EP3192046A1

EP3192046A1 - Centralized framework for storing, processing and utilizing proprietary genetic data

Info

Publication number: EP3192046A1
Application number: EP15840273.5A
Authority: EP
Inventors: Ryan Downs; Ferdinand LOS; Orhan Soykan; Roger Hahn
Original assignee: Yougene Corp
Current assignee: Yougene Corp
Priority date: 2014-09-11
Filing date: 2015-09-11
Publication date: 2017-07-19
Also published as: EP3192046A4; KR20170097603A; WO2016040909A1

Abstract

Disclosed are systems and methods for carrying out medical testing. The systems and methods allow for the creation of, and use of, a medical test. The systems and methods can provide for the use of proprietary information in the medical testing from multiple proprietary rights holders. The system and methods allow for protection of the proprietary information while allowing users to receive test results. Also disclosed are systems and methods for facilitating detection of structural variants in a genetic sequence that are not readily detectable when the genetic information is sequenced using short read data. The system and methods identify parameters that co-vary with the not readily detectable structural variants, and use the co-varying parameters in order to determine the existence of the structural variants.

Description

CENTRALIZED FRAMEWORK FOR STORING, PROCESSING AND UTILIZING

PROPRIETARY GENETIC DATA

FIELD OF THE INVENTION

[0001] This disclosure relates to methods and systems for facilitating the use of proprietary biomarkers across users and facilitating payment for the use of intellectual property rights between users of the systems and methods. The methods and systems of the invention further provide genetic data that can be securely searched and interpreted to generate results of genetic tests without the need to send large genome files over the internet.

BACKGROUND

[0002] Diagnostic tests employing the use of biomarkers are frequently protected by intellectual property rights usually in the form of issued patent claims or trade secrets if a method or patent is deemed to in eligble subject matter. Often times, identifying the presence of particular biomarkers does not necessarily require the acquisition of materials or equipment from the owner of the intellectual property associated with the biomarkers. By means of example, the presence or absence of specific genomic mutations can be performed through the use of multipurpose sequencing equipment or genechips.

[0003] The number of laboratories and clinical settings having access to equipment for determining genetic information and other biomarkers is widespread as cost barriers are decreased. Certain corporations and researchers have been carrying out studies to determine the effects of some of these structural variants of unknown effect. This research entails large volumes of data and large amounts of money to carry out. The researchers often will not wish to divulge the results of their testing, and instead keep the determined effects of the genetic variants secret, such as in proprietary information. Although numerous data sharing services exist, many researchers choose not to submit this proprietary data to data sharing services. As a result, only the persons or entities that carry out the research have the necessary information to determine the physiological effects of the genetic variants. In order for a patient to determine whether or not these genetic variants are present in either the patient's germline DNA or somatic DNA of a tumor, the patient must submit a genetic test directly to the owner of the information. This results in a multiplicity of genetic tests and inefficiency of data. Further, there is currently no method by which a patient can undergo a single genetic sequencing and have all relevant genetic tests conducted on the single genome, resulting in an increased potential for errors.

[0004] Licensing for the use of intellectual property traditionally results from direct negotiation between the rights holder and one or more users or licensees. However, transaction costs become prohibitive when many potential users or licensees are present on the landscape. This is particularly true when potential users or licensees occasionally perform diagnostic tests associated with particular intellectual property rights. In addition, a diagnostic service may perform a test resulting in a wide range of information such as whole genome (WGS) or exome sequencing (WES) or a genome-wide SNP analysis using a genechip, where a wide range of potential proprietary markers useful for diagnostic purposes can be revealed. However, the individual or organization performing the diagnostic service is unaware how the generated information may be used by other parties or what intellectual property rights may be implicated. A further complication is that certain diagnostic tests may require the evaluation of biomarkers that may be covered by multiple patents or trade secrets belonging to multiple different rights holders. The acquisition of a comprehensive profile of biomarkers associated with a specific condition may implicate patents owned by several different entities thereby creating large transactional costs in directly licensing the relevant intellectual property.

[0005] The need to negotiate and manage a large number of licensing agreements is a disincentive for potential users or licensees to respect the intellectual property rights of patent rights holders. Alternatively, the need to manage a large number of licensing agreements can discourage the use, development and/or validation of biomarker-based diagnostic techniques, particularly in situations where it is difficult to determine all the rights holders that may be implicated. This challenge has been recognized as creating "patent thickets," where commercial activity or legal compliance in an area is discouraged by a "thicket" of patent rights controlled by several different entities.

[0006] Transmitting genetic data across the internet raises security concerns, as the private genetic information may be intercepted by others. Further, whole genomes, or even portions of genomes, are extremely large files requiring a large amount of bandwidth and memory to transmit and store. Hence, there is a need for a system by which genetic data can be searched and interpreted to generate results of genetic tests without the need to send the large genome files over the internet.

[0007] Finally, scanning, interrogating and storing patient genetic data can be accomplished with next generation sequencing, or exome, technologies linked to electronic health records and their associated decision support tools. However, the lack of a single "point of truth" for genetic data that is stored, queried, interpreted and accessed on-demand reduces accuracy and increases medical error. Without a canonical source of personal genetic data, different laboratories can execute sequence queries on a patient's genetic sequence and conclude different results with potentially dangerous outcomes. Although disseminating a patient's genomic profile to providers is critical, ordering data electronically via different enterprise-based systems inherently introduces safety, security, and liability concerns. Regulatory scrutiny has been heightened and can be expected to increase. Further, intellectual property owners may not be aware of and/or compensated for the use of their patents and know-how across a distributed system.

[0008] Hence, there is a need for genetic testing utilizing in-silico tests in order to increase the speed and decrease the costs of genetic testing, while providing a range of genetic tests from a single sample. There is a further need for a system that can detect these mutations through parameterization of other mutations or markers in a genetic sequence that co-vary with the large insertions or deletions. Hence, there is a need for a system that can detect mutations or other biomarkers present in somatic cancer cell DNA. There is a further need for a system that can simplify the sample and data analysis in order to improve the accuracy of mutation detection in somatic cancer cell DNA. There is also a need for a system that can identify some or all identified important mutations that may be present in tumor cells, where the tumor cell DNA is sequenced using next generation sequencing techniques.

[0009] As such, there is a need for a single system that can conduct tests on genetic or other medical information for patients without the need for owners of proprietary medical information to disclose the proprietary information to third parties. There is further a need for a system wherein owners of proprietary medical information can upload this information for the purpose of medical testing without fear of disclosure to the public at large.

SUMMARY OF THE INVENTION

[0010] A system is provided for facilitating the use of proprietary biomarkers in genetic testing, and analyzing and reporting the results of genetic tests. The system can comprise a control server connected to a remote application, the remote application configured to obtain results of a genetic test. The control server can also be connected to a proprietary records database containing records of proprietary biomarkers and rights holders of the proprietary biomarker. A genetic data storage server containing genetic information for one or more patients can be in communication with the remote application. The remote application can be configured to send and receive data for conducting the genetic test. The control server can be configured to send and receive data for accounting for payment from a payer party to the rights holder. The control server can also be configured to account for payments from a payer party to the owner of the genetic data storage server. The sytem can a black box containing encrypted proprietary information for performing the genetic test.

[0011] The remote application can be collocated with the genetic data storage server on the cloud. The remote application can be configured to receive data from the genetic data storage server, and to carry out the genetic test. Alternatively, a third party scanning application can carry out the genetic test. A request for a genetic test can be initiated by the control server, or can be initiated by the third party scanning application. The control server can account for payments from a payer party to the third party and/or the rights holders, or from the third party to the rights holders. The third party scanning application can be collocated with the genetic data storage server.

[0012] The data storage server and the genetic data interpretations server can be selected from any one of a server, cloud, or web hosted data repository. The remote client and the control server can be selected from any one of a server, cloud, or web hosted application. The connections can be selected, but not limited to, from any one or more of TCP, UDP, VPN, SQL, sockets, or OS Messaging or other known connection technologies. One of ordinary skill in the art will further understand any present, future equivalent protocols are contemplated by the invention that are suitable to transmit secure and unsecure information between two collocated or non-collocated software instances.

[0013] A method for obtaining a genetic test and accounting for payments to rights holders is provided. The method can comprise obtaining genetic usage information from a payer party. The method can comprise proprietary records database, the proprietary records database containing records of proprietary biomarkers and the rights holders of proprietary biomarkers. The biomarkers required for a genetic test can be determined, and payment to the rights holders can be accounted for. The genetic testing can be carried out by a remote application, or can be carried out by a third party scan application.

[0014] The genetic usage information can comprise a prescription for a genetic test, the biomarkers to be searched during a genetic test, and/or the portions of the genome to be scanned during a genetic test.

[0015] Licenses for the use of proprietary biomarkers can be obtained before or after a request for a genetic test is created. These applications can be transferred to the scanning party in order to carry out the test. The system and methods can account for the payment of royalties or licensing fees associated with the biomarkers.

[0016] The system can also determine tests for new biomarkers based on the results obtained from tests including known biomarkers. Patients being tested for a particular disease can be separated into subgroups, and the genetic information of the patients in each subgroup searched to determine a correlation at various genetic locations to the disease.

[0017] In any embodiment of the invention, a method can include receiving a request over the internet to identify a structural variant on a genetic sequence stored on a genetic server; querying the genetic sequence wherein the genetic sequence is obtained from short read data; using one or more parameters that co-vary with the structural variant to identify the structural variant; and returning a result over the internet. The method can detect structural variants that cause increased risk of any one or more of cancer, cardiovascular disease, neurodegenerative disease, mood disorders, or any Mendelian disease.

[0018] In any embodiment, the parameters that co-vary with the structural variant can be deletions, duplications, copy-number variants, insertions, inversions and translocations.

[0019] In any embodiment of the invention, the structural variant can selected from the group consisting of insertions, deletions, mutations, translocations, and copy number variations. In any embodiment, the structural variant can comprise at least 100 base pairs. In any embodiment the structural variant can comprise at least 1000 base pairs. [0020] In any embodiment of the invention, the request to identify a structural variant can be received from a patient's electronic health records or electronic medical records.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 shows a schematic for a system for facilitating the use of proprietary biomarkers across users and facilitating payment for the use of intellectual property rights between users of the system.

[0022] FIG. 2 shows the functionality of user interfaces of the system.

[0023] FIG. 3 shows a flow chart for querying the system for the presence of proprietary biomarkers in a patient record.

[0024] FIG. 4 shows an exemplary relational database structure for a system for facilitating the use of proprietary biomarkers across users and facilitating payment for the use of intellectual property rights between users of the system.

[0025] FIG. 5 shows an exemplary hardware implementation for implementing the methods described herein.

[0026] FIG. 6 shows an exemplary large-scale hardware implementation for implementing the methods described herein.

[0027] FIG. 7 shows an overview of a system for providing biomarker test results.

[0028] FIG. 8 shows the genetic testing and reporting system according to one embodiment of the invention.

[0029] FIG. 9 shows the interactions of the servers and databases according to one embodiment of the invention.

[0030] FIG. 10 shows the interactions of the servers and databases including a third party request application.

[0031] FIG. 11 shows a genetic testing and reporting system including multiple genetic data storage servers and multiple sources of test requests.

[0032] FIG. 12 shows a genetic testing and reporting system with multiple genetic data storage servers and third party request applications.

[0033] FIG. 13 shows a genetic testing and proprietary biomarker accounting system with a third party requesting and conducting a genetic test.

[0034] FIG. 14 shows a genetic testing and proprietary biomarker accounting system with a control system initiating a request for a genetic test and a third party conducting the genetic test.

[0035] FIG. 15 shows a genetic testing and proprietary biomarker accounting system with a control system initiating a request for a genetic test and the same system conducting the genetic test.

[0036] FIG. 16 shows a medical testing system using proprietary information.

[0037] FIG. 17 shows a non-limiting example of encryption of a genetic sequence. [0038] FIG. 18 shows a method of using an encrypted genetic sequence in a genetic test by encrypting a patient genetic sequence.

[0039] FIG. 19 shows a method of using an encrypted genetic sequence in a genetic test by unencrypting the genetic sequence for a comparison.

[0040] FIG. 20 shows implementation of a medical testing system configured to test using proprietary information.

[0041] FIG. 21 shows implementation of a medical testing system configured to conduct multiple tests using proprietary information.

[0042] FIG. 22 shows a non-limiting embodiment of accounting for payments based on medical tests using proprietary information.

[0043] FIG. 23 shows an embodiment for running a genetic test using a standalone software application.

[0044] FIG. 24 shows an embodiment using an encrypted medical test.

[0045] FIG. 25 shows an embodiment using an encrypted medical test with an external biomarker server.

[0046] FIG. 26 shows use of a genetic testing system with a third party conducting genetic sequencing and biomarker research.

[0047] FIG. 27 shows use of a genetic testing system wherein different parties conduct genetic sequencing and biomarker research.

[0048] FIG. 28 shows use of a genetic testing system for patients that have already had their genome sequenced.

[0049] FIG. 29 shows a flow chart for a method of creating a biomarker script and conducting a scan of a genome.

[0050] FIG. 30 shows a screenshot of an exemplary prescription creation interface.

[0051] FIG. 31 shows a screenshot of an exemplary interface while the patient's information is obtained and scanned.

[0052] FIG. 32 shows a screenshot of an exemplary result of the scan for a patient with none of the defined genetic mutations.

[0053] FIG. 33 shows an exemplary result provided for a scan of a patient with some of the defined genetic mutations.

[0054] FIG. 34 shows examples of genetic mutations that may cause disease.

[0055] FIG. 35 shows examples of methods to determine parameters that co-vary with large genetic mutations.

[0056] FIG. 36 is a flow chart showing the process of obtaining and querying genetic information from somatic cancer cells. [0057] FIG. 37 shows an overview of the system for obtaining, querying, and accounting for payments corresponding to genetic testing.

[0058] FIG. 38 shows a system for obtaining a prescription for a genetic test from electronic medical records and returning results to electronic medical records.

DETAILED DESCRIPTION

Definitions

[0059] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the relevant art.

[0060] The articles "a" and "an" are used herein to refer to one or to more than one {i.e. , to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0061] The term "administrator" or "administrator user" refers to one or more individuals or parties responsible for maintaining the soundness and usability of the systems and methods described herein.

[0062] The term "authority" refers to having the right to access certain information stored in a system or database.

[0063] The term "biomarker" refers to a feature which quantitative or qualitative characteristics are used to determine a biological state or the presence or risk for a disease or condition, or response to therapy or drug. Biomarkers include, but are not limited to, genomic information as indicated by a sequence or presence of one or more nucleotide bases in a DNA molecule. Other non-limiting examples of biomarkers include quantitative or qualitative information regarding single nucleotide polymorphisms (SNPs), copy number variants, insertions and deletions, haplotypes, genetic mutations, genetic linkage disequilibrium, metabolite information, proteomic information, lipidomic information, and combinations thereof.

[0064] A "biomarker script" is a set of computer readable instructions that cause the system to scan the genetic sequence for the presence of one or more particular biomarkers.

[0065] "Black box" refers to any one or more combination of computers, servers, processors, applications, or software that can prevent an unauthorized user from ascertaining the information protected by the black box. The protected information can include algorithims, databases, data elements, data attributes, data features, data structures, and the like. The black box can encrypt the protected information in order to maintain the proprietary nature of the information, such as for the maintenance of a trade secret.

[0066] The term "clinical parameter," "clinical data" or "clinical information" refers to either physiological parameters or demographic parameters.

[0067] The term "cloud" refers to any shared pool of networks or servers. [0068] The term "collocated" refers to two or more servers, databases, computers, software applications, or any other computing module being in the same location. The same location can mean on the same server, virtual instance, or computer, on a single intranet, or located in the cloud behind the same firewall. "Collocated" can also refer to two or more modules configured such that data can be transmitted between the two or more modules without transmitting the data over the internet. "Collocated" can also refer to two or more modules configured such that one of the modules is embedded within the other module.

[0069] "Companion diagnostics" or "CoDx" refers to tests intended to assist physicians in making treatment decisions for their patients by elucidating the efficacy and/or safety of a specific drug or class of drugs for a targeted patient group or sub-groups.

[0070] The term "comprising" includes, but is not limited to, whatever follows the word

"comprising." Thus, use of the term indicates that the listed elements are required or mandatory but that other elements are optional and may or may not be present.

[0071] The term "consisting of includes and is limited to whatever follows the phrase

"consisting of." Thus, the phrase indicates that the limited elements are required or mandatory and that no other elements may be present.

[0072] The phrase "consisting essentially of includes any elements listed after the phrase and is limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase indicates that the listed elements are required or mandatory but that other elements are optional and may or may not be present, depending upon whether or not they affect the activity or action of the listed elements.

[0073] The term "control server," "control application," or "CS" refers to a server or application configured to communicate with other servers, databases, or applications and to send and receive information from the other servers, databases or applications.

[0074] The term "co-vary" refers to at least two parameters, wherein a particular variant of one of the parameters is indicative of an increased probability of a particular variant of the other parameter.

[0075] The term "diagnostic test" refers to any process performed on a biological sample that results in information, termed "diagnostic information," about the sample. The "diagnostic information" can include, but is not limited to, genomic, proteomic, and lipidomic information regarding the biological sample and standard blood tests for determining blood chemistry.

