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WO2005116890A1 - Systemes et methodes informatiques permettant de fournir des soins de sante - Google Patents

Systemes et methodes informatiques permettant de fournir des soins de sante Download PDF

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Publication number
WO2005116890A1
WO2005116890A1 PCT/US2004/015133 US2004015133W WO2005116890A1 WO 2005116890 A1 WO2005116890 A1 WO 2005116890A1 US 2004015133 W US2004015133 W US 2004015133W WO 2005116890 A1 WO2005116890 A1 WO 2005116890A1
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Prior art keywords
patient
computer
instructions
health care
patients
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PCT/US2004/015133
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English (en)
Inventor
William S. Dalton
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H Lee Moffitt Cancer Center and Research Institute Inc
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H Lee Moffitt Cancer Center and Research Institute Inc
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Priority to PCT/US2004/015133 priority Critical patent/WO2005116890A1/fr
Publication of WO2005116890A1 publication Critical patent/WO2005116890A1/fr
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
    • G16H10/20—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for electronic clinical trials or questionnaires
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B25/00—ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
    • G16B25/10—Gene or protein expression profiling; Expression-ratio estimation or normalisation
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B25/00—ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
    • G16H10/60—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for patient-specific data, e.g. for electronic patient records

Definitions

  • FIELD OF THE INVENTION The field of this invention relates to computer systems and methods for identifying and optimizing treatment regimens using molecular profiling and clinical characterization.
  • the present invention provides systems and methods by which patient specific treatment regimens are identified for each patient that is enrolled in a health care program.
  • the invention uses a novel approach in which molecular profiles are obtained from one or more biological specimens from the patient.
  • the molecular profiles are combined with a classical clinical characterization that is made by the patient's physician to form a comprehensive characterization of the patient's medical status.
  • the comprehensive characterization is used to select a treatment regimen for the patient.
  • classical treatment regimens for known diseases are refined using the outcome of clinical trials as well as the clinical outcome of patients enrolled in the health care program.
  • Another aspect of the present invention comprises novel systems and methods for using molecular profiling data from patients of remote facilities, termed affiliate facilities.
  • affiliate facilities are typically small medical facilities found in local communities.
  • Patients that are too sick or otherwise handicapped to travel to a centralized medical facility can receive the same quality of care at the affiliate facility that is available at the centralized medical facility.
  • patients visit the affiliate facility and a physician makes a clinical characterization of the patient.
  • a biological specimen is taken from the patient.
  • the biological specimen is both a blood sample and a tumor sample.
  • the biological specimens are shipped to a central health care facility or other form of diagnostic facility where molecular profiling of the samples is performed. The results of the clinical characterization and the molecular characterization are then reduced to electronic form and used to search for one or more treatment regimens.
  • the computer program product comprises a computer readable storage medium and a computer program mechanism embedded therein.
  • the computer program mechanism comprises one or more data structures associated with each patient in a plurality of patients enrolled in a health care program.
  • the one or more data structures associated with each respective patient in the plurality of patients collectively comprise (i) a patient identifier for the respective patient, (ii) a molecular profile from a biological specimen obtained from the respective patient, and (iii) a clinical characterization of the respective patient.
  • the computer program mechanism further comprises a plurality of treatment regimens and a therapeutic determination module.
  • the therapeutic determination module includes instructions for identifying a treatment regimen, from among the plurality of treatment regimens, for a patient in the plurality of patients.
  • An aspect of the present invention provides a computer program product for use in conjunction with a computer system.
  • the computer program product comprises a computer readable storage medium and a computer program mechanism embedded . i i. i i p arri mec an sm comp ses one or more ⁇ ata structures. 1 e one or more data structures are dimensioned and configured to store medical information for a plurality of patients.
  • the computer program mechanism further comprises a data entry module.
  • the data entry module includes instructions for inputting a patient identifier for a patient in the plurality of patients into a data structure in the one or more data structures.
  • the data entry module further includes instructions for inputting a molecular profile from a biological specimen obtained from the patient into a data structure in the one or more data structures.
  • the data entry module also includes instructions for inputting a clinical characterization of the patient into a data structure in the one or more data structures.
  • the computer program mechanism further comprises a treatment regimen module having instructions for receiving a plurality of treatment regimens.
  • the computer program mechanism further comprises a therapeutic determination module having instructions for identifying a treatment regimen, from among the plurality of treatment regimens, for a patient.
  • Still another aspect of the invention provides a computer comprising a central processing unit and a memory, coupled to the central processing unit.
  • the memory stores instructions for accessing one or more data structures associated with each patient in a plurality of patients enrolled in a health care program.
  • the one or more data structures associated with each respective patient in the plurality of patients collectively comprises (i) a patient identifier for the respective patient, (ii) a molecular profile from a biological specimen obtained from the respective patient, and (iii) a clinical characterization of the respective patient.
  • the memory further stores instructions for accessing a plurality of treatment regimens and instructions for accessing a therapeutic determination module.
  • the therapeutic determination module comprises instructions for identifying a treatment regimen, from among the plurality of treatment regimens, for a patient in the plurality of patients.
  • Another aspect of the invention provides a computer for providing health care in accordance with a health care program.
  • the computer comprises a central processing unit and a memory, coupled to the central processing unit.
  • the memory stores one or more data structures.
  • the one or more data structures are dimensioned and configured to store medical information for a plurality of patients.
  • the memory further stores a data entry module comprising (i) instructions for inputting a patient identifier for a patient into a data structure in the one or more data structures, and (ii) instructions for inputting a molecular profile from a biological specimen obtained from the patient into a data structure in the one or more data structures, and (iii) instructions for inputting a clinical o epa e t nto a ata structure in t e one or more data structures.
  • e memory further stores a treatment regimen module comprising instructions for receiving a plurality of treatment regimens.
  • the memory further stores a therapeutic determination module comprising instructions for identifying a treatment regimen, from among the plurality of treatment regimens, for a patient.
  • the present invention also provides a method of providing health care in accordance with a health care program.
  • a treatment regimen from among a plurality of treatment regimens, is identified for a patient based upon a molecular profile associated with the patient and a clinical characterization associated with the patient.
  • the patient is one of a plurality of patients enrolled in a health care program.
  • medical information is stored in one or more data structures associated with the respective patient, the one or more data structures for each respective patient in the plurality of patients collectively comprising (i) a patient identifier, (ii) a molecular profile from a biological specimen obtained from the respective patient, and (iii) a clinical characterization of the respective patient.
  • Still another aspect of the invention provides a medical card defined by a base constructed from a substantially flat piece of plastic having a first face and second face, at least one of the faces comprising indicia placed thereon.
  • the indicia comprise an identification of a patient uniquely associated with the medical card and a magnetic strip bearing electronic information.
  • the electronic information comprises an identification of the patient, a diagnosis of the patient, and an identification of a doctor that made the diagnosis.
  • Another aspect of the invention comprises a method implemented by a computer system coupled to a wide-area network (WAN).
  • the method comprises retrieving, over the WAN, one or more data structures for a patient in a plurality of patients enrolled in a health care program.
  • the one or more data structures for the patient collectively comprise (i) a patient identifier, (ii) a molecular profile from a biological specimen, whereby the biological specimen was obtained from the patient at a first health care facility; and (iii) a clinical characterization of the patient.
  • a signed consent form is obtained from a patient at a first health care facility, thereby enrolling a patient in a health care program.
  • a biological specimen is removed care aci i y an a c ini ca c arac tenzation oi tne pati en t t is made at the first health care facility.
  • a molecular profile is created from the biological specimen at a location other than the first health care facility.
  • Data relating to the patient is stored at one or more locations addressable by a wide-area network (WAN) 5 that includes a node at the health care facility.
  • the data that is stored includes an identification of the patient, the clinical characterization of the patient, and the molecular profile of the patient.
  • Still another aspect of the invention comprises a first computer and one or more second computers.
  • the first computer is in electronic communication with each of one or
  • the first computer is associated with a first health care facility.
  • the first computer comprises a first memory having instructions for retrieving, over the WAN, one or more data structures for a patient in a plurality of patients enrolled in a health care program.
  • the one or more data structures for the patient collectively comprise (i) a patient identifier, (ii) a molecular
  • the first memory further comprises instructions for retrieving, over the WAN, one or a plurality of treatment regimens that are deemed suitable for the patient based upon the molecular profile and the clinical
  • the one or more second computers are at one or more locations other than the first health care facility. Further, the one or more second computers comprise one or more second memories that collectively comprise one or more data structures for each patient in a plurality of patients enrolled in the health care program. The one or more data structures for each respective patient in the plurality of patients collectively
  • 25 comprises (i) a patient identifier for the respective patient, (ii) a molecular profile from a biological specimen obtained from the respective patient, (iii) and a clinical characterization of the respective patient.
  • Fig. 1 illustrates a computer system for providing health care to patients enrolled in a health care program in accordance with one embodiment of the present invention.
  • Fig. 2. illustrates a method for selecting a treatment regimen for a patient based upon a clinical characterization and a molecular profile of a specimen taken from the 35 patient in accordance with an embodiment of the present invention.
  • Fig. 3. illustrates a data structure for storing a clinical characterization of a patient in accordance with one embodiment of the present invention.
  • Fig. 4 illustrates a data structure for storing a demographic characterization of a patient in accordance with one embodiment of the present invention.
  • Fig. 5 illustrates a networked based topology for how a patient can receive health care at an affiliate health care facility in accordance with an embodiment of the present invention.
  • Fig. 6 illustrates a data structure for storing the results of a clinical trial and a plurality of treatment regimens in accordance with one embodiment of the present invention.
  • Fig. 7 illustrates a network topology for facilitating health care at an affiliate health care center using resources of a central health care facility in accordance with an embodiment of the present invention.
  • Fig. 8 illustrates a data structure for storing a molecular profile of a biological specimen obtained from a patient in accordance with an embodiment of the present invention.
  • Fig. 9 illustrates how clinical trial data is used to develop treatment protocols, including "molecular signals" from biological specimens obtained from clinical trial participants, in accordance with one embodiment of the present invention.
  • a newly diagnosed lung cancer patient who elects to participate in a health care program in accordance with the present invention either at a centralized health care facility or at an affiliate health care facility that is closer to home.
  • the patient signs a consent form that allows their data, including a biological specimen such as a tumor and/or blood sample, to be collected and studied to provide, in conjunction with the primary physician's clinical observations, a basis for care.
  • the patient will have the opportunity to receive the best treatment protocols available to patients in the health care program and will have the option to enroll in a clinical trial.
  • the patient will be monitored throughout their battle with their disease including diagnosis, prognosis and treatment.
  • the system is preferably a computer system 10 having: • a central processing unit 22; • a main non- volatile storage unit 14, for example a hard disk drive, for storing software and data, the storage unit 14 controlled by storage controller 12; • a system memory 36, preferably high speed random-access memory (RAM), for storing system control programs, data, and application programs, comprising programs % a ' e r ⁇ n non- vo a ile s orage uni ; sys em mcm ⁇ y JO may a so include read-only memory (ROM); • a user interface 32, comprising one or more input devices (e.g., keyboard 28) and a display 26 or other output device; • a network interface card 20 for connecting to any wired or wireless communication network 34 (e.g., a wide area network such as the Internet); • an internal bus 30 for interconnecting the aforementioned elements of the system
  • ROM read-only memory
  • a user interface 32 comprising one or more input devices (e.g
  • Operating system 40 can be stored in system memory 36.
  • system memory 36 includes: • operating system 40; • file system 42 for controlling access to the various files and data structures used by the present invention; • one or more patient databases 44 for storing medical information associated with patients enrolled in a health care program; • a relapse module 70 for determining when a patient has relapsed; • a patient risk module 72 for identifying a patient registered in patient database 44 that is at risk for a disease; • a cost analysis module 74 for computing a cost for treating a patient; • a feedback module 76 for computing a cost for treating a patient; • a therapeutic determination module 78 for identifying a treatment regimen, from among a plurality of treatment regimens, for a patient registered in patient database 44; • a data entry module 80 for inputting a patient information into database 46; • treatment regimen module 82 for receiving a plurality of treatment regimens; and • a
  • database 44 can be any form of data storage system including, but not limited to, a flat file, a relational database (SQL), and an on-line analytical processing (OLAP) database (MDX and/or variants thereof).
  • database 44 is a hierarchical OLAP cube.
  • database 44 comprises a star schema that is not s or as a 1 c e u - as mension a es a e ine ierarc y. in m ⁇ ner, m
  • database 44 has hierarchy that is not explicitly broken out in the underlying database or database schema (e.g., dimension tables are not hierarchically ananged).
  • patient database 44 is a single database that includes patient data.
  • patient database 44 in fact comprises a plurality of databases that may or may not all be hosted by the same computer 10.
  • some component databases of "patient database 44" are stored on computer systems that are not illustrated by Fig. 1 but that are addressable by wide area network 34.
  • Section 5.11 describes exemplary architectures for patient database 44. It will be appreciated that many of the modules illustrated in Fig. 1 can be located on one or more remote computers.
  • some embodiments of the present application are web service-type implementations.
