WO2008088343A1 - Procedes de fourniture de service d'evaluation d'etat de sante individualise - Google Patents

Procedes de fourniture de service d'evaluation d'etat de sante individualise Download PDF

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Publication number
WO2008088343A1
WO2008088343A1 PCT/US2007/001567 US2007001567W WO2008088343A1 WO 2008088343 A1 WO2008088343 A1 WO 2008088343A1 US 2007001567 W US2007001567 W US 2007001567W WO 2008088343 A1 WO2008088343 A1 WO 2008088343A1
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antibody
biomarkers
biomarker
condition
consumer
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PCT/US2007/001567
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English (en)
Inventor
Mark B. Chandler
George Rodgers
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Biophysical Corporation
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Priority to PCT/US2007/001567 priority Critical patent/WO2008088343A1/fr
Publication of WO2008088343A1 publication Critical patent/WO2008088343A1/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
    • G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H15/00—ICT specially adapted for medical reports, e.g. generation or transmission thereof
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

  • This invention generally relates to methods for providing individualized health assessment service.
  • the present invention provides a method for providing a Health Assessment Service (HAS).
  • HAS Health Assessment Service
  • the method can be practiced by marketing the HAS to a consumer, initiating the HAS with the consumer, obtaining information and a bi ⁇ sample from the consumer, subjecting the biosample to one or more biomarker test panels, evaluating the results of the test panel or panels, generating a report for the customer containing the results and evaluation, and/or consulting with the consumer regarding the results and evaluation.
  • the present HAS invention is advantageous in one respect in that it allows individuals direct and convenient access to a comprehensive assessment of their total health picture, which is heretofore prohibitively impractical, time consuming, costly, or altogether unavailable.
  • the present invention has as another advantage in that it screens for numerous biomarkers that may indicate the presence of many medical conditions and diseases, such as cancer, cardiovascular disease, metabolic disorders, autoimmune disease, viral and bacterial diseases, and hormonal imbalance.
  • biomarkers whose affects on health are broadly recognized
  • the HAS tests biomarkers whose effects or implications in health are recognized by clinical specialists and medical and scientific researchers.
  • the present invention has as another advantage that it allows an individual consumer of the HAS and/or the individual's personal physician to monitor changes and trends in blood chemistry over time.
  • the present invention has as yet another advantage that a medical team reviews the results of the biomarker tests and provides a consultation with the individual consumer and/or the individual consumer's personal physician regarding the meaning and • implications of the test results.
  • the present invention has still another advantage in that an understandable report is generated for the consumer, which comprises color codes and flagged biomarkers that are found to be present in levels different than those found in the normal population and therefore possibly indicative of a medical condition, a possible onset of a medical condition, or a predisposition to a medical condition that the consumer will want to seek additional diagnosis of, treatment for, or closer monitoring.
  • HAS Health Assessment Service
  • a marketing function that brings to the attention of potential consumers an ability to purchase an individualized health assessment service
  • a testing function that obtains one or more test samples taken from a consumer who has elected to purchase the service, which one or more samples are subjected to one or more test panels, each of said one or more test panels comprising qualitative and/or quantitative tests for the presence or absence of a plurality of biomarkers in said one or more samples;
  • a method of providing a Health Assessment Service comprising: (i) soliciting one or more consumers who might be interested in purchasing an individualized health assessment service;
  • test panels comprising qualitative and/or quantitative tests for the presence or absence of a plurality of biomarkers in said one or more samples
  • a method of diagnosing a condition selected from the group consisting of autoimmune disorder, cancer, cardiovascular disease, disease and repair associated with cell signaling, diabetes, endocrine condition, hematological abnormality, hormonal imbalance, immune reaction/inflammation, infectious disease, metabolic disorder, malnutrition, impaired organ function, and osteoarthritis in a . patient comprising (a) measuring levels of biomarkers in a test panel comprising one or more of biomarkers in a first sample from a patient at a first time, wherein the biomarkers are associated with the condition;
  • FIG. 1 is a block diagram depicting the steps involved in the method of providing the Individualized Health Assessment Service.
  • the method begins with acquiring customers via marketing, promoting, word of mouth, and branding.
  • the method continues with the customer initiating the purchase of the service and providing to the provider of the service information necessary to create a customer profile.
  • the customer submits to the provider necessary documents, including a Medical History Questionnaire and an Informed Consent Form.
  • the customer arranges a time and place to provide a biosample. For instance, the customer's blood sample is obtained and sent to a laboratory, preferably, the provider's laboratory, for testing. Results of the biomarker testing are analyzed by a medical team and a hard copy report is generated and sent to the customer.
  • the customer then consults with the provider's medical team regarding the test results and implications.