[0076] The term "diagnostic information" or "raw diagnostic information" refers to information generated from a laboratory or other test that contains biomarker information, where information regarding a biomarker need not be tagged, highlighted or identified within the diagnostic information. [0077] The term "demographic parameter," demographic data" or "demographic information" refers to information that can be used to predict or determine the health status or risk for a disease or condition for an individual that does not necessarily require the physical examination of the individual. Non- limiting examples include medical history of the individual or relatives of the individual, life-style habits such as diet, exercise, smoking alcohol consumption patterns or sexual activity, prior medical procedures or medical appliances such as a pacemaker or a stent, exposure to environmental health risks, etc.

[0078] The term "database" refers to any organization of data or information that can be queried.

[0079] The term "diagnostic" or "Dx" refers to a test intended to determine a disease affecting a patient.

[0080] Electronic health records" and "electronic medical records" are digitized versions of official health records for an individual.

[0081] The phrase "equivalent to a known diagnostic test" means that the biomarker script determines the presence of the same genetic mutations as in the known diagnostic test. In the case of PCR based tests, this means that the biomarker script scans the genome for the same mutations for which the PCR based test provides probes. In the case of an enzyme based test, this means that the biomarker script scans the genome for the genetic mutations that give rise to the enzyme levels determined in the known test.

[0082] A "genetic data interpretations server" or "GDIS" is a server or database containing instructions on interpreting genetic or other biological data.

[0083] A "genetic data storage server" or "GDSS" is a server or database containing genetic or other biological data pertaining to one or more patients.

[0084] "Genetic information" refers to data of any kind, related to one or more nucleotides.

The nucleotides can include point mutations, whole genome sequences, or whole exome sequences, or portions thereof such as targeted sequences at specific locations.

[0085] "Genetic usage information" refers to the information necessary for conducting a genetic test. As use herein, genetic usage information can refer to a prescription for a genetic test, the biomarkers to be searched during a genetic test, related algorithms, and/or the portions of the genome to be scanned during a genetic test.

[0086] "Genetic test" refers to any one of newborn screening diagnostics testing, carrier testing, prenatal testing. The genetic tests can confirm a suspected diagnosis, predict the possibility of future illness, detect the presence of a carrier state in unaffected individuals, and predict response to therapy or drug. The genetic test can include indentifying genetic variants including, but not limited to single nucleotide polymorphisms, copy number variants, insertions, deletions, and other kown variants. The genetic test can include algoritimns, decision trees, and statistical analysis. [0087] "Germline DNA" refers to DNA in cells that is passed on to future generations of cells.

[0088] The term "field" refers to a category of information entered into a database, where the field contains the same quality or type of data between records.

[0089] The term "information" refers to any algorithm, script, association, or any other data that can be stored by a computer.

[0090] A "prescription for a test" is a request by any party to search or analyze biological information.

[0091] The term "record" refers to a set of data present in a database that is associated with the same object such as a patient or biomarker.

[0092] A "remote client," "remote client application," "remote application," or "RCA" is an application residing on a computer that can be physically or separated virtually using VM ware. The remote application can access or manipulate via a computer network of any kind including but limited to Personal area network, or PAN, Local area network, or LAN, Metropolitan area network, or MAN, Wide area network, or WAN, or any other general purpose network such as Storage area network, or SAN, Enterprise private network, or EPN, Virtual private network, or VPN. In one instace, the remote application sends and receives instructions for interpreting data. The data can be genetic variant data, algorithms, and similar to interpret the genetic data according to the instructions. Optionally, the remote application can be collocated with a genetic data storage server, as defined herein.

[0093] The term "risk factor" refers to the change in probability of a patient developing a disease based on a particular factor or factors. The risk factors can be expressed as a multiple, such as 1.2X, wherein the probability of a patient with the particular factor developing the disease is 1.2 times greater than the probability of a patient without the factor developing the disease.

[0094] "Short read data" refers to portions of a genome of between about 10 to about 100 base pairs.

[0095] A "structural variant" is a particular portion of a genetic code, wherein some percentage of the population will have a different sequence of base pairs at that portion than others. Structural variants can refer, without limitation, to insertions of base pairs into the genetic code, deletions of base pairs from the genetic code, rearrangements of base pairs within the genetic code, duplications of portions of the genetic code, translocations of one or more base pairs, inversions of portions of the genetic code, or mutations of one or more base pairs within the portion of the genetic code.

[0096] A "third party request application" is an application collocated with a genetic data storage server and remote client that allows a request for a test to be made directly to the remote client. [0097] The terms "diagnostic service provider, "diagnostic service user" and "diagnostic service provider user" refer to a party or organization that performs tests or other laboratory work to generate information concerning the presence of biomarkers in a patient.

[0098] The term "payment" refers to the creation of a record detailing the obligation of one user of the systems or methods described herein to pay another user of the systems or methods described here. The actual receipt of financial funds is not necessary to complete a "payment." Rather, the financial funds can be escrowed by an administrator or another party who receives funds from one user and holds them for benefit of another user. Alternatively, payment can be completed by updating a log, database, or sending a notification that payment is due from one party to another where the transfer of financial funds can occur at some later time. However, a "payment" can also occur by the transfer of financial funds from one user to another user.

[0099] The term "physiological parameter," "physiological data" or "physiological information" refers to here to refer to measurements of physiological functions that are not necessarily limited to the quantitative or qualitative of chemical substances and biomarkers. Non- limiting examples include sex, age, height, weight, blood pressure, heart atrial or ventricle pressure, heart rate, pulse, blood chemistry, glomerular filtration rate (GFR), EKG data, PET data, MRI data, and other data indicating the homeostasis or condition of the body.

[00100] The term "privacy rules" refers to a set of rules implemented to control the level of access or authority for information stored on a system or database.

[00101] The term "proprietary biomarker" refers to a biomarker associated with certain intellectual property rights, where such intellectual property rights can include patent claims providing for specific methods for using, detecting or deriving information from the biomarker as well as compositions of matter for detecting the biomarker.

[00102] A "proprietary records database" refers to a data stored on the database that is owned by an intellectual property owner. The proprietary description can refer to either patents or trade secrets.

[00103] The terms "restricting," "restricting information," and similar terms refer to limiting the access to information stored on the system described herein or accessible using the methods described herein to specific users.

[00104] The terms "rights holder" or "rights holder user" refers to a user or party that is the owner of intellectual property rights. For example, the systems and methods described herein provide an accounting or payment for the use of subject matter within the domain of those intellectual property rights. The "rights" can include pending and issued patents, trade secrets, know-how, and any other forom of recognized intellectual property right.

[00105] The term "payer party" or "payer party user" refers to an insurer or other party that is responsible for at least a partial payment to another user of the system and methods described herein. The payer party in addition to an insurance company can include a patient receiving the benefit of a diagnostic service.

[00106] The term "patient" or "patient user" refers to an individual, human or animal, from whom diagnostic information concerning biomarkers is taken.

[00107] The term "physician" or "physician user" refers to an individual, regardless of any licenses issued by a governmental authority, which uses the systems or methods described herein to identify or access biomarkers for purposes of making a medical evaluation using the systems or methods described herein.

[00108] The term "user" refers to any party or agent of a party who sends or receives information from the systems described herein or by means of the methods described herein.

[00109] The term "table" refers to an organization of data in a database.

[00110] The term "foreign key" refers to a parameter that serves as a restraint on data that can be entered on a database table.

[00111] The term "proteomic" refers to information relating to any of the quantity, identity, primary structure (sequence of amino acid residues), pi (isoelectric point), or any other qualitative information related to proteins present in a biological sample.

[00112] The term "lipidomic" refers to information relating to any of the quantity, identity, chemical structure, oxidation state or any other qualitative information related to lipids present in a biological sample.

[00113] The term "patient identification information" refers to any data that contributes to the personal identity of an individual.

[00114] The term "relational database" refers to a database that can be queried to match data by common characteristics found within the dataset.

[00115] The term "server" means any structure capable of storing digital information. As used herein, "server" can also refer to a database, application, intranet, virtual instance, or other digital structure.

Privacy facilitating system for transferring payment to a rights holder

[00116] The systems and methods disclosed herein provide for the linkage of patient- and/or specimen-centric molecular, genetic or other biomarker data to proprietary information useful for making medical diagnoses or risk assessments. The described systems can search multiple databases, indexes, catalogs or databases, and in various languages, for patented or proprietary genetic biomarkers and related information to populate and maintain the system database(s). Genetic biomarkers can include polymorphisms, linkage disequilibrium of alleles at multiple loci, and mutations in genomic or mitochondrial DNA. The systems can receive input from a third party database or databases where the third party database can automatically upload new proprietary genetic information. The system database(s) contains proprietary genetic information and/or biomarkers including owner information, clinical, diagnostic, and treatment data. The system database(s) can further contain error logs and/or audit logs to document data inconsistencies in the system database(s). Those skilled in the art will readily recognize that the data structure for maintaining the databases is not particularly limited and can, for example, employ a relational database management system or an object-oriented database management system. The present invention incorporates by reference U.S. Patent Application No. 13/371,422, filed February 11, 2012, U.S. Patent Application 14/452,979, filed August 6, 2014, U.S. Patent Application 14/483,921, filed September 11, 2014, and U.S. Patent Application. 14/511,293, filed October 10, 2014, the entire contents of which are incorporated herein.

[00117] Our research relates to a unified framework intended for all clinical genetic tests, and for purposes of the present grant, specifically for Hereditary Breast and Ovarian Cancer (HBOC). The framework, YouGene-Connect™ (YG-C), is implemented on a cloud-based platform, which centralizes in silico genetic testing for reliable detection of genetic features using a clinical-grade database. Insofar as certain detection techniques, variants, and variant classification are proprietary, our neutral platform enables usage of genetic related intellectual property (IP) rights, which is critical to fostering and implementing innovation. This need is exacerbated by recent Supreme Court decisions eviscerating IP rights in gene patents (see Myriad, Prometheus). One area ripe for protection is algorithms for identifying large Insertions or Deletions (INDELs) or Structural Variants (SVs) using Next Generation Sequencing (NGS) derived sequence data. We intend to use SBIR Phase I funds to establish the scientific merit and feasibility of digitally interrogating genome sequences using our machine learning techniques, implementing the resulting techniques on a centralized, clinical-grade database, and delivering test results to an Electronic Medical Record (EMR) for clinical use. We intend to investigate HBOC as a first case, because the disease is well- studied and contains a number of SVs, which are challenging to reliably identify using current NGS technologies.

[00118] Since our initial submission in December 2014, the market has clearly spoken on our framework. Illumina publicly announced a 100 million dollar investment in Helix, a consumer- focused, "neutral" platform storing DNA and providing centralized in-silico interrogation that is functionally identical to YG-C. A 30% revenue share has been published. Illumina also announced that LabCorp and the Mayo Clinic as the first app developers for Helix using a model similar to Apple's app store. As shown in the attached letter of support, Illumina supports our plan to develop a web-enabled and cloud based genetic testing platform to securely store and test patient DNA data for clinical use. The market has also confirmed the value of a clinical-grade database for storing proprietary biomarkers. Quest Diagnostics and INSERM recently co-founded BRCA Share™, a data-share initiative that provides commercial access to BRCAl and BRCA2 genetic data on a subscription basis. [00119] The system also has a component for storing patient information in a system patient records database(s). A physician user or another user can enter the patient's clinical data including medical history, attributes, physiological parameters, demographic parameters and/or laboratory test results in appropriate fields of a database. The system patient database(s) also contains information for genetic biomarkers or other biomarkers associated with specific patients. In some cases, a patient's biomarker information, such as, for example, Single Nucleotide Polymorphism (SNP) information, will be unknown at the time of examination or diagnosis by a physician. Therefore, in certain embodiments, the physician or another user can enter the patient's biomarker information into the system patient database(s) at a later time. In light of the increase in personalized medicine, patients are increasingly encouraged to actively engage in the collection and management of their personal health records. As such, in certain embodiments described herein, a patient-centric model for determining usage of proprietary biomarker information is employed where the determination of the need for payment to stakeholders can be triggered on the patient level rather than as a result of a licensing agreements or other relationships between the rights holders in particular biomarkers and particular diagnostic labs or physicians.

[00120] In other embodiments, diagnostic laboratories or physicians can perform required tests to determine patient biomarkers and directly upload the information into the system patient records database(s). The system can then correlate the patient's clinical and/or biomarker information with information in the system database(s), and/or access one or more public or private domain databases and generates a match for any proprietary biomarker information. In addition, a patient's clinical and/or demographic information can be compared with other patient records in the patient records database(s) to determine whether common attributes are present in the population identified by the system as sharing a common SNP or other biomarker for use in diagnosis and treatment. Information can then be communicated to the physician indicating that the individual shares attributes with a population of individuals having a common SNP or other biomarker. Accordingly, this method provides a means for identifying patients possessing genetic information and biomarkers that might read on proprietary uses and methods of utilizing the information. Further, notice to insurance companies or payer parties and payments to stakeholders of proprietary information can be made in an automated fashion.

[00121] With reference to FIG. 1, systems for implementation of the innovations disclosed herein will be described. In FIG. 1, a system 100 having a trusted server 101(inside dashed rectangle) is provided to control access to one or more databases and manage the transfer of payment between users. Those skilled in the art will understand that trusted server 101 may be any configuration of one or more processors 103 (rectangles), data storage devices (rounded rectangles) and servers for communication capable of performing the functions disclosed herein. The system 100 can host various user interfaces (pentagons) and functional facilities (hexagons). The trusted server 101, and more particularly the one or more processors 103, controls access to information stored in a proprietary records database 110 and a patient records database 105 according to privacy rules that govern access to information contained in the proprietary records database 110 and the patient records database 105.

[00122] The patient records database 105 contains individual patient records that include patient identification information and diagnostic information, where each patient record is associated with a particular individual patient. The individual patient identification information can include such fields as first and last name, data of birth, physician information, address, social security or other identification number, or any other information that may potentially give an indication as to the identity of the patient associated with the identification information. Those skilled in the art will appreciate that the patient records database 105 is not limited to any particular device or hardware.

[00123] The proprietary records database 110 contains records of proprietary biomarkers, information regarding the rights holders of the biomarkers, and data or rules for the use of the biomarkers to diagnose specific diseases or conditions or indicate risk for specific diseases or conditions. In addition to biomarkers, the proprietary records 110 database can optionally contain demographic or clinical information that can be used to evaluate risk for specific diseases or conditions. Many biomarkers have increased predictive power when used in combination with certain demographic and/or physiological parameters. For example, the presence of a specific SNP may indicate an increased risk for certain diseases or conditions in combination with certain demographic and/or physiological parameters or information, such as age, sex, weight, height, blood pressure, EKG characteristics or certain prior medical history such as a vascular stent. Alternatively, the presence of specific SNP may indicate a particular therapeutic regimen such as administration of drug or use of a medical device. In particular, the presence of a SNP may indicate the implantation of an Implantable Cardio defibrillator Device (ICD). In some instances, the patent claims of a rights holder may only extend to the use of one or more biomarkers in combination with certain demographic and/or physiological parameters. In such instances, the intellectual property rights of a rights holder may only be implicated when a biomarker is present in a patient record in conjunction with certain demographic and/or physiological parameters.

[00124] A function of the system 100 is that access to the information in the patient records database 105 is restricted. Regarding information in the proprietary records database 110, the extent and owners of intellectual property rights, particularly patent rights, is usually publically known. As such, access to information in the proprietary records database 110 does not need to be restricted in certain embodiments. In particular, access to patient identification information is restricted to protect the privacy of the patients. In some embodiments, access to patient identification information is only granted by the privacy rules to a patient's physician and optionally a payer party having responsibility for a patient. Access to demographic and clinical information and biomarkers can be granted for the purposes of making comparisons between populations, as described above.

[00125] Medical information is oftentimes regarding as personal by many individuals, where disclosure of medical information that can be associated with a specific individual is often times regarded as a violation of trust or an intrusion into personal privacy under social norms. In addition to the social sensitivity of medical information, physicians and other medical providers can have ethical or legal obligations to shield the privacy of patient medical information. Still further, the presence of certain biomarkers, particularly genetic information, can be used to discriminate against specific patients. For example, knowledge of particular genetic information may be used by employers to discriminate in hiring or by health insurers to decline coverage. The potential illegality of such discrimination is not an absolute deterrent to its occurrence.

[00126] Medical information is entered into individual records in the patient records database 105 via a physician user interface 115 or a diagnostic service provider interface 120. As shown in FIG. 1, the physician user interface 115 is in communication with the trusted server 101. The physician user interface 115, in certain embodiments, is located on an internet web server where the physician user interface 115 can be accessed using a standard HTML web browsers. In other instances, the physician user interface 115 can be a specialized executable program running on a processor remote from the trusted server 101 or processor 103, where communication with the trusted server 101 is accomplished through the internet or other network.

[00127] The physician user interface 115 is accessible by a user having authentication credentials to identify the user as a physician user 115. A physician user 115 is a health care provider or an individual supervised by the health care provider who is authorized by a patient to enter or populate information associated with a specific patient record in the patient records database 105. A physician user 115 can have the ability to enter information into a patient record including patient identification information and demographic information either manually or in an automated fashion through electronic data provided by a separate electronic records system maintained by the physician user. Security rules can be set such that the physician user has access to the information contained in a patient record for which the physician has authority but not to identification information for patient records for which the physician does not have authority.

[00128] The authority of a physician user for a particular patient record in the patient records database can be established automatically upon the establishment of a new patient record. That is, the possession of identifying patient information used to establish the patient records presumes that the physician user has authority concerning that patient. Alternatively, the authority of a physician user can be verified or certified by a physician user already having access to the system, for example, where a patient switches medical providers. Alternatively, a patient user interface 125 can optionally be provided to allow the patient to designate the authority of a specific physician user. In certain embodiments, the patient user interface 125 does not have access to change the content of the patient records in the patient records database 105 to prevent an unsophisticated user from inadvertently changing the content of the patient record.