  • treatment regimen module 82 and other modules used by a physician to treat a patient can reside on a client computer that is in communication with computer 10 via network 34.
  • treatment regimen module 82 and other modules used by a physician to treat a patient can be an interactive web page.
  • the database 44 and modules (e.g. modules 70, 72, 74, 76, 78, 80, and 82) illustrated in Fig. 1 are on a single computer (computer 10) and in other embodiments the database 44 and modules are hosted by several computers (not shown). Any anangement of database 44 and the modules illustrated in Fig. 1 on one or more computers is within the scope of the present invention so long as these components are addressable with respect to each other across network 34 or other electronic means. Thus, the present invention fully encompasses a broad array of computer systems. 5.2.
  • Patient database 44 includes a plurality of patient records 46. There is no limit on the number of patient records 46 that can be held in patient database 44. Database 44 can hold as few as one patient record 46. More typically, database 44 holds between 1 and 100 patient records, more than 100 patient records, more than a thousand patient records, more than ten thousand patient records, more than 100 thousand patient records, or between 1 patient record and one million patient records. Each patient record 46 preferably includes a patient identifier 48.
  • a patient identifier 48 need not be expftCmy-enurnera e - tt-cer ain a a ase sys ems. or ins ance, m bume by& ⁇ cn ⁇ _>, ⁇ patient identifier 48 can simply be a patient record 46 identifier. However, in some embodiments, a patient identifier 48 can be a number that uniquely identifies a patient within a health care program.
  • An advantage of database 44 is that it has the capability of tracking molecular profile information 50 and clinical characterization information 52 for each patient registered in database 44.
  • a molecular profile 50 is the abundance levels of a plurality of cellular constituents in a biological specimen obtained from the patient. In some embodiments, such abundance levels are normalized using any of the techniques disclosed in Section 5.6.
  • Representative biological specimens include, but are not limited to, a blood sample, a component of the patient's blood, and/or all or a portion of a tumor obtained from the patient.
  • a biological specimen is a tumor that is surgically removed from the patient, grossly dissected, and snap frozen in liquid nitrogen within twenty minutes of surgical resection.
  • a molecular profile 50 comprises the processed microarray image data from the biological specimen obtained from the patient.
  • molecular profile data 50 comprise cellular constituent abundance information for all or a portion of the cellular constituents represented in a microarray, optional background signal information, and optional associated annotation information describing the probe used for the respective cellular constituent.
  • Cellular constituents include, but are not limited to RNA (e.g., mRNA) and protein.
  • a molecular profile 50 represents the transcriptional state of cellular constituents in a biological specimen. See, for example, Section 5.8 below.
  • a molecular profile can track aspects of the biological state other than or in addition to transcriptional state. Such other aspects of the biological state include, but are not limited to, the translational state, the activity state of cellular constituents in a biological sample.
  • molecular profile data 50 is, in fact, protein levels for various proteins in the biological specimen from the patient.
  • molecular profiles 50 comprise amounts or concentrations of the cellular constituent in biological specimens, cellular constituent activity levels in biological specimens, the state of cellular constituent modification (e.g., phosphorylation) in biological specimens, or other measurements.
  • the amount of at least one cellular constituent that is tracked in a molecular profile 50 comprises abundances of at least one RNA species present in one O ⁇ i ' ⁇ i l o e '' c ' el s"in ⁇ he biole ⁇ gical specimen obtained from the patient.
  • Such abundances can be measured by a method comprising contacting a gene transcript array with RNA derived from one or more cells of the biological specimen, or with cDNA derived therefrom.
  • a gene transcript array comprises a surface with attached nucleic acids or nucleic acid mimics. The nucleic acids or nucleic acid mimics are capable of hybridizing with the RNA species or with cDNA derived from the RNA species.
  • the abundance of the RNA is measured by contacting a gene transcript array with the RNA from one or more cells of the biological speciment, or with nucleic acid derived from the RNA, such that the gene transcript arcay comprises a positionally addressable surface with attached nucleic acids or nucleic acid mimics, where the nucleic acids or nucleic acid mimics are capable of hybridizing with the RNA species, or with nucleic acid derived from the RNA species.
  • a molecular profile 50 can include abundance information or activity information about ten or more cellular constituents (e.g., genes or proteins), between ten and one thousand cellular constituents, between one thousand and twenty thousand cellular constituents, or more than twenty thousand cellular constituents.
  • a molecular profile 50 tracks cellular constituent marker information.
  • genetic marker information includes, but is not limited to, single nucleotide polymorphisms (SNPs), SNP haplotypes, microsatelhte markers, restriction fragment length polymorphisms (RFLPs), short tandem repeats, sequence length polymorphisms, DNA methylation, random amplified polymorphic DNA (RAPD), amplified fragment length polymorphisms (AFLP), and "simple sequence repeats.”
  • RFLPs are the product of allelic differences between DNA restriction fragments caused by nucleotide sequence variability. As is well known to those of skill in the art, RFLPs are typically detected by extraction of genomic DNA and digestion with a restriction endonuclease. Generally, the resulting fragments are separated according to size and hybridized with a probe; single copy probes are preferred. As a result, restriction fragments from homologous chromosomes are revealed. Differences in fragment size among alleles represent an RFLP (see, for example, Helentjaris et al, 1985, Plant Mol. Bio. 5:109-118, and U.S. Pat. No. 5,324,631).
  • RAPD random amplified polymorphic DNA
  • RAPD random amplified polymorphic DNA
  • SSRs are di-, tri- or tetra-nucleotide tandem repeats within a genome.
  • the repeat region can vary in length between genotypes while the DNA flanking the repeat is conserved such that the same primers will work in a plurality of genotypes.
  • a polymorphism between two genotypes represents repeats of different lengths between the two flanking conserved DNA sequences (see, for example, Akagi et al, 1996, Theor. Appl. Genet. 93, 1071-1077; Bligh et al, 1995, Euphytica 86:83-85; Struss et al, 1998, Theor. Appl. Genet.
  • patient records 46 include clinical characterizations 52.
  • a clinical characterization 52 comprises observations made by a patient's physician.
  • the observations made by a physician include a code from the International Classification of Diseases, 9 th Revision, prepared by the Department of Health and Human Services (ICD-9 codes), or an equivalent, and dates such observations were made.
  • Fig. 3 illustrates a clinical characterization data structure in accordance with the present invention.
  • Clinical characterization 52 complements information found within molecular profile 50.
  • the clinical characterization 52 can include laboratory test results (e.g. , cholesterol level, high density lipoprotein / low density lipoprotein ratios, triglyceride levels, etc.), statements made by the patient about their health, x-rays, biopsy results, and any other medical information typically relied upon by a doctor to make a diagnosis of the patient.
  • Patient records 46 further include diagnosis field 54.
  • Diagnosis field 54 represents the diagnosis for the patient corresponding to the patient data record 46 based upon an analysis of the molecular profile 50 associated with the patient and the clinical characterization 52 associated with the patient.
  • Patients enrolled in health care programs in accordance with the present invention preferably have the opportunity to enroll in clinical trials that are designed to test, discover and/or optimize application of one or more drugs or other forms of treatment regimens.
  • patient record 46 can optionally include a reference 56 to a clinical trial to which the patient is enrolled.
  • patient record 46 can store, reference, or otherwise include the results and/or clinical outcome of such a clinical trial in field 58.
  • Patient records 46 can optionally further include a demographic characterization 60 of respective patients. In some instances, relevant portions of the demographic characterization 60 can be used in conjunction with diagnosis 54 to select a treatment regimen for a patient. Referring to Fig.
  • the demographic characterization for a respective patient comprises a gender 402 of the patient, a marital status 404 of the patient, an ethnicity 406 of the patient, a primary language 408 spoken by the patient, the color of the eyes 410 of the patient, the hair color 412 of the patient, the height 414 of the patient, the weight 416 of the patient, the social security number 418 of the patient, the name 420 of the patient, the date of birth 422 of the patient, the educational status 424 of the patient, an identity of the primary physician 426 for the patient, a name of a referring physician 428 for the patient, a referral source 430 for the patient, an indication 432 as to whether the patient is disabled and a description of the .. , , . • ,
  • Patient data records 46 further includes a patient treatment history 62.
  • Treatment history 62 indicates the treatment given to a patient and when such treatment was given.
  • Treatment history 62 includes all prescriptions given to the patient and all medical procedures undergone on the patient.
  • a patient data record 46 includes a family medical history 64 in order to guide the selection of an appropriate treatment regimen for the patient.
  • Family medical history 64 can include data such as whether or not a member of the patient's family has a disease, the molecular profile of biological samples taken from family members and the like.
  • pathology data e.g. , world health organization (classification, tumor, nodes, metastases staging, images), radiographic images (e.g.
  • raw, processed, cat scans, positron emission tomography demographic data 60 (e.g., age, sex, etc.), laboratory data, Cerner electronic medical record data (hospital based data), molecular profile 50 (e.g. gene expression data), family history 64, risk factor data, access to a clinical reporting and data system, reference to vaccine production data / quality assurance, reference to a clinical data manager (e.g., OPTX), and reference to a cancer registry such as a research specimen banking database.
  • demographic data 60 e.g., age, sex, etc.
  • laboratory data Cerner electronic medical record data (hospital based data)
  • molecular profile 50 e.g. gene expression data
  • family history 64 e.g. gene expression data
  • risk factor data access to a clinical reporting and data system
  • reference to vaccine production data / quality assurance reference to a clinical data manager (e.g., OPTX)
  • a cancer registry such as a research specimen banking database.
  • steps 210-220 a diagnosis is made and a treatment regimen is selected based upon a molecular profile from one or more iO ogical'specimen o aine om e pa ien in a i ion o a c micai cnaracie ⁇ zau ⁇ n o the patient that is prepared by the patient's physician.
  • treatment regimens and selection criteria for choosing treatment regimens are modified based upon the clinical outcome of the patient in part two. Now that an overview of the method has been described, a more detailed description of the method will be presented.
  • Step 202 a population is enrolled in a clinical trial. In some embodiments, 10 or more subjects are enrolled in a clinical trial.
  • between 10 and 100 subjects are enrolled in a clinical trial.
  • between 100 and 500, between 500 and 1000, or more than 1000 subjects are enrolled in a clinical trial.
  • the clinical trial is a prevention trial, screening trial, quality-of-life trial, a treatment trial, or a diagnostic trial.
  • Prevention trials look for ways to reduce the risk of developing a particular disease or preventing it from coming back. These trials test the usefulness of certain medicines, vitamins, minerals or other supplements. The medicine or supplement that is chosen for a clinical trial is one that researchers believe may be able to lower cancer risk.
  • Other prevention trials explore whether exercise, quitting smoking, eating more vegetables and fruit or other lifestyle choices help to prevent the disease.
  • Screening trials test or evaluate the best ways to detect the disease, especially in its early stages. In some cases, detecting the disease early can improve the results of treatment and increase the chances of survival.
  • One example of a screening trial is the study of new medical imaging methods.
  • Another example might be a new type of blood test that would detect clues that, for example, cancer can be present in a person's body.
  • These trials usually involve people who may be at higher-than-average risk of developing the disease.
  • Quality-of-life trials also called supportive care trials
  • Cancer treatment trials involve people with the disease.
  • These trials usually compare new disease treatments with ones that already exist.
  • the trials can be designed to answer issues such as (i) does the new treatment work better than the curcent best standard of care, (ii) will the new treatment reduce the chance that the disease will spread or come back, (iii) does the new treatment have fewer side effects than the current standard of treatment, and (iv) do most patients tolerate the side effects from the new treatment better.
  • Treatments tested in clinical trials for cancer include, but are not limited . , . , t .
  • Phase I treatment trials are carried out in steps called "phases", the most prominent of which are phases I, II, and III.
  • Phase I treatment trials are primarily concerned with assessing the safety of a drug.
  • Phase I testing in humans is typically done in about 20 to 100 healthy volunteers.
  • a phase I clinical study is designed to determine what happens to the drug in the patient. That is, how it is absorbed, metabolized, and excreted.
  • a phase I study provides information on optimal drug dosage. While a phase I treatment trial is directed to drug safety, a phase II treatment trial is directed to drug efficacy.
  • a phase II treatment trial occurs after successful completion of a phase I treatment trial.
  • phase II treatment trial can last from several months to two years, and involve up to several hundred patients at numerous clinical sites throughout the world. Most phase II treatment trials are randomized trials. One group of patients receives the experimental drug while a control group receives a placebo or best standard treatment available. Often phase II treatment trials are "blinded" in the sense that neither the patients nor the researchers know who is getting the experimental drug. In this manner, the phase II treatment trial can provide a pharmaceutical company and a regulatory body, such as the United States Food and Drug Administration (FDA) of the United States or the European Commission (EC) of the European Union, comparative information about the efficacy of the new drug. If the phase II treatment trial is successful, a phase III treatment trial can be authorized.
  • FDA United States Food and Drug Administration
  • EC European Commission
  • phase III trial can be obtained based on a phase II trial, with a phase III trial following post- approval.