  • the present invention involves marketing the service to consumers, typically outwardly healthy or asymptomatic consumers, testing a panel of biomarkers on a sample of the consumer's blood, evaluating the test results, and reporting the results and evaluation to the consumer.
  • the marketing function comprises reaching potential consumers directly via internet or other advertising means that do not typically involve communicating through consumers' physicians, although word of mouth referrals are not precluded. Consumers who might be interested in purchasing an individualized health assessment service (“HAS”) are so solicited.
  • HAS individualized health assessment service
  • the testing function comprises obtaining one or more biological (e.g., whole blood, plasma, serum or urine and the like) samples taken from a consumer who has elected to purchase the HAS.
  • the blood or other sample may be collected at a location specified by the consumer, such as at a health clinic or at the consumer's residence.
  • the blood sample is carefully collected by a phlebotomist, nurse, or other trained health professional affiliated with, designated by, or approved by the provider of the HAS ("HAS Provider").
  • blood includes any blood fraction, for example serum, that can be analyzed according to the methods described herein.
  • Serum is a standard blood fraction that can be tested, and is tested in the Examples below.
  • the blood levels of a biomarker can be presented as 50 pg/mL serum.
  • the testing function further comprises the consumer completing a confidential Medical History Questionnaire ("Questionnaire").
  • the Questionnaire supplies the HAS Provider with important information about the consumer's current state of health, medical history, and family medical history.
  • the Questionnaire and biological sample may be submitted to the HAS Provider simultaneously or independently.
  • the testing function further comprises the consumer completing an Informed Consent Form.
  • the Informed Consent Form apprises the consumer of his or her rights regarding the confidentiality of personal and medical data.
  • the Informed Consent Form also apprises the consumer of the procedures involved in the HAS 5 what are the limitations of the HAS, what are the risks of the HAS, and what are the alternatives to the HAS.
  • the Informed Consent Form is to be completed preferably prior to the time the consumer's biological sample is scheduled to be collected.
  • biomarkers useful to include as part of a broad assessment of one's personal health status.
  • the majority of the following biomarkers are known to exist within a particular range of concentrations or levels in individuals from a basically healthy, asymptomatic, middle-aged population ("normal" individuals).
  • Each of those biomarkers is further known to be relevant to the biochemistry, pathology, diagnosis, or treatment of, or the risk for, one or more medical conditions if the biomarker is present at a concentration significantly outside the range at which it is present in normal individuals.
  • concentration ranges presented represent merely exemplary examples of what may constitute normal ranges for these biomarkers and should not be construed as limiting what can be designated as normal • ranges in the present or other assays.
  • the remaining of the following biomarkers are normally absent from an individual's biosample.
  • the presence of a detectable concentration of each of those biomarkers is known to be indicative of exposure to and contraction of certain infectious agents, for example viruses, and the possible presence of certain associated medical conditions.
  • Table 1 Analytes Included in Health Assessment Service
  • a "normal" test result for each biomarker is typically defined to include biomarker levels that fall within the range of concentrations seen in normal, healthy individuals, as well as biomarker levels that fall within a set number of standard deviations of the range of concentrations seen in normal individuals.
  • the preferred embodiment further comprises adjusting for each biomarker the standard deviation criteria that define a normal test result. For example and without limitation, where defining a normal test result as being within only one standard deviation of the range of concentrations seen in normal individuals would yield a number of positive indications that is too high based on the known incidence in the general population of a medical condition associated with the biomarker, the definition of a normal test result may be adjusted to include biomarker levels within two standard deviations of the range of concentrations seen in normal individuals, so as to reduce the number of false positives.
  • the preferred embodiment also comprises adjusting for each biomarker the standard deviation criteria that define a normal test result such that the non- incorporated results does not have to be equally divided between above the range and below the range.
  • a "normal” test is defined with, respect to changes in serial results, as discussed below.
  • a "normal" test result for each biomarker can be defined to include biomarker levels that do not necessarily fall within the range of concentrations seen in normal, healthy individuals, as well as biomarker levels that fall within a set number of standard deviations of the range of concentrations seen in normal individuals.
  • a significant change in serial results in a level of a biomarker can indicate a positive diagnosis of a condition or that more investigation is needed, even though the level of the biomarker is within a range of concentrations seen in normal, healthy individuals.
  • Changes in serial results from an individual can occur because of pre-analytical, analytical, within-subject biological variation, and changes in a condition of a patient.
  • a change in a condition such as change in levels of biomarkers over time, can be compared to the variation due to analytical variation (CV A ) and within-subject biological variation (CVw)- Analytical variation (CVA) and within-subject biological variation (CVw) can be calculated into a reference change value (RCV).
  • CV A analytical variation
  • CVw within-subject biological variation
  • CVA within-subject biological variation
  • RCV reference change value
  • Pre-analytic variation occurs before the analytical phase of generation of observed value.
