the relevant genetic variants and their phenotype associations that were detected, including for the male: genetic variants in the genes HFE, MTTL1, BMP2, and RYR1, and for the female: genetic variants in the genes HFE, MTTLl, BMP2, MTHFD1.
  • the couple meets with their same GC and the managing physician.
  • the GC tells them that they are both carriers of a genetic polymorphism in their HFE gene and that, if they each pass on these genetic variants to their child, the child may have the disease Hemochromatosis. This is an iron-storage disease and can lead to problems with the pancreas, severe liver disease and also liver cancer if not detected and treated properly.
  • the GC explains that because they each have one Hemochromatosis gene, their child has a 25% chance of being likely affected by the disease (which requires both copies of the gene to be present) or a 50% chance of being a carrier or a 25% chance of being neither a carrier nor affected.
  • the GC utilizes a Punnett Square so that the couple can visualize the information (FIG. 3).
  • the GC goes on to explain that Hemochromatosis actually has a varied degree of expressivity and penetrance and that even if their child has both abnormal genes, the disease itself may never manifest or, if it does, it may not be detrimental enough to cause any noticeable disease.
  • reflex testing determines that they both contain polymorphisms in two other genes, MTTLl and BMP2, which have both been shown to increase the risk of Hemochromatosis manifesting as a serious disease in organisms who have polymorphisms in the HFE gene, as they do. Therefore, the risk of Hemochromatosis is a possibility for their future offspring.
  • Hemochromatosis is a recessive disease, which means that both copies of the gene must be mutated in order for the disease to manifest.
  • the normal gene is usually represented by a capital “H” and the mutated gene, the gene that causes Hemochromatosis, is usually represented by a lower case "h”.
  • this Punnett Square has been simplified so that the normal gene is represented by the words “Normal Gene”, also may be represented as “Normal Allele” and the Hemochromatosis gene is represented by words “Disease Gene”, also may be represented as "Disease Allele” in FIG. 3.
  • the GC states that their HFE genetic polymorphism is actually one of the most common human polymorphisms and occurs with a carrier frequency of around 10% of the Caucasian population and a disease prevalence of approximately 1 in 300 organisms in the US (Merryweather- Clarke, A.T., J Med Genet. 1997 April; 34(4): 275-278 Dr. Hady Sfeir, "Hemochromatosis", eMedicine Article, www.emedicine.com/MED/topic975.htm, 6/2005).
  • the person can be easily monitored and, if disease manifests, treated by scheduled blood draws in order to decrease the overall iron content of blood.
  • the GC recommends that the couple review information available about Hemochromatosis and gives them information about and the web address of the American Hemochromatosis Society (www.americanhs.org).
  • the GC states that, many times organisms with these genetic variants never experience any noticeable disease but, if they do, as long as it is treated, organisms with Hemochromatosis can lead a normal life and have a normal life span. Because of this, the GC may recommend that the couple pursue a routine pregnancy (instead of other fertility options, which include in-vitro fertilization (IVF) with pre-implantation genetic diagnosis (PGD), having an egg or sperm donor, or adoption).
  • IVF in-vitro fertilization
  • PTD pre-implantation genetic diagnosis
  • the GC may have talked more about other options, such as IVF with PGD, which allows for the embryo fertilized in-vitro to be screened for the disease before it is implanted into the uterus.
  • the male organism of the couple also has a polymorphism in his RYR1 gene, which means that he is is very likely affected with malignant hyperthermia and that their children each have a 50% chance of also having this polymorphism and disease.
  • Malignant hyperthermia is a very serious disease that is triggered by general anesthesia. Therefore, it is important that the male organism inform his primary care physician that he is genetically predisposed to malignant hyperthermia so that this information can be added to his permanent medical record. He is also advised to always inform the surgeon and anesthesiologist of this predisposition if he ever needs surgery for any reason.
  • the GC explains that his primary care physician may be interested in ordering a simple blood test to measure serum creatine kinase levels, which has shown to be elevated in organisms with this specific polymorphism. All of this information is included in a report that he can give to his physician.
  • the female organism is Irish Caucasian and is found to have a homozygous polymorphism in her MTHFDl gene that has been associated with both an increased risk of having severe abruptio placentae (in Irish populations) and also with an increased risk of having a child with neural tube defects (in Italian and Irish populations).
  • the managing physician explains what abruptio placentae is and how it may threaten a pregnancy.