  • the new drug is tested in several hundred to several thousand patients at hundreds of clinical sites throughout the world. This large- scale testing provides hospitals, pharmaceutical companies, and the regulatory agency •w ⁇ more 'th ⁇ rou'gh 'riderstanding of the drug's effectiveness, benefits, and the range of possible adverse reactions.
  • Most phase III treatment trials are randomized and blinded trials. Phase III treatment trials typically last several years. Step 204. As is typically the case in a clinical trial, each clinical trial participant undergoes a clinical characterization. This clinical characterization is typically performed by a physician or other attending health care professional.
  • a clinical characterization is a physical examination, an electrocardiogram (EKG) a urinalysis, and/or a urine drug screen.
  • EKG electrocardiogram
  • ECG electrocardiogram
  • chest x-ray a bone marrow biopsy
  • skin tests a complete physical examination
  • ECG electrocardiogram
  • chest x-ray a bone marrow biopsy
  • skin tests a complete physical examination
  • ECG electrocardiogram
  • chest x-ray chest x-ray
  • a bone marrow biopsy a complete physical examination
  • Still another example of a clinical characterization is muscle strength testing, vital lung capacity testing (breathing test) and/or questionnaires that ask specific questions about the participant's health, ability to function and quality of life.
  • each such clinical characterization is designed to obtain the information necessary to further the goals of the clinical trial. Step 206.
  • a biological sample is obtained from trial participants in order to perform molecular profiling. This molecular profiling is used to obtain abundance levels and/or activity levels of a plurality of cellular constituents in the biological sample and/or to genotype the trial participants for a set of genetic markers. More details on molecular profiles that can be obtained in step 206 are found in Section 5.2. Step 208.
  • one or more treatment regimens are developed based upon the clinical outcome and the molecular profile of participants in the clinical trial, optionally as a function of time.
  • a clinical research repository 84 across all clinical research initiatives is maintained.
  • Repository 84 serves as a single access, entry and retrieval point for clinical data including pathology, laboratory, patient record, and outcome data along with molecular profile data to create a unique data set. The synthesis of this clinical information is used to develop effective treatment regimens.
  • Fig. 9 illustrates how clinical trial data are used to develop treatment protocols. Central to this approach is the ability to read the "molecular signals" from biological specimens, such as tumors, obtained from clinical trial participants. In the approach described in Fig. 2, the molecular profiles of biological specimens from clinical trial participants will be classified based on the analysis of cellular constituents (e.g., gene transcripts, proteins) and/or characterization of genetic markers.
  • cellular constituents e.g., gene transcripts, proteins
  • g ⁇ a specimens are umors, e mo ecu ar pr ⁇ me im ⁇ mi-ui ⁇ ii is used to determine how tumors differ from normal tissues and how tumors differ from each other.
  • Such molecular profiles can provide insights on how chemotherapies and radiation therapies affect the tumor, thereby leading to better understanding of the right treatment for the right patient at the right time.
  • the skilled artisan can use techniques similar to those in described in Malek et al, 2002, Oncogene 17, 7256-65.
  • orthologous genes present on the Affymetrix Hu95A GeneChip (12k named genes, Santa Clara, California) and compared expression profiles between the Src-induced rodent cell line model of transformation and staged colon tumors where Src is known to be activated.
  • a similar gene expression pattern between the cell line model and staged colon tumors for components of the cell cycle, cytoskeletal associated proteins, transcription factors and lysosomal proteins suggests the need for co-regulation of several cellular processes in the progression of cancer.
  • Genes not previously implicated in tumorigenesis were detected, as well as a set of 14 novel, highly conserved genes with here-to-fore unknown function.
  • Northern blot analysis was used to validate the findings. All statistical tests were two-sided. The study identified more than 300 candidate tumor markers and more than 100 markers of tumor progression. Northern analysis of 11 candidate tumor markers confirmed the gene expression changes.
  • step 210 a patient is enrolled in a health care program.
  • a patient identifier is assigned to the patient and a molecular profile is derived from a molecular profile obtained from the patient.
  • a clinical characterization of the patient is made.
  • demographic data relating to patient is taken. More details on these types of information are described in Sections 5.1 and 5.2.
  • a treatment regimen for a patient is selected from among the plurality of treatment regimens available to treat a disease based upon the patient's molecular profile 50 and clinical characterization 52.
  • a treatment regimen for a patient is selected from among the plurality of treatment regimens available to treat a disease based upon the patient's molecular profile 50 and clinical characterization 52.
  • the level of osteopontin can be used to determine colon cancer stage (adenoma, AC stage C2 tumor, liver metastases). An appropriate therapy regimen can then be selected based upon the colon cancer stage.
  • identification of gene mutations in BRCAl and BRCA2 in women is used as a basis for determining whether they have familial (genetic) related breast cancer
  • prostrate-specific antigen levels in men are used as a basis for determining whether the prostrate is undergoing changes that might indicate the presence of cancer
  • the presence of HER2 is used as an indicator to suggest certain breast cancer patients should be given the cancer drug Herceptin.
  • Steps 214-220 Once a patient has been assigned a treatment regimen, the clinical outcome of the patient over time is periodically monitored. The frequency with which a patient is monitored will vary and is generally determined by the patient diagnosis. In some embodiments, the patient is monitored almost continuously. In other embodiments, the patient is monitored once a year, once a month, weekly, or daily. .
  • the biological sample can be, for example, a blood sample, a tissue sample, or a tumor sample.
  • a molecular profile of each successive biological sample is preferably made.
  • Fig. 8 illustrates a data structure 610 in which each of the successive molecular profiles can be stored.
  • the data structure includes an identity of a plurality of a plurality of cellular constituents 802.
  • each cellular constituent is a human gene and each identifier 802 uniquely identifies a human gene.
  • record 804-1-1 stores the abundance level of the corresponding cellular constituent at a first time point
  • record 804-1-2 stores the abundance level of the corresponding cellular constituent at a second time point, and so forth.
  • a clinical assessment of the patient is made and stored in the patient's record (step 218).
  • the clinical assessment (218) and updated molecular profile (216) can be used to identify a different treatment regimen from among the treatment regimens available to the patient when a determination has been made that the patient has relapsed.
  • Step 222 The longitudinal clinical assessments of patients in health care plans of the present invention that are obtained in step 214 above represents a resource for validating the efficacy of treatment regimens.
  • such longitudinal clinical assessments are used to modify treatment regimens and selection criteria for choosing such treatment regimens. For example, consider the case in which osteopontin levels are used as a basis for predicting colon cancer severity based on clinical trial research described in steps 202-206, above, and that, further, such levels are used as a basis for selecting the aggressiveness of the colon cancer treatment.
  • the historical longitudinal data from step 214 can be used to verify that osteopontin levels are an accurate indicator of colon cancer severity and that such levels provide a sound basis for deciding which treatment regimen to follow for a given patient.
  • AFFILIATE-BASED HEALTH CARE Longitudinal data derived using the methods disclosed in Section 5.3, including molecular signatures and outcome data should accelerate improvements in health care. Following a patient population having a disease or a population with significant rates of a disease, extracting tissue and blood samples, and applying genomics and proteomics ultimately to the prevention and cure of significant diseases.
  • molecular profiling in Section 5.3 for individual patients can lead to problems for patients that live far away from centralized health care facilities that have molecular profiling capabilities. This problem is particularly acute in instances where patients are too sick to travel to the health care facility or where frequent visits to the health care facility are required because of the protocol requirements of a clinical trial in which they are participating.
  • Fig. 7 illustrates a computer network that can be used to facilitate affiliated based implementation of the methods of the present invention.
  • Fig. 7 describes a computer 10a that is at or accessible to an affiliate health care facility and a computer 10b that is at or accessible to a central health care facility.
  • Computers 10a and 10b are in electronic communication with each other via a network such as a wide-area network (e.g., WAN).
  • a wide-area network e.g., WAN
  • Computer 10a includes a central processing unit 22a, a main non-volatile storage unit 14a, for example a hard disk drive, for storing software and data. Storage unit 14a is controlled by storage controller 12a.
  • Computer 10a includes a system memory 36a, preferably high speed random-access memory (RAM), for storing system control programs, data, and application programs comprising programs and data loaded from non-volatile storage unit 14b. System memory 36a can also include read-only memory (ROM).
  • Computer 10a further includes a user interface 32a, comprising one or more input devices (e.g., keyboard 28a) and a display 26a or other output device.
  • Computer 10a further includes a network interface card 20a for connecting to any wired or wireless communication network (e.g., a wide area network such as the Internet) and an internal bus 30a for interconnecting the aforementioned elements of the system.
  • Computer 10a further includes a power source 24a to power the aforementioned elements.
  • Operation of computer 10a is controlled primarily by operating system 40a, which is executed by central processing unit 22a.
  • Operating system 40a can be stored in system memory 36a.
  • system memory 36a includes operating system 40a and file system 42a for controlling access to the various files and data structures used by the present invention.
  • Computer 10b includes a central processing unit 22b, a main non- volatile storage unit 14b, for example a hard disk drive, for storing software and data.
  • Storage unit 14b is . 36b, preferably high speed random-access memory (RAM), for storing system control programs, data, and application programs comprising programs and data loaded from non- volatile storage unit 14b.
  • System memory 36b can also include read-only memory (ROM).
  • Computer 10b further includes a user interface 32b, comprising one or more input devices (e.g., keyboard 28b) and a display 26b or other output device.
  • Computer 10b further includes a network interface card 20b for connecting to any wired or wireless communication network (e.g., a wide area network such as the Internet) and an internal bus 30b for interconnecting the aforementioned elements of the system.
  • Computer 10b further includes a power source 24b to power the aforementioned elements.
  • Computer 10b Operation of computer 10b is controlled primarily by operating system 40b, which is executed by central processing unit 22b.
  • Operating system 40b can be stored in system memory 36b.
  • system memory 36b includes operating system 40b and file system 42b for controlling access to the various files and data structures used by the present invention.
  • Computers 10a and 10b can exchange data using any form of network such as a direct link network (e.g., ethernet, token ring, etc.) or a packet switched network (e.g., Asynchronous Transfer Mode networks) using any suitable communication protocol such as the Internet Protocol.
  • computers 10a and 10b can be configured in any network using any communication protocol described in Peterson and Davie, Computer Networks A Systems Approach, Morgan Kaufmann Publishers, Inc., San Francisco, California.
  • steps 502 thorough 506 can be repeated for as many different diseases as desired so that there exists treatment regimens for any disease of interest.
  • steps 502 through 506 of Fig. 5 bear similarity to steps 202 through 208 of Fig. 2.
  • steps 502 through 506 are performed at a central health care facility, an affiliate health care facility, or some other facility such as a research University or a hospital that is not affiliated with the affiliate health care facility of the central health care facility.
  • the results of steps 502 through 506 are taken from a publication, e.g. a peer reviewed journal article.
  • step 502 subjects are examined using general research tools such as clinical trials in order to study diseases.
  • Subjects in the clinical trial provide biological specimens (e.g., tumor sample, blood sample, etc.) for molecular profiling.
  • the molecular profiling c'a ' e perf rme ⁇ at tne centra ea t care ac ty or some ot er t ird party health care facility or some other facility that does not provide health care.
  • step 504. patients are tracked over time in order to develop longitudinal clinical trial results.
  • biological specimens are removed from trial participants each or at least some of the times they are examined during step 504 and successive molecular profiles of the biological specimens are made.
  • the successive molecular profiles can be stored in a data structure such as 610 (Fig. 8).
  • Data structure 610 is discussed in detail in Section 5.3.
  • Fig. 6 illustrates a clinical research repository 84 for storing clinical trial results that are obtained in step 502-506 of Fig. 5.
  • Clinical research repository 84 can be used to store the results of any number of clinical trials 600. For instance, the results of a first clinical trial are stored in data structure 600, the results of a second clinical trial are stored in data structure 600-2, the results of a third clinical trial are stores in data structure 600-3, and so forth.
  • clinical research repository 84 tracks only one clinical trial. In some embodiments, clinical research repository 84 tracks between two and twenty clinical trials.
  • clinical research repository 84 tracks between twenty and one hundred clinical trials. In still other embodiments, clinical research repository 84 tracks between one hundred and five hundred clinical trials. In still other embodiments, data structure tracks more than five hundred clinical trials. In some embodiments, clinical research repository 84 is resident on a single computer. In other embodiments, clinical research repository 84 is partitioned across more than one computer. In some embodiments, clinical research repository 84 is partitioned across two or more computers, ten or more computers, or between five and one hundred computers. In some embodiments, each data structure 600 is partitioned across one or more computers at different locations. Each clinical trial 600 includes a plurality of participants. In the data structure 84 illustrated in Fig. 6, each participant is assigned their own data structure 602.
  • Each data structure 602 includes information about the conesponding subject such as an initial molecular profile base on a biological specimen that is obtained from the subject. In some embodiments, more than one type of biological specimen is obtained from the subject and another record is present (not shown) in the data structure 602 in order to store the molecular profile obtained from the biological specimen. In some embodiments, two or more different types of molecular profiles are created from a single biological specimen (e.g., gene expression profile, protein abundance assays, and genetic marker assays). . . respective data structure 602 includes an initial clinical characterization 606 of the subject. Such initial clinical characterizations can be the results of a physical examination, conventional assay test results, or any of the tests described in conjunction with the clinical characterizations of Fig. 1.