  • the sources of variation can be divided into two types: factors that affect the individual before specimen collection occurs and factors inherent in the collection and handling of the specimens.
  • Pre-analytic variation can be minimized by adoption of strict protocols for sample patient preparation, and sample collection, transport, and handling.
  • CV- A is analytic precision obtained from internal quality control at the appropriate clinical decision making level and is commonly available for analytes in laboratories.
  • Analytical variation can be expressed as the weighted mean of variances from the data. After obtaining raw data, CVA can be calculated with analysis of variance. Optionally, presence of outliers in the raw data is evaluated before analysis of variance is applied to calculate analytical variation.
  • Analytical variation can be minimized by setting internal quality control and evaluation of laboratory performance.
  • Analytical characteristics that are taken into account are imprecision and change in bias.
  • Imprecision is random error and is defined as the closeness of agreement between independent results of measurements obtained under stipulated conditions.
  • imprecision is determined by replicate analysis and the dispersion calculated as standard deviation (SD) or coefficient of variation (CV).
  • Bias is systematic error and is defined as the difference between the expectation of measurement results and the true value.
  • bias is the difference between observed values and some estimate of the true value. Changes in bias can be a source of variation in serial results: these can be caused by re-calibration of methodology, lot-to-lot variation in commercial calibrants, and lot-to-lot variation in reagents.
  • CVw is mean within-subject biological variation that can be calculated for certain conditions or can be taken from comprehensive literature. (Fraser CGF (2001) Biological variation: from principles to practice. AACC Press, Washington DC; Ricos C, et al. (1999) Scand J. Clin Lab Invest 59:491; Ricos C, et al. http://westgard.com/guestl7.htm; all of which are herein incorporated by reference in their entirety.) After obtaining raw data, CVw can be calculated with analysis of variance.
  • Biological variation can be described as random around a homeostatic setting point. Data for biological variation can be generated with more than one sample obtained from each of a small cohort of subjects rather than a single sample obtained from a large number of subjects.
  • ⁇ " A is 1.414.
  • Bidirectional Z score is found in standard statistical tables. Most often, 1.96 is used as significant, that is, P ⁇ 0.05 (95% confidence level), and 2.58 is used for highly significant, that is, P ⁇ 0.01 (99% confidence level). Other values can be used for bidirectional Z score aligned with other confidence values.
  • the RCVs can be used to point out results on reports and to invoke verification by professionals.
  • a "normal" test result for each biomarker can be defined with respect to RCV.
  • a significant change in serial results in a level of a biomarker can indicate a positive diagnosis of a condition or that more investigation is needed, even though the level of the biomarker is within a range of concentrations seen in normal, healthy individuals.
  • embodiments provide for a method of producing a reference change value for a biomarker comprising (a) obtaining levels of the biomarker from a population of at least 20 healthy individuals at least five times from each individual;
  • RCV reference change value
  • percentage change in (c) that is lower than the reference change value indicates a decreased possibility of a presence of the condition in the patient.
  • a possibility of a presence of the condition is a positive diagnosis of the condition.
  • a decreased possibility of a presence of the condition is a negative diagnosis of the condition.
  • the condition is selected from the group consisting of autoimmunity, cardiovascular disease, cancer, cell signaling, diabetes, endocrine function, • hematology, immunity/inflammation, infectious disease, nutrition, organ system function, and osteoarthritis.
  • specimens are then stored in conditions that ensure stability; • when specimens have been collected, they are prepared for examination by thawing and mixing for example, and then they are examined in random duplicate in a single analytic batch;
  • Table 2 shows within-subject biological variation of certain analytes. These values can be used to calculate RCVs. Table 2
  • Biomarkers are naturally occurring substances that can signal disease or indicate conditions when found at concentrations different from levels in normal healthy individuals or change significantly within an individual.
  • the biomarkers in Tables 1 and 2 can be grouped into panels based on their association with certain diseases and organ system functions. These panels include biomarkers specific for conditions such as autoimmunity, cardiovascular disease, cancer, cell signaling, diabetes, endocrine function, hematology, immunity/inflammation, infectious disease, nutrition, organ system function, and osteoarthritis.
  • a panel for a condition comprises at least 1 biomarker associated with the condition.
  • a panel for a condition comprises at least 2, 2 or more, 5, 5 or more, 10, or 10 or more biomarkers associated with the condition.
  • a practitioner runs a panel for the condition with at least one biomarker associated with the condition resulting in positive diagnosis for the biomarker.
  • a practitioner runs a panel for the condition with at least 2 biomarkers associated with the condition resulting in positive diagnosis for one or two biomarkers.
  • a practitioner runs a panel for the condition with at least 5 biomarkers associated with the condition resulting in positive diagnosis for 1, 2, 3, 4, or 5 biomarkers.