  • Her risk of having abruptio placentae is significantly elevated over that of the general population and therefore this is a very important predisposition that her obstetrician may find important and may need to know about.
  • the obstetrician may be able to institute measures that will actually avoid pregnancy loss if this should occur. Also, due to her having a significantly increased risk over the general population's risk of having a child with a neural tube defect, such as spina bifida, it may be very important that she begins taking daily prenatal vitamins even before she becomes pregnant, since the vitamins are most effective during the first few weeks immediately after conception. Her obstetrician may also want to be made aware of her increased risk of having a child with neural tube defects since many times this can be detected very early in the pregnancy through the use of modern ultra-sound machines and maternal blood tests.
  • the genetic counselor continues to review all the other significant findings and also goes over a condensed list of the multitude of genes that did not contain any polymorphisms and they also discuss some of the diseases that they are actually protected against, and that their children may most likely be protected against as well.
  • the GC tells them that the male organism's genes contain a genetic change that protects him against Alzheimer Disease and that the female's genes contain genetic polymorphisms that protect her against obesity and diabetes.
  • the GC gives the enhanced genetic reports to the couple, making sure to give them a copy that they can give to their primary care physician and their obstetrician.
  • the GC tells them that if they would like further genetic counseling, they can schedule that now or anytime in the future.
  • a mother has two children, a boy aged five and a girl aged two.
  • the mother is interested in a special genetic testing panel specifically for children that tests not only for diseases but also certain conditions that may influence a child's learning and development.
  • the mother schedules an appointment for herself and her two children with a Pediatric Genetic Counselor (GC).
  • GC Pediatric Genetic Counselor
  • the Pediatric GC explains to the mother the pediatric genetic testing panel can detect diseases that the children could possibly be afflicted with either now as children or later-on as adults, and also detect disorders that could impede the children's ability to learn and develop properly. For instance, if a gene for obesity is discovered then preemptive modifications such as diet, exercise, and parental oversight may greatly limit the predisposition to gain significant weight.
  • knowing that someone has a genetic predisposition for obesity may actually help that organism come to terms with their weight because it isn't fully in their control.
  • Another example discussed is a gene that controls medication metabolism and what would happen if it is abnormal. In this case, the child may not properly metabolize some medications, which could then cause very high levels of that medication in the blood and this could lead to adverse drug reactions and serious complications.
  • the mother agrees to the genetic testing and chooses to have the "Complete Pediatrics Panel", also known as Pediatric Panel Alpha, run on both of her children.
  • the GC discusses with the mother the different cut-off value options available as well as their meaning, and the mother chooses for a GVP score equal to or greater than 0.5.
  • the GC discusses the implications of allowing genetic variant-phenotype associations with lower GVP scores to be included in the analysis and the mother states that she understands and wants to proceed. The GC then takes cheek swabs of both children and gives the mother their Confidential Client Numbers.
  • the GC packages the cheek swab specimens and sends them to the lab.
  • the results are transmitted electronically and are reviewed by the GC and the managing doctor.
  • Some of the relevelent results include genetic variants, such as polymorphisms, in the genes HCRT, ACTN3, HLA-C*0602, and TIRAP detected in the daughter, and the polymorphisms CFTR, MCIR, and DRD4 detected in the son.
  • the mother returns and meets with the same GC and the managing doctor.
  • the GC first reviews the daughter' s genetic profile and states that she only has a few non- serious genetic changes.
  • the first is a polymorphism in her HCRT gene, which means that she may be predisposed to narcolepsy.
  • the GC explains the symptoms of narcolepsy include excessive sleepiness and possibly falling asleep in situations where most organisms would remain awake (such as while in class or when driving a car). Because of this, the mother should be aware that if her daughter is having difficulty in school or ever shows signs of excessive sleepiness, this could actually be a treatable medical condition and that the daughter should then see a sleep specialist (the GC can refer them to or may give them a list of qualified sleep medicine physicians in their community, if necessary).
  • the daughter possesses a genetic polymorphism in the ACTN3 gene that has been associated with exceptional athletic performance.
  • This specific genetic polymorphism promotes much more efficient aerobic muscle metabolism that may allow the daughter to perform physical activities, such as running and swimming, for much longer continuous periods of time (estimated at 33% in some studies) without reaching exhaustion.