  • each trial participant is assigned a treatment regimen.
  • Such treatment regimens may describe the admimstration and dosage of a drug, the administration of placebo, or some other form of treatment.
  • the treatment for each trial participant 602 may be different. Therefore, each data structure 602 includes a field 608 to describe the treatment regimen assigned to the corresponding clinical trial participant.
  • subsequent assessments can be made of the clinical trial participants in order to gauge the effectiveness of their treatment regimens 608. For example, at defined time points, additional biological specimens can be obtained from trial participants and used as the basis for additional molecular profiles. Such additional molecular profiles are stored in data structure 610.
  • a molecular profile obtained from a biological specimen from clinical participant 1 at a first time point after the initial time point is stored in data structure 610-1-1
  • a molecular profile obtained from a biological specimen from clinical participant 1 at a second time point after the initial time point is stored in data structure 610-2-1
  • a representative data structure 610 has been described above in conjunction with Fig. 8.
  • additional clinical characterizations can be made at each successive time point and stored in data structures 612.
  • a clinical characterization made of clinical participant 1 at a first time point after the initial time point is stored in data structure 612-1-1
  • a clinical characterization made of clinical participant 1 at a second time point after the initial time point is stored in data structure 612-2-1
  • Step 506 one or a plurality of treatment regimens are deduced for a disease based on the longitudinal results of the clinical trial.
  • clinical trial results are analyzed by module 614 (clinical trial analysis module for developing treatment regimens based upon clinical trial results).
  • the clinical trial results 600 are analyzed with pattern classification techniques such as clustering in order to identified cellular constituents that are up- regulated or down-regulated in the diseased state. In some embodiments, the clinical trial results 600 are analyzed to identify genetic markers that tend to be present (or absent) in the diseased states and absent (or present) in the normal state.
  • Pattern classification tecnriiq ⁇ es t at can'De'use 'to make these association include but are not limited to (i) Bayesian analysis, (ii) nonparametric techniques such as Parzen windows, ⁇ -Nearest- neighbor estimation and fuzzy classification, (iii) linear discriminant functions such as Ho-Kashyap procedures and support vector machines, (iv) multilayer neural networks, (v) stochastic methods such as simulated annealing, deterministic simulated annealing, and genetic algorithms, (vi) nonmetric methods such as decision trees, classification and regression trees (CAR), (vii) algorithm-independent machine leaning techniques such as mixture-of-expert model, (viii) application of statistical tests such as chi-square tests, student's t-test or regression, (ix) supervised learning techniques such as linear regression and Kernel methods, boosting and additive trees, and (x) Markov networks.
  • nonparametric techniques such as Parzen windows, ⁇ -Nearest- neighbor estimation and fuzzy classification
  • the molecular profile data comprises cellular constituent abundance data (e.g., gene expression data, or data derived from proteomics).
  • the molecular profile data include genetic marker data (e.g., genotypes) techniques such as the mapping and characterization of quantitative trait loci in outbred population and association techniques are useful. See, for example, Lynch and Walsh, Genetics and Analysis of Quantitative Traits, 1998, Sinauer Associates, Inc. Sunderland, Massachusetts (in particular, Chapter 16).
  • Fig. 6 there is shown a data structure 620 that stores the details of a treatment regimen for a disease under study. In prefened embodiments, each treatment regimen is stored in a different data structure 620.
  • Each treatment regimen optionally has a name 622 and other information such as the clinical study or peer reviewed journal article that formed the basis of the treatment.
  • Each treatment regimen 620 further includes selection criteria 622 that are used to select the treatment regimen 620 for use by a patient. There can be two types of selection criteria, clinical-based selection criteria and molecular profile-based selection criteria. Clinical-based selection criteria include determinations that the patient has a particular cancer (e.g., based on classical diagnostic - - , , ranges for particular cellular constituents, the presence, absence, or specific values of specific genetic markers, and the like.
  • Each treatment regimen 620 further includes a treatment time course 624.
  • a treatment time course 624 specifies what treatment is to be given to a patient and when the treatment is to be given.
  • treatment is divided into discrete longitudinal intervals and the treatment to be administered at each interval can be the same or different.
  • the Current Procedure Terminology code 626 for one or more medical procedures to be performed on the patient is enumerated.
  • one or more drugs 628 and the respective drug dosages and time intervals 630 to be administered to the patient are enumerated.
  • the treatment regimen is not divided into time intervals.
  • the treatment regimen is divided into two or more time intervals. In such embodiments, the patient progresses from one time interval to the next when predetermined clinical criteria have been satisfied.
  • each treatment regimen time interval corresponds to a different degree of severity in the patient's disease.
  • Step 508 the one or more treatment protocols developed in step 506 are communicated to the central health care facility where the treatment protocols are registered.
  • computer 10b can be associated with a central health care facility and, in step 508, the treatment regimens 620 developed in steps 502-506 can be stored in memory 36b of computer 10b.
  • Steps 502 through 508 can be used in embodiments that do not involve or use affiliate health care facilities. In such embodiments, patients make use of the plurality of treatment regimens developed in preceding steps using methods such as those disclosed in Section 5.3 in conjunction with Fig. 2.
  • affiliate health care facilities are used to expand the patient population that can be considered for clinical trial participants, and to widen the network in which health care programs of the present invention can be implemented.
  • usage of affiliate health care facilities allows patients that cannot readily travel to a centralized health care facility to fully participate in the health care program.
  • the affiliate-based aspects of the method begin when a patient is enrolled in a health care program at an affiliate health care facility.
  • the patient signs a consent form that grants permission to have medical data obtained from the patient to be used to develop treatment protocols that can be applied to future patients. More specifically, the ' • 'c ⁇ en orm grants nea t care wor ers permission to per orm molecular profiling on biological specimens that is obtained from patients.
  • the affiliate health care facility has 500 hospital beds or less. In some embodiments, the affiliate health care facility has greater than 500 hospital beds. In some embodiments, the affiliate health care facility has no hospital beds, between 1 and 500 hospital beds, between 500 and 1000 hospital beds, or more than 1000 hospital beds. In some embodiments, the central health care facility has 500 hospital beds or greater. In some embodiments, the central health care facility has between 500 and 1000 hospital beds, or more than 1000 hospital beds. Step 512. In step 512, a clinical characterization of the patient is performed. In preferred embodiments, the clinical characterization is performed by the patient's primary physician at the affiliate health care facility.
  • the clinical characterization is performed by any health care official at the affiliate health care facility.
  • the clinical characterization can include any form of medical test that is classically relied upon in the medical profession to diagnose a patient.
  • the forms of clinical characterization that can be obtained in step 512 can include any of the examples provided in preceding sections, such as the examples of the clinical characterizations 52 (Fig. 1).
  • the clinical characterization is stored in date structure 612 of the patient record 46 created for the patient in computer 10a.
  • One or more biological specimens are also obtained from the patient while the affiliate is at the affiliate health care facility.
  • the affiliate health care facility does not have the laboratory resources necessary to obtain a molecular profile from the biological specimens. Therefore, in typical embodiments, the biological specimens are transported to a central health care facility or other form of facility that is capable of performing molecular profiling.
  • the central health care facility is several miles away from the affiliate health care facility. For example, in some embodiments, the central health care facility is more than 10 miles away from the affiliate health care facility. In other embodiments, the health care facility is more than 100 miles away from the affiliate health care facility.
  • the molecular profile from the biological specimen is created at a location that is in a state other than the state where the affiliate health care facility is located.
  • the molecular profile from the biological specimen is created at a location that is in a country other than the country where the first health care facility is located.
  • the central health care tacihty, the affiliate health care facility, and the facility that performs the molecular profiling are separated by a distance. Typically this distance is a number of miles.
  • the central health care facility, the affiliate health care facility, and the profiling facility are each separated by one or more miles, between 1 and 100 miles, between 100 and 300 miles, or more than 300 miles.
  • At least two of the central health care facility, the affiliate health care facility, and the profiling facility are separated by one or more miles, between 1 and 100 miles, between 100 and 300 miles, or more than 300 miles.
  • the central health care facility, the affiliate health care facility, and the profiling facility are each in a different town, city, or county.
  • at least two of the central health care facility, the affiliate health care facility, and the profiling facility are in a different town, city, or county.
  • the central health care facility, the affiliate health care facility, and the profiling facility are each in a different state or country.
  • at least two of the central health care facility, the affiliate health care facility, and the profiling facility are in a different state or country.
  • the one or more molecular profiles for the patient are ultimately stored in data structure 610 of the patient's record 46 so that the patient's physician can review the profile in subsequent steps. Steps 516-518.
  • the biological specimen and clinical characterization for a given patient are received from an affiliate health care facility.
  • the biological specimen is sent to a third party testing facility in order to perform molecular profiling. Regardless of whether the molecular profiling is performed, in prefened embodiments at least a portion of the biological sample is sent to the central health care facility for permanent storage and reference.
  • the type of molecular profile obtained in the embodiment illustrated in Fig. 5 can be any of the molecular profiles described in previous sections, including molecular profiles 50 (Fig. 1).
  • the clinical characterization and molecular profile for the patient under examination in steps 510 through 514 is stored is stored in the patient record 46 associated with the patient.
  • computer 10b stores or has access to the patient record 46 for each patient enrolled in a given health care program so that the data can be used to refine treatment regimens 620 elucidated in steps 502 through 506, as disclosed in more detail in step 526, below.
  • Step 520. The molecular profile and clinical characterization are used as a basis for selecting one or more treatment regimens 620.
  • Therapeutic determination module 620 plurality of treatment regimens stored in compute 10b, for the patient. Module 78 performs this task by matching the molecular profile and the clinical characterization of the patient to the selection criteria 622 of each treatment regimen 620.
  • Selection criteria 622 are discussed in step 506, above.
  • One or more matching treatment regimens are sent from computer 10b to computer 10a where they are received and stored by treatment regimen module 82.
  • treatment regimen module is simply a web browser (e.g., Internet Explorer, Microsoft, Redmond, Washington) that has been instructed to review select treatment regimens stored on computer 10b.
  • an attending medical practitioner e.g., the patient's primary physician
  • Step 524 the clinical outcome of the patient is monitored.
  • step 524 encompasses steps 214-220 of Fig.
  • step 526 the clinical outcome of the patient under study is used as a basis for refining the treatment regimens relating to the disease that the patient had. More typically, the patients clinical outcome is combined with the climcal outcome of other patients having the same disease as the patient. These outcomes are correlated with the molecular profiles and other clinical characteristics of the patients to determine new correlations and relationships and to test the assumptions relied upon in the initial development of the clinical trials.
  • step 526 the historical longitudinal data from successive instances of step 524, where each instance of step 524 represents a different patient, can be used to verify that osteopontin levels are an accurate indicator of colon cancer severity and that such levels provide a sound basis for deciding which treatment regimen to follow for a given patient.
  • step 528 the refined treatment regimens of step 526 are used as the basis for hypothesis for subsequent clinical trials.
  • 5 represents a repeating cycle in which the results of clinical trials f pe ' er reVieWed' journeyfl'ai articles are used to develop treatment regimens, the success of these treatment regimens is judged using a consenting patient population.
  • the clinical outcome of the patient population is used as the basis for new clinical trials thereby completing the cycle.
  • MEDICAL CARDS Another aspect of the invention is a medical card defined by a base constructed from a substantially flat piece of plastic having a first face and second face, at least one of the first face and the second face comprising indicia placed thereon, the indicia comprising (i) an identification of a patient uniquely associated with the medical card and (ii) a magnetic strip bearing electronic information.
  • the electronic information comprises (i) an identification of the patient, a diagnosis of the patient, and (iii) an identification of a doctor that made the diagnosis.
  • the electronic information in the magnetic strip further comprises at least one demographic characteristic describing the patient. Such demographic characteristics can be, for example, any of the characteristics illustrated in Fig. 4.
  • the electronic information further comprises an analysis of a molecular profile 50 from a biological specimen obtained from the patient. Irrsome embodiments, the electronic information further comprises a clinical characterization 52 of the patient. In some embodiments, the diagnosis is that the patient has a disease such as a type of cancer, a heart disease, an autoimmune disease, a neurodegenerative disorder, an infectious disease and/or any of the diseases described in Section 5.10, below.
  • the medical card further comprises an identification of a treatment regimen 620 that has been assigned to the patient.
  • the electronic information stored in the magnetic strip of the card includes a clinical characterization 52 that comprises a clinical diagnosis having an ICD-9 code and a date the clinical diagnosis was made for the patient.
  • the electronic information further comprises an objective progress assessment for the patient or a subjective progress assessment for the patient.
  • the electronic information further comprises a Current Procedural Terminology (CPT) code for a procedure performed on the patient and a date the procedure was performed on the patient.
  • CPT Current Procedural Terminology
  • the electronic information further comprises a detail about a drug prescribed to the patient.
  • the detail about the drug can include at least one of a name of the drug prescribed, a strength of the drug prescribed, a quantity of the drug prescribed, and a number of refills of the drug prescribed.