  • a practitioner runs a panel for the condition with at least 10 biomarkers associated with the condition resulting in positive diagnosis for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 biomarkers.
  • B-type natriuretic peptide endothelin 1 lipoprotein (a) myeloperoxidase antibody myoglobin plasminogen activator inhibitor type 1 proliferating cell nuclear antigen antibody proteinase 3 antibody .
  • Cortisol follicle stimulating hormone growth hormone luteinizing hormone prolactin thyroid stimulating hormone calcium parathyroid hormone phosphorus thyroglobulin antibody thyroid microsomal antibody thyroid stimulating hormone thyroxine thyroxine binding globulin triiodothyronine calcitonin thyroglobulin antigen thyroxine antibody triiodothyronine antibody dihydroepiandrosterone sulfate estradiol
  • Herpes simplex virus types 1 and 2 antibodies human papilloma virus antibody human T-cell lymphotropic virus types 1 and 2 antibodies influenza A antibody influenza B antibody mumps antibody parainfluenza type 1 antibody parainfluenza type 2 antibody parainfluenza type 3 antibody polio antibody respiratory syncytial virus antibody
  • Analyte levels can be measured using an immunoassay such as an ELISA or a multiplexed method as described below, and in more detail by Chandler et al., U.S. 5,981,180 (Luminex Corporation).
  • the analytes "used in the method of the invention can be detected, for example, by a binding assay.
  • binding reagent and like terms, refers to any compound, composition or molecule capable of specifically or substantially specifically (that is with limited cross- reactivity) binding another compound or molecule, which, in the case of i ⁇ nmune- recognition is an epitope.
  • the binding reagents typically are antibodies, preferably monoclonal antibodies, or derivatives or analogs thereof, but also include, without limitation: Fv fragments; single chain Fv (scFv) fragments; Fab' fragments; F(ab')2 fragments; humanized antibodies and antibody fragments; camelized antibodies and antibody fragments; and multivalent versions of the foregoing.
  • Multivalent binding reagents also may be "used, as appropriate, including without limitation: monospecific or bispecific antibodies, such as disulfide stabilized Fv fragments, scFv tandems ((scFv)2 fragments), diabodies, tribodies or tetrabodies, which typically are covalently linked or otherwise stabilized (i.e., leucine zipper or helix stabilized) scFv fragments.
  • Boding reagents also include aptamers, as are described in the art. [0037] Methods of making antigen-specific binding reagents, including antibodies and their derivatives and analogs and aptamers, are well-known in the art. Polyclonal antibodies can be generated by immunization of an animal.
  • Monoclonal antibodies can be prepared according to standard (hybridoma) methodology.
  • Antibody derivatives and analogs, including humanized antibodies can be prepared recombinantly by isolating a DNA fragment from DNA encoding a monoclonal antibody and subcloning the appropriate V regions into an appropriate expression vector according to standard methods.
  • Phage display and aptamer technology are described in the literature and permit in vitro clonal amplification of antigen-specific binding reagents with very low affinity and cross- reactivity.
  • Phage display reagents and systems are available commercially, and include the Recombinant Phage Antibody System (RPAS), commercially available from Amersham Pharmacia Biotech, Inc. of Piscataway, NJ.
  • RPAS Recombinant Phage Antibody System
  • immunoassays refer to immune assays, typically, but not exclusively to any one assay, capable of detecting and quantifying a desired blood biomarker, namely at least one of the analytes listed in Table 1, or any combination thereof.
  • binding reagents typically antibodies — the first binding reagent/antibody being attached to a surface and the second binding reagent/antibody comprising a detectable group.
  • detectable groups include, for example and without limitation: fhiorochromes, enzymes, or epitopes for binding an additional binding reagent (for example, when the second binding reagent/antibody is a mouse antibody, such an epitope is detectable by an additional fluorescently labeled anti-mouse antibody), such as an antigen or member of a binding pair, such as biotin.
  • the surface may be a planar surface, such as in the case of a typical grid-type array (for example, but without limitation, 96-well plates and planar microarrays), as described herein, or a non-planar surface, as with coated bead array technologies, where each "species" of bead is labeled with, for example, a fluorochrome (such as the Luminex technology described herein and in U.S. Pat. Nos. 6,599,331 , 6,592,822, and 6,268,222), or quantum dot technology (for example, as described in U.S. Pat. No. 6,306,610).
  • a fluorochrome such as the Luminex technology described herein and in U.S. Pat. Nos. 6,599,331 , 6,592,822, and 6,268,222
  • quantum dot technology for example, as described in U.S. Pat. No. 6,306,610.