  • This polymorphism has been found to be overrepresented in endurance athletes around the world. Because of this, the mother may want to encourage her daughter to participate in endurance-related sports and athletic programs both at school and during the summer.
  • the GC explains that the daughter contains a specific form of HLA-C, known as *0602, and that this genetic marker has been associated with a very significant increased risk of early-onset psoriasis.
  • This genetic predisposition is important for the mother to be aware of since psoriasis is a condition that is usually treatable by a dermatologist.
  • Her daughter can receive the proper care right at the onset if the disease manifests, rather than at a later time when emotional and psychological stress may have had a significant impact upon the child.
  • the dermatologist may also be more likely to treat the problem more aggressively right at the onset since her daughter is known to be genetically predisposed to it.
  • the managing doctor describes the symptoms of psoriasis and states that there are many different types of treatments available if the disease should manifest.
  • the daughter has a polymorphism in her TIRAP gene. This polymorphism has recently been shown to confer protection against infectious diseases, such as invasive pneumococcal disease. Because of this, she may actually find that she is more resistant to serious infections than most organisms are.
  • the son is a carrier of a cystic fibrosis genetic polymorphism. However, he most likely has one normal gene since only a single genetic polymorphism is detected, so he will most likely not be affected by this disease.
  • any melanoma that develops may be detected and removed from his body very quickly.
  • Increased monitoring due to a known genetic predisposition has the potential to greatly limit the morbidity and high mortality of this disease. If his predisposition to melanoma was not known, then a suspicious lesion may have been discovered either months or years after it developed, which may then necessitate radical surgery with resultant physical deformity and also a high likelihood of metastatic disease (even after surgical removal) and possibly death.
  • the GC notes that while the vast number of genes screened for were all normal, the son does have another change in his DRD4 gene, which may predispose to attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • the GC describes the symptoms of this disease, stating that some children who have ADHD have significant learning difficulties until this disease is diagnosed and properly treated.
  • the GC states that if behavorial or learning issues arise, the son may benefit from seeing a psychiatrist who specializes in ADHD (and the GC can recommend the a list of names of child psychiatrists in her community, if needed). With proper oversight and treatment, it is very likely that the son may do just fine in school if it is found that his trouble concentrating and learning new material is due to this disorder.
  • the GC gives the mother a copy of the results and recommendations for both children, as well as referrals to a dermatologist and a pediatric psychiatrist. Additional copies of the reports are included for these doctors and also for the children's pediatrician. The mother is told that the GC would be happy to discuss these results with any of the doctors if they have any questions.
  • An organism has intense pain with breastfeeding her child and wants to switch to formula. Before switching she wants to determine whether breastfeeding may increase her baby's IQ level.
  • a single gene, such as the breastfeeding intelligence gene is tested for in the baby by having a managing physician or the child's pediatrician roll a small q-tip-like swab on the inside of the baby's cheek to obtain a genetic sample.
  • the baby is found to contain the gene that may increase her intelligence only if she is breastfed.
  • the physician also states that they can refer the mother to a nurse who specializes in breastfeeding and may be able to assist with some techniques to make it less painful, if the mother decides to continue with breastfeeding.
  • the following example utilizes the multiplicative model but any algorithm known in the art may also be utilized instead of the multiplicative model, such as the additive model.
  • the Greek letters ⁇ , ⁇ , and y is used to represent different alleles.
  • these Greek letters may represent nucleotides (adenine, cytosine, guanine, or thymine), such as with single nucleotide polymorphisms where, for example, a may represent a cytosine, ⁇ may represent a thymine, and ⁇ may represent an adenine.
  • the Greek letters ⁇ , ⁇ , and ⁇ may represent alleles of any other type of genetic variant, such as insertions and deletions, for example where a may represent the insertion and ⁇ may represent the deletion, or for copy number variations, where a may represent 1 copy, ⁇ may represent 2 copies, and y may represent 3 copies.
  • the Greek letters are used to represent the different possible alleles of any type of genetic variant, such as any type of mutations, SNPs, DIPs, CNVs, translocations, repeats, etc.
  • genetic variants are biallelic, meaning that there are two possible alleles (Allele a and Allele ⁇ ) and therefore three possible genotypes: ⁇ , ⁇ , ⁇ . At times, however, genetic variants may have more than two possible alleles.
  • triallelic genetic variants have three possible alleles (Allele a, Allele ⁇ , and Allele ⁇ ) and therefore six possible genotypes: ⁇ , ⁇ , ⁇ , ⁇ , ⁇ .
