Classifications

• • G—PHYSICS
  • G06—COMPUTING OR CALCULATING; COUNTING
  • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
  • G06Q10/00—Administration; Management
• • G—PHYSICS
  • G06—COMPUTING OR CALCULATING; COUNTING
  • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
  • G06Q10/00—Administration; Management
  • G06Q10/10—Office automation; Time management
• • 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
  • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• • 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
  • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
  • G16B20/20—Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• • 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
  • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
  • G16B20/40—Population genetics; Linkage disequilibrium
• • 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
  • G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• • 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
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
  • G16H50/70—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for mining of medical data, e.g. analysing previous cases of other patients
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
  • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

• the present invention relates to individualized health care, immunology and medical informatics, and more particularly to systems and methods for acquiring, storing, processing and utilizing immunologic and other information of individuals and populations in various applications.
• Personalized medicine is considered by many to be the wave of the future.
• a personalized medicine approach seeks to identify whether a given individual needs a given treatment or intervention prior to administering it, rather than relying on "standards" representing an average person in a group or population.
• This approach is based on the well known fact that some individuals in a demographic population have naturally low or naturally high values which are not best measured against a statistical mean for the demographic population, but against that individual's own measured history.
• vaccines are a immunologic prophylactic whose frequency and dose is determined at the population level.
• Vaccines are approved for routine human use by regulatory agencies from different countries where the vaccines are to be applied, such as, for example, the U.S. the Food and Drug Administration (FDA).
• FDA Food and Drug Administration
• population-wide recommendations for use are made by various medical agencies, such as the Advisory Committee on Immunization Practices (ACIP), whose members represent experts in the vaccine field.
• ACIP a U.S. committee, to assist and advise the Secretary of Health and Human Services, as well as the Centers for Disease Control and Prevention (CDC), on how to best implement vaccination strategies to prevent disease.
• Written recommendations are developed with immunization schedules that are published and updated as needed for both pediatric and adult populations. From these recommendations, certain vaccines are mandated for school entry and government- sponsored programs.
• Td diphtheria, tetanus, and pertussis vaccines
• a solution for the prevention of such a type III hypersensitivity problem resulting from over- vaccination would be to assess a person's immune status with respect to the offending antigen, and make an existential determination of when to optimally administer the vaccine booster.
• the CDC states: "If avoiding unnecessary injections is desired, judicious use of serologic testing might be helpful in determining which immunizations are needed.”
• the CDC also states: "If a revaccination approach is adopted and a severe local reaction occurs, serologic testing for specific IgG antibody to tetanus and diphtheria toxins can be measured before administering additional doses.” (see pages 20 and 21 of the CDC 2002 reference cited above.) In this way, serologic testing could be used to determine whether an antibody level is low enough to warrant further boosting of the immune system for a specific antigen, minimizing the risk of adverse reactions from over- vaccinations.
• Certain individuals may be genetically predisposed to infections as a result of a compromised immune system. For example, there are people that have been identified to be at greater risk of meningococcal disease due to late-stage complement deficiency, since complement usually mediates antibody-dependent killing of meningococci.
• HLA haplotypes e.g., leprosy, salmonellosis, Pseudomonas aeruginosa infections, Yersinia infections, Listeria monocytogenes infections, streptococcal diseases, tuberculosis, Lyme disease, Chlamydia trachomatis infections, Helicobacter pylori infections, HTV disease, and various other viral infections
• diseases e.g., leprosy, salmonellosis, Pseudomonas aeruginosa infections, Yersinia infections, Listeria monocytogenes infections, streptococcal diseases, tuberculosis, Lyme disease, Chlamydia trachomatis infections, Helicobacter pylori infections, HTV disease, and various other viral infections
• Determination of the immune status of individuals to, for example, vaccine-preventable diseases requires an assay system that can detect antibodies that may be present at very low levels, especially when natural or vaccine exposure may have been many years previously.
• an assay system could be used more generally to assess an individual's immune competence at different stages of that individual's life, a ⁇ well as to also measure the vaccine status of individuals with varying special needs and requirements ⁇ e.g., military personnel or travelers).
• What is thus needed in the art is a system and method for measuring and processing immunologic information of individuals and populations through various points in time of their lives so as to better track each individual's immune status and make appropriate diagnostic, prophylactic and therapeutic recommendations.
• What is further needed in the art is a supporting structure to conveniently store the results of such screenings for easy access and processing, for data mining purposes as well as for use in a variety of commercial, research and governmental applications where a knowledge of the immunological indicia of customers, subjects and citizens can create efficiencies and optimizations, as well as allow for the exploitation of commercial opportunities and improve the quality of life.