  • the Luminex LabMAP system incorporates polystyrene microspheres that are dyed internally with two spectrally distinct fluorochromes. Using precise ratios of these fluorochromes, an array is created consisting of 100 different microsphere sets with specific spectral addresses. Each microsphere set can possess a different reactant on its surface. Because microsphere sets can be distinguished by their spectral addresses, they can be combined, allowing up to 100 different analytes to be measured simultaneously in a single reaction vessel. A third fluorochrome coupled to a reporter molecule quantifies the biomolecular interaction that has occurred at the microsphere surface.
  • Microspheres are interrogated individually in a rapidly flowing fluid stream as they pass by two separate lasers in the Luminex analyzer.
  • High-speed digital signal processing classifies the microsphere based on its spectral address and quantifies the reaction on the surface in a few seconds per sample.
  • the bead-type immunoassays are preferable for a number of reasons. As compared to ELISAs, costs and throughput are far superior. As • compared to typical planar antibody microarray technology (for example, in the nature of the BD Clontech Antibody arrays, commercially available form BD Biosciences Clontech of Palo Alto, Calif.), the beads are superior for quantitation purposes because the bead technology does not require pre-processing or titering of the plasma or serum sample, with its inherent difficulties in reproducibility, cost and technician time. For this reason, although other immunoassays, such as, without limitation, ELISA, RIA, and antibody microarray technologies, are capable of use in the context of the present invention, they are not preferred.
  • the evaluation function comprises a medical team reviewing the results of the testing function.
  • the medical team preferably comprises two or more physicians or other medical practitioners, such as registered nurses.
  • the medical team analyzes the results of a given consumer's biomarker panel assay in order to determine which, if any, of the tested biomarkers are present at concentrations outside the normal range. For those biomarkers that are present outside the normal range, the medical team reviews and discusses the latest information from the medical and research fields, in preparation for briefing the consumer about the implications of the test results.
  • the reporting function comprises generating a report of a consumer's individual test results, providing that report to the consumer, and consulting with the consumer regarding the implications of the test results.
  • the report typically highlights, typically via color coded flags, those biomarkers that in a particular consumer's biosample were present at levels outside the normal range.
  • Biomarkers present at levels far outside the normal range are flagged in the color red, designated as the "alert” category, and information about those biomarkers is presented in a prominent section typically near the beginning of the report.
  • Biomarkers present at levels slightly outside, but not far outside, the normal range are flagged in the color yellow, designated as the "caution” category, and information about those biomarkers is presented in a prominent section typically near the beginning of the report.
  • Biomarkers present within the normal range are set to the color green, designated as the "low risk” category, and information about these biomarkers is presented in a "Glossary" section typically near the end of the report.
  • the information presented in the report includes up-to- date knowledge from the clinical medical and scientific research communities regarding associations between the biomarkers and various medical conditions. The consumer may then use this information to follow up with their personal physician and elect to pursue any prudent counseling, monitoring, preventive lifestyle modifications, or medical treatments.
  • a percentage change between levels of a biomarker is compared to RCV for the biomarker.
  • the reporting function further comprises a consultation, typically over the telephone, with physicians from the HAS Provider.
  • This consultation may, at the consumer's option, be conducted so as to allow the consumer's personal physician to participate.
  • the HAS Provider physicians will advise the consumer regarding the consumer's overall wellness picture as evidenced by the results of the testing function.
  • HAS Health Assessment Service
  • a marketing function that brings to the attention of potential consumers an ability to purchase an individualized health assessment service
  • a testing function that obtains one or more test samples taken from a consumer who has elected to purchase the service, which one or more samples are subjected to one or more test panels, each of said one or more test panels comprising qualitative and/or quantitative tests for the presence or absence of a plurality of biomarkers in said one or more samples;
  • the test in (ii) is quantitative and comprises (a) measuring a level of a biomarker in the test sample from the consumer at a first time;
  • the reference change value is obtained by (a) obtaining levels of the biomarker from a population of at least 20 healthy individuals and at least five times from each individual; (b) using the levels obtained from (a) to determine mean within-subject biological variation (CVw);
  • the one or more test panels include test panels for autoimmune disorder, cancer, cardiovascular disease, cell signaling, diabetes, endocrine, hematology, hormonal imbalance, immune/inflammation, infectious disease, metabolic disorder, nutritional, organ systems, and osteoarthritis.
  • Preferred embodiment provide a method of providing a Health Assessment Service " (HAS) comprising: (i) soliciting one or more consumers who might be interested in purchasing an individualized health assessment service;
  • test panels comprising qualitative and/or quantitative tests for the presence or absence of a plurality of biomarkers in said one or more samples
  • the one or more consumers exhibit little or no symptoms of disease, medical condition, potential health risks and/or problems.