  • This can be expanded out to include as many alleles and genotype combinations as is necessary to capture all the possible variations at a specific genetic variant. Therefore, while many times there are usually just two alleles and three possible genotypes, there can also be three alleles and six possible genotypes, and there can also be more than three alleles and more than six possible genotypes.
  • the following example considers the scenario where two genetic variants and their genotypes have been detected through genetic testing that are associated with risk for phenotype X. While two genetic variants are utilized in this example to convey the application of the algorithm to multiple independent and relevant genetic variants associated with risk for the same phenotype, any number of genetic variants may be used and this algorithm is applicable to any number of genetic variants.
  • a and B are detected that are associated with phenotype X, and the genotypes for these two genetic variants are associated with risk for phenotype X.
  • results from genetic testing yield the following raw genotypic data for the genetic variants:
  • ⁇ , ⁇ , ⁇ , and ⁇ are meant to represent different alleles and, as stated above, they can represent any type of allelic variant, such as a nucleotide, an insertion or deletion, a copy number variation, etc.
  • Genetic variants A and B are distinct and represent separate genetic variants that are both associated with and relevant for phenotype X. For example, if genetic variants A and B are both SNPs, genetic variant A's a may represent a cytosine and genetic variant A's ⁇ may represent a thymine while genetic variant B's ⁇ may represent a thymine and genetic variant B's ⁇ may represent a guanine.
  • genetic variant A having the ⁇ genotype means it is heterozygous for its two alleles and genetic variant B having the ⁇ genotype means it is homozygous for one of its alleles.
  • genotype detected ⁇ - ⁇ risk value ⁇ ⁇ for phenotype X
  • risk values for the genetic variants alleles or genotypes are given as RRs, then skip to step 2. If the risk value for either or both of the genetic variants and their alleles or genotypes are given as ORs, then proceed to step 1.
  • ORs (ORA aa , ORA ap , ORA pp )
  • Step 2 Assess allele or genotype frequencies from matched reference population for the allele or genotypes of genetic variants A and B
  • Genotype Frequency (GF) of genetic variant A GFA aa , GFA ⁇ , ⁇ ⁇
  • Genotype Frequency (GF) of genetic variant B ⁇ , GFB Y g, GFBgg
  • Step 3 Calculate Cumulative Generic Population Risk Load (GPL)
  • Step 4 Calculate the organism's Proband Risk Load (PRL) [00445]
  • Step 5 Calculate the Cumulative Genetic Risk (CGR)
  • Step 6 Calculate the Predictive Medicine Risk (PMR)
  • the upper bound for the PMR of multifactorial phenotypes may be set at an upper limit, such as 95%, as these phenotypes may not be fully determined by genetic factors alone.
  • the lower bound for the PMR of multifactorial phenotypes may be set at a lower limit, such as 0.0001%, as these phenotypes may not be fully determined by genetic factors alone.
  • a raw polymorphism data chart for the organism is generated (for example, Table 13).
  • the SNP-Disease Coefficient Rating also known as the GVP score, is obtained by analyzing studies determining the correlation between a genetic variant, such as a SNP, and a phenotype, such as a disease or trait.
  • SDCR SNP-Disease Coefficient Rating
  • GVP GVP score
  • the Generic Absolute Risk also known as the GLR
  • CGR Cumulative Genetic Risk
  • CGR Cumulative Genetic Risk
  • HapMap data for the referenece population such as CEU HapMap data for a Caucasian or European American population
  • genotype frequencies for each of the two alleles (Allelel and Allele2) or each of the three genotype possibilities (Allelel/Allelel, Allelel/Allele2, and Allele2/Allele2) as there are usually three genotype possibilities, such as with biallelic SNPs, although there may be more genotype possibilities, such as with triallelic SNPs, as discussed in Example 5, for each of the genetic variants can be ascertained and these may then be multiplied by the risk value (RV), such as relative risks, for each of the respective allele or genotypes for that same genetic variant and specific phenotype, such as disease, association and these values (taking into account all the possible allele or genotypes, the frequency in the population for each allele or genotype added or multipled, depending on whether an additive or multiplicative or other methodology is used, by the allele or genotype risk value for each of the genetic variant's all
  • the odds ratios may be converted to relative risks first and then either added together or multiplied together as before, again depending on whether the additive or multiplicative methodology is utilized. If no risk value (NRV) is available, a placeholder risk can be assigned by a physician or genetic counselor or bioinformatics specialist analyzing the organism's genetic profile.