[00129] Optionally, the trusted server 101 can also be accessed through a diagnostic service provider interface user 120. Biomarkers are physical traits that are determined through laboratory testing often requiring sophisticated equipment. As such, a specialized testing laboratory or diagnostic service may be employed to directly perform diagnostic tests and generate diagnostic information. The diagnostic information can be reported to the physician whereupon the physician may update the diagnostic information contained in a patient record through the physician user interface 115. Alternatively, the diagnostic service provider user interface 120 may be provided to allow the testing laboratory or diagnostic service to directly update the diagnostic information of a patient record in the patient records database 105. The diagnostic service user interface may be accessible through an HTML viewer or a specialized executable program in a manner similar to the physician user interface 115.

[00130] The privacy rules operating on the trusted server 101 can be configured to allow a physician user a large degree of access to the patient records of the patient records database 105 for which the physician has authority, since a physician generally requires access to all of the patient identification information and diagnostic information contained in a patient record. In contrast, a diagnostic service provider typically does not need to have any significant access to patient information. As such, the privacy rules can be set to allow the diagnostic service provider to use the diagnostic service provider user interface 120 to upload diagnostic information to the patient records database 105. In certain embodiments, the diagnostic service provider need not be informed or have access to basic patient identification information such as name and date of birth. Rather, unique and/or one-time reference number for the particular diagnostic test can be provided to the diagnostic service provider while the trusted server 101 can correlate the reference number with a particular patient record to be updated.

[00131] Additional users of the system include a payer party user and a rights holder user, who access the trusted server 101 through a payer party interface 130 and rights holder interface 135, respectively. A function of the system 100 is to allow for the transfer of payment from a payer party to a rights holder when proprietary biomarker information is accessed through the physician user interface 115. The process for a physician to access proprietary biomarker information using the system 100 will be described in greater detail below.

[00132] Health care services, including diagnostic tests for biomarkers and physician treatment and advice based upon the presence of biomarkers, are often covered by health insurance where the patient receiving the services is not responsible for 100% of the necessary payment. The payer party user in some embodiments is a health insurer or other third party payer having responsibility for a specific patient represented by a patient record in the patient records database 105. Further, the patient themselves may also be responsible for all or part of the payment due for accessing certain proprietary biomarkers in the course of their care by a physician. As such, the payer party can further include a patient in addition to or in place of an insurer.

[00133] The privacy rules operating on the trusted server 101 can be configured to allow the payer party user access to only information necessary to verify the obligation to authorize a payment or review the validity of payments already sent. In some embodiments, the payer party user need not have access to the nature of the diagnostic query or test actually performed, rather only a guarantee that the service performed is of the type normally authorized by a specific health plan. As such, a patient record in the patient records database 105 can contain details of the identity of a payer party for that patient along with details of the extent of medical coverage provided by the payer party. A payer party user can choose to receive notification, as set in the privacy rules, that an insured patient has received an evaluation based upon proprietary biomarkers covered by insurance and choose to allow payments to processed without knowing the precise identity of the biomarkers concerned, although the payer party user can require the identity of the insured patient to verify coverage. As such, the system 100 can guarantee a high degree of patient privacy for sensitive medical information.

[00134] Typically, payer parties and insurers have access to the nature of medical diagnostic tests performed on insured persons, where such medical diagnostic tests are billed to the insurer. Here, a diagnostic service provider can still directly bill a payer party or insurer directly for their services performed as is the usual custom. For example, a diagnostic service provider can bill a payer party or insurer for the performance of a genome-wide SNP analysis using a genechip or similar test or a blood protein analysis; the nature of these diagnostic tests may be directly reportable to the payer party or insurer. However, as will be explained below in greater detail, the system 100 allows a physician user to access information concerning specific biomarkers measured by such tests. While a payer party user or insurer may have knowledge that a genome wide SNP analysis was performed on a specific insured patient, the payer party user's access to knowledge that a physician specifically evaluated biomarkers related to heart disease, cancer or other specific diseases or conditions can be shielded using the privacy rules of the system. Alternatively, payments to and from a diagnostic service provider user can be made through the system 100 as necessary to protect confidential patient information.

[00135] Similarly, a rights holder user typically does not require access to the identity of a patient or physician that has accessed information related to specific proprietary biomarkers. As such, the privacy rules can be configured to allow the rights holder user interface 135 to access information regarding the frequency of use of their proprietary biomarkers and verify the receipt of proper payment. However, the identification information of patients as well as the names of physicians and insurers can be shielded by the system 100 as required.

[00136] Those skilled in the art will readily understand that the privacy rules described above can be modified from the description above as required by certain users. For example, a payer party user can require a greater degree of information to authorize or review payments for the use of certain proprietary biomarkers, and the privacy rules can be modified to vary the degree of access to identification information and diagnostic information contained in the patient records database 105. The system 100 facilitates anonymous transfer of rights to use proprietary biomarkers and the anonymous transfer of payments to rights holders in such proprietary biomarkers. The invention specifically contemplates the use of any set of privacy rules that fulfill the aforementioned criteria.

[00137] The system 100 can include an optional notification server 140 that functions to send an email or other notification to any user containing the availability of new information from the system or a notice that new information is available upon accessing the appropriate interface. Such notification can be done using email or like notification or displayed by prompt upon a user logging into the system 100 after new information becomes available.

[00138] With reference to FIG. 2, the access to the patient records database 105 and privileges granted to different categories of users will be discussed. The physician user interface 115 provides the ability i) to log into the system 100; ii) to modify the patient records database 105 for authorized patient records including patient identification information and diagnostic information; iii) to submit a query to the system 100; and iv) to receive a results record from the query by email or by logging into the system 100. The diagnostic service provider interface 120 provides the ability i) to log into the system; ii) to update patient records in the patient records database 105 through use of a reference ID number and/or a doctor ID number with diagnostic information; iii) to view previous uploads; iv) to review previous updates to patient records and v) to optionally provide for encryption or other means to hide the diagnostic information from a technician performing the transfer of data to the system 100.

[00139] The rights holder user interface 135 provides the ability i) to log into the system; ii) to review history of use or matches of proprietary biomarkers associated with the rights holder user; and iii) to review billing, payment and accounting history for use or matches of proprietary biomarkers. The payer party user interface 130 provides the ability i) to log into the system 100; ii) to review account balances for insured patients; iii) to authorize, make or acknowledge the need to make payments to rights holder users; iv) to review the history of financial transactions; and v) to optionally authorized payments to the providers of diagnostic services. The patient user interface 125 provides the ability i) to log into the system; and ii) to provide authority to other users to access patient-specific information. [00140] Phase I research will focus on assessing current methods for detection of SVs and CNVs from NGS data in cancer; developing a machine learning algorithm to bring CNV detection into clinical-grade accuracy; and validating and scaling these methods to demonstrate clinical utility. Once implemented on YG-C, our algorithm has the potential for reducing treatment times by initiating tests using personal genetic characteristics for difficult to identify SVs. Further, a patient's genome can be stored on YG-C and instantaneously recalled and rescreened for new biomarkers without the need for the patient to return for sequencing. Our approach eliminates manufacturing, transportation and disposal costs associated with single-use, single-purpose test kits. Finally, our unified framework is suitable for all clinical genetic tests, thereby serving as a template for future in silico testing. The developments are generally applicable to any type of genetic mutation, not only those involved in cancer.

[00141]

[00142] The goals and purposes of the SBIR program are aligned with our proposal, which attempts to lay the framework for an innovative approach for standardizing genetic testing for cancer and other non-cancer conditions

Querying the System

[00143] As describe with regards to FIG. 1, the system 100 contains a trusted server 101 that functions to interact with users and implement privacy rules to control access to the patient records database 105. The physician user interface 115 and optionally the diagnostic service interface 120 are used to populate the patient records of the patient records database 105 with diagnostic information. The diagnostic information can contain a large quantity of data that requires analysis to determine the presence of proprietary biomarker information. For example, the diagnostic information can contain genome-wide genetic information that requires parsing to identify the presence of certain alleles, SNPs or mutations.

[00144] In certain embodiments, the diagnostic information is only accessed in regards to a specific query from a physician initiated through the physician user interface 115. As such, only biomarker information that is used by a physician to assess the risk for a specific disease or condition of concern is granted to the physician user, where such access results in the potential need for payment to a rights holder. For example, if genome-wide information is taken for a patient and present in the diagnostic information in the patient record, many potential proprietary SNPs or other biomarkers can potentially be present in the acquired diagnostic information. However, it would be impractical under most scenarios to require payment for all the proprietary SNPs that may be present in an individual patient's genome as determined through genome- wide diagnostic information. Further, the intellectual property of rights holders may only extend to certain uses of particular proprietary SNPs rather than only detection during a diagnostic test. Further, intellectual property rights may only extend to multiple biomarkers and/or clinical parameters present in one patient for the indication of risk for a specific disease or condition.

[00145] As such, a physician user can access the diagnostic information in a patient record by querying the system 100 with at least one search criterion. The search criterion can be specific biomarkers and/or a search for biomarkers that are correlated with specific diseases or conditions. Search algorithms and methods to parse through genetic information are known. Other biomarker data, such as lipidomic and proteomic data, can also be searched in response to a query.

[00146] The proprietary records database 110, in addition the identity of specific biomarkers, can contain information regarding specific diseases or conditions associated with certain biomarkers. Often, these specific diseases or conditions are specified in the patent or other intellectual property grant upon which the associated rights holder relies upon. Specific diseases or conditions can be assigned unique codes for use within the system 100 to avoid the uncertainty of key word searching.

[00147] By means of a non-limiting example, a physician can request a whole or partial genome evaluation of a patient, where the generated diagnostic information is loaded into the patient record in the patient records database 105. The physician can then submit a query to the system 100 through the physician user interface 115 to search for SNPs associated with the risk for heart disease. In certain embodiments, the trusted server 101 or another processor can iteratively search the genetic information contained in the diagnostic information for proprietary biomarker SNPs and/or other SNPs associated with heart disease. Known search engines and parser algorithms such as BLAST, BioJava (http://www.biojava.org/wiki/Main Page) or BioParser

(http://bioinformatics.tgen.org/brunit software/bioparser/) can be used to search the diagnostic information for relevant proprietary biomarkers. A sub-database table or results record can be populated in the relevant patient record of the patient records database 105 with the information extracted using the parser algorithm, which will eliminate the need to parse the raw diagnostic data only one time to extract biomarkers relevant to the query.

[00148] Upon the identification of proprietary biomarkers in response to a physician query, the intellectual property of one or more rights holders can be thereby used and the process to transfer, to account for or to escrow a payment to the rights holders can then be initiated. The trusted server 101 updates a payment log or database 150 to credit an appropriate rights holder user with a monetary amount for use of proprietary biomarkers upon a successful query by a physician user that returns proprietary biomarkers in response to the query. A payment facility 160 can be present to process payments from a payer party user to a rights holder user. Payment can be automatic or only after authorization by a payer party user using the payer party user interface 130. In certain embodiments, the system 100 does not complete an actual transfer of funds between bank accounts. Rather, payment is completed for the purposes of the invention and the attached Claims when a balance in a payment log or database 150 is updated reflecting the obligation of a payer party user to remit funds. Funds can be remitted by payer parties to an Administrator of the system 100 or another party in escrow on a periodic basis, at which time the Administrator can send funds to the appropriate rights holders, and the remittance of the payment noted in the log or database 150. In other embodiments, the payment facility 160 can be programmed with the banking information of the relevant users and periodically initiate payment between the payer party users and the rights holder users using the automated clearing house (ACH) or other electronic means in a manner that ensures the anonymity of the rights holder user and the payer party user. Funds may be first transferred through a bank account set-up for the administration of the system to protect the identity of the payer party, which may in turn reveal patient identification information.

[00149] If one or more rights holder users own rights to the returned proprietary biomarker information from the query in the results record, an agreed upon calculation can be used to divide payment from a payer party user automatically between the rights holders of the proprietary biomarker information using the system 100. For example, a first rights holder user can own patent claims for a first SNP biomarker to indicate heart disease risk, and a second rights holder user can own patent claims for a second SNP biomarker to indicate heart disease risk. The system 100 and the payment facility 160 can automatically and simultaneously inform both the first and second rights holder users of the found biomarkers in one patient, and then a pre-arranged calculation can be performed to apportion payments to each rights holder user. In this manner, individual patient costs can be distributed across all patients using the system 100 whereby using the systems and methods of the invention, the rights holder users are blinded to specific patient identification information.

[00150] An additional feature of the system 100 is that the use of proprietary biomarkers can be attributed to a specific patient. That is, the patient record can be annotated to indicate, for example by means of the results record, that the use of particular biomarkers have been accessed and paid for in the past. In certain embodiments, a patient can go to another physician to get a second opinion and/or the same or a different diagnostic test can be performed that implicates biomarkers for which payment has already been made in the past. The patient can be granted a limited license to allow for the future use of a proprietary biomarker accessed in the past. As such, the patient can get a second physician's opinion and/or an additional diagnostic test without additional payment.

[00151] For example, a patient record can be updated to indicate proprietary biomarkers that have been accessed in the past and payment previously made. If a future query is made that generates a results record containing a previously accessed biomarker, the system can be set to allow further usage of that proprietary biomarker without additional payment. In certain embodiments, the length of time for which future use can be made of a previously accessed proprietary biomarker can be limited to a set period of time. The patient record can be annotated to indicate a date that a biomarker was first accessed to allow the calculation of the expiration a license for future use, where the amount of time rights to use of a biomarker can be indicated in the proprietary records database 110.

[00152] The system can also correlate a patient's demographic and physiological information with information in the system and/or accessed from one or more public or private domain databases, such as a SNP consortium, and generating a result set that includes a suggestion for genetic, proteomic, and/or other type of diagnostic testing. In a further embodiment, the present invention also relates to displaying the identified correlation to aid in determining the statistical significance of the identified correlation. In addition, the patient's diagnostic, clinical and physiological information may be compared with other patient records in the database to determine whether common attributes are present in the population identified by the system of the invention as sharing common biomarkers for use in diagnosis and treatment. Information can then be communicated to the physician indicating that the individual shares attributes with a population of individuals having a common biomarker. Such information can be included with the results record generated the physician's query.

[00153] With reference to FIG. 3, an exemplary process to query the system 100 for proprietary biomarkers and remit payment to a rights holder user in a blinded fashion will be described. In step 310, a physician requests a certain diagnostic test be performed, where the raw diagnostic data generated by the diagnostic test can include proprietary biomarkers. In step 320, the raw diagnostic data is uploaded to the system 100 for addition to a specific patient record in the patient records database 105. The raw diagnostic data can be uploaded by a diagnostic service provider and the patient record identified by a reference number that maintains the anonymity of the patient. In other embodiments Step 320 can occur prior to Step 310 and the data previously uploaded can be recalled from the system 100.

[00154] In step 330, a physician queries the system to look for particular biomarkers in the raw diagnostic data and/or to look for biomarkers predictive or indicative for risk for specific diseases or conditions. The patient's record database is accessed by the system 100 and the raw diagnostic data is parsed to identify proprietary biomarkers having characteristics conforming to the query. In step 340, a results record is generated containing biomarkers returned by the query and optionally the physician and/or a payer party user having responsibility for the patient or rights holder user associated with the propriety biomarkers are notified. The patient record can be updated with the contents of the results record or the query. In step 350, a payment log or database is updated to reflect the need for a payment between a payer party user and a rights holder user in a blinded fashion.

Database Structure

[00155] FIG. 4 shows a non-limiting example of a database structure that can be employed in conjunction with the methods and systems described herein. Those skilled in the art will readily recognize that other database structures and organizations can be equally employed to practice the methods and systems described here. FIG. 4 illustrates a structure for a relational database that can be accessed and search queries obtained through the use of structured query language (SQL).

[00156] FIG. 4 shows a relational database having several Tables having rows and columns related to the category stated in the header. As presented in tables 410-445 in FIG. 4, exemplary attributes for each table are listed. The first attribute in each of tables 410-445 can be used as a key to relate information in that table to another related table using SQL. More specifically, the first attribute in each table can serve as a candidate key that is not duplicated within any one table. The organization of tables 410-445 will now be described.

[00157] Table 410 contains patient identification information. The attributes can include a patient identification number, the patient's name, contact information, physician name and/or physician user identification number, and insurer information and/or payer user identification number. Those skilled in the art will readily recognized that other attributes may be contained in patient identification table 410. As described, protection of the information contained in the patient identification information table 410 is strictly controlled in order to protect patient privacy. As such, sensitive information regarding patient identity can be segregated on table 410 to prevent unauthorized disclosure of such information.

[00158] Data and information associated with specific patients that may have less strict control over access can be stored on tables separate from table 410. As shown in FIG. 4, a diagnostic data table 415 can be provided. In addition to containing the patient identification number attribute, table 415 can contain additional attributes related to various diagnostic tests performed on the patient associated with a patient identification number. Examples of attributes that can be provided on the diagnostic data table 415 include the presence of specific SNPs, WGS, WES, or targeted gene information, proteomic and/or lipidomic information, and results of blood tests reflecting blood chemistry. Similarly, table 420 can contain information regarding a specific patient's medical history. In addition to containing the patient identification number attribute, table 420 can contain additional attributes such as previous diagnoses, current prescriptions, height, weight, age, and other attributes typically contained in medical records. Specific attributes of tables 415 and 420 may be represented by a reference numeral rather than a word string to facilitate querying of the system.