  • the test in (iii) comprises (a) measuring a level of a biomarker in the test sample from the consumer at a first time;
  • RCV 2 > ⁇ Z(CVA 2 + CVw 2 ) 14 , wherein Z is standard deviate appropriate for chosen probability, CV A is analytic precision, CVw is mean within-subject biological variation.
  • test results are compared against putative reference ranges.
  • the putative reference ranges are attributed to "normal" ranges.
  • the putative reference ranges are established or refined over time.
  • a putative reference range is adjusted based on the prevalence of a particular disease or condition in a general population.
  • the reference range is adjusted such that the percentage of results in the "abnormal" range inversely correlates with the prevalence of a particular disease or condition in the general population.
  • the reference range for biomarkers of diseases of common prevalence is set at two standard deviations and the reference range for biomarkers of diseases of uncommon prevalence is set at four standard deviations.
  • the reference range for CA 19-9 as a biomarker for pancreatic cancer is set at four or more standard deviations.
  • a putative reference range for a particular biomarker is adjusted to increase specificity at the expense of sensitivity.
  • Preferred embodiments provide a method of diagnosing a condition selected from the group consisting of autoimmune disorder, cancer, cardiovascular disease, disease and repair associated with cell signaling, diabetes, endocrine condition, hematological abnormality, hormonal imbalance, immune reaction/inflammation, infectious disease, metabolic disorder, malnutrition, impaired organ function, and osteoarthritis in a patient comprising
  • the calculation of the range of reference change values for a biomarker comprises
  • RCV reference change value
  • C-reactive protein double-stranded DNA antibody, ferritin, haptoglobulin, rheumatoid factor, beta-2- glycoprotein, centromere protein B antibody, collagen type 6 antibody, complement factor ClQ antibody, histone antibody, histone Hl antibody, histone H2A antibody, histone H2B antibody, histone H3 antibody, histone H4 antibody, JO-I antibody, myeloperoxidase antibody, PM-I antibody, proliferating cell nuclear antigen antibody, proteinase 3 antibody, ribosomal nuclear protein antibody, ribosomal nuclear protein A antibody, ribosomal nuclear protein C antibody, ribosomal P antibody, scleroderma 70 antibody, smith antibody, SSA antibody, and SSB antibody.
  • the condition is cancer and the biomarker is selected from the group consisting of basophil count, basophil percentage, beta-2 microglobulin, cancer antigen 125, carcinoembryonic antigen, dihydroepiandrosterone sulfate, eosinophil count, eosinophil percentage, erythropoietin, follicle stimulating hormone, globulin, growth hormone, haptoglobin, Helicobacter pylori IgG antibody, hematocrit, hemoglobin, hepatitis C antibody, human chorionic gonadotropin, immunoglobulin A, immunoglobulin M, insulin, lactate dehydrogenase, luteinizing hormone, lymphocyte count, lymphocyte percentage, monocyte count, monocyte percentage, neutrophil count, neutrophil percentage, platelet count, prolactin, prostate- specific antigen-free, prostate specific antigen-total, testosterone, total protein, white blood cell count, alpha feto
  • the condition is cardiovascular disease and the biomarker is selected from the group consisting of C-reactive protein, cholesterol, creatine kinase MB, creatine kinase-total, ferritin, fibrinogen, haptoglobin, high-density lipoprotein, homocysteine, low-density lipoprotein, low-density lipoprotein/high-density lipoprotein ratio, triglycerides, von Willebrand factor, apolipoprotein Al, B-type natriuretic peptide, endothelin 1, lipoprotein (a), myeloperoxidase antibody, myoglobin, plasminogen activator inhibitor type 1, proliferating cell nuclear antigen antibody, proteinase 3 antibody, apolipoprotein CIII, apolipoprotein H, fatty acid binding protein, fibroblast growth factor- basic form, heat shock cognate protein 70 antibody, heat shock protein 32 antibody, heat shock protein 66 antibody,
  • the condition is disease and repair associated with cell signaling and the biomarker is selected from the group consisting of brain-derived neurotrophic factor, eotaxin, epidermal growth factor, fibroblast growth factor-basic form, granulocyte macrophage colony stimulating factor, insulin-like growth factor binding protein 3, insulin-like growth factor 1, intercellular adhesion molecule 1 , interleukin-1 alpha, interleukin-1 beta, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-10, interleukin-12 ⁇ 40, interleukin-12 ⁇ 70, interleukin-13, interleukin-15, interleukin-16, interleukin-18, lymphotactin, macrophage-derived chemokine, macrophage inflammatory protein 1 alpha, macrophage inflammatory protein 1 -beta, matrix metalloproteinase 2, matrix
  • the condition is diabetes and the biomarker is selected from the group consisting of glucose, insulin, insulin antibody, C-peptide, hemoglobin AIc, leptin, pancreatic islet cell antibody, adiponectin, insulin-like growth factor binding protein 3 , and insulin- like growth factor- 1.