  • the normalization comprises normalizing the expression level measurement of each gene in a plurality of genes that is expressed by patient.
  • Many of the normalization protocols described in this section are used to normalize microanay data. It will be appreciated that there are many other suitable normalization protocols that may be used in accordance with the present invention. All such protocols are within the scope of the present invention. Many of the normalization protocols found in this section are found in publicly available software, such as Microarray Explorer (Image Processing Section, Laboratory of Experimental and Computational Biology, National Cancer Institute, Frederick, MD 21702, USA).
  • One normalization protocol is Z-score of intensity. In this protocol, raw expression intensities are normalized by the (mean intensity)/(standard deviation) of raw intensities for all spots in a sample.
  • the Z-score of intensity method normalizes each hybridized sample by the mean and standard deviation of the raw intensities for all of the spots in that sample.
  • the mean intensity mnl; and the standard deviation sdlj are computed for the raw intensity of control genes. It is useful for standardizing the mean (to 0.0) and the range of data between hybridized samples to about -3.0 to +3.0.
  • the Z differences (Z diff ) are computed rather than ratios.
  • Another normalization protocol is the median intensity normalization protocol in which the raw intensities for all spots in each sample are normalized by the median of the raw intensities.
  • the median intensity normalization method normalizes each hybridized sample by the median of the raw intensities of control genes (medianlj) for all of the spots in that sample.
  • the raw intensity I y for probe i and spot j has the value
  • Another normalization protocol is the log median intensity protocol.
  • raw expression intensities are normalized by the log of the median scaled raw intensities of representative spots for all spots in the sample.
  • the log median intensity method normalizes each hybridized sample by the log of median scaled raw intensities of control genes (median!;) for all of the spots in that sample.
  • control genes are a set of genes that have reproducible accurately measured expression values. The value 1.0 is added to the intensity value to avoid taking the log(O.O) when intensity has zero value.
  • the raw intensity I l ⁇ for probe i and spot j has the value Inij j where,
  • Im, j log(1.0 + (Ii j / medianli)).
  • Z-score standard deviation log of intensity protocol Yet another normalization protocol is the Z-score standard deviation log of intensity protocol.
  • raw expression intensities are normalized by the mean log intensity (mnLI;) and standard deviation log intensity (sdLIj).
  • mnLI mean log intensity
  • sdLIj standard deviation log intensity
  • the mean log intensity and the standard deviation log intensity is computed for the log of raw intensity of control genes.
  • the Z-score intensity ZlogS y for probe i and spot j is:
  • Still another normalization protocol is the Z-score mean absolute deviation of log intensity protocol.
  • raw expression intensities are normalized by the Z- score of the log intensity using the equation (log(intensity)-mean logarithm) / standard deviation logarithm.
  • the Z-score mean absolute deviation of log intensity protocol normalizes each bound sample by the mean and mean absolute deviation of the logs of the raw intensities for all of the spots in the sample.
  • the mean log intensity mnLIi and the mean absolute deviation log intensity madLIj are computed for the log of raw intensity of control genes. Then, the Z-score intensity ZlogA y for probe i and spot j is:
  • ZlogAy (log(Ij j ) - mnLIi)/madLIj.
  • protocol raw expression intensities are normalized by the sum of the genes in a user defined gene set in each sample. This method is useful if a subset of genes has been determined to have relatively constant expression across a set of samples.
  • calibration DNA gene set protocol in which each sample is normalized by the sum of calibration DNA genes.
  • calibration DNA genes are genes that produce reproducible expression values that are accurately measured. Such genes tend to have the same expression values on each of several different microarrays.
  • the algorithm is the same as user normalization gene set protocol described above, but the set is predefined as the genes flagged as calibration DNA.
  • Yet another normalization protocol is the ratio median intensity correction protocol.
  • This protocol is useful in embodiments in which a two-color fluorescence labeling and detection scheme is used. See, for example, section 5.8.1.5.
  • the two fluors in a two-color fluorescence labeling and detection scheme are Cy3 and Cy5
  • measurements are normalized by multiplying the ratio (Cy3/Cy5) by medianCy5/medianCy3 intensities.
  • background correction is enabled, measurements are normalized by multiplying the ratio (Cy3/Cy5) by (medianCy5-medianBkgdCy5) / (medianCy3-medianBkgdCy3) where medianBkgd means median background levels.
  • intensity background correction is used to normalize measurements.
  • kits contain microarrays, such as those described in Subsections below.
  • the microarcays contained in such kits comprise a solid phase, e.g., a surface, to which probes are hybridized or bound at a known location of the solid phase.
  • these probes consist of nucleic acids of known, different sequence, with each nucleic acid being capable of hybridizing to an RNA species or to a cDNA species derived therefrom.
  • the probes contained in the kits of this invention are nucleic acids capable of hybridizing specifically to nucleic acid sequences derived from RNA species in cells collected from an organism of interest.
  • a kit of the invention also contains one or more databases described above and in Figs. 1, 6, and 7, encoded on computer readable medium, and/or an access authorization to use the databases described above from a remote networked computer.
  • kits of the invention further contains software capable of being loaded into the memory of a.computer system such as the one described supra, and illustrated in Fig. 1 and/or Fig. 7.
  • the software contained in the kit of this invention is essentially identical to the software described above in conjunction with Fig. 1 and/or Fig. 7.
  • Alternative kits for implementing the analytic methods of this invention will be apparent to one of skill in the art and are intended to be comprehended within the accompanying claims.
  • TRANSCRIPT ASSAY USING MICROARRAYS The techniques described in this section are particularly useful for the determination of the expression state or the transcriptional state of a cell or cell type or any other cell sample by monitoring expression profiles. These techniques include the provision of polynucleotide probe arrays that can be used to provide simultaneous determination of the expression levels of a plurality of genes. These techniques further provide methods for designing and making such polynucleotide probe arcays.
  • the expression level of a nucleotide sequence in a gene can be measured by any high throughput techniques. However measured, the result is either the absolute or relative amounts of transcripts or response data, including but not limited to values representing abundances or abundance ratios.
  • a molecular profile 50 is an expression profile that is obtained by hybridizing detectably labeled polynucleotides representing the nucleotide sequences in mRNA transcripts present in a cell (e.g.
  • a microarray is an anay of positionally-addressable binding (e.g., hybridization) sites on a support for representing many of the nucleotide sequences in the genome of a cell or organism, preferably most or almost all of the genes. Each of such binding sites consists of polynucleotide probes bound to the predetermined region on the support.
  • Microarrays can be made in a number of ways, of which several are described herein below. However produced, microarrays share certain characteristics. The arrays are reproducible, allowing multiple copies of a given anay to be produced and easily compared with each other.
  • the microarrays are made from materials that are stable under binding (e.g., nucleic acid hybridization) conditions.
  • Microanays are preferably small, e.g., between 1 cm 2 and 25 cm 2 , preferably 1 to 3 cm 2 .
  • both larger and smaller anays are also contemplated and may be preferable, e.g., for simultaneously evaluating a very large number or very small number of different probes.
  • a given binding site or unique set of binding sites in the microanay will specifically bind (e.g., hybridize) to a nucleotide sequence in a single gene from a cell or organism (e.g.
  • the microarray is a first edition Human HuFL6800 (6800 elements) or a second edition HuU95A (12,000 elements) GeneChip.
  • the HuFL6800 chip contains probes corresponding to 5000 named genes (based on the National Center for Biotechnology Information UniGene Build 139, as provided by Affymetrix, Santa Clara, California), whereas the HuU95A contains more than 12,000 probe sets conesponding to 8900 names genes (UniGene Build 139).
  • the microanays used can include one or more test probes, each of which has a polynucleotide sequence that is complementary to a subsequence of RNA or DNA to be detected.
  • Each probe typically has a different nucleic acid sequence, and the position of each probe on the solid surface of the anay is usually known.
  • the microarrays are preferably addressable arrays, more preferably positionally addressable arrays.
  • Each probe of the anay is preferably located at a known, predetermined position on the solid support so that the identity (e.g., the sequence) of each probe can be determined from its _ positi n ' ri 't e"array' e:g.”;"On e support or sur ace .
  • tne arrays are ordered arrays.
  • the density of probes on a microanay or a set of microanays is 100 different (e.g., non-identical) probes per 1 cm 2 or higher.
  • a microarray used in the methods of the invention will have at least 550 probes per 1 cm 2 , at least 1,000 probes per 1 cm 2 , at least 1,500 probes per 1 cm 2 or at least 2,000 probes per 1 cm 2 .
  • the microarray is a high density anay, preferably having a density of at least 2,500 different probes per 1 cm .
  • the microanays used in the invention therefore preferably contain at least 2,500, at least 5,000, at least 10,000, at least 15,000, at least 20,000, at least 25,000, at least 50,000 or at least 55,000 different (e.g., non-identical) probes.
  • the microanay is an anay (e.g., a matrix) in which each position represents a discrete binding site for a nucleotide sequence of a transcript encoded by a gene (e.g. , for an exon of an mRNA or a cDNA derived therefrom).
  • the collection of binding sites on a microanay contains sets of binding sites for a plurality of genes.
  • the microanays of the invention can comprise binding sites for products encoded by fewer than 50% of the genes in the genome of an organism.
  • the microanays of the invention can have binding sites for the products encoded by at least 50%, at least 75%, at least 85%, at least 90%, at least 95%, at least 99% or 100% of the genes in the genome of an organism.
  • the microanays of the invention can having binding sites for products encoded by fewer than 50%, by at least 50%, by at least 75%, by at least 85%, by at least 90%, by at least 95%, by at least 99% or by 100% of the genes expressed by a cell of an organism.
  • the binding site can be a DNA or DNA analog to which a particular RNA can specifically hybridize.
  • the DNA or DNA analog can be, e.g., a synthetic oligomer or a gene fragment, e.g. conesponding to an exon.
  • a gene or an exon in a gene is represented in the profiling anays by a set of binding sites comprising probes with different polynucleotides that are complementary to different sequence segments of the gene or the exon.
  • Such polynucleotides are preferably of the length of 15 to 200 bases, more preferably of the length of 20 to 100 bases, most preferably 40-60 bases.
  • Each probe sequence can also comprise linker sequences in addition to the sequence that is complementary to its target sequence.
  • a linker sequence is a sequence between the sequence that is complementary to its target sequence and the surface of support.
  • the profiling anays of the invention cornpnse'one probe specmc to eac target gene or exon. owever, it desired, the profiling anays can contain at least 2, 5, 10, 100, or 1000 or more probes specific to some target genes or exons.
  • the anay can contain probes tiled across the sequence of the longest mRNA isoform of a gene at single base steps.
  • a set of polynucleotide probes of successive overlapping sequences, e.g., tiled sequences, across the genomic region containing the longest variant of an exon can be included in the exon profiling anays.
  • the set of polynucleotide probes can comprise successive overlapping sequences at steps of a predetermined base intervals, e.g. at steps of 1, 5, or 10 base intervals, span, or are tiled across, the mRNA containing the longest variant.
  • Such sets of probes therefore can be used to scan the genomic region containing all variants of an exon to determine the expressed variant or variants of the exon to determine the expressed variant or variants of the exon.
  • a set of polynucleotide probes comprising exon specific probes and/or variant junction probes can be included in the exon profiling anay.
  • a variant junction probe refers to a probe specific to the junction region of the particular exon variant and the neighboring exon.
  • the probe set contains variant junction probes specifically hybridizable to each of all different splice junction sequences of the exon.
  • the probe set contains exon specific probes specifically hybridizable to the common sequences in all different variants of the exon, and/or variant junction probes specifically hybridizable to the different splice junction sequences of the exon.
  • an exon is represented in the exon profiling anays by a probe comprising a polynucleotide that is complementary to the full length exon.
  • an exon is represented by a single binding site on the profiling anays.
  • an exon is represented by one or more binding sites on the profiling anays, each of the binding sites comprising a probe with a polynucleotide sequence that is complementary to an RNA fragment that is a substantial portion of the target exon.
  • the lengths of such probes are normally between 15-600 bases, preferably between 20-200 bases, more preferably between 30-100 bases, and most preferably between 40-80 bases.
  • the average length of an exon is about 200 bases in some embodiments of the present invention (see, e.g., Lewin, Genes V, Oxford University Press, Oxford, 1994).
  • a probe of length of 40-80 allows more specific binding of the exon than a probe of shorter length, thereby increasing the specificity of the probe to the target exon.
  • one or more targeted exons can have sequence lengths less than 40-80 bases.
  • probes with sequences longer than the target exons are to be used, it can be desirable to 'des ⁇ g ⁇ Tpit' ⁇ ' bes' comprising sequences that include the entire target exon flanked by sequences from the adjacent constitutively splice exon or exons such that the probe sequences are complementary to the conesponding sequence segments in the mRNAs.
  • flanking sequences from adjacent constitutively spliced exon or exons rather than the genomic flanking sequences, e.g. , intron sequences, permits comparable hybridization stringency with other probes of the same length.