[00159] Tables 415 and 420 can be constrained through the use of a foreign key, shown as FK1 in FIG. 4. The foreign key FK1 can be used to insure that a patient identification number attribute on tables 415 and 420 occurs and has a valid entry on patient identification information table 410. The foreign key FK1 can also be used as a constraint to ensure that a patient identification number contained on other tables, as shown in FIG. 4, occurs on tables sharing a relationship. For example, the foreign FK1 can constrain the system or any user from entering information on diagnostic data table 415 with a patient identification number that does not appear as an attribute on patient identification information table 410. [00160] As described, the systems described herein provide for various user interfaces for interacting with the system including entering information in the system and submitting a query. User table 425 can have attributes including user identification number, user name, user type, and login credentials. The user type (e.g. physician user, rights holder user, etc.) can be used by the system to present the appropriate user interface to a user logging onto the system. The user table 425 can be related to a privileges table 430 that defines the access rights within the privacy rules operating on the system including which patient identification numbers certain users have privileges and concerning access to patient identification table 410. Foreign key F2 can be implemented to constrain privilege table 430 to only contain user identification number attributes that appear in user table 425.

[00161 ] Biomarkers table 435 can be further related to user table 420. Biomarkers table 435 contains the combination of biomarkers and other information that represent the intellectual property owned by specific rights holder users. In general, the user identification number attributes on table 435 are associated with rights holder users. A diagnostic reference number can be provided as an attribute that represents discrete diagnostic tests that represent an intellectual property right held by a rights holder user.

[00162] For example, a certain combination of biomarkers can represent an increased risk for cancer. By means of illustration, a rights holder can be the holder of a patent claim that recites that the presences of a G nucleotide at SNP1 , and a C nucleotide at SNP2, and a weight above 200 pounds for males represents an elevated risk for certain kinds of cancers, where SNP1 and SNP2 represent specific genomic loci in the genome. The biomarkers SNP1 and SNP2 and the clinical parameters regarding weight and sex can be organized in the same row of biomarkers table 435 associated with a unique diagnostic reference number attribute. FIG. 4 shows non-limiting examples of biomarkers including SNPs, WGS, proteomic and/or lipidomic information, physiological parameters, and demographic parameters that can be associated with specific intellectual property rights. The rows of table 435 can also contain fee information associated with the use of the diagnostic test represented by that row of the table 435.

[00163] As described above, the system can be queried to identify patients having specific biomarkers or combinations of biomarkers and/or clinical parameters that represent an elevated risk or decreased risk for certain diseases and conditions. The search engine associated with the system can search for the concurrence between the specific intellectual property rights stored in biomarkers table 435 with the information stored on the diagnostic data table 415 and the medical history table 420. As described, the system, for example, can be queried to determine if a specific patient has any biomarkers and/or clinical parameters associated with an increased risk for cancer. The system will then systematically search the appearance of any combination of biomarkers and/or clinical parameters associated with a diagnostic reference number annotated to be correlated with a risk for cancer against the information stored in diagnostic data table 415 and/or medical history table 420.

[00164] Any matches from a query can be recorded in results record table 440 as shown in FIG. 4. The results record table 440 can list the patient identification number for the patient having at least one match to a diagnostic reference number. A foreign key FK3 can be employed to constrain results record table 440 to contain only diagnostic reference numbers that appear on biomarkers table 435. A payment log table 445 can be provided to record activity of the payment facility 160. The payment log table 445 can contain the patient identification numbers and diagnostic reference numbers representing a match from a query as in results record table 440. A foreign key FK4 can be provided to constrain payment log table 445 to only contain entries for combinations of patient identification number attributes and diagnostic reference number attributes that occur in results records table 440. The payment log 445 can contain further attributes concerning the status of notification to users regarding payments and the status of any pending payments between any users of the system.

Hardware

[00165] FIG. 1 illustrates the functionality of the systems and methods disclosed herein. The above-described functionality can be implemented on any hardware system adaptable to carrying out the above described functions. However, non-limiting examples of hardware systems to carry out the invention are presented in FIG.s 5 and 6.

[00166] FIG. 5 shows a hardware implementation that can be deployed on a single server 501, where the single server can be laptop or desktop computer. The server 501 serves as the trusted server 101 described in FIG. 1. Users 505 of the server 501 can communicate with the server 501. Communication can be accomplished via the internet or by other network means; an internet connection is not required to practice the invention. In certain embodiments, users 505 can communicate with the server 501 using widely- available HTML viewers.

[00167] Users 505 first communicate with a security module 510 implemented on the server 501. The security module 510 can be a form-based authentication where users are verified using a username and password combination. A username and password combination will identify the user 510 as a physician user, diagnostic test provider, patient user, payer party user or rights holder user and implement the proper interface and related privacy rules to control access to information. Alternatively, access to the server 501 can be granted based upon the user uploading a security file containing encrypted identification information.

[00168] The server 501 implements a web server that includes a user interface (UI) 525 that is presented to the user 505. The UI 525 is not limited to any particular software, standard or language. In certain embodiments, the UI 525 can be based on a JavaScript Library including HTML5, css3.0 and a robust JavaScript Library Toolkit that supports Web 2.0 standards. The UI 525 can therefore be a graphical interface that can be intuitively operated by the user 505. As described, one or more parser algorithm tools or search engines 530 can be implemented on the server 501 to parse genetic data. In one embodiment, the parser algorithm tool 530 can be BioJava (http://www.biojava.org/wiki/Main Page), which has the advantage of being readily implemented with a JAVA-based web server. In another embodiment, the parser algorithm tool 530 can be BioParser (http://bioinformatics.tgen.org/brunit software/bioparser). Since BioParser is written in PERL, a wrapper is required to implement BioParser with a JAVA-based web server, for example, JPL or JNI. The notification server 140, described in FIG. 1 , can be implemented with an included JAVA mail client 535 to send notifications to users 505 even when a user 505 is not logged onto the server 501. The mail client 535 can also implement the payment facility 160 where a payer party user and/or rights holder user can be notified of the obligation for a payment to be made in a blinded fashion.

[00169] The patient records database 105, the proprietary records database 110 and the payment log or database 150 can be accommodated on a storage device 540. The databases stored on storage device 540 are not limited to any particular structure. In some embodiments, the patient records database 105, proprietary records database 110 and the payment log or database 150 are structured to be assessable and/or queryable using structured query language (SQL) used to maintain relational databases. In one embodiment, the databases use a relational database management system such as the Oracle 8i™ product (version 8.1.7) by Oracle. In another embodiment of the databases, object-oriented database management system architecture is used.

[00170] FIG. 6 shows a hardware implementation that employs several processors for a large- scale implementation. The function of the one or more processors 103 described in FIG. 1 is carried out by one or more processing units 603 that provide the computational power to implement a UI, a parser algorithm and a security module 610 and provide services to users 605 in the same manner as described above in FIG. 5. A load balancer 612 is also present to manage work flow in implementations where more than on processing unit 601 is present. The load balancer 612 divides the workload multiple processing units 601. If a fault occurs with one of the processing units 601, the load balancer 612 can automatically route requests from users 605 until the fault has been corrected.

[00171] The processing units 601 can access a storage area network (SAN) that houses the patient records database 105, the proprietary records database 110 and the payment log or database 150. A separate mail server 635 containing dedicated processor capability can be present to generate a large volume of outgoing email. The payment facility 160 can be implemented using the one or more processing units 603.

[00172] An overview of a system for providing biomarker test results is shown in FIG. 7. A control server 751 can connect 760 to a remote client 752. In some embodiments, the control server 751 can be on a separate server, virtual instance, intranet, or cloud than the remote client 752. In other embodiments, the control server 751 can be located on the same server, intranet, or cloud as the remote client 752. It is critical that the remote client 752 can be collocated on the same server, intranet, or cloud 758 as a genetic data storage server 753 to avoid requiring the transmission of large data genetic files to be transmitted over the internet and/or beyond a firewall. The genetic data storage server 753 contains the genetic, or other biological data of the patient. The control server 751 can also connect 761 to a genetic data interpretation server 755. The genetic data interpretation server 755 contains biomarker scripts that enable the interpretation of the genetic or other biological data stored on the genetic data storage server 753. In some embodiments, a listener 754 can be optionally used to create dedicated server processes with the genetic data interpretation server 755. The listener 754 and genetic data interpretation server 755 can be optionally collocated on the same server, intranet, or cloud as the control server 751, or they may be located on a separate server, intranet, or cloud from the control server 751.

[00173] A request for a genetic test, or other biological test, can be made 762 to the control server 751 by a health care provider or other user 756. In some embodiments a request can be made through a patient's electronic health records or electronic medical records. In some embodiments, a request can be made directly to the remote client 752 through a third party request application 757. The request can be transmitted to the control server 751. The control server can obtain the required biomarker script from the genetic data interpretation server 755 and transmit the biomarker script to the remote client 752. The remote client can execute the biomarker script on the data stored in the genetic data storage server 753. The results of the biomarker script can be sent back to the control server 751, which can transmit the results 763 to the user 756.

[00174] The query system of the present invention according to one embodiment is described in FIG. 8. The users of the system, such as hospitals 703, research laboratories 704, government agencies 705, or any other authorized user, can access the YouGene portal 700 positioned on an opposite side of a firewall 706. In some embodiments, the requests for test can come directly from the patient's electronic health records or electronic medical records. In other embodiments, the request for a test can come through a health information exchange. The users can access the portal through, for example, the internet 702 using a web browser such as Firefox, Internet Explorer or any other web browser. Communication between users and the portal can be established using SSL, HTTP, HTTPS, SOAP, or any other method known to those of ordinary skill in the art. Users can be authenticated and authorized through services authentication manager 715 LDAP 716 or any other authentication mechanism. The signal can be routed through load balancer 707 and switch 708 to reach the portal 700. Once the user logs in, the user will access to information based on the type of user according to a set of business rules 709. The ability to access information can be governed through content manager 710. [00175] A query of genetic or other information can be sent through the application server 711 to databases 714. In some embodiments, the databases 714 can be owned and operated by a private company. In other embodiments the databases 714 can be owned and operated by third parties. Search engine 712 can query the databases according to the request. Reporting engine 713 can compile the results from the query. The results can be transferred to the user through file transfer system 701. The security and effectiveness of the entire system can be monitored by monitoring system 717 and administrative console 718. The communications between servers can be established by any means known in the art, including TCP/IP. Communication with the database can be established through any means known in the art, including JDBC.

[00176] The system described herein has efficiency based on data aggregation, consistent/unified UI, standardized security such as authentication and authorization, and security enforcement of roles based on access control. In some embodiments, it can also offer standardized business events notifications when new or updated or relevant information becomes available.

[00177] The modules and functions of the system are represented in FIG. 9. The control server (CS) 816 can be hosted on the web, cloud, server or any other location. The CS 816 is capable of exchanging information between one or more databases located on the same or different servers.

[00178] In one embodiment, a remote client application (RCA) 815 owned by a first company can also be a web, cloud, intranet or server hosted application. The RCA 815 can be affiliated with the CS 816. Multiple RCA's can exist on the same or separate cloud, intranet, or server. In some embodiments, the RCA 815 can be a temporary application on the remote cloud, intranet or server. In other embodiments, the RCA 815 can be permanent.

[00179] The genetic data storage server (GDSS) 810 can be a web, cloud, intranet or server data repository owned and, optionally operated by a second company behind a firewall. In some embodiments, the GDSS 810 can be operated and maintained by the first company. In other embodiments, the GDSS 810 can be operated by a third party, e.g. second company. The GDSS 810 can contain one or more digital test records. In some embodiments, the digital test records can comprise genetic test records. In other embodiments the digital test records can comprise other biological test data, such as protein or enzyme information. The GDSS 810 can communicate with the collocated RCA 815, responding to requests from RCA 815 and providing test results. Critically, GDSS 810 is on the same server, virtual instance, intranet, behind the same firewall, or in the same cloud environment 821, as RCA 815. This eliminates the need to send the sensitive, and very large, digital test results across the internet. In some embodiments the RCA 815 can be embedded as part of the GDSS 810. In other embodiments, the RCA 815 can operate outside of the GDSS 810, so long as the RCA 815 is collocated with GDSS 810. [00180] One example of a genetic data storage server (GDSS) is the Illumina® Sequencing and Array Based Solutions system, e.g. BaseSpace. Other genetic data storage servers presently known can include Curoverse, GA Biobank, or any other known biorepository. The GDSS system typically offers the sequencing and storage of genetic data. However, any storage system, biobank, data repository, biorepository, or data commons capable of storing genetic data either in WGS, WES or any other known suitable output is contemplated by this invention. In some embodiments, the genetic data storage server can be any HIPAA compliant server capable of storing genetic data.

[00181] The genetic data interpretations server (GDIS) 817 can be a web, cloud, virtual instance, intranet, or server based data repository. The GDIS 817 can be operated by the first company or by a third party. The GDIS 817 can contain one or more biomarker scripts, with clinical interpretations based on results generated for the biomarker scripts.

[00182] The digital patient information storage server (PISS) 818 can be a web, cloud, intranet, or server hosted data repository. In some embodiments, the PISS 818 can be operated by the first company. In other embodiments, the PISS 818 can be operated by a third party. The PISS 818 can contain one or more patient records. The PISS 818 can communicate with CS 816 and can operate to update, edit or delete patient information.

[00183] One or more listeners can be used on any of the data repositories in order to create dedicated server processes for each user, and thereby increase efficiency and decrease memory constraints. In some embodiments, the data can be communicated using JSON or other communication protocol.

[00184] The CS 816 can be hosted in a separate cloud environment, intranet, or server 822 as RCA 815. However, in some embodiments, CS 816 can be in the same cloud environment, intranet, or server as RCA 815. In some embodiments, CS 816 and RCA 815 can be located on a single intranet. GDIS 817 and PISS 818 are shown in FIG. 9 as being in a single cloud, intranet, or server 823. In other embodiments, GDIS 817 and PISS 818 can be in separate clouds or servers. In some embodiments, GDIS 817 and PISS 818 can be in the same cloud, server or intranet as CS 816.

[00185] After all the software is installed, a communications portal 801 can be established between the CS 816 and the RCA 815. A second communications portal 802 can be established between the CS 816 and PISS 818. A third communications portal 803 can be established between the CS 816 and GDIS 817. A fourth communications portal 814 can be established between the RCA 815 and GDSS 810. The Communication portals 801, 802, 803 and 814 can be established and maintained via any combination of TCP, UDP, VPN, sockets, OS messaging or equivalent technologies suitable to transmit secure and unsecure information between two collocated or non- collocated software instances.

[00186] In any embodiment, a library, DLL, extension or API can be written into the genetic data storage server (GDSS) such as an operator, e.g. Illumina Basespace or any local hosting server, that can be incorporated into the GDSS owner's software that would allow the GDSS owner to run scans within their module by incorporating an outside code. In this manner, a GDSS can remain isolated and protected yet receive instructions via the Remote Client described herein. In particular, the embedded software, DLL or API can operate as the Remote Client, communicating with the Control Server, but embedded within another application.

[00187] For example, a prescription to test a biomarker 804 can be obtained by the CS 816 from a patient's electronic health records or electronic medical records, or from a health care provider 820. In some embodiments, health services providers can generate prescriptions directly through electronic health records and the prescription can be directly sent to the CS 816. Non- limiting examples of services for generating prescriptions directly through electronic medical records include Allscripts® or Surescripts®. However, any electronic prescription service is contemplated by this invention. In other embodiments, the prescription 804 can be transmitted to CS 816 by the health services provider through a user interface (not shown).

[00188] In any embodiment, an environment can be provided that runs open source and/or commercial tools (e.g. Galaxy, GATK, etc.). The environment can provide for deep provenance and reproducibility across all connections and provide a means to flexibly organize data and ensure data integrity. In any embodiment, the invention contemplates means for running distributed batch processing jobs that provide for secure sharing of data sets. The invention also contemplates providing a set of common APIs that enable application and pipeline portability across systems. The invention can be platform and system agnostic. In each instance, the invention can handle storing and organizing large data sets (e.g. BAM, FASTQ, VCF, etc.) and handle storing metadata about files for a wide variety of organizational schema. The invention further provides for an environment where stakeholders such as the genetic data storer, the prescriber, or control application owner can receive access to virtual machines (VMs) on a private or public cloud thereby eliminating the need to manage separate physical servers. In any embodiment, any of the services described herein including prescription, connections and scripts can be accessed through APIs.

[00189] For example, the prescription 804 can be communicated to CS 816. Digital test identification information 805 can be retrieved from the PISS 818 and communicated to the CS 816. The digital test identification information can comprise information necessary for locating one or more digital test records from GDSS 810. The digital test identification information can be sent 806 to RCA 815 for the purpose of locating one or more digital test records from GDSS 810. The digital test records can be retrieved and sent back 807 to the RCA 815. The digital biomarker script can be retrieved 808 from the GDIS 817 and sent to CS 816. The CS 816 can send the digital biomarker script 809 to the RCA 815. The script can be responsible for providing instructions to the RCA 815 necessary for the interpretation of the genetic or other biological data in accordance with the biomarker test prescription 804. [00190] In any embodiment, the biomarker test prescription 804 can comprise any one or more of a biomarker identifier, a patient identifier, a physician identifier, a payer identifier, a test data identifier, and a test data location identifier where one or multiple GDSSs and RCAs are used as described herein.