  • the condition is an endocrine condition and the biomarker is selected from the group consisting of Cortisol, follicle stimulating hormone, growth hormone, luteinizing hormone, prolactin, thyroid stimulating hormone, calcium, parathyroid hormone, phosphorus, thyroglobulin antibody, thyroid microsomal antibody, thyroid stimulating hormone, thyroxine, thyroxine binding globulin, triiodothyronine, calcitonin, thyroglobulin antigen, thyroxine antibody, triiodothyronine antibody, dihydroepiandrosterone sulfate, estradiol, follicle stimulating hormone, luteinizing hormone, progesterone, prolactin, testosterone, androstenedipne, estriol, unconjugated, and sex hormone-binding globulin.
  • the biomarker is selected from the group consisting of Cortisol, follicle stimulating hormone, growth hormone, luteinizing hormone
  • the condition is a hematological abnormality and the biomarker is selected from the group consisting of bilirubin-total, eosinophil count, eosinophil percentage, erythropoietin, ferritin, fibrinogen, hematocrit, hemoglobin, iron binding capacity-total, iron-serum, lactate dehydrogenase, lymphocyte count, lymphocyte percentage, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, monocyte count, monocyte percentage, platelet count, red blood cell count, red cell distribution width, vitamin B-12, white blood cell count, basophil count, basophile percentage, Factor VII, haptoglobin, thromobopoietin, tissue factor, and von Willebrand factor.
  • the biomarker is selected from the group consisting of bilirubin-total, eosinophil count, eosinophil percentage, erythropoietin, ferrit
  • the condition is an immune reaction or an inflammatory response and the biomarker is selected from the group consisting of aspartate aminotransferase antigen, C-reactive protein, haptoglobin, immunoglobulin A, immunoglobulin E, immunoglobulin M, von Willebrand factor, Factor VII, alpha-2- macroglobulin, complement-3, epithelial neutrophil activating peptide 78, heat shock cognate protein 70 antibody, heat shock protein 32 antibody, heat shock protein 65 antibody, heat shock protein 71 antibody, heat shock protein 90 alpha antibody, heat shock protein 90 beta antibody, and serum amyloid P.
  • the biomarker is selected from the group consisting of aspartate aminotransferase antigen, C-reactive protein, haptoglobin, immunoglobulin A, immunoglobulin E, immunoglobulin M, von Willebrand factor, Factor VII, alpha-2- macroglobulin, complement-3, epithelial neutrophil activating peptide 78, heat shock cognate protein 70 antibody, heat shock protein
  • the condition is an infectious disease and the biomarker is selected from the group consisting of Helicobacter pylori IgG antibody, Mycoplasma pneumoniae antibody, Streptolysin O antibody, Bordetella pertussis antibody, Campylobacter jejuni antibody, Chlamydia pneumoniae antibody, Chlamydia trachomatis antibody, Diphtheria toxin antibody, Leishmania donovani antibody, Lyme disease antibody, Mycobacteria tuberculosis antibody, Tetanus antibody, Toxoplasma gondi antibody, Trypanosoma cruzi antibody, Cytomegalovirus antibody, Epstein-Barr virus early antigen antibody, Hepatitis A antibody, Hepatitis B core antibody, Hepatitis B e antibody, Hepatitis B surface antibody, Hepatitis B surface antigen, Hepatitis C antibody, Hepatitis D antibody, Hepatitis E orf 2.3 kD antibody, Hepatitis
  • the condition is malnutrition and the biomarker is selected from the group consisting of albumin, albumin/globulin ratio, amylase, calcium, carbon dioxide, chloride, cholesterol, ferritin, folic acid, globulin, glucose, hematocrit, hemoglobin, iron binding capacity-total, iron binding capacity- unsaturated, iron-percent saturated, iron-serum, magnesium, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, phosphorus, potassium, sodium, total protein, triglycerides, uric acid, and vitamin B-12.