• a system and method for assessing the immunological status of one or more individuals in a patient population includes establishing a database comprising a plurality of records of information each representative of the immune status of an individual in the population, each of said records including (1) current information from one or more assays for the presence of a biochemical, and (2) individual specific information comprising one or more of said individual's medical history, said individual's doctors' observations and historical, demographic, lifestyle, and familial information relating to said individual.
• the method further includes processing the information in said database to find trends or patterns relating to the immune status of individuals in said patient population; and using the said trends or patterns as part of a health care related decision making process.
• processing the information in the database includes generating a list of correlations between variables or fields in the database, and for each correlation in the list generating a set of hypotheses that may explain said correlation.
• processing the information in the database includes generating a list of correlations between variables or fields in the database, and for each correlation in the list generating a set of hypotheses that may explain said correlation.
• as to each hypothesis in the set automatically refuting, supporting or stating that there is insufficient data to analyze said hypothesis by further processing of the database; and reporting the correlations, their associated hypotheses and the refutation, support, or determination of insufficient data to refute or support, to a user.
• Fig. 1 depicts a generalized exemplary process flow according to exemplary embodiments of the present invention
• FIG. 2 depicts an exemplary system overview according to exemplary embodiments of the present invention
• FIG. 2A depicts an alternate exemplary system overview according to exemplary embodiments of the present invention
• FIG. 2B depicts yet another alternate exemplary system overview according to exemplary embodiments of the present invention.
• FIGs. 3 and 4 depict various exemplary configurations for assaying a patient sample according to an exemplary embodiment of the present invention
• Fig. 5 depicts a detailed system diagram according to an exemplary embodiment of the present invention
• Fig. 5 A depicts a detailed system diagram according to an alternate exemplary embodiment of the present invention
• Fig. 5B depicts exemplary process flow for automimmune disease screening and follow-up according to an exemplary embodiment of the present invention
• Fig. 5C is an exemplary bar graph depicting CMV prevalence by age group in Australia;
• Fig. 5D illustrates mechanisms of downregulation or attenuation of immune response
• Fig. 6 depicts exemplary assay results in an exemplary database according to the present invention
• Fig. 7 depicts exemplary diagnostic module recommendation types according to an exemplary embodiment of the present invention.
• Fig. 8 illustrates an exemplary perceptron network which implements a rule for a normal individual using as inputs the results of an exemplary menigicoccal diagnostic panel
• Fig. 8 A illustrates the exemplary perceptron network of Fig. 8 implementing a similar rule for an abnormal individual
• Fig. 9 depicts an XML representation of the exemplary perceptron networks of Figs. 8 and 8 A;
• Fig. 10 depicts an exemplary symbology for diagnostic goals which can be used to articulate diagnostic goals in an exemplary embodiment of the present invention
• Fig. 11 illustrates exemplary diagnostic goals using the symbology of Fig. 10
• Fig. 12 illustrates an exemplary database schema for patient information according to an exemplary embodiment of the present invention
• Fig. 13 illustrates an exemplary database schema for visit information according to an exemplary embodiment of the present invention
• Fig. 14 illustrates an exemplary database schema for test results according to an exemplary embodiment of the present invention
• Fig. 15 depicts exemplary patient age intervals used in an exemplary database according to an exemplary embodiment of the present invention
• Fig. 16 is a plot of an exemplary female antibody comparison over a number of years according to an exemplary embodiment of the present invention.
• Fig. 17 is a plot of an exemplary comparison of two individual females, one vaccinated and one not vaccinated, according to an exemplary embodiment of the present invention.
• Fig. 18 is a plot of exemplary antibody levels in a compliment-deficient individual according to an exemplary embodiment of the present invention.
• Fig. 19 is a plot of exemplary antibody levels in a healthy individual according to an exemplary embodiment of the present invention.
• Fig. 19A is an example SQL query according to an exemplary embodiment of the present invention.
• Fig. 19B is a table illustrating the correlation among antibody levels in an exemplary female population according to an exemplary embodiment of the present invention
• Figs. 20 through 2OF illustrate exemplary data mining results obtained from operating on an exemplary database according to an exemplary embodiment of the present invention
• Figs. 20Gl through 20G41 illustrate additional exemplary data mining results obtained from operating on an expanded version of an exemplary database according to an exemplary embodiment of the present invention
• Fig. 21 A illustrates an exemplary pattern detection process flow according to an exemplary embodiment of the present invention
• Fig. 21B illustrates an exemplary pattern detection process flow with hypothesis generation according to an exemplary embodiment of the present invention
• Fig. 21 C illustrates an exemplary automatic pattern detection process flow according to an exemplary embodiment of the present invention
• Fig. 22 is a process flow diagram for use in a healthcare management embodiment according to the present invention.