[00191] The RCA 815 can execute the instructions in the biomarker script, operating on the digital test record. The results of the script can be returned 811 to the CS 816. The results of the script can be communicated 812 to the prescriber 819. In some embodiments, the results can be communicated 812 electronically. In other embodiments, the results can be communicated 812 to the prescriber 819 via any possible means of communication. The results of the script can also be archived 813 on the PISS 818.

[00192] In this way, a patient's genetic information can be queried, analyzed, and the results transmitted, without the need for transmitting the patient's actual genome across the internet. In other embodiments, PISS 818 is unnecessary. The specific patient information can be obtained directly from the prescriber 820 and transmitted to CS 816.

[00193] In an alternative embodiment, shown in FIG. 10, a request for a test result can be made directly by a third party requester through third party request application 922 from the same server, virtual instance, intranet, or cloud 923 as the RCA 918. The third party requester can directly connect to the RCA 918. Such an embodiment allows a request and the results from the testing to be executed and returned without the need to send the information across the internet. In any embodiment, the third party request application 922 and the RCA 918 can be collocated. A communications portal 915 can be established between third party request application 922 and RCA 918. A communications portal 914 can be established between the RCA 918 and GDSS 910, communications portal 901 can be established between RCA 918 and CS 919, communications portal 903 can be established between CS 919 and GDIS 920, and communications portal 902 can optionally be established between CS 919 and PISS 921. In operation, the system works similar to the system in FIG. 9. A request for test results 904 is transmitted from the third party request application 922 to the RCA 918. In some embodiments, the third party request application can be embedded in the GDSS 910 as described herein. RCA 918 communicates a request for patient information 916 to CS 919. The digital test identification information 905 corresponding to the request can be retrieved from the PISS 921 and communicated to the CS 919. The digital test identification information can be sent 906 to RCA 918 for the purpose of locating one or more digital test records from GDSS 910. The digital test records can be retrieved and sent back 907 to the RCA 918. A request for a digital biomarker script 917 can be sent from the RCA 918 to the CS 919. The digital biomarker script can be retrieved 908 from the GDIS 920 and sent to CS 919. The CS 919 can send the digital biomarker script 909 to the RCA 918. The script can be responsible for providing instructions to the RCA 918. [00194] The RCA 918 can execute the instructions in the biomarker script, operating on the digital test record. The results of the script can be returned 911 to the CS 919, and the results can be sent 912 to the third party request application 922. In some embodiments, the results of the script can also be archived 913 on the PISS 921.

[00195] Critically, RCA 918 can be located on the same server, virtual instance, intranet, or in the same cloud 923 as GDSS 910. CS 919 may be located on a separate server, virtual instance, intranet, or cloud 924 from the RCA 918. GDIS 920 and PISS 921 are shown on a single server, intranet or cloud 925. In some embodiments, GDIS 920 and PISS 921 can be on separate servers, intranets or clouds. In other embodiments, one or both of GDIS 920 and PISS 921 can be located on the same cloud, virtual instance, intranet or server 924 as the CS 919.

[00196] The system is not limited to one source of prescriptions, or one digital test database. Multiple databases and request sources can be accommodated as shown in FIG. 11. CS 1001 can communicate with a first RCA 1002 collocated with a first GDSS 1003, a second RCA 1004 collocated with a second GDSS 1005, a third RCA 1006 collocated with a third GDSS 1007, a fourth RCA 1008 collocated with a fourth GDSS 1009 and a fifth RCA 1010 collocated with a fifth GDSS 1011. Any number of RCAs each corresponding to a separate GDSS is contemplated by this invention.

[00197] Similarly, CS 1001 can receive prescriptions from multiple sources. First provider or requester 1012 can provide a biomarker test prescription 1016 either through a subject-host machine interface 1013, or through electronic medical records or electronic health records 1014 which can communicate the biomarker test prescription 1016 through interface application 1015. Second provider or requester 1017 can provide a biomarker test prescription 1021 either through a subject- host machine interface 1018, or through electronic medical records or electronic health records 1019 which can communicate the biomarker test prescription 1021 through interface application 1020. Third provider or requester 1022 can provide a biomarker test prescription 1026 either through a subject-host machine interface 1023, or through electronic medical records or electronic health records 1024 which can communicate the biomarker test prescription 1026 through interface application 1025. Again, any number of providers or requesters is contemplated by this invention. In embodiments, as shown in FIG. 11, the biomarker test prescription can include a test data location identifier, which can point to the particular RCA and GDSS for the CS to communicate.

[00198] As shown in FIG. 12, in embodiments where a third party request is initiated from the same server, intranet, or cloud as the RCA the system is not limited to a single GDSS and RCA. CS 1101 can communicate with first RCA 1117 collocated with first GDSS 1118, second RCA 1119 collocated with second GDSS 1120, and third RCA 1121 collocated with third GDSS 1122. Any number of RCAs each collocated with a GDSS is contemplated by this invention. A first provider or requester 1102 can initiate a test with a third party request application 1103 or through electronic health records or electronic medical records 1104, which can act through interface application 1105. The biomarker test prescription 1106 can be directly communicated to the first RCA 1117. RCA 1117 can communicate with CS 1101 and GDSS 1118 as explained above to carry out the test and reporting procedure. A second provider or requester 1107 can initiate a test with a third party request application 1108 or through electronic health records or electronic medical records 1109, which can act through interface application 1110. The biomarker test prescription 1111 can be directly communicated to the second RCA 1119, which can communicate with collocated GDSS 1120 and CS 1101 to carry out the biomarker test. A third provider or requester 1112 can initiate a test with a third party request application 1113 or through electronic health records or electronic medical records 1114, which can act through interface application 1115. The biomarker test prescription 1116 can be directly communicated to the third RCA 1121, which can communicate with collocated GDSS 1122 and CS 1101 to carry out the biomarker test.

[00199] It will be understood that any number of providers or requesters can initiate a test through a single RCA. It will also be understood that any number of RCAs each collocated with a GDSS is contemplated by this invention.

[00200] In any embodiment, the genetic scanning functions described herein can be combined with the proprietary biomarker functions. One embodiment of the implementation of the combined system is shown in FIG. 13. A third party requester can initiate and carry out the genetic testing, while the control server of the present invention can act to facilitate the transfer of proprietary biomarker rights. A third party requester 1205 can initiate a genetic test from GDSS 1206. In order to ensure that licenses for proprietary biomarkers or test information are properly obtained, a third party scan application 1205 can transmit the genetic usage data 1212 to a remote application 1204. The genetic usage data can comprise information concerning the tests to be run and the biomarkers to be searched. The remote application 1204 can transmit this genetic usage data 1215 to the control server 1201. The control server 1201 can contain information concerning the ownership and licensing agreements of proprietary biomarker or test information. The control server 1201 can send the genetic usage information to the proprietary biomarker or test owners 1202. As explained herein, for a given genetic test, more than one right holder may be implicated. As such, the control server 1201 can transmit the genetic usage information to any and all rights holders 1202. This is shown as three different parties in FIG. 13, however it will be understood that any number of parties can hold rights implicated by any test. The rights holders 1202 can transfer licenses 1216 to the owner of the control server 1201. The control server 1201 can transmit the genetic usage information 1219 back to the third party 1203 for payment. In FIG. 13, the third party scan application 1205 is owned by a third party, and not the owner of the control system. The licenses obtained by the rights holders can also be transferred 1218 to the third party 1203 as discussed herein. The third party 1203 can make the licensing fee payments 1208 to the owner of the control server 1201. The control server 1201 can also transfer royalty payments 1217 to the rights holders 1202. As explained herein, the scanning applications can be collocated with the GDSS 1206 on cloud or server 1207. To protect privacy, the GDSS 1206 and collocated applications can be protected behind firewall 1220. The modules described in FIG. 13 allow for the accounting and transfer of proprietary rights necessary for genetic testing and payment for those rights by a centralized control system.

[00201] It will be understood that the timing or order of the steps described in FIG. 13 can be varied. For example, it may not be necessary to obtain a license for a proprietary test unless the test shows a positive result. As such, the royalty payment 1217, licensing fee 1208, and licensing transactions 1216 and 1218 can occur after all of the scanning of genetic information. In other embodiments, the transmission of the results 1219 can be delayed until after the license fee has been paid 1208.

[00202] In some embodiments, the control server 1201 can act as a licensing warehouse as explained herein. The control server 1201 can obtain licenses for proprietary genetic testing from various genetic IP owners 1202. The control server 1201 can then transfer those licenses to third party test requesters 1203 as necessary. The licenses can be obtained independently of requests for genetic tests, or can be obtained each time a particular proprietary test is requested. In some embodiments, the control server 1201 can periodically or continuously search databases, indexes, catalogs, and in various languages, for patented or proprietary genetic biomarkers and related information as discussed herein. Licenses for the use of these biomarkers or tests can be obtained whether or not a request has been made.

[00203] A different embodiment is shown in FIG. 14. The request for a genetic test can be initiated by the control system 1301. This request can come from an outside source 1307, including requests from electronic health records or electronic medical records. The requestor 1307 can send the genetic test request 1317 to the control server 1301. The control server 1301 can transmit this request to remote application 1304. In some embodiments, the testing can be carried out by third party scan application 1305. In such embodiments, the remote application 1304 can transmit the genetic request 1309 to the third party scan application 1305. The third party scan application 1305 can make a request 1310 to GDSS 1306 for the particular patient's genetic information. The GDSS can transmit the genetic data 1311 back to the third party scan application 1305 where the scan can be conducted. The results of the scan can be transmitted back 1312 to remote application 1304, as well as the genetic usage data 1313 necessary for coordinating licensing agreements. The remote application 1304 can transmit the genetic usage information 1314, as well as transmit the results of the testing 1315 back to control server 1301. The results of the test can be sent 1316 to the original requester 1307. Similar to the embodiment shown in FIG. 13, control server 1301 of FIG. 14 can determine the rights holders 1302 of proprietary biomarkers or tests and transmit the information concerning the test 1323 to the rights holders 1302. Licenses can be obtained 1322 from the rights holders, and transferred 1321 to the third party 1303 that carried out the genetic testing, along with the genetic usage information 1320 concerning the tests carried out. In FIG. 14, the third party scan application 1305 is owned by a third party, and not the owner of the control system. The requestor, or a separate payer party, can make a payment 1318 to the control server 1301. This payment can include the costs of testing, which can be transferred 1319 to the third party 1303 that carried out the test. The payment from the requester can also include licensing fees, which can be paid as royalties 1324 by the control server 1301 to the rights holders 1302. As discussed herein, to protect privacy, the scanning application 1305 can be collocated on a cloud or server 1325 with the GDSS 1306 behind a firewall or other security 1326. In some embodiments, all of the payment, licensing and other functions of the system can occur on the opposite side of the firewall 1326.

[00204] As discussed herein, the order of the events shown in FIG. 14 can be varied. For example, the payment of licensing fees and royalties may occur before the genetic testing. In some embodiments, the control server can obtain licenses for proprietary genetic tests or biomarkers before any requests are made that implicate the proprietary information. In some embodiments the payment from the requestor can be made in separate transactions, such as a payment covering the licensing fees first, and payment for the genetic testing second. It will be understood that some of the steps shown can be omitted. For example, the genetic testing fee can be negotiated and accounted for between the requestor and third party directly, without the use of the control server.

[00205] As discussed herein, the genetic scanning need not be carried out by a third party. As shown in FIG. 15, a remote application 1404 in communication with control server 1401 can carry out the genetic testing directly, without a third party scanning application. A requester 1406 can transmit the request for a genetic test 1407 to control server 1401. The control server can be collocated with GDSS 1405 on a cloud or server 1419 behind firewall 1420. The control server can transmit the request 1408 to remote application 1404. The remote application can make a request for a patient's genetic data 1409 to GDSS 1405. The GDSS can transmit the genetic information 1410 back to the remote application 1404 for scanning. After scanning the data, the results of the test can be sent 1411 to control server 1401. The genetic usage information 1412 can also be sent to control server 1401. The control server 1401 can transmit the genetic usage data 1413 to the rights holders 1402 of proprietary biomarkers or tests that were used. Licenses for use of the proprietary information can be obtained 1414. The results of the genetic tests can be sent 1415 to the requester 1406. The requester or payer party 1406 can make a payment 1421 through control server 1401. This payment can include royalties which can be transferred 1416 to the rights holders 1402, and payment for use of the genetic data storage server, which can be transferred 1417 to the owner of the GDSS 1403. In the system described in FIG. 15, it will be understood that the GDSS 1403 is owned by a third party, and not the owner of the control server. Genetic usage information can also be sent 1418 to the owner of the GDSS 1403 if necessary to account for the costs. [00206] In some embodiments, the system can be configured to determine new biomarkers for a genetic disease. Because several of the genetic tests may be run multiple times, the system can automatically determine if a new biomarker exists. For example, the system can be configured to automatically start searching for a new biomarker for a particular disease associated with a known biomarker whenever the number of tests for the known biomarker exceeds a pre-set number. In some embodiments, the pre-set number can be 500. In other embodiments, the pre-set number of tests for a given biomarker can be between any of 200-500, 400-600, 500-1000 or more, before the system can automatically start to search for new biomarkers.

[00207] The genetic data of many patients can be saved into the system as explained above. The genetic tests run on each of the patients, along with the results of the test, can also be saved. Using the results, and the genetic data saved into the system, a search for a new biomarker becomes possible.

[00208] For example, in one non-limiting embodiment, once 500 tests for a particular biomarker associated with a particular disease are run, the system can search for a new biomarker for the same disease. The system can separate the patients that have been tested for the disease into a subgroup, and search only those patients that have been tested for the particular biomarker, as these patients are known candidates for the disease.

[00209] By searching only the subgroup of patients that have been tested for a particular biomarker associated with a disease, the search becomes significantly faster and more reliable. Without breaking the population into particular subgroups, there would be so many possible associations that the system would return false positives. To prevent the return of false positives, a very low p-value as demanded by the Bonferonni Criteria would be required, which may be impossible to achieve. By using only the subgroup that has been tested for a particular disease, the demands are relaxed. For example, if there are 100 diseases being tested, a p-value can be 100 times larger using subgroups than without using the subgroups.

[00210] In some embodiments, the test for a new biomarker can be repeated each time a new test for a particular disease is ordered. This can be done to ensure the reliability of a biomarker found in the initial search, or to continue the search for a new biomarker. Because each new test creates a larger subgroup of patients for searching, the search for a new biomarker becomes more reliable.

[00211] Without the system described herein, each time a new test is ordered, and the biomarker search repeated, every new patient will have to be compared to every patient in the subgroup. If 50 new tests are ordered for a particular biomarker or disease, and there were 500 previous tests for the same biomarker or disease, 50 new correspondence tests would need to be run, each with over 500 patients having millions of nucleotides in their genetic sequence. The testing would be prohibitively arduous. However, the system can be configured to determine the base pair that exists at each genetic location for each patient, determining the number of A bases, C bases, T bases and G bases for each location. When a new test is ordered, the system can determine the new patient's base pair at each location and add this base pair to the appropriate tally. Only one of the counts for each location needs to be updated for each new test. The updated tallies can then be used in determining a correlation to a possible new biomarker. By tallying the base pairs in this manner, the system can increase the speed of the search for new biomarkers by a factor equal to the total number of patients for whom a test has been ordered. For example, if 500 patients have been tested for a particular disease, the search for a new biomarker can be 500 times faster using the system described herein. Instead of each correlation test being run for each of the 500 patients, only one test needs to be run using the tallies at each location.

[00212] In any embodiment, each of the functions for determining a new biomarker can take place in any module of the system. For example, the control server can create and update the list of patients for each subgroup that has been tested for a particular biomarker or disease; the genetic data storage server can keep and update the tally of the number of base pairs at each location for each subgroup, and the remote application can determine the correlation between a new biomarker and a disease. In other embodiments, the control server, remote application, or genetic data storage server can conduct each of the tasks described. The location of each of the tasks is not critical to the invention.

[00213] In any embodiment of the invention, the proprietary records database can be configured so that an owner of proprietary information can input this information into the proprietary records database without disclosing this information to any other parties. The system can allow a proprietary information owner to upload proprietary information and the system can automatically encrypt the information, so that no other party has access to the uploaded information. In any embodiment of the invention, the encryption can be such that even the operator of the overall system does not have access to the proprietary information. This system allows the owner of proprietary information to run a medical test on information in the patient information storage server or the genetic data storage server, without the need to disclose to the system or any party the proprietary information. As opposed to known methods of using proprietary information in medical testing, which requires a new genetic sequencing each time the patient requests a test from a different proprietary information owner, the system described herein allows for a single genetic sequence to be obtained for a patient, and all proprietary information owners can run genetic tests using that single genetic sequence.

[00214] FIG. 16 shows a system configured to allow for genetic or other medical testing on patients using proprietary information. A testing laboratory 1501, such as an independent genetic testing service, or any other source of patient clinical information, can upload the patient genetic or other medical information to a patient information server 1502 as explained herein. The information can be uploaded to patient information server 1502 through a web portal 1515, an application, or by any method known in the art. A patient or clinician 1509 can then order a test regarding the information in the patient information server 1502, including a test requiring proprietary information. In any embodiment, this test request can be sent directly through a user interface associated with the system, or the request can be made through a patient' s electronic health records or electronic medical records.