  • the biomarker is selected from the group consisting of albumin, albumin/globulin ratio, amylase, calcium, carbon dioxide, chloride, cholesterol, ferritin, folic acid, globulin, glucose, hematocrit, hemoglobin, iron binding capacity-total, iron binding capacity- unsaturated, iron-percent saturated, iron-serum, magnesium, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration
  • the condition is impaired organ function and the biomarker is selected from the group consisting of Helicobacter pylori IgG antibody, Campylobacter jejuni antibody, anti-Saccharomyces cerevisiae antibody, gastin, tissue transglutaminase antibody, blood urea nitrogen, blood urea nitrogen/creatinine ratio, carbon dioxide, chloride, creatinine, potassium, sodium, uric acid, beta-2-microglobulin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin-total, ferritin, fibrinogen, gamma glutamyl transferase, haptoglobin, hepatitis A antibody, hepatitis B core antibody, hepatitis B e antibody, hepatitis B surface antibody, hepatitis B surface antigen, hepatitis C antibody, hepatitis D antibody,
  • the condition is osteoarthritis and the biomarker is selected from the group consisting of C-reactive protein, ferritin, haptoglobin, rheumatoid factor, von Willebrand factor, anti-nuclear antibody, collagen type 1 antibody, collagen type 2 antibody, collagen type 4 antibody, collagen type 6 antibody, heat shock cognate protein 70 antibody, heat shock protein 32 antibody, heat shock protein 65 antibody, heat shock protein 71 antibody, heat shock protein 90 alpha antibody, and heat shock protein 90 beta antibody.
  • at least 2 biomarkers are measured.
  • at least 5 biomarkers are measured.
  • at least 10 biomarkers are measured.
  • the sample is serum, blood, urine, saliva, a cell, or a portion of tissue.
  • the tubes were covered using plate cover film but were not capped, as capping creates pressure that could have forced the liquid through the separation device.
  • the microcentrifuge tubes containing the separation devices, elution buffer, and punched out blood spot holes were placed on a microcentrifuge and spun for a minimum 12 hours, at 2-8 0 C. Samples were removed from the centrifuge and the cover film was carefully removed from the samples. The tubes were capped and placed back in the centrifuge and spun at 14,000 rpm, for a minimum of 1 minute, at 2-8 °C.
  • the devices were removed from the centrifuge and each microcentrifuge tube was inspected to confirm complete elution, such that liquid was at the bottom of the microcentrifuge tube and the filter paper appeared almost dry and with no traces eluent.
  • the separation devices were removed from the 1.5 mL tubes and discarded.
  • the microcentrifuge tubes containing eluent were recapped and stored at 2-8 0 C until further processing.
  • Luminex assays were developed to efficiently and accurately test the majority of the biomarkers described in Table 1. Luminex technology is described in the art and incorporated herein by reference. [0085] Serum concentrations of biomarkers. Circulating concentrations of different serum biomarkers were evaluated in multiplexed assays using LabMap technology in blood of individuals that elected to utilize the HAS. Example 2 Calculation of RCV
  • Patient A's PSA level is measured as a baseline or reference value.
  • a number is reported, for example, 1.1 ng/mL.
  • the value 1.1 ng/mL can be reported along with a reference range (taken from the laboratory's experience of the population as a whole), which says that a value under 4.0 ng/mL indicates negative diagnosis for prostate cancer.
  • a reference range taken from the laboratory's experience of the population as a whole

Abstract

L'invention concerne un service d'évaluation d'état de santé comprenant une fonction de marketing, une fonction de test, une fonction d'évaluation et une fonction de rapport, ainsi qu'un procédé de fourniture dudit service. L'invention concerne également une méthode permettant de diagnostiquer une affection, consistant à mesurer des taux de biomarqueurs pour ladite affection à un premier point dans le temps et à un deuxième point dans le temps, et à comparer le changement dans les taux de biomarqueurs avec des valeurs de changement de référence pour cette affection.
PCT/US2007/001567 2007-01-19 2007-01-19 Procedes de fourniture de service d'evaluation d'etat de sante individualise WO2008088343A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020015964A1 (en) * 1999-03-01 2002-02-07 University Of Mississippi Medical Center Method of diagnosing and monitoring malignant breast carcinomas
US20020133386A1 (en) * 2001-01-09 2002-09-19 Align Technology, Inc. Method and system for distributing patient referrals
WO2002099452A1 (fr) * 2001-06-04 2002-12-12 Metabometrix Limited Procedes d'analyse spectrale et leurs applications dans l'evaluation de la fiabilite
WO2004034903A1 (fr) * 2002-10-21 2004-04-29 University Of Leicester Methode de prediction d'une maladie cardiaque
US20050010435A1 (en) * 2002-04-09 2005-01-13 Makoto Kato Health management system and health management method

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020015964A1 (en) * 1999-03-01 2002-02-07 University Of Mississippi Medical Center Method of diagnosing and monitoring malignant breast carcinomas
US20020133386A1 (en) * 2001-01-09 2002-09-19 Align Technology, Inc. Method and system for distributing patient referrals
WO2002099452A1 (fr) * 2001-06-04 2002-12-12 Metabometrix Limited Procedes d'analyse spectrale et leurs applications dans l'evaluation de la fiabilite
US20050010435A1 (en) * 2002-04-09 2005-01-13 Makoto Kato Health management system and health management method
WO2004034903A1 (fr) * 2002-10-21 2004-04-29 University Of Leicester Methode de prediction d'une maladie cardiaque

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