  • flanking sequences used are from the adjacent constitutively spliced exon or exons that are not involved in any alternative pathways. More preferably, the flanking sequences used do not comprise a significant portion of the sequence of the adjacent exon or exons so that cross- hybridization can be minimized.
  • probes comprising flanking sequences in different alternatively spliced mRNAs are designed so that expression level of the exon expressed in different alternatively spliced mRNAs can be measured.
  • the DNA anay or set of anays can also comprise probes that are complementary to sequences spanning the junction regions of two adjacent exons.
  • probes comprise sequences from the two exons which are not substantially overlapped with probes for each individual exons so that cross hybridization can be minimized.
  • Probes that comprise sequences from more than one exons are useful in distinguishing alternative splicing pathways and/or expression of duplicated exons in separate genes if the exons occurs in one or more alternative spliced mRNAs and/or one or more separated genes that contain the duplicated exons but not in other alternatively spliced mRNAs and/or other genes that contain the duplicated exons.
  • any of the probe schemes, supra can be combined on the same profiling array and/or on different anays within the same set of profiling anays so that a more accurate determination of the expression profile for a plurality of genes can be accomplished.
  • the different probe schemes can also be used for different levels of accuracies in profiling. For example, a profiling anay or anay set comprising a small set of probes for each exon can be used to determine the relevant genes and/or RNA splicing pathways under certain specific conditions. .
  • an anay or array set comprising larger sets of probes tor , tti'e''ex ⁇ ns' i t at'are , r nterest is t en use to more accurate y etermine tne exon expression profile under such specific conditions.
  • Other DNA array strategies that allow more advantageous use of different probe schemes are also encompassed.
  • the microanays used in the invention have binding sites (e.g., probes) for sets of exons for one or more genes relevant to the action of a drug of interest or in a biological pathway of interest.
  • a "gene” is identified as a portion of DNA that is transcribed by RNA polymerase, which may include a 5N untranslated region ("UTR"), introns, exons and a 3N UTR.
  • the number of genes in a genome can be estimated from the number of mRNAs expressed by the cell or organism, or by extrapolation of a well characterized portion of the genome.
  • the number of ORFs can be determined and mRNA coding regions identified by analysis of the DNA sequence. For example, the genome of Saccharomyces cerevisiae has been completely sequenced and is reported to have approximately 6275 ORFs encoding sequences longer than 99 amino acid residues in length.
  • an anay set comprising, in total, probes for all known or predicted exons in the genome of an organism are provided.
  • the present invention provides an anay set comprising one or two probes for all or a portion of the known exons in the human genome.
  • the level of hybridization to the site in the anay conesponding to an exon of any particular gene will reflect the prevalence in the cell of mRNA or mRNAs containing the exon transcribed from that gene.
  • detectably labeled e.g.
  • cDNA complementary to the total cellular mRNA is hybridized to a microanay, the site on the anay conesponding to an exon of a gene (i.e., capable of specifically binding the product or products of the gene expressing) that is not transcribed or is removed during RNA splicing in the cell will have little or no signal (e.g., fluorescent signal), and an exon of a gene for which the encoded mRNA expressing the exon is prevalent will have a relatively strong signal.
  • the relative abundance of different mRNAs produced from the same gene by alternative splicing is then determined by the signal strength pattern across the whole set of exons monitored for the gene.
  • cDNAs from cell samples from two different conditions are hybridized to the binding sites of the microanay using a two-color protocol.
  • a two-color protocol In the case or ru r s onses one e-ei samp e is expose o a rug an ano er ce samp e o e same type is not exposed to the drug.
  • pathway responses one cell is exposed to a pathway perturbation and another cell of the same type is not exposed to the pathway perturbation.
  • the cDNA derived from each of the two cell types are differently labeled (e.g., with Cy3 and Cy5) so that they can be distinguished.
  • cDNA from a cell treated with a drug is synthesized using a fluorescein-labeled dNTP
  • cDNA from a second cell, not drug-exposed is synthesized using a rhodamine-labeled dNTP.
  • the cDNA from the drug-treated (or pathway perturbed) cell will fluoresce green when the fluorophore is stimulated and the cDNA from the untreated cell will fluoresce red.
  • the drug treatment has no effect, either directly or indirectly, on the transcription and/or post-transcriptional splicing of a particular gene in a cell
  • the exon expression patterns will be indistinguishable in both cells and, upon reverse transcription, red-labeled and green-labeled cDNA will be equally prevalent.
  • the binding site(s) for that species of RNA will emit wavelengths characteristic of both fluorophores.
  • the exon expression pattern as represented by ratio of green to red fluorescence for each exon binding site will change.
  • the ratios for each exon expressed in the mRNA will increase, whereas when the drug decreases the prevalence of an mRNA, the ratio for each exons expressed in the mRNA will decrease.
  • C 1 trom a sing -ce an compare, or examp e, e a so ute amount oi a particular exon in, e.g., a drug-treated or pathway-perturbed cell and an untreated cell.
  • labeling with more than two colors is also contemplated in the present invention.
  • at least 5, 10, 20, or 100 dyes of different colors can be used for labeling.
  • Such labeling permits simultaneous hybridizing of the distinguishably labeled cDNA populations to the same anay, and thus measuring, and optionally comparing the expression levels of, mRNA molecules derived from more than two samples.
  • Dyes that can be used include, but are not limited to, fluorescein and its derivatives, rhodamine and its derivatives, texas red, 5Ncarboxy-fluorescein (“FMA”), 2N,7N-dimethoxy-4N,5N-dichloro-6-carboxy-fluorescein (“JOE”), N,N,NN,NN- tetramethyl-6-carboxy-rhodamine (“TAMRA”), 6Ncarboxy-X-rhodamine (“ROX”), HEX, TET, LRD40, and IRD41, cyamine dyes, including but are not limited to Cy3, Cy3.5 and Cy5; BODIPY dyes including but are not limited to BODIPY-FL, BODLPY- TR, BODIPY-TMR, BODIPY-630/650, and BODIPY-650/670; and ALEXA dyes, including but are not limited to ALEXA-488, ALEXA-5
  • hybridization data are measured at a plurality of different hybridization times so that the evolution of hybridization levels to equilibrium can be determined.
  • hybridization levels are most preferably measured at hybridization times spanning the range from 0 to in excess of what is required for sampling of the bound polynucleotides (i.e., the probe or probes) by the labeled polynucleotides so that the mixture is close to or substantially reached equilibrium, and duplexes are at concentrations dependent on affinity and abundance rather than diffusion.
  • the hybridization times are preferably short enough that ineversible binding interactions between the labeled polynucleotide and the probes and/or the surface do not occur, or are at least limited.
  • hybridization times may be approximately 0-72 hours. Appropriate hybridization times for other embodiments will depend on the particular polynucleotide sequences and probes used, and may be determined by those skilled in the art (see, e.g., Sambrook et al, Eds., 1989, Molecular Cloning: A Laboratory Manual, 2nd ed., Vol. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York). In one embodiment, hybridization levels at different hybridization times are measured separately on different, identical microanays.
  • t e microanay is washed briefly, preferably in room temperature in an aqueous solution of high to moderate salt concentration (e.g., 0.5 to 3 M salt concentration) under conditions which retain all bound or hybridized polynucleotides while removing all unbound polynucleotides.
  • high to moderate salt concentration e.g., 0.5 to 3 M salt concentration
  • hybridization levels are then combined to form a hybridization curve.
  • hybridization levels are measured in real time using a single microarray.
  • the microanay is allowed to hybridize to the sample without interruption and the microanay is inteno gated at each hybridization time in a non-invasive manner.
  • At least two hybridization levels at two different hybridization times are measured, a first one at a hybridization time that is close to the time scale of cross- hybridization equilibrium and a second one measured at a hybridization time that is longer than the first one.
  • the time scale of cross-hybridization equilibrium depends, inter alia, on sample composition and probe sequence and may be determined by one skilled in the art.
  • the first hybridization level is measured at between 1 to 10 hours, whereas the second hybridization time is measured at 2, 4, 6, 10, 12, 16, 18, 48 or 72 times as long as the first hybridization time.
  • the "probe" to which a particular polynucleotide molecule, such as an exon, specifically hybridizes according to the invention is a complementary polynucleotide sequence.
  • one or more probes are selected for each target exon.
  • the probes normally comprise nucleotide sequences greater than 40 bases in length.
  • the probes normally comprise nucleotide sequences of 40-60 bases.
  • the probes can also comprise sequences complementary to full length exons.
  • the lengths of exons can range from less than 50 bases to more than 200 bases. Therefore, when a probe length longer than exon is to be used, it is preferable to augment the exon sequence with adjacent constitutively spliced exon sequences such that the probe sequence is complementary to the continuous target exon.
  • m Thi.s wi •lpenl a researcherllow com parable hybndizati.on stringency among the probes of an exon profiling anay.
  • each probe sequence may also comprise linker sequences in addition to the sequence that is complementary to its target sequence.
  • the probes may comprise DNA or DNA "mimics" (e.g. , derivatives and analogues) conesponding to a portion of each exon of each gene in an organism's genome.
  • the probes of the microanay are complementary RNA or
  • DNA mimics are polymers composed of subunits capable of specific,
  • DNA can be obtained, e.g., by polymerase chain reaction (PCR) amplification of exon segments from genomic DNA, cDNA (e.g., by RT-PCR), or cloned sequences.
  • PCR primers are preferably chosen based on known sequence of the exons or cDNA that result in amplification of unique fragments (i.e., fragments that do not share more than 10 bases of contiguous identical sequence with any other fragment on the microanay).
  • each probe on the microanay will be between 20 bases and 600 bases, and usually between 30 and 200 bases in length.
  • PCR methods are well known in the art, and are described, for example, in Innis et al, eds., 1990, PCR Protocols: A Guide to Methods and Applications, Academic Press Inc., San Diego, CA. It will be apparent to one skilled in the art that controlled robotic systems are useful for isolating and amplifying nucleic acids.
  • An alternative, prefened means for generating the polynucleotide probes of the microanay is by synthesis of synthetic polynucleotides or oligonucleotides, e.g., using N- phosphonate or phosphoramidite chemistries (Froehler et al, 1986, Nucleic Acid Res. 74:5399-5407; McBride et al, 1983, Tetrahedron Lett. 24:246-248). Synthetic sequences are typically between 15 and 600 bases in length, more typically between 20 and 100 bases, most preferably between 40 and 70 bases in length. In some embodiments, synthetic nucleic acids include non-natural bases, such as, but by no means limited to, inosine.
  • nucleic acid analogues may be used as binding sites for hybridization.
  • An example of a suitable nucleic acid analogue is peptide nucleic acid (see, e.g., Egholm et al, 1993, Nature 363:566-568; and U.S. Patent No. 5,539,083).
  • the hybndization sites e.g., the probes
  • the hybndization sites are made from plasmid or phage clones of genes, cDNAs (e.g., expressed sequence tags), or inserts therefrom (Nguyen et al, 1995, Genomics 29:207-209). 5.8.1.2.
  • polynucleotide probes can be deposited on a support to form the anay.
  • polynucleotide probes can be synthesized directly on the support to form the anay.
  • the probes are attached to a solid support or surface, which may be made, e.g., from glass, plastic (e.g., polypropylene, nylon), polyacrylamide, nitrocellulose, gel, or other porous or nonporous material.
  • a prefened method for attaching the nucleic acids to a surface is by printing on glass plates, as is described generally by Schena et al, 1995, Science 270:467-470.
  • microarrays This method is especially useful for preparing microanays of cDNA (See also, DeRisi et al, 1996, Nature Genetics 14:457-460; Shalon et al, 1996, Genome Res. 6:639-645; and Schena et al, 1995, Proc. Natl. Acad. Sci. U.S.A. 93:10539-11286).
  • a second prefened method for making microarrays is by making high-density polynucleotide anays.
  • oligonucleotides e.g., 60-mers
  • the anay produced can be redundant, with several polynucleotide molecules per exon.
  • Other methods for making microanays e.g., by masking (Maskos and Southern, 1992, Nucl. Acids. Res. 20:1679-1684), may also be used.
  • microanays of the invention are manufactured by means of an ink jet printing device for oligonucleotide synthesis, e.g., using the methods and systems described by Blanchard in International Patent Publication o.
  • the polynucleotide probes in such microanays are preferably synthesized in anays, e.g., on a glass slide, by serially depositing individual nucleotide bases in "microdroplets" of a high surface tension solvent such as propylene carbonate.
  • the microdroplets have small volumes (e.g., 100 pL or less, more preferably 50 pL or less) and are separated from each other on the microanay (e.g., by hydrophobic domains) to form circular surface tension wells which define the locations of the anay elements (i.e., the different probes).
  • Polynucleotide probes are normally attached to the surface covalently at the 3N end of the polynucleotide. Alternatively, polynucleotide probes can be attached to the surface covalently at the 5N end of the polynucleotide (see for example, Blanchard, 1998, in Synthetic DNA Arrays in Genetic Engineering, Vol. 20, J.K. Setlow, Ed., Plenum Press, New York at pages 111-123).