[00215] A proprietary information owner 1507 can upload the information necessary to conduct the testing to a biomarker research data server 1504. The information can be entered through a web portal 1512 or other application. The application 1512 can automatically encrypt the uploaded information as shown in FIG. 16, ensuring that no other party has access to this information. For example, a test for an SNP, shown as 1510 can be encrypted as shown in 1511. One skilled in the art will understand that other variations besides SNPs can be encrypted in a similar fashion. In any embodiment, the system can include options allowing the proprietary information owner to inform doctors, patients or payer parties of the existence of a particular proprietary test which can be saved to a proprietary information marketplace 1503. This information can be sent to physicians or patients through web portal 1518. Results of the testing can be transmitted to physicians or patients through application 1519.

[00216] In any embodiment of the invention, the testing can be carried out by a program located on the biomarker research data server 1504. The program can unencrypt the proprietary information automatically, and use the proprietary information to scan the information in the patient data server 1502 for a particular patient. Because the unencryption and scanning is carried out automatically by the system, no party ever needs access to the information in the proprietary biomarker research data server 1504. That is, the biomarker research data server 1504 can act as a black box, wherein proprietary information is uploaded into the black box, used in medical testing, and is never disclosed outside of the black box.

[00217] In any embodiment of the invention, the encrypted information in the biomarker research data server 1504 can be in any form. In any embodiment of the invention the encrypted information in the biomarker research data server can comprise a list of specific locations in a genetic sequence and the specific base pairs in that location or locations corresponding to a particular outcome, as shown in FIG. 16 as 1510. In any embodiment of the invention, the information in the biomarker research server 1510 can be a series of logic instructions for the system to carry out. For example, the system may be instructed to determine the presence of a specific genetic mutation in the genome of a patient. If the mutation is present, the system can then be instructed to determine the presence of a second mutation, or to search the patient information database for specific medical information, such as hospitalization or symptoms. Only if all logic steps are met would the system output a specific outcome from the testing. [00218] In any embodiment of the invention, the output of the testing can take any form. In any embodiment of the invention, the output can be the presence of a particular disease or condition, a risk factor corresponding to a probability that a patient will develop a particular disease or condition, or an optimal course of treatment, such as a particular course of drugs that will work better for the particular patient as a result of the genetic or other medical information of the patient.

[00219] When a patient or physician 1509 orders a proprietary test for information in the patient data server, the test pricing can be sent to a payer party 1506 through web portal or application 1517. The payer party 1506 can make a payment through application or portal 1516, which can be accounted for by a biomarker escrow server 1505. The fee charged for using the proprietary test can be transferred to the proprietary information owner 1507 through application 1513, as explained herein. Neither the physician, patient or payer party needs to see or have access to the proprietary information. The system can provide an output to the user, but the users would not be able to determine how the output was generated. Although shown as different parties in FIG. 16, one of skill in the art will understand that the patient can act as a payer party 1509.

[00220] In any embodiment, the system can monitor and maintain control over payments, usage of testing, available tests or any other information through a control server 1508 operating through web portal or application 1514. In any embodiment, the system owner can receive any necessary payments obtain any necessary data through the control server 1508. One of skill in the art will understand that the system can be set so that the owner of the system does not have access to unencrypted genetic testing information.

[00221] Although the patient data server, the biomarker research data server, the biomarker marketplace server and the biomarker escrow server are shown as separate servers in FIG. 16, one of skill in the art will understand that in any embodiment any two or more of these functions can be carried out by a single server. Because the proprietary information is encrypted prior to entering the biomarker research data server, no party using the system can have access to this information.

[00222] Although the patient and proprietary information is generally explained with regard to genetic information, one of skill in the art will understand that the system is not necessary limited to genetic information. In any embodiment of the invention, the patient data can comprise any medical data of the patient, including medical history, demographic data, familial history, and insurance information, any of which may be linked to a particular condition or optimal course of treatment. The condition or optimal course of treatment indicated by any patient information may be considered proprietary information by any party that has linked any of the patient information to a particular disease or optimal course of treatment.

[00223] The method of encryption used for encrypting the proprietary information can be any encryption method known in the art. Non-limiting examples of encryption technology that can be used include AES, Blowfish, CAST, GOST 28147-89, RC-6, Serpent and Twofish. One skilled in the art will understand that other encryption methods that can protect proprietary information uploaded into the system exist, and are within the scope of the invention.

[00224] FIG. 17 shows an embodiment describing the process encrypting a genetic test for use with the invention. A proprietary information owner can input a genetic sequence 1601 corresponding to an outcome for a patient, including the position of the particular variant in the genome. The system can automatically encrypt the genetic sequence and location information as listing 1602. The encrypted sequence can then be transmitted to a proprietary data server 1603, as explained herein. In any embodiment of the invention, the encryption can be a one-way encryption. The genetic sequence and location data can be encrypted into an encrypted string of data, but the encrypted string of data cannot be used to recreate the original genetic sequence. In any embodiment of the invention, any method of encrypted the genetic sequence can be used. In any embodiment of the invention, the loci of the particular base pairs can be shuffled during the encryption to make unencryption more difficult.

[00225] FIG. 18 shows one embodiment of using the encrypted test to determine the presence or absence of the genetic sequence in the genome of a patient. The encrypted genetic test 1702 can be retrieved from the proprietary data server 1701 and transmitted to a comparer 1703. A patient's genetic information can be transmitted from a patient data server 1705, and subjected to the same encryption method as used to encrypt the original genetic test, generating an analogous encrypted sequence 1704. The encrypted patient genetic data can also be transmitted to the comparer 1703. The comparer 1703 can compare the two encrypted sequences to determine whether the sequences match, or whether the search logic of the genetic test is present in the patient sequence. In any embodiment, the comparison can be carried out by a scanning operation running on the described system, and the comparer 1703 can be omitted.

[00226] FIG. 19 shows a second method of using the encrypted test to determine the presence or absence of the genetic sequence in a genome of the patient. In embodiments of the invention that use a two-way encryption technique, an encrypted genetic test 1802 stored in a proprietary data server 1801 can be unencrypted when a patient or physician orders the test. The original genetic sequence 1803 can be reconstructed at transmitted to a comparer 1804. The patient's genetic information can be transmitted from a patient data server 1805 to the comparer 1804. The comparer 1804 can compare the two sequences to determine whether the two sequences match, or whether the search logic of the genetic test produces a match. Because the unencryption is carried out automatically by the system, no party has access to the unencrypted genetic test 1802, preserving the proprietary nature of the information.

[00227] One skilled in the art will understand that the genetic test need not be a single portion of a genome. Multiple portions of the same genome may be necessary to determine the effects of the genetic variants on the health or treatment of the patient. In any embodiment of the invention, multiple genetic portions making up a single test can be encrypted together, or the multiple genetic portions can be encrypted separately, using the same or different encryption techniques. One skilled in the art will also understand that the genetic test may comprise logic instructions, such as if, then instructions. These instructions can also be encrypted. The comparer can determine if a first portion of the genome matches the test, and then repeat the process with a second portion of the genome. In any embodiment of the invention, the test can comprise any number of steps, including 2, 3, 4, 5 or more steps to determine an outcome.

[00228] Although shown as a separate component in FIG.'s 18 and 19, the comparer need not be a separate component. In any embodiment of the invention, the comparer can be a program designed to run on the patient data server, the proprietary biomarker server, or any other portion of the system.

[00229] In any embodiment of the invention, the interface between the proprietary information owner and the system can be in the form of a web portal. The proprietary information owner can log into the system, upload the proprietary information, and the system will automatically encrypt the information before placing the information on the biomarker research server. The same web portal can be used by the proprietary information owner to track usage of the proprietary information and collect payments or royalties for the use of the proprietary information. In any embodiment of the invention, the proprietary information owner can have access to the proprietary information stored in the system. The proprietary information owner can be given a specific key for unencrypting the information for the purposes of adding new information, updating the existing information, or removing information from the system. In any embodiment of the invention, the proprietary information owner can have the option of allowing access to the proprietary information to one or more other parties, such as for the purposes of gaining FDA approval for a test, or disclosing the information publically.

[00230] Although the genetic testing system described herein has been described with respect to DNA information, either germline or somatic cell DNA, the system is not limited to DNA information. Next generation sequencing can additionally be used to sequence RNA molecules, which have been shown to reveal previously unknown transcripts and splicing isoforms, and provide quantitative measurements of alternatively spliced isoforms. RNA sequencing expands the possibilities of studies to the analysis of gene isoforms, translocation events, nucleotide variations, and posttranscriptional base modifications. In any embodiment of the invention, RNA information from patients and proprietary or non-proprietary RNA testing information can be used in the described systems.

[00231] In any embodiment, the RNA sequencing can be accomplished by using known sequencing technology to produce cDNA molecules reversibly transcribed from the original RNA. The relative abundance of individual transcripts, splice variants, isoforms, novel transcripts, and chimeric transcripts can be determined from mapped RNA sequences. Using RNA sequencing allows for qualitative data concerning the identity of mutations, transcription sites, expressed transcripts, and exon/intron boundaries, along with quantitative data concerning differences in expression, alternative splicing, alternative TSS, and alternative polyadenylation between two or more patients or treatments. Each of these types of information can be indicative of one or more genetic characteristics of a patient, and can be included in the genetic testing systems described herein.

[00232] FIG. 20 shows an example of how the system described herein may be implemented. A specimen may be sent to a sequencing laboratory 1901 in order to carry out sequencing of a genetic sample with a sequencer 1902. The resulting sequence can be uploaded to the system 1907 through a bioinformatics pipeline 1908 using application 1903, as described herein. As shown in FIG. 20 the sequence can be uploaded in the form of a FASTQ sequence, however, one of skill in the art will understand that the genetic sequence can be uploaded in any form known in the art.

[00233] An individual or physician 1910 can request a genetic test on the genetic sample. As shown in FIG. 20, the request can be made as a prescription through an electronic medical record 1912 through electronic medical records interface 1911, however the request can also be made by an individual or doctor through any method known in the art. The request can be sent to the described system 1907 to carry out a genetic test.

[00234] A proprietary rights holder 1904 may upload information necessary to carry out a genetic test from a proprietary database 1905 or any other source, as described herein. The proprietary information may be encrypted using any known encryption method 1906 and uploaded to the system 1907. The encrypted information may be kept in a "black box" 1908, as described herein, in order to maintain the proprietary nature of the information. The system 1907 can carry out the prescribed test and return a result to the patient or physician 1910. As shown in FIG. 20, the result may be sent directly to the patient' s electronic medical records 1912.

[00235] As shown in FIG. 21 , the system described herein provides for the ability to carry out multiple tests for a patient. Multiple databases 1905 containing information necessary to carry out genetic tests can be uploaded to the system 1907, each into a black box 1909 that provides protection of the proprietary information. In any embodiment, the multiple databases can come from a single proprietary information owner 1904 or from multiple proprietary information owners. A hospital or individual 1910 can create multiple requests for genetic testing of a patient with all requests made through the single system 1907 described herein. As described, the multiple genetic test requests can take the form of prescriptions from a patient's electronic medical records 1912 through interface 1911. A single sample may be sequenced by the laboratory 1901 and uploaded to the system 1907. Any number of genetic tests using proprietary information can be carried out using the single genetic sequence. Because the multiple tests can be carried out on a single sequenced sample, the uploaded patient sequence serves as a single "point of truth" for conducting genetic testing, reducing errors caused by multiple sequences for the same patient.

[00236] FIG. 22 shows a non-limiting example of payments that can be accounted for by the described system. Patient' s 1910 may pay for each genetic test carried out, as represented by arrow 1913. The sequencing laboratory 1901 may be paid for the sequencing of the genetic sample as represented by arrow 1915. The proprietary rights holder 1904 may be paid for usage of the proprietary information, as noted by arrow 1914. In any embodiment, sequenced data may be provided to the proprietary rights holders 1904 or researchers in order to determine new possible genetic tests, as represented by arrow 1916.

[00237] In any embodiment, the testing of patient data can be carried out by a standalone application, as shown in FIG. 23. The remote client or control server 2003 can receive a request to carry out a medical test on a patient whose records are located in a patient records database 2001, as represented by arrow 2004. The remote client or control server 2003 can call a standalone application 2002 that contains instructions for conducting a medical test, as represented by arrow 2005. In any embodiment, the standalone application 2002 can contain all of the instructions, scripts or discrete steps required to execute a medical test or a collection of medical tests, such as a genetic test, without the need to reference a database such as a GDIS. In any embodiment, the standalone application 2002 can contain only some of the instructions, scripts or discrete steps required to execute a medical test or a collection of medical tests and may require additional information or instructions from a database (not shown in FIG. 23) to complete the genetic test or tests.

[00238] In any embodiment, the standalone application 2002 can access the patient records database 2001, as represented by arrow 2006 to obtain the patient records necessary for conducting the requested test, such as the patient's genetic sequence. The required patient records can be transmitted to the standalone application 2002 as represented by arrow 2007. The standalone application 2002 can run the internal instructions to execute the medical test. In any embodiment, the standalone application 2002 can produce a test result as a test report document or as test result data. The test results can be transmitted to the remote client or control server 2003 as represented by arrow 2008. In any embodiment, the standalone application 2002 can additionally or alternatively transmit the test results to third party software or a user (not shown). The test results can be transmitted by the remote client or control server 2003 to the original requestor as shown by arrow 2010.

[00239] In any embodiment, the RCA can be the standalone application described herein and can contain the instructions, scripts or discrete steps to execute a genetic test or a collection of genetic tests without the need to reference a database. In any embodiment, the remote client can contain some of the instructions; scripts or discrete steps required to execute a genetic test or a collection of genetic tests and may require additional information or instructions from a database to complete the genetic test or tests. In any embodiment, the remote client as the standalone application can produce a test report document or as a test result data provided to another application or a user. In any embodiment, the system can include a collection of precompiled or uncompiled software applications callable by a user or an automated system, such as the RCA, to accomplish one or multiple genetic tests.

[00240] FIG. 24 illustrates a non-limiting embodiment of the use of an encrypted test by the described systems. A third party test owner 2101, such as a proprietary rights holder, can create a new unencrypted test entry 2102, which may include proprietary information and instructions for carrying out a medical test. The unencrypted test entry 2102 can be input into the system through an API, Web Portal, Script or uploaded text file, as represented by arrow 2106. The unencrypted test

2102 can be encrypted upon entry to generate an encrypted test entry 2103, such that only the test creator may access the proprietary instructions, as shown by arrow 2107. The encrypted test entry

2103 can be stored in a biomarker server 2105, as explained herein. The encrypted test entry 2103 can be retrieved by a remote client (not shown) on a per test basis, as explained herein, and can be used by the remote client to carry out the medical test, as shown by arrow 2108.

[00241] In any embodiment, the biomarker server can be located outside of the system, as illustrated in FIG. 25. A third party test owner 2201 can create a new unencrypted test entry 2202, as represented by arrow 2207. The unencrypted test entry 2202 can contain the instructions necessary for carrying out a medical test and interpreting the results. The unencrypted test entry 2202 can be stored in a biomarker server 2203, as represented by arrow 2208. In any embodiment, the unencrypted test entry 2202 can be encrypted prior to storing the test entry in the biomarker database 2203. In any embodiment the unencrypted test entry can encrypted as encrypted test entry 2205 after storage in the biomarker server 2203.

[00242] When a medical test is requested encrypted test entry 2204 can be requested by a remote client or control server 2206 from the biomarker server 2203, as represented by arrow 2209. The test can be requested by the remote client 2206 on a per test basis, and can be requested through an API, web portal, script or text file 2204. The encrypted test entry 2205 can be retrieved through the API, web portal, script or text file 2204 on a per test basis and decrypted and used by the remote client or control server 2206 to execute a test on information stored in a patient information database (not shown).

[00243] The proprietary biomarker testing system described herein provides numerous advantages to all parties, some of which are illustrated in FIG.'s 26-28. FIG. 26 shows the process wherein a third party conducts both genetic research and genetic sequencing. As shown in FIG. 26, a patient that has not yet had a genome sequenced 2301 can have their genome sequenced by a third party sequencer 2303. The patient's genome can be sequenced and stored with the proprietary biomarker testing system 2305, as described herein. As required, a physician or medical practice 2302 can request one or more genetic tests from the testing system 2305, with payment made on a per test basis. In any embodiment, the physician or medical practice 2302 can be affiliated with the third party sequencer 2303, but affiliation is not necessary. The third party, acting as a researcher or proprietary rights holder 2304 can also store in the system 2305 one or more proprietary genetic tests, which can be encrypted to protect the information as described herein. The system 2305 can use the proprietary information to conduct the genetic tests, returning a result to the physician 2302. The third party can be paid for the genetic sequencing carried out by the third party lab services 2303, as well as a licensing fee or royalty payment for the use of a proprietary test from the third party research services 2304. The described system allows for a third party to ensure that proprietary information is protected, while allowing the proprietary information to be used in genetic testing. Further, depending on agreements with patients, the third party research services 2304 may obtain additional genetic sequences from the patient 2301 to conduct further genetic research.

[00244] As illustrated in FIG. 27, the system creates several benefits, even if the genetic sequencing is carried out by a different party than the proprietary rights holder. As shown in FIG. 27, a patient 2401 may have a genetic test carried out by a fourth party laboratory 2403, that is unaffiliated with a third party researcher 2405. The genetic sequence of the patient may be stored on a patient data server as part of the proprietary testing system 2404 described herein. The third party researcher or rights holder 2405 can upload a genetic test as described herein to the system 2404. A physician 2402 or individual may order testing through the described system 2404 as described herein, including proprietary tests developed by the third party researchers or rights holders 2405. The sequencing laboratory 2403 can be paid for sequencing services, while the rights holders 2405 can be paid royalties or licensing fees for the use of the proprietary test. The use of the single testing system 2404 described herein allows the third party to access customers of different sequencing laboratories, providing additional royalty revenues without utilizing existing assets. The sequencing laboratory and affiliated physicians can gain access to use the third party's genetic tests, without the ability to reverse engineer the test.