  • NMV risk value
  • a Predictive Medicine Risk can be determined by, in one iteration, relating back to the previous models multiplying the GAR, also referred to as the GLR, by the CGR or in another iteration methodology relating back as stated by adding the GAR, also referred to as the GLR, with the CGR depending on the methodology, GAR, prevalence, and incidence of the specific multifactorial phenotype, such as disease, that is being analyzed at that time.
  • a Clinical Significance Rating can also be determined, where 0 would indicate no clinical use, 1 would indicate limited clinical significance, value, or use, 2 would indicate moderate clinical significance, 3 would indicate very useful in a clinical setting, where a medical professional would likely find the result valuable, and 4 would indicate extreme clinical significance, possibly relating to a life-threatening condition.
  • the DIR, or Disease and Trait Impact Rating also referred to as the PIR, indicates the severity of a phenotype that is correlated with a genetic profile.
  • the DIR ranges from -3 to +3, where -3 causes sudden death or debilitating disease, -2 indicates a serious disease, a disease or condition that is difficult to cure, may cause death, or has significant negative life consequences, -1 indicates a condition that is usually manageable, 0 is a neutral condition or trait, +1 a slightly positive impact; +2 is a helpful trait, and +3 is a provides a significant advantage to the organism.
  • the CGR Multiplier and PMR (Predictive Medicine Risk) or NRV (No Risk Value) Multiplier is chosen (see for example FIG. 9), as is the CSR (Clinical Significance Rating) and the DIR (Disease and Trait Impact Rating also known as the Phenotype Impact Rating or PIR) and the NMF (Notice Me Factor).
  • the Action Score (AS) may be determined by multiplying the SDCR, CGR Multiplier, PMR or NRV Multiplier, CSR and DIR or by multiplying the CSR, DIR, and NMF, or the CSR, PIR, and NMF.
  • the Cumulative Action Score may be determined by adding all the AS's for all of the phenotypes, such as diseases or traits, that fall under the same organ system, which may also be identified by medical specialty and then dividing by the total number of AS's, The Cumulative Action Score may therefore be the average action score for that organ system, which can also be identified by medical specialty.
  • Each of the organism AS's is already weighted in terms of clinical significance, degree of phenotype benefit or harm, and significance of the change in risk, as previously discussed.
  • a chart for scores by organ system and an overall genetic health score can be used, such as shown in FIG. 10.
  • the Cumulative Action Score (CAS) can be filled in for more than one organ system and determined for an organ system.
  • the organ system score or Indicator of Genetic Health of an Organ System can be indicated by a color.
  • Red would be used for scores less than -10, indicating highly important to discuss with client and may be highly important for client to follow-up with their physician or specialist based on this information, pink can be used for scores between -1 to -10 to indicate moderately important risk, green can be used for scores of 0 to indicate no pertinent deleterious or protective information discovered although organ system was accessed, blue can be used for scores between +1 to +10, to indicate moderately important protection, gold can be used for scores >+10 indicating very beneficial protection, and no color can be used for an Organ System or Medical Specialty if it was not accessed.