  • Target polynucleotides that can be analyzed by the methods and compositions of the invention include RNA molecules such as, but by no means limited to, messenger RNA (mRNA) molecules, ribosomal RNA (rRNA) molecules, cRNA molecules (i. e. , RNA molecules prepared from cDNA molecules that are transcribed in vivo) and fragments thereof.
  • Target polynucleotides that can also be analyzed by the methods of the present invention include, but are not limited to DNA molecules such as genomic DNA molecules, cDNA molecules, and fragments thereof including oligonucleotides, ESTs, STSs, etc.
  • the target polynucleotides can be from any source.
  • the target polynucleotide molecules can be naturally occurring nucleic acid molecules such as genomic or extragenomic DNA molecules isolated from a patient, or RNA molecules, such as mRNA molecules, isolated from a patient.
  • the polynucleotide molecules can be synthesized, including, e.g., nucleic acid molecules synthesized enzymatically in vivo or in vitro, such as cDNA molecules, or polynucleotide molecules synthesized by PCR, RNA molecules synthesized by in vitro transcription, etc.
  • the sample of target polynucleotides can comprise, e.g., molecules of DNA, RNA, or copolymers of DNA and RNA.
  • the target polynucleotides of the invention will conespond to particular genes or to particular gene transcripts (e.g., to ' particular mRNA sequences expressed in cells or to particular cDNA sequences derived from such mRNA sequences).
  • the target polynucleotides can conespond to particular fragments of a gene transcript.
  • the target polynucleotides may conespond to different exons of the same gene, e.g., so that different splice variants of the gene can be detected and/or analyzed.
  • the target polynucleotides to be analyzed are prepared in vitro from nucleic acids extracted from cells.
  • RNA is extracted from cells (e.g. , total cellular RNA, poly(A) + messenger RNA, fraction thereof) and messenger RNA is purified from the total extracted RNA.
  • Methods for preparing total and poly(A) + RNA are well known in the art, and are described generally, e.g., in Sambrook et al, supra.
  • RNA is extracted from cells of the various types of interest in this invention using guanidinium thiocyanate lysis followed by CsCl centrifugation and an oligo dT purification (Chirgwin et al, 1979, Biochemistry 75:5294-5299).
  • RNA is extracted from cells using guanidinium thiocyanate lysis followed by purification on RNeasy columns (Qiagen).
  • cDNA is then synthesized from the purified mRNA using, e.g., oligo-dT or random primers.
  • the target polynucleotides are cRNA prepared from purified messenger RNA extracted from cells.
  • cRNA is defined here as RNA complementary to the source RNA.
  • the extracted RNAs are amplified using a process in which doubled-stranded cDNAs are synthesized from the RNAs using a primer linked to an RNA polymerase promoter in a direction capable of directing transcription of anti- sense RNA.
  • Anti-sense RNAs or cRNAs are then transcribed from the second strand of the double-stranded cDNAs using an RNA polymerase (see, e.g., U.S. Patent Nos. 5,891,636, 5,716,785; 5,545,522 and 6,132,997; see also, U.S. Patent No. 6,271,002, and U.S. Provisional Patent Application Serial No. 60/253,641, filed on November 28, 2000, by Ziman et al). Both oligo-dT primers (U.S. Patent Nos. 5,545,522 and 6,132,997) or random primers (U.S. Provisional Patent Application Serial No.
  • the target polynucleotides are short and/or fragmented polynucleotide molecules that are representative of the original nucleic acid population of the cell.
  • the target polynucleotides to be analyzed by the methods of the invention are preferably detectably labeled.
  • cDNA can be labeled directly, e.g., with nucleotide analogs, or indirectly, e.g., by making a second, labeled cDNA strand using the first'sffand'as't te'tn ' pla'te:' ' A ternat vely, t e ou le-stran e c can be transcribed into cRNA and labeled.
  • the detectable label is a fluorescent label, e.g., by incorporation of nucleotide analogs.
  • radioactive isotopes include 32 P, 35 S, 14 C, 15 N and 125 I.
  • Fluorescent molecules suitable for the present invention include, but are not limited to, fluorescein and its derivatives, rhodamine and its derivatives, texas red, 5Ncarboxy- fluorescein (“FMA”), 2N,7N-dimethoxy-4N,5N-dichloro-6-carboxy-fluorescein (“JOE”), N,N,NN,NN- tetramethyl-6-carboxy-rhodamine (“TAMRA”), 6Ncarboxy-X-rhodamine (“ROX”), HEX, TET, IRD40, and IRD41.
  • FMA 5Ncarboxy- fluorescein
  • JE 2N,7N-dimethoxy-4N,5N-dichloro-6-carboxy-fluorescein
  • TAMRA N,N,NN,NN- tetramethyl-6-carboxy-rhodamine
  • ROX 6Ncarboxy-X-rhodamine
  • Fluorescent molecules that are suitable for the invention further include: cyamine dyes, including by not limited to Cy3, Cy3.5 and Cy5; BODIPY dyes including but not limited to BODIPY-FL, BODIPY-TR, BODIP Y-TMR, BODIPY- 630/650, and BODJJPY-650/670; and ALEXA dyes, including but not limited to ALEXA- 488, ALEXA-532, ALEXA-546, ALEXA-568, and ALEXA-594; as well as other fluorescent dyes which will be known to those who are skilled in the art.
  • Electron rich indicator molecules suitable for the present invention include, but are not limited to, ferritin, hemocyanin, and colloidal gold.
  • the target polynucleotides may be labeled by specifically complexing a first group to the polynucleotide.
  • a second group covalently linked to an indicator molecules and which has an affinity for the first group, can be used to indirectly detect the target polynucleotide.
  • compounds suitable for use as a first group include, but are not limited to, biotin and iminobiotin.
  • Compounds suitable for use as a second group include, but are not limited to, avidin and streptavidin.
  • nucleic acid hybridization and wash conditions are chosen so that the polynucleotide molecules to be analyzed by the invention (refened to herein as the "target polynucleotide molecules) specifically bind or specifically hybridize to the complementary polynucleotide sequences of the anay, preferably to a specific anay site, wherein its complementary DNA is located.
  • Anays containing double-stranded probe DNA situated thereon are preferably subjected to denaturing conditions to render the DNA single-stranded prior to contacting wiih'the' t ⁇ rget'p ⁇ '1'ynucledt ⁇ de molecules.
  • Arrays containing single-stranded probe DNA may need to be denatured prior to contacting with the target polynucleotide molecules, e.g., to remove hairpins or dimers which form due to self complementary sequences.
  • Optimal hybridization conditions will depend on the length (e.g. , oligomer versus polynucleotide greater than 200 bases) and type (e.g., RNA, or DNA) of probe and target nucleic acids.
  • hybridization conditions are also provided in, e.g., Tijessen, 1993, Hybridization With Nucleic Acid Probes, Elsevier Science Publishers B.V. and Kricka, 1992, Nonisotopic DNA Probe Techniques, Academic Press, San Diego, California.
  • Particularly preferred hybridization conditions for use with the screening and/or signaling chips of the present invention include hybridization at a temperature at or near the mean melting temperature of the probes (e.g., within 5 °C, more preferably within 2 °C) in 1 M NaCl, 50 mM MES buffer (pH 6.5), 0.5% sodium Sarcosine and 30% formamide.
  • cDNA complementary to the total cellular mRNA is hybridized to a microanay, the site on the anay conesponding to an exon of a gene (e.g., capable of specifically binding the product or products of the gene expressing) that is not transcribed or is removed during RNA splicing in the cell will have little or no signal (e.g., fluorescent signal), and an exon of a gene for which the encoded mRNA expressing the exon is prevalent will have a relatively strong signal.
  • a gene e.g., capable of specifically binding the product or products of the gene expressing
  • target sequences e.g., cDNAs or cRNAs
  • target sequences e.g., cDNAs or cRNAs
  • drug responses one cell sample is exposed to a drug and another cell sample of the same type is not exposed to the drug.
  • pathway responses one cell is exposed to a pathway perturbation and another cell of the same type is not exposed to the pathway perturbation.
  • cDNA or cRNA derived from each of the two cell types are differently labeled so that they can be distinguished.
  • cDNA from a cell treated with a drug (or exposed to a pathway perturbation) is synthesized using a fluorescein-labeled dNTP
  • cDNA from a second cell, not drug-exposed is synthesized using a rhodamine-labeled dNTP.
  • the exon expression pattern as represented by ratio of green to red fluorescence for each exon binding site will change.
  • the ratios for each exon expressed in the mRNA will increase, whereas when the drug decreases the prevalence of an mRNA, the ratio for each exons expressed in the mRNA will decrease.
  • target sequences e.g., cDNAs or cRNAs, labeled with two i erent ⁇ rOp r s
  • target sequences e.g., cDNAs or cRNAs
  • labeled with two i erent ⁇ rOp r s is a a irec an in erna y con ro e companson ot the m or exon expression levels conesponding to each anayed gene in two cell states can be made, and variations due to minor differences in experimental conditions (e.g., hybridization conditions) will not affect subsequent analyses.
  • cDNA from a single cell, and compare, for example, the absolute amount of a particular exon in, e.g., a drug-treated or pathway-perturbed cell and an untreated cell.
  • the fluorescence emissions at each site of a transcript anay can be, preferably, detected by scanning confocal laser microscopy.
  • a separate scan, using the appropriate excitation line, is carried out for each of the two fluorophores used.
  • a laser can be used that allows simultaneous specimen illumination at wavelengths specific to the two fluorophores and emissions from the two fluorophores can be analyzed simultaneously (see Shalon et al, 1996, Genome Res. 6:639-645).
  • the anays are scanned with a laser fluorescence scanner with a computer controlled X-Y stage and a microscope objective.
  • Sequential excitation of the two fluorophores is achieved with a multi-line, mixed gas laser, and the emitted light is split by wavelength and detected with two photomultiplier tubes.
  • fluorescence laser scanning devices are described, e.g., in Schena et al, 1996, Genome Res. 6:639-645.
  • the fiber-optic bundle described by Ferguson et al, 1996, Nature Biotech. 7 :1681-1684, can be used to monitor mRNA abundance levels at a large number of sites simultaneously. Signals are recorded and, in a prefened embodiment, analyzed by computer.
  • the scanned image is despeckled using a graphics program (e.g., Hijaak Graphics Suite) and then analyzed using an image gridding program that creates a spreadsheet of the average hybridization at each wavelength at each site. If necessary, an experimentally determined correction for "cross talk" (or overlap) between the channels for the two fluors can be made.
  • a ratio of the emission of the two fluorophores can be calculated. The ratio is independent of the absolute expression level of the cognate gene, but is useful for genes whose expression is significantly modulated by drug admimstration, gene deletion, or any other tested event.
  • the relative abundance of an mRNA and/or an exon expressed in an mRNA in two cells or cell lines is scored as perturbed (e.g., the abundance is different in the two sources of mRNA tested) or as not perturbed (e.g., the relative abundance is the same).
  • a difference between the two s u e o o a eas a ac or o e.g., is more aounoant in one source than in the other source), more usually 50%, even more often by a factor of 2 (e.g., twice as abundant), 3 (three times as abundant), or 5 (five times as abundant) is scored as a perturbation.
  • Present detection methods allow reliable detection of differences of an order of 1.5 fold to 3-fold. It is, however, also advantageous to determine the magnitude of the relative difference in abundances for an mRNA and/or an exon expressed in an mRNA in two cells or in two cell lines. This can be carried out, as noted above, by calculating the ratio of the emission of the two fluorophores used for differential labeling, or by analogous methods that will be readily apparent to those of skill in the art.
  • the transcriptional state of cellular constituent in a biological specimen can be measured by other gene expression technologies known in the art.
  • Several such technologies produce pools of restriction fragments of limited complexity for electrophoretic analysis, such as methods combining double restriction enzyme digestion with phasing primers (see, e.g., European Patent O 534858 Al, filed September 24, 1992, by Zabeau et al), or methods selecting restriction fragments with sites closest to a defined mRNA end (see, e.g., Prashar et al, 1996, Proc. Natl. Acad. Sci. USA 93:659-663).
  • cDNA pools statistically sample cDNA pools, such as by sequencing sufficient bases (e.g., 20-50 bases) in each of multiple cDNAs to identify each cDNA, or by sequencing short tags (e.g., 9-10 bases) that are generated at known positions relative to a defined mRNA end (see, e.g., Velculescu, 1995, Science 270:484-487). 5.9. MEASUREMENT OF OTHER ASPECTS OF THE BIOLOGICAL STATE
  • aspects of the biological state other than the transcriptional state such as the translational state, the activity state, or mixed aspects can be measured.
  • cellular constituent data used in molecular profile 50 can include translational state measurements or even protein expression measurements. Details of embodiments in which aspects of the biological state other than the transcriptional state are described in this section.
  • TRANSLATIONAL STATE MEASUREMENTS Measurement of the translational state can be performed according to several methods.
  • whole genome monitoring of protein e.g., the "proteome,"
  • antibodies are present for a substantial fraction of the encoded proteins, or at least for those proteins relevant to the action of a drug of interest.
  • monoclonal antibodies are raised against synthetic peptide fragments designed based on genomic sequence of the cell.
  • proteins from the cell are contacted to the array and their binding is assayed with assays known in the art.