[00245] FIG. 28 illustrates benefits of the described system for patients 2501 that have already had their genome sequenced and entered into the testing system 2503. A physician can order genetic testing from the described system 2503, including the use of proprietary genetic tests previously entered into the system by the third party researchers or rights holders 2504. Thus, even for patients who have already had their genome sequenced, the third party rights holders 2504 may obtain additional royalty revenues without utilizing existing assets such as genome sequencers. The system and method for encoding a script to query the patient's genetic sequence is shown in FIG. 29. In particular, the method of creating a new biomarker script is shown in box 2601 of FIG. 29.

[00246] To create a new biomarker script 2601, a new biomarker entry can be created 2604 in a biomarker script database 2602. A list of SNPs and associated mutations that are linked to the biomarker can be created 2605 in the biomarker script database 2602. An interpretation list linked to the new biomarker can be created 2606 in the biomarker script database 2602. The list of SNPs and associated mutations can include such information as the mutation value and where to look in the sequence for the mutation. The interpretations list can include such information as risk factors based on each mutation and confidence intervals for combinations of SNP mutations found. The biomarker is able to combine various SNPs and mutations within the same gene or from multiple genes to calculate a single risk value based on this combination of multiple factors.

[00247] The biomarker scripts of the present invention confer advantages over tests that determine outcomes based on protein or enzymes. Unlike protein or enzyme levels, which can vary with time, the patient's genome is static. As a result, a patient's genome only needs to be scanned a single time. By contrast, tests that measure protein or enzyme levels may need to be repeated several times to account for changes in protein or enzyme levels. Further, once a genetic scan is completed, any biomarker can be searched in the future using the same genetic scan.

[00248] In any embodiment, the biomarker script can be the equivalent to any known enzyme or PCR based diagnostic test kit. For PCR based test kits, this can be accomplished by using the probes utilized by known diagnostic test kits as the list of SNPs in the biomarker script. For enzyme tests, the equivalence can be accomplished by determining the identity of an expression quantitative trait loci (eQTL) corresponding to the particular enzyme or enzymes. The eQTLs are the regions of the genome that cause the particular enzyme to be expressed. An enzyme based test may determine a genetic disorder by measuring the levels of the enzyme in the patient' s blood. A biomarker script of the present invention can instead search for the underlying mutation in the patient's genome that causes the discrepancy in the enzyme levels. In other embodiments, the biomarker script can be different from known diagnostic test kits.

[00249] An example of a list of SNPs and mutations associated with a particular biomarker is shown in Table 1 for breast cancer. Each of the mutations shown in Table 1 corresponds to a particular location in the genome where a mutation is associated with an increased risk of breast cancer. The mutations are defined according to the location of the mutation in the genetic sequence, and which bases in the location correspond to an increased risk of the disease. The list, including the location, mutation and matching criteria can be created in the biomarker script database 2602.

TABLE 1

B CA1 gene SNP Mutation Matching Criteria

rs766173 G Either Position in SNP Pair rsl44848 G Either Position in SNP Pair rs4987117 T Either Position in SNP Pair rs2799954 T Either Position in SNP Pair rsl l571746 c Either Position in SNP Pair rsl l571747 c Either Position in SNP Pair rs4987047 T Either Position in SNP Pair rsl l571833 T Either Position in SNP Pair rsl801426 G Either Position in SNP Pair

ATM gene SNP Mutation Matching Criteria

rs3218707 C Either Position in SNP Pair rs4987945 G Either Position in SNP Pair rs4986761 C Either Position in SNP Pair rs3218695 A Either Position in SNP Pair rsl800056 C Either Position in SNP Pair rsl800057 G Either Position in SNP Pair rs3092856 T Either Position in SNP Pair rsl800058 T Either Position in SNP Pair rsl801673 T Either Position in SNP Pair

CHEK2 gene SNP Mutation Matching Criteria

rsl7879961 C Either Position in SNP Pair

TP53 Mutation Matching Criteria

rsl042522 G Either Position in SNP Pair

[00250] An example of an interpretation list for the BRCA gene is shown in Table 2. The interpretation list can determine the increase in risk of a particular disease, such as breast cancer, based on the mutations found in the patient's genetic sequence. The risk factors in Table 2 are shown as multiples representing the increase in risk due to the patient having the genetic mutations. The low and high confidence intervals represent the 95% confidence levels of the risk factors. A patient that has no mutated SNPs, by definition, has a risk factor of 1. Patients with one or more of the listed SNPs have a higher risk of developing cancer in their lifetime. A unique interpretation list for each diagnostic test available can be created in the biomarker script database 2602.

TABLE 2 1 1.46X 0.89X 2.40X

2 1.39X 0.86X 2.25X

3 1.75X 1.09X 2.80X

4 1.56X 0.95X 2.55X

5 1.31X 0.76X 2.24X

6 1.84X 1.04X 3.26X

7 2.10X 1.06X 4.16X

8 4.02X 1.56X 10.38X

9 or more 8.04X 1.89X 34.26X

[00251] In some embodiments, the list of SNPs in the biomarker script and the interpretation list can be the same as what is provided for by known or commercially available test kits. One example of such a test kit MammoPrint by Myraid Genetics. The same SNPs that are searched for with the test kit can be made part of the SNP list of the present invention. The same interpretations provided by the test kit can be made part of the interpretation list of the present invention. In this way, the encoded biomarker script would be the equivalent of the known test kits.

[00252] Once the biomarker entry has been created with the list of SNPs and interpretations, the system scan a sequence for a biomarker, as shown in box 2603 in FIG. 29. At the start of the scan 2607 a prescription for a particular genetic sequence to be scanned is created 2608. Based on the prescription, the system can retrieve the particular genetic sequence from a genetic sequences database 2609. The genetic sequences database can in some embodiments be a remote database, separate from the biomarker script database 2602. In other embodiments, the genetic sequences database can be local to the biomarker script database 2602. In some embodiments, either one of the genetic sequences database or biomarker script database 2602 can be embedded within the other.

[00253] The biomarker information can be retrieved 2610 from the biomarker script database 2602. The list of SNPs and associated mutations can be retrieved 2611 from the biomarker script database 2602. Using the list of SNPs, the system can scan the genetic sequence and locate the position of one of the SNPs 2612. The system can determine if the SNP is found in the genetic sequence file 2613. If the SNP is found in the genetic sequence file, the system can then compare the base pair at the particular location in the sequence to the mutation definition in the list of mutations 2614. The system determines if a mutation is detected at the particular location 2615, and if so increments a positive mutation counter 2616. The system next determines if there are any other SNPs associated with the biomarker 2617. If there are any more SNPs associated with the biomarker, the system again determines if the next SNP is found in the genetic sequence file 2613. If any mutation is not detected, or if any SNP is not found in the genetic sequence file, the system can skip to step 2617 without incrementing the positive mutation counter, and can determine if there are any other SNPs associated with the biomarker. [00254] Once all SNPs associated with a biomarker have been searched in the genetic sequence, the system can retrieve the interpretation list 2618 from the biomarker script database 2602. The system can look up the positive mutation counter value determined in step 2616 and find the corresponding risk value in the interpretation list 2619. The results can be returned 2620 and the process ended 2621. In any embodiment, the results can include one or both of the risk factor and the mutations detected at each SNP.

[00255] A physician can create a prescription using the secure log-in as explained above. A screenshot step of creating a prescription is shown in FIG. 30. The physician can enter in a physician ID 2701 which will allow the physician to access the information in a particular sequence. The physician can also enter a patient ID 2702, which identifies the particular sequence to be tested. The biomarker ID 2703 can be entered, which determines which biomarker script the system will use. Finally, the physician can enter whether this is a new or tumor specific scan 2704. This informs the system whether a specific tumor is being scanned, which can determine which SNPs are of particular value. In some embodiments, the prescription can be created automatically from the patient's electronic medical records. This can be done using a third party application interface to automatically create the prescription in the system.

[00256] After the physician creates the prescription, the system can automatically locate the patient's genetic sequence and the necessary biomarker script. Upon retrieval of the sequence and biomarker script, the system can automatically scan the patient's sequence as explained in FIG. 29. A screenshot of the system during the retrieval and scanning processes is shown in FIG. 31. This screen can notify the physician that the requested patient sequence is on file in the database and that the test is being or will be run. Depending on the capacity of the system, the scanning process can be completed in less than two seconds.

[00257] FIG. 32 shows a screenshot of the results output after running the scan. The test results can be provided to the prescribing physician or to the patient. The output includes the overall risk factor 2801 and the 95% confidence intervals 2802. In any embodiment, the output can also include the particular locations searched 2803, the result of the search at those locations 2804, the mutation 2805, the genotype found 2806, and the criteria to be counted as a mutation 1007. It will be understood that not all of the information provided in FIG. 32 needs to be included, and that any output providing the results of the genetic test are within the scope of the invention.

[00258] As can be seen in FIG. 32, the particular sample genetic sequence did not test positive for any of the mutations shown in Table 1. As such, the patient's risk factor for breast cancer based on the test is IX, by definition.

[00259] An example of an output provided for a patient that does test positive for some mutations is shown in FIG. 33. As can be seen, the patient tested positive at the positions rs 16942 2901, rs766173 2902, and rsl44848 2903. Because three positive mutations were found, the system reported the risk factor from Table 2 corresponding to three mutations, and returned that the patient had a breast cancer risk factor of 1.75X with 95% confidence intervals between 1.09X and 2.80X.

[00260] Next generation sequencing techniques have reduced the costs and time necessary to obtain a genetic sequence of a subject. These techniques generally use short read data in order to determine the genetic sequence of a subject. Next generation sequencing techniques utilize short sequences, typically between 10-100 base pairs. Because of the short read sequences used in next generation sequencing, the techniques cannot reliably detect large mutations in a genetic sequence.

[00261] Structural variants in a genetic sequence can result in adverse health effects for a subject. FIG. 34 shows the types of mutations that can lead to an increased risk of disease. Deletion of a base pair is shown by 3001. The original sequence 3006 included a base pair T 3008 in the sequence. The mutated sequence 3007 does not contain the base pair 3008. Insertion of a base pair is shown by 3002. The original sequence 3009 can be changed into mutated sequence 3010 by insertion of a base pair 3011. A mutation of a base pair is shown by 3003. The original sequence 3012 includes base pair T 3014. The mutated sequence has base pair G 3015 at this location. These variants lead to a base pair in a genetic sequence that is different than the typical base pair at the same location. A copy number variation is shown by 3004. The original sequence 3016 has the base pairs ACTA 3018 repeating twice. The mutated sequence 3017 has base pairs 3018 repeating four times. Copy number variants may be caused by structural rearrangements of the genome, such as deletions, duplications, inversions and translocations. Low copy repeats are particularly susceptible to such genomic rearrangements resulting in copy number variants. Factors such as size, orientation, percentage similarity and the distance between copies influence the susceptibility of low copy repeats to genomic rearrangement resulting in copy number variants.

[00262] A translocation is shown by 3005. A portion 3023 of a sequence 3019 switch with a corresponding portion 3024 of the complimentary sequence 3020. The result is mutated sequences 3021 and 3022, wherein the portions 3023 and 3024 have been translocated to the complimentary sequence. An inversion is shown by 3029. The original sequence 3025 has the base pairs shown by 3027 as ATC. The mutated portion of the sequence 3026 has this portion inverted as CTA 3028. One of skill in the art will understand that any of the mutations described herein can involve sequences larger than shown in FIG. 34. Insertions, deletions, copy number variations and translocations can involve sequences that are hundreds or thousands of base pairs long.

[00263] Table 3 shows an abbreviated listing of some large structural variants that are known to cause disease. One of skill in the art will understand that this is not an exhaustive list. Any embodiment of the invention contemplates detection of any structural variants, including those known to cause cancer, neurodegenerative disease, cardiovascular disease, mood disorders or any other Mendelian disease that can be diagnosed from germline DNA.

Table 4 Structural Variants Leading to Known Diseases

[00264] Because next generation sequencing cannot reliably detect variants in a genetic sequence that are significantly lager than the read length used in the sequencing, additional techniques are necessary to determine whether large structural variants are present in a sequence decoded using short read data.

[00265] Certain genetic structural variants are inherited with other co-varying parameters. That is, a large insertion or deletion may tend to be inherited with another structural variant that may be more readily detectable with next generation sequencing techniques. As such, the presence of the co-varying parameter can be used as a predictor of the large structural variant. These co-varying parameters may be more readily detected in genomes sequenced by next generation sequencing techniques. Therefore, it is possible to predict the presence of a large structural variant that cannot be readily detected in genomes sequenced by next generation sequencing techniques based on more readily detectable co-varying parameters. These co-varying parameters can provide a useful way to detect the larger variants even when using small read data to prepare the original sequence. The co- varying parameters can be insertions, deletions, duplications, copy-number variants, inversions and translocations all of any size,

[00266] As described herein, certain parameters can co-vary with large structural variants that can cause disease. There are several techniques that can be used to determine these parameters. One non-limiting technique that can be used to determine parameters that co-vary with large structural variants is machine learning. Machine learning is a technique wherein a computer determines patterns in a complex system. For example, several whole or portions of genomes can be sequenced using traditional sequencing techniques in order to determine whether a large structural variant exists. A computer can be programmed to scan these genomes to determine whether other parameters are present in the genomes that test positive for the large structural variants that are not present in the genomes that test negative for the large structural variants. After identifying a parameter that is present only in genomes that test positive for a particular large structural variant, or that are present in a disproportionally high number of the genomes that test positive for the large structural variant, the computer can be said to have learned a co- varying parameter. One skilled in the art will understand that other methods of determining co- varying parameters can be used.

[00267] FIG. 35 shows steps that can be taken to identify co-varying parameters. As explained herein, machine learning 3101 can be used an identifying source of co-varying parameters 3104. In any embodiment, literature searches 3102 can be conducted to identify parameters 3104 determined to co-vary with large structural variants. Additionally, proprietary research 3103 can be conducted to also identify co-varying parameters 3104. The proprietary research 1603 can include searches of patents or patent applications or any other public or private sources of data. Once co- varying parameters 3104 are identified, the system can be configured to query genetic sequences to search for these parameters, thus identifying large structural variants even in genetic sequences that have been sequenced with short read data.

[00268] After identifying parameters that may co-vary with a large structural variant, a second set of genomes that contain or do not contain the large structural variant can be queried for the identified co-varying parameter. This is important in order to test the predictive value of the identified parameter. If the system properly identifies whether or not each of the second set of genomes contain the large structural variant, then the identified parameter can be used to predict the presence of the large variant. One skilled in the art will understand that there are other techniques that can be used to identify parameters that co-vary with a large structural variant. Any technique of determining parameters that co-vary is contemplated by this invention.

[00269] Once parameters are identified that co-vary with large structural variants not readily detectable by next generation sequencing techniques using short read data, new genetic tests for these large structural variants can be created. Because the new genetic tests will search for parameters that are detectable with next generation sequencing techniques using short read data, the new tests can be performed on genomes that have been sequenced with short read data. This allows for faster, less expensive, and reliable genetic testing for a variety of diseases.

[00270] The querying of a genetic sequence for the co- varying parameters can be conducted as described herein. In any embodiment, any of the querying, storage or payment functions of the systems described can be used to determine the presence of a large structural variant using a co- varying parameter. Algorithms utilizing the identified co-varying parameters can be added to the querying modules described herein to determine the presence of large structural variants even in genomes sequenced using short read data.

[00271] The systems described herein allow for the centralization of in silico testing for standardized, consistent and high quality tests without necessitating the use of single-use, kit-based assays. Further, the system and methods described herein allow for the development of computational methods for analyzing short read sequence data obtain from next generation sequencing technologies for difficult to identify mutations. Example 1

[00272] Provided herein is an example of a method for determining co-varying parameters that co-vary with the BRCA gene mutations. A number of DNA samples of Triple Negative Breast cancer can be obtained from a laboratory. Assuming a combined incidence for BRCA mutations of 30% in the samples, the odds of obtaining at least one sample with a BRCA mutation will be at least 99.9% if at least 30 samples are obtained. An additional set of DNA samples can be reserved for later testing. The samples can be de-identified, and accompanied with co-variate information, such as gender, diet, body mass index and race, in addition to complete diagnostic and treatment history. A significant number of the BRCA mutations present should be the 6kb exon 13 founder mutation duplication.

[00273] Commercially available BRCA analysis testing, such as the Myriad BRACAnalysis

Large Rearrangement test (BART), can be performed on each of the samples. Additionally, the samples can be sequenced using any sequencing platform, such as Illumina's sequencing platform. The sequencing can be targeted to the regions on chromosomes 13 and 17 that code for the BRCA genes - including a region of 10 kb flanking the genes.

[00274] As a result of the BART testing, a set of large genomic variations that are present in the samples can be identified. The results of the testing will be a set of raw images, processed sequence files, mapped sequences and called variants. The processed sequence files can be analyzed to identify genomic features of the BART test that have one-to-one correspondence to next generation sequencing variant calls. The analysis can consist of running the processed sequence files through a suite of alignment and calling tools, such as GATK or Tuxedo. One skilled in the art will understand that the same method can be used to identify any large insertions, deletions, mutations, translocations or structural variants that are indicative of any genetic diseases.