  • the overall genetic health score can be determined, as described above, by adding all the CAS, which may be used as an indicator for genetic wellness and is also represented by a color as is the Indicator of Genetic Health of an Organ System, and dividing by the total number of CAS's, as previously described
  • Chemotherapeutic Drugs Etoposide, Mitoxantrone, Amsacrine, and
  • SNP- Disease Coefficient Polymorphisms not detected in RAD51 & XRCC3

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Abstract

La présente invention concerne des procédés permettant de générer des profils ou des analyses génétiques, y compris des procédés pour mener des tests et/ou des analyses génétiques, dynamiques, complets. La présente invention porte également sur des procédés de détermination de scores de santé génétique pour des phénotypes spécifiques ainsi que pour des organes, pour certaines spécialités et pour la santé en général.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013028739A1 (fr) * 2011-08-25 2013-02-28 Complete Genomics Phasage de loci hétérozygotes pour déterminer des haplotypes génomiques
US8620594B2 (en) 2009-10-20 2013-12-31 Genepeeks, Inc. Method and system for generating a virtual progeny genome
WO2014068195A1 (fr) * 2012-11-01 2014-05-08 Genoscoper Oy Procédé et dispositif permettant de déterminer des caractéristiques d'un mammifère
WO2015063376A1 (fr) * 2013-11-04 2015-05-07 Medisapiens Oy Procédé et système permettant d'évaluer la santé génomique
WO2015085326A1 (fr) * 2013-12-07 2015-06-11 Brandon Colby Système et procédé de personnalisation en temps réel utilisant des données génomiques d'une personne
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US9524369B2 (en) 2009-06-15 2016-12-20 Complete Genomics, Inc. Processing and analysis of complex nucleic acid sequence data
US20170032080A1 (en) * 2013-12-19 2017-02-02 Genoscoper Method and arrangement for matching mammals by comparing genotypes
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000007252A (ko) * 1998-07-01 2000-02-07 윤종용 네트워크 접속 프로그램
KR100314666B1 (ko) * 2000-07-28 2001-11-17 이종인 게놈족보 및 가계 유전정보 제공 방법과 시스템
US6730023B1 (en) * 1999-10-15 2004-05-04 Hemopet Animal genetic and health profile database management
US20040091933A1 (en) * 2001-07-02 2004-05-13 Roland Stoughton Methods for genetic interpretation and prediction of phenotype
US20080131887A1 (en) * 2006-11-30 2008-06-05 Stephan Dietrich A Genetic Analysis Systems and Methods
WO2009117122A2 (fr) * 2008-03-19 2009-09-24 Existence Genetics Llc Analyse génétique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000007252A (ko) * 1998-07-01 2000-02-07 윤종용 네트워크 접속 프로그램
US6730023B1 (en) * 1999-10-15 2004-05-04 Hemopet Animal genetic and health profile database management
KR100314666B1 (ko) * 2000-07-28 2001-11-17 이종인 게놈족보 및 가계 유전정보 제공 방법과 시스템
US20040091933A1 (en) * 2001-07-02 2004-05-13 Roland Stoughton Methods for genetic interpretation and prediction of phenotype
US20080131887A1 (en) * 2006-11-30 2008-06-05 Stephan Dietrich A Genetic Analysis Systems and Methods
WO2009117122A2 (fr) * 2008-03-19 2009-09-24 Existence Genetics Llc Analyse génétique

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US10916332B2 (en) 2009-10-20 2021-02-09 Ancestry.Com Dna, Llc Methods and systems for generating a virtual progeny genome
US8620594B2 (en) 2009-10-20 2013-12-31 Genepeeks, Inc. Method and system for generating a virtual progeny genome
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US9679103B2 (en) 2011-08-25 2017-06-13 Complete Genomics, Inc. Phasing of heterozygous loci to determine genomic haplotypes
US8880456B2 (en) 2011-08-25 2014-11-04 Complete Genomics, Inc. Analyzing genome sequencing information to determine likelihood of co-segregating alleles on haplotypes
WO2013028739A1 (fr) * 2011-08-25 2013-02-28 Complete Genomics Phasage de loci hétérozygotes pour déterminer des haplotypes génomiques
JP2016500888A (ja) * 2012-11-01 2016-01-14 ゲノスコーペル オサケユイチア 哺乳類の形態を決定するための方法及びアレンジメント
WO2014068195A1 (fr) * 2012-11-01 2014-05-08 Genoscoper Oy Procédé et dispositif permettant de déterminer des caractéristiques d'un mammifère
WO2015063376A1 (fr) * 2013-11-04 2015-05-07 Medisapiens Oy Procédé et système permettant d'évaluer la santé génomique
EP3066603A4 (fr) * 2013-11-04 2017-08-02 MediSapiens Oy Procédé et système permettant d'évaluer la santé génomique
WO2015085326A1 (fr) * 2013-12-07 2015-06-11 Brandon Colby Système et procédé de personnalisation en temps réel utilisant des données génomiques d'une personne
JP2017510892A (ja) * 2013-12-07 2017-04-13 シーケンシング．コム 個人のゲノムデータを使用するリアルタイムパーソナライズシステムおよび方法
US20170032080A1 (en) * 2013-12-19 2017-02-02 Genoscoper Method and arrangement for matching mammals by comparing genotypes
US20200294672A1 (en) * 2014-06-09 2020-09-17 Georgetown University Automatic re-analysis of genetic testing data
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