  • proteins can be separated by two-dimensional gel electrophoresis systems. Two-dimensional gel electrophoresis is well-known in the art and typically involves iso-electric focusing along a first dimension followed by SDS-PAGE electrophoresis along a second dimension.
  • the methods of the invention are applicable to any cellular constituent that can be monitored. For example, where activities of proteins can be measured, embodiments of this invention can use such measurements. Activity measurements can be performed by any functional, biochemical, or physical means appropriate to the particular activity being characterized. Where the activity involves a chemical transformation, the cellular protein can be contacted with the natural substrate(s), and the rate of transformation measured.
  • the activity involves association in multimeric units, for example association of an activated DNA binding complex with DNA
  • the amount of associated protein or secondary consequences of the association can be « . measured. so, wnere ' n y a unc iona ac ivi y is nown, or example, as m ce cyc e control, performance of the function can be observed.
  • the changes in protein activities form the response data analyzed by the foregoing methods of this invention.
  • cellular constituent measurements are derived from cellular phenotypic techniques. • One such cellular phenotypic technique uses cell respiration as a universal reporter.
  • 96-well microtiter plate in which each well contains its own unique chemistry is provided.
  • Each unique chemistry is designed to test a particular phenotype.
  • Cells from the organism of interest are pipetted into each well. If the cells exhibits the appropriate phenotype, they will respire and actively reduce a tetrazolium dye, forming a strong purple color. A weak phenotype results in a lighter color. No color means that the cells don't have the specific phenotype. Color changes can be recorded as often as several times each hour. During one incubation, more than 5,000 phenotypes can be tested. See, for example, Bochner et al, 2001 , Genome Research 11 , p. 1246.
  • cellular constituent measurements are derived from cellular phenotypic techniques.
  • One such cellular phenotypic technique uses cell respiration as a universal reporter.
  • 96-well microtiter plates in which each well contains its own unique chemistry is provided. Each unique chemistry is designed to test a particular phenotype.
  • Cells from a biological specimen obtained from the patient are pipetted into each well. If the cells exhibit the appropriate phenotype, they will respire and actively reduce a tetrazolium dye, forming a strong purple color. A weak phenotype results in a lighter color. No color means that the cells don't have the specific phenotype. Color changes can be recorded as often as several times each hour.
  • the cellular constituents that are measured are metabolites.
  • Metabolites include, but are not limited to, amino acids, metals, soluble sugars, sugar phosphates, and complex carbohydrates.
  • Such metabolites can be measured, for example, at the whole-cell level using methods such as pyrolysis mass spectrometry (Irwin, 1982, Analytical Pyrolysis: A Comprehensive Guide, Marcel Dekker, New York; Meuzelaar et al, 1982, Pyrolysis Mass Spectrometry of Recent and Fossil Biomaterials, Elsevier, Amsterdam), fourier-transform infrared spectrometry (Griffiths and de Haseth,1986, Fourier transform infrared spectrometry, John Wiley, New York; Helm et al, 1991, J. Gen. Microbiol.
  • the present invention provides an method for treating patients that have a disease.
  • diseases that can be treated include asthma, cancers, common late-onset Alzheimer's disease, diabetes, heart disease, hereditary early-onset Alzheimer's disease (George-Hyslop et al, 1990, Nature 347: 194), hereditary nonpolyposis colon cancer, hypertension, infection, maturity-onset diabetes of the young (Barbosa et al, 1976, Diabete Metab.
  • NAFL nonalcoholic fatty liver
  • NASH nonalcoholic steatohepatitis
  • Cancers that can be treated in accordance with the present invention include, but are not limited to, human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarc ma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hep
  • patient database 44 and/or clinical research repository 84 is (Figs. 1, 6, and 7) is a data warehouse.
  • Data warehouses are typically structured as either relational databases or multidimensional data cubes.
  • exemplary databases 44 and/or clinical research repository 84 having a relational database or a multidimensional data cube architecture are described.
  • relational databases and multidimensional data cubes see Berson and Smith, 1997, Data Warehousing, Data Mining and OLAP, McGraw-Hill, New York; Freeze, 2000, Unlocking OLAP with Microsoft SQL Server and Excel 2000, IDG Books Worldwide, Inc., Foster City, California; and Thomson, 1997, OLAP Solutions: Building
  • database 44 and/or clinical research repository 84 does not have a forma) hierarchical structure.
  • 5.11.1 DATA ORGANIZATION Databases have typically been used for operational purposes (OLTP), such as order entry, accounting and inventory control. More recently, corporations and scientific projects have been building databases, called data warehouses or large on-line analytical processing (OLAP) databases, explicitly for the purposes of exploration and analysis.
  • the "data warehouse” can be described as a subject-oriented, integrated, time- variant, nonvolatile collection of data in support of management decisions. Data warehouses are built using both relational databases and specialized multidimensional structures called data cubes.
  • database 44 and/or clinical research repository 84 is a datacube or a relational database.
  • Relational databases organize data into tables where each row conesponds to a basic entity or fact and each column represents a property of that entity.
  • a table can represent transactions in a bank, where each row conesponds to a single transaction, and each transaction has multiple attributes, such as the transaction amount, the account balance, the bank branch, and the customer.
  • the relational table is refened to u ⁇ m a co um ⁇ as an a r u e or w n a relation can be partitioned into two types: dimensions and measures. Dimensions and measures are similar to independent and dependent variables in traditional analysis. For example, the bank branch and the customer would be dimensions, while the account balance would be a measure.
  • a single relational database will often describe many heterogeneous but intenelated entities.
  • a database designed for a restaurant chain might maintain information about employees, products, and sales.
  • the database schema defines the relations in a database, the relationships between those relations, and how the relations model the entities of interest.
  • a data warehouse can be constructed as a relational database using either a star or snowflake schema and will provide a conceptual model of a multidimensional data set.
  • Each axis in the conesponding data cube represents a dimension in a relational schema and consists of every possible value for that dimension. For example, an axis conesponding to states would have fifty values, one for each state.
  • each cell contains one value per measure of the data cube. So if product production and consumption information is needed, then each cell would contain two values, one for the number of products of each type consumed in that state, and one for the number of products of each type produced in that state. Dimensions within a data warehouse are often augmented with a hierarchical structure. If each dimension has a hierarchical structure, then the data warehouse is not a single data cube but rather a lattice of data cubes.
  • the loiiow g is a summary ⁇ rtnose product and serv ce opportun t es both short and long- term that result from such methods:
  • I. A longitudinal database with information on patients including tissue and blood sample information. The containment of these specimens will facilitate the determination of better treatment and prevention. Such a database could be commercialized by transactions with a number of constituents including pharmaceutical companies, diagnostic companies, payers, healthcare providers, and other research centers.
  • assessing the value is more nebulous than drug target deals.
  • the value may be predicated on a "cost approach," e.g., what the buyer would have to do to recreate the data plus some additional value for analysis less any obsolete costs of the data.
  • the question of value lies with the buyer and what they ultimately gain from the information.
  • Clinical practice consensus guidelines are available through the NCCN website as well as other cancer websites. These guidelines are based on the consensus of practice and are not necessarily evidence-based. Though evidence-based studies do exist for certain disease sites, they continue to evolve as genomics and proteomics develop.
  • the systems and methods of the present invention can be used to provide evidence-based guidelines to affiliates as part of their participation in the health care plans of the present invention.
  • Long-Term! The" data that results from the longitudinal information that the systems and methods of the present invention will collect, the discoveries that may occur through large-scale gene expression and protein analysis, and the tumor banking activities of TCC may yield insights into new drug targets, therapies and diagnostics as the processes illustrated in Figs. 2, 5, and 9 progress over time. For example, new biomarkers may be discovered that assist in diagnosing the presence of cancer in a patient and how the patient is responding to therapies. Extensive gene expression and proteomics analysis may produce new drug targets and/or insights into how existing therapies can be administered or modified.
  • a central health care facility preferably has an affiliate network.
  • This affiliate network provides a foundation upon which to launch a health care plan in accordance with the present invention and ensures that the plan is sustainable.
  • the central health care facility ensure that the affiliate network is a true "partner" in the development and implementation of the health care plan by actively enrolling a significant portion of the affiliate patients in clinical trials run by the central health care facility and by providing continual updates of their prognosis.
  • the present invention can be implemented as a computer program product that comprises a computer program mechanism embedded in a computer readable storage medium.
  • the computer program product could contain the program modules shown in Fig. 1 and/or Fig. 7 and/or Fig. 9.
  • program modules may be stored on a CD-ROM, DVD, magnetic disk storage product, or any other computer readable data or prOgYam'stor'a l ge''p ⁇ d ⁇ cf'
  • the software modules in the computer program product can also be distributed electronically, via the Internet or otherwise, by transmission of a computer data signal (in which the software modules are embedded) on a carrier wave.

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Abstract

L'invention concerne un réseau informatique (34) comprenant un premier ordinateur et un ou plusieurs seconds ordinateurs qui sont reliés les uns aux autres par voie électronique. Le premier ordinateur est associé à un premier établissement sanitaire et utilise des instructions pour récupérer, sur un réseau, une ou plusieurs structures de données pour un patient impliqué dans un programme de soins de santé. Ces structures de données pour le patient comprennent (i) un identificateur de patient (48-1), (ii) un profil moléculaire (50-1) d'un échantillon biologique prélevé sur un patient dans le premier établissement sanitaire et (iii) une caractérisation clinique (52-1) du patient, fournie par le premier établissement sanitaire. Le premier ordinateur utilise des instructions pour récupérer, sur la connexion au réseau, un ou plusieurs schémas thérapeutiques convenant au patient, sur la base du profil moléculaire et de la caractérisation clinique du patient. Les seconds ordinateurs sont situés à un ou plusieurs emplacements différents du premier établissement sanitaire et comportent une ou plusieurs structures de données pour chaque patient impliqué dans le programme de soins de santé.
PCT/US2004/015133 2004-05-14 2004-05-14 Systemes et methodes informatiques permettant de fournir des soins de sante Ceased WO2005116890A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8095389B2 (en) 2006-07-17 2012-01-10 H. Lee Moffitt Cancer Center And Research Institute, Inc. Computer systems and methods for selecting subjects for clinical trials
US9724190B2 (en) 2007-12-13 2017-08-08 Amo Groningen B.V. Customized multifocal ophthalmic lens
CN113130039A (zh) * 2021-04-16 2021-07-16 广州中康数字科技有限公司 一种基于微信公众号的在线开方系统及方法
US20220223230A1 (en) * 2019-08-28 2022-07-14 Ventana Medical Systems, Inc. Assessing antigen retrieval and target retrieval progression with vibrational spectroscopy

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030027223A1 (en) * 2001-06-29 2003-02-06 Muraca Patrick J. Specimen-linked G protein coupled receptor database
US20030046110A1 (en) * 2001-08-29 2003-03-06 Victor Gogolak Method and system for creating, storing and using patient-specific and population-based genomic drug safety data
US6572562B2 (en) * 2001-03-06 2003-06-03 Eyetracking, Inc. Methods for monitoring affective brain function
US20030163348A1 (en) * 2002-02-27 2003-08-28 Stead William W. Method and system for clinical action support
US20030229517A1 (en) * 2002-03-15 2003-12-11 Peter Meserol Medical management system and method
US20040006492A1 (en) * 2002-01-30 2004-01-08 Nec Infrontia Corporation Health care service system

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6572562B2 (en) * 2001-03-06 2003-06-03 Eyetracking, Inc. Methods for monitoring affective brain function
US20030027223A1 (en) * 2001-06-29 2003-02-06 Muraca Patrick J. Specimen-linked G protein coupled receptor database
US20030046110A1 (en) * 2001-08-29 2003-03-06 Victor Gogolak Method and system for creating, storing and using patient-specific and population-based genomic drug safety data
US20040006492A1 (en) * 2002-01-30 2004-01-08 Nec Infrontia Corporation Health care service system
US20030163348A1 (en) * 2002-02-27 2003-08-28 Stead William W. Method and system for clinical action support
US20030229517A1 (en) * 2002-03-15 2003-12-11 Peter Meserol Medical management system and method

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8095389B2 (en) 2006-07-17 2012-01-10 H. Lee Moffitt Cancer Center And Research Institute, Inc. Computer systems and methods for selecting subjects for clinical trials
US8175896B2 (en) 2006-07-17 2012-05-08 H. Lee Moffitt Cancer Center And Research Institute, Inc. Computer systems and methods for selecting subjects for clinical trials
US9724190B2 (en) 2007-12-13 2017-08-08 Amo Groningen B.V. Customized multifocal ophthalmic lens
US20220223230A1 (en) * 2019-08-28 2022-07-14 Ventana Medical Systems, Inc. Assessing antigen retrieval and target retrieval progression with vibrational spectroscopy
CN113130039A (zh) * 2021-04-16 2021-07-16 广州中康数字科技有限公司 一种基于微信公众号的在线开方系统及方法
CN113130039B (zh) * 2021-04-16 2024-02-13 广州中康数字科技有限公司 一种基于微信公众号的在线开方系统及方法

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