[00275] The systems described herein are not limited to analysis of germ-line DNA. In any embodiment, the systems and methods described can be used in analysis of somatic cancer cell DNA. As described herein, mutations present in somatic cancer cell DNA can have a dramatic effect on the efficacy of treatments for the cancers. The systems and methods described herein can be used for mutation calling of somatic tumor cell DNA. In any embodiment, the system can use any cell samples in order to test for mutations. The systems can utilize primary or metastatic tumor tissue. Additionally the systems can utilize tumor tissue or circulating tumor cells. In any embodiment, the systems can utilize samples from fine-needle aspiration biopsies, extensive necrotic rather than viable tumor tissue, tumor heterogeneity for mutations and other genetic abnormalities, and samples that feature a very low percentage of tumor DNA. Because next generation sequencing techniques have a significantly higher sensitivity, NGS sequencing can be used with samples in which a mutation is present in only a small percentage of the total DNA extracted from a specimen. However, as explained herein, NGS sequencing technologies cannot readily detect many larger structural variants. As such, the methods and systems described herein can be used for mutation calling in somatic tumor cell DNA that has been sequenced using short read data, by identifying and utilizing co-varying parameters as described herein.

[00276] An example of the process of testing somatic cancer cell DNA is shown in FIG. 36. A health care provider can biopsy a cancer patient tumor in step 3201. The tumor DNA can be sequenced at the point of care, or through any DNA sequencing facility in step 3202. The tumor DNA sequence and any other biological information can be added to the patient records database as explained herein in step 3203. In step 3204, the tumor cell DNA sequence can be queried for relevant mutations or other biomarkers, as explained herein for patient germline DNA. The necessary payments from the payer party to any proprietary rights holders, server owners and application owners can be processed and accounted for in step 3205. A clinical report can be generated by the system, as explained herein, in step 3206, determining the presence of any relevant mutations or other biomarkers in the tumor cell DNA sample.

[00277] The systems and method described herein can be used for diagnostics or for companion diagnostics. As an example of a companion diagnostic genetic test, the BRCA1 and BRCA2 analysis is currently being used in ovarian cancer patients to determine patients eligible for treatment with Lynparza™ (olaparib). The particular mutations present in the germ-line DNA of a patient, or in somatic tumor cell DNA can inform a physician of the cause of present or future symptoms affecting the patient. Querying the tumor cell DNA sample can be especially helpful for the purpose of companion diagnostics. As explained herein, the particular mutations present in the tumor cells can have a profound effect on the efficacy of certain treatments. By determining which mutations exist in the tumor cells, the physician can better tailor treatment to the individual patient.

[00278] In any embodiment, no matter the source of the genetic information, the system can operate as shown in FIG. 37. The testing and diagnostic system 3301 can communicate with physicians 3304, laboratories 3302, insurers 3305, and rights holders 3306. In any embodiment, a physician 3304 may prescribe a genetic test 3307 for a patient 3302, including whole genome sequencing, germline DNA testing or somatic tumor cell DNA testing. The patient can have a DNA sample sequenced 3308 by the hospital or laboratory 3302. The sequenced data can be transferred 3309 into the system 3301. The physician 3304 can inform the system of the specific genetic tests to be carried out 3310. The actual prescription for specific tests 3310 can be transferred directly by the physician 3304, or in any embodiment, through a patient's electronic medical records. The system can conduct the genetic testing 3318 using algorithms as described herein, generating a test result 3319. The result of the testing can be transferred 3311 to the physician 3304, either directly or through the patient's electronic medical records. The physician can use the results to more efficiently treat 3312 the patient 3303. [00279] In order to facilitate payment, the system 3301 can communicate the tests to be conducted 3313 to the insurers or payer parties 3305. Any necessary fees for the use of proprietary biomarkers in the testing can be transferred 3314 from the insurers 3305 to the system 3301. The system can obtain information regarding proprietary biomarkers 3317 from the rights holders 3306. As described herein, a given test, or series of tests may involve more than one rights holder. As such, the system can obtain necessary information from any number of rights holders 3306. Based on the testing, the system can inform the insurers 3305 of the costs associated with conducting the genetic testing 3315, including licensing fees or any service fees. The system can collect these fees 3316 from the insurers 3305. The system can also inform the rights holders 3306 of any proprietary information used for the testing 3320 and account for any necessary licensing fees 3321. Any service fees for use of the system can also be accounted for 3322.

[00280] FIG. 38 shows a simplified flow chart of one embodiment of the invention using electronic health records or electronic medical records. A prescription for a test 3401 can be sent to a patient's electronic health record or electronic health record 3402. An application 3403 can obtain the necessary information from the patient' s electronic records 3402 to conduct the genetic test. The system can process the prescription 3404, determining the genetic tests necessary and the patient to which the tests pertain. A second application 3406 can transmit the necessary information from the processed prescription to the genome scanning application 3407. The genome scanning application 3407 can obtain the genetic information either directly from a database or through an application 3408. The results of the genetic tests can be transmitted back into the processing system for interpretation and visualization 3409. The interpreted results can be transferred back through application 3403 to the patient' s electronic health records or electronic medical records 3402. Here, the results can be presented to the patient or physicians through the electronic health records or electronic medical records 3410.

[00281] In any embodiment of the invention, the transfer of data and patient information can be compliant with all applicable standards for patient privacy and security. In particular, because the prescription for genetic testing, and results reporting can be accomplished entirely within an electronic medical record, the system provides an efficient mechanism for transfer of information in a manner that is compliant with HIPP A or Health Level Seven (HL7) standards.

[00282] The systems and methods described herein can provide for a single point for raw genetic information that can be stored, queried, and accessed on-demand by patients or physicians. The use of a single point or single database for raw genetic information eliminates the need for large genomic data to be sent electronically over the internet, enabling a much faster and more efficient genome scanning process. A request for scanning a genome in order to find specific structural variants can be sent received through an API, as explained herein. The API can process the request, and cause the described system to scan a genome in the database and return the results. In any embodiment, the request for a scan and the results can be transmitted through a patient' s electronic health records or electronic medical records. The patient's genetic data can remain in the database, without the need for transmitting the data over the internet.

[00283] Further, without a single, centralized repository of genetic data, laboratories can execute sequence queries on different patient's genetic sequences and conclude different results. The systems and methods described herein also allow for a patient's genetic sequence and record of diagnostic scans to be consistently available, discoverable and understandable. In order to accomplish these goals, the electronic medical records must contain seamless genetic prescribing functionality that is supported by automated clinical decision, machine-processing, and by structured data formats borne of the fruit of HL7 and ONC standardization efforts.

[00284] The systems and methods described herein allow for development and support of electronic genetic test ordering between an electronic medical record and the system of the invention. The systems and methods described herein also allow for genetic testing delivery within an electronic medical record. The applications described for the interfaces between physicians, testing and licensing can allow seamless interoperability between the systems of the invention, hospital systems, insurers and clinicians in line with all applicable standards such as HL7, FHIR or any other standards.

[00285] In particular, the present invention can facilitate information transfer between organizations developing, electronic health records vendors, laboratories, standards development organizations, health information exchanges and federal or state agencies that may be developing laboratory order interfaces, developing implementation guides or regulating the use of health information technology. Because the systems described herein can serve as a single point for genetic storage and testing, the present invention is uniquely situated for development of standards and ordering interfaces.

[00286] The software implementing the above processes can be coded in any language known in the art. This includes, but is not limited to, ASP, APS.NET, Java, JavaScript, C, C++, C#, C#.NET, Objective C, F#, F#.NET, Basic, Visual Basic, VB.NET, Go, Python, Perl, Hack, PHP, Erlang, XHP, Scala, Ruby, J2EE, SQL, CGI, HTTP, or XML.

[00287] It will be apparent to one skilled in the art that various combinations and/or modifications and variations can be made in the system depending upon the specific needs for operation. Moreover features illustrated or described as being part of one embodiment may be used on another embodiment to yield a still further embodiment.

Claims

We claim:

1. A system, comprising:

a control server in communication with a remote application, the remote application providing results of a genetic test;

a proprietary records database in communication with the control server, the proprietary records database containing records of proprietary biomarkers and/or rights holders of the proprietary biomarker; and

a genetic data storage server in communication with the remote application, the genetic data storage server containing genetic information of one or more patients;

the remote application sending and receiving data for conducting the genetic test; and the control server sending and receiving data for accounting for payment from a payer party to the rights holder.

2. The system of claim 1, further comprising a black box containing encrypted proprietary information for performing the genetic test, and wherein the remote application is collocated with the genetic data storage server.

3. The system of claim 1, wherein the control server is configured to account for a payment to the owner of the genetic data storage server for storage of the genetic data.

4. The system of claim 1, wherein the remote application is in communication with a scan application, the scan application configured to carry out the genetic test, and wherein the control server is configured to account for payment to the owner of the scan application based on the genetic test.

5. The system of claim 1, wherein the control server is configured to receive a request for a genetic test from a third party.

6. The system of claim 1, wherein the control system is configured to determine a genetic test requested for more than one patient; and wherein the control system is configured to create a subgroup of patients, wherein the subgroup of patients are patients for which the same genetic test is requested.

7. The system of claim 6, wherein either the genetic data storage server or the remote application is configured to determine an association between the genetic information at a particular genetic location for the more than one patients and a genetic disease.

8. The system of claim 7, wherein either the genetic data storage server or the remote application creates a tally of base pairs for each of the more than one patients at one or more genetic locations; wherein the tally comprises the number of patients with each of the base pairs at the at least one genetic location.

9. The system of claim 8 wherein the system updates the tally of base pairs with the base pairs for a new patient each time a new test is ordered for the genetic disease.

10. The system of claim 9 wherein either the genetic data storage server or the remote application determines an association between the genetic information at each of the one or more genetic locations for the more than one patients and a genetic disease each time a new test is ordered for the genetic disease.

11. A system, comprising:

a control server communicating with a black box containing encrypted medical database from a first user; the control server in communication with at least one remote application;

wherein the remote application is in communication with at least one patient records database containing data concerning one or more patients; the remote application configured to query the patient records database based on the information in the encrypted medical database to provide an output of the query.

12. The system of claim 11, wherein the encrypted medical database cannot be unencrypted by any other user.

13. The system of claim 11, wherein the control server and the patient records database are not collocated.

14. The system of claim 11, wherein the encrypted database contains information for genetic variants and/or biomarkers.

15. The system of claim 11, wherein the encrypted database contains information for medical histories.

16. The system of claim 11, wherein the system is configured to receive a set of allowed users from the first user, and to allow unencryption of the database by the set of allowed users.

17. The system of claim 11, wherein the system is configured to receive a request for a medical test using the information in the encrypted database by a requesting party, and wherein the information in the encrypted database is not provided to the requesting party.

18. The system of claim 11, wherein the system is configured to allow the first user to update the data in the encrypted database.

19. The system of claim 11, wherein the patient records database contains genetic information of at least one patient.

20. The system of claim 11, wherein the control server is configured to electronically receive multiple encrypted medical databases from one or more users.

21. The system of claim 20, further comprising a proprietary research data server;

wherein each encrypted medical database is stored on the proprietary research data server.

22. The system of claim 11 , further comprising an encrypting program configured to encrypt a medical database prior to the proprietary server receiving the encrypted medical database.

23. The system of claim 11, further comprising a prescription application in

communication with the remote application, wherein the prescription application is configured to receive a prescription for a medical test; and wherein the prescription application is configured to transmit the prescription to the remote application.

24. The system of claim 23, wherein the prescription for a medical test comprises information necessary for identifying a record in the patient records database corresponding to a patient for which the medical test is prescribed.

25. A system for conducting a genetic test comprising;

a biomarker script database, wherein the biomarker script database comprises at least one biomarker entry corresponding to a biomarker; the biomarker entry comprising a list of genetic variants corresponding to the biomarker and a list of interpretations corresponding to a list of genetic variant definitions; wherein the list of interpretations comprises a risk factor based on the genetic variant definitions;

the biomarker script database configured to communicate with a patient records database comprising patient identification information for at least one patient, and a genome or portion of a genome for the at least one patient.

26. The system of claim 25, further comprising, a black box having an application configured to search the genome or portion of a genome based on the biomarker script in order to determine the identity and number of genetic mutations present in the genome corresponding to the biomarker and provide the risk factor associated with the mutations present in the genome based on the list of interpretations.

27. The system of claim 26 wherein the biomarker script is equivalent to a known diagnostic test.

28. The system of claim 25, further including a privacy facility that can set rules to control user access to any database accessible by the privacy facilitating system or any record generated by the privacy facilitating system.

29. The system of claim 25 further comprising a proprietary records database containing information regarding the rights holders to one or more proprietary biomarkers and wherein the system is configured to search the proprietary records database and determine if the biomarker is a proprietary biomarker.

30. The system of claim 29, further comprising a payment facility configured to account for a payment from a payer party to the rights holders if the biomarker is a proprietary biomarker.

31. The system of claim 26, wherein the system is configured to obtain a prescription for a genetic test and the application configured to search the genome or portion of a genome is configured to receive the prescription for a genetic test and conduct the search based on the prescription for a genetic test.

32. The system of claim 31 wherein the system is configured to receive the prescription for a genetic test from electronic health records.

33. The system of claim 25 wherein the patient records database is remote from the biomarker script database.

34. A method for conducting genetic testing, comprising:

creating a biomarker entry in a biomarker script database;

encoding a list of single nucleotide polymorphisms and mutation definitions corresponding to the biomarker entry in the biomarker script database, wherein the list of single nucleotide polymorphisms and mutation definitions is associated with the biomarker entry;

encoding an interpretations list in the biomarker database, the interpretations list associated with the biomarker entry, wherein the interpretations list provides a risk factor for a disease based on the mutations in the list of single nucleotide polymorphisms and mutation definitions;

scanning a genome or portion of a genome of a patient to determine the presence of the mutation definitions; and

providing the risk factor corresponding to the determination of the presence of the mutation definitions.

35. The method of claim 34, further comprising:

accessing a patient record in a patient record database, wherein the patient record database is configured to communicate with the biomarker script database and wherein the patient record comprises a genome or portion of a genome of a patient and patient identification information; and restricting information contained in the patient records database such that one or more fields of information are not available to one or more users of the genetic testing system.

36. The method of claim 34, further comprising:

accessing a proprietary records database containing records of proprietary biomarkers and rights holders of the proprietary biomarkers;

utilizing the biomarker script to scan the patient records database and the proprietary records database to determine the presence of a proprietary biomarker in a patient record of the patient records database and generating a result set including at least one results record;

optionally updating the patient records database to include the identification of a proprietary biomarker; automatically forwarding information obtained from the query to one or more of a payer party user and a rights holder user associated with the proprietary biomarker used by the query of the patient records database; and

accounting for a payment or escrow between a payer party user and a rights holder user of the proprietary biomarker used by the scan.

37. The method of claim 34, wherein the biomarker script is equivalent to a known diagnostic test.

38. The method of claim 34, wherein the information of a patient record is populated by a diagnostic service provider or by a physician.

39. The method of claim 34, wherein the information forwarded to the rights holder user does not contain patient identification information of the patient record containing the proprietary biomarker in the diagnostic information.

40. The method of claim 34, wherein the step of scanning a genome or portion of a genome of a patient to determine the presence of the mutation definitions comprises:

obtaining a prescription for a genome or portion of a genome of the patient, the prescription comprising a patient identifier, a genetic sequence identifier and a biomarker identifier;

retrieving list of single nucleotide polymorphisms and mutation definitions in the biomarker script database corresponding to the biomarker identifier;

scanning the genome or portion of a genome of the patient for each of the mutation definitions; and

determining the number of mutations present in the genome or portion of a genome.

41. The method of claim 34, wherein the interpretations list provides a risk factor based on a number of mutations found corresponding to the mutation definitions.

42. The method of claim 34, further comprising the step of counting a number of mutations found in the genome or portion of a genome that correspond to the mutation definitions.

43. The method of claim 34, further comprising providing a list of each mutation found in the genome or portion of a genome corresponding to a mutation definition.

44. The method of claim 43 wherein the step of obtaining a prescription for a genome or portion of a genome comprises obtaining the prescription through electronic medical records of a patient.

45. A system for conducting a genetic test comprising;

a biomarker script database, wherein the biomarker script database comprises at least one biomarker entry corresponding to a biomarker; the biomarker entry comprising a list of variant definitions corresponding to the biomarker and a list of interpretations corresponding to the list of list of variant definitions; wherein the list of interpretations comprises a risk factor based on the single nucleotide polymorphisms and mutation definitions;

46. The system of claim 45, further comprising, an application configured to search the genome or portion of a genome based on the biomarker script in order to determine the identity and number of genetic mutations present in the genome corresponding to the biomarker and provide the risk factor associated with the mutations present in the genome based on the list of interpretations.

47. The system of claim 46, wherein the biomarker script is equivalent to a known diagnostic test.

48. The system of claim 45, further including a privacy facility that can set rules to control user access to any database accessible by the privacy facilitating system or any record generated by the privacy facilitating system.

49. The system of claim 45, further comprising a proprietary records database containing information regarding the rights holders to one or more proprietary biomarkers and wherein the system is configured to search the proprietary records database and determine if the biomarker is a proprietary biomarker.

50. The system of claim 49, further comprising a payment facility configured to account for a payment from a payer party to the rights holders if the biomarker is a proprietary biomarker.

51. The system of claim 46, wherein the system is configured to obtain a prescription for a genetic test and the application configured to search the genome or portion of a genome is configured to receive the prescription for a genetic test and conduct the search based on the prescription for a genetic test.

52. The system of claim 51, wherein the system is configured to receive the prescription for a genetic test from electronic health records.

53. The system of claim 45, wherein the patient records database is remote from the biomarker script database.