• Fig. 23 is a subset of the process flow depicted in Fig. 22;
• Fig. 24 is an alternative process flow chart for healthcare management according to the exemplary embodiment of the present invention.
• Fig. 24A is a more detailed process flow chart similar to that of Fig 22;
• Fig. 25 is an alternative process flow chart for managing healthcare according the exemplary embodiment of the present invention.
• Fig. 25 A is the process flow chart of Fig.25 with an additional optional element
• Fig. 26 is an alternative process flow chart for managing healthcare according to the exemplary embodiment of the present invention.
• Fig. 26 A is an alternative version of the process flow of Fig. 26 with greater detail;
• Fig. 27 is a process flow chart for cervical cancer prevention according to the exemplary embodiment of the present invention.
• Fig. 28 is a process flow chart for managing the care of women of childbearing age according to the exemplary embodiment of the present invention.
• Fig. 29 is a process flow chart for an exemplary "Vaccine-O-Mat” application according to an exemplary embodiment of the present invention.
• Fig. 29 A is a system diagram of entities involved in the vaccine distribution application according to an exemplary embodiment of the present invention.
• Fig. 29B illustrates the necessary connectivity for the vaccine distribution application illustrated in Fig. 29A;
• Figl 29C is the connectivity displayed in that Fig. 29B recast by use of an interapplication connectivity provider according to an exemplary embodiment of the present invention
• Fig. 30 is an exemplary flow chart for use in a life insurance optimization application according to an exemplary embodiment of the present invention
• Fig. 31 is an exemplary process flow chart for use in an immunosenescence management application according to an exemplary embodiment of the present invention.
• Fig. 32 is an exemplary process flow chart for a disaster management application according to an exemplary embodiment of the present invention.
• Fig. 33 is an alternative process flow chart for the psychological aspects of disaster response for a disaster response application according to an exemplary embodiment of the present invention.
• Fig. 34 depicts exemplary process flow in an immunogenicity discovery application according to an exemplary embodiment of the present invention
• Fig. 35 illustrates components of an exemplary two-sided market application according to an exemplary embodiment of the present invention.
• Fig. 36 illustrates components of an exemplary drug hypersensitivity two-sided market application according to an exemplary embodiment of the present invention.
• Applicant notes that the TOC is defective, especially as regards Section I. Applicant reserves the night to amend the Specification to correct the TOC via Preliminary Amendment.
• ImmunoScore systems and methods of the present invention will be often referred to as the "ImmunoScore” system, method and/or database, as the case may be.
• “ImmunoScore” is a trademark and/or service mark currently envisioned by the assignee hereof to be utilized in connection with exemplary embodiments of the present invention.
• the present invention is directed to the collection, processing, and use of immunologic information.
• Immunologic information is to be understood in a broad sense, including any information which may be useful as an indicator of any immunological function of a mammalian body.
• the present invention includes acquiring information that is indicative of the immune status of an individual, processing that information, storing the raw information as well as the outputs from the processing stage, and of that information at various times and in various ways to recommend various actions such as prophylactic or further diagnostic interventions, or abstention from action, for individual or population.
• the present invention exploits a number of advances in technology as well as advances in how people think about medical treatment.
• a number of immunological or immunological related (in a broad sense) assays can be administered to an individual.
• modern technology such as, for example, the MlM Analyzer marketed by BioVerisTM Corporation of Gaithersburg, Maryland, one can run a large number of assays, such as, for example 20, 40 or 60, and obtain results therefrom in a relatively short period of time.
• these assay results can be stored in a memory, either locally or at one or more central servers or in associated databases, and can be operated upon by various algorithms or rules which can generate information as to that individual's immune status as well as recommendations for further augmenting that immune status or taking further action in response to the information acquired, from the assays and their processing.
• This information can be used in a variety of commercial, research, and healthcare contexts.
• a variety of business methods or opportunities can be created or facilitated using the information obtained according to the methods of the present invention.
• the present invention is described in three distinct sections.
• the first section describes the scientific background and motivation for creating various assay panels to be administered, singularly or in combination with other assay panels, to different individuals in different populations at different times in each individual's life cycle. This discussion culminates in suggested or exemplary assay super panels which can be administered in various contexts to various individuals.
• a second section describes how information obtained from results of the administered assays can be stored, processed, and utilized.
• This discussion comprises, inter alia, a description of an exemplary database in which (i) results from numerous assays can be stored along with (ii) individual-specific information and (iii) the outputs of various algorithms which operate upon the assay results of that individual.
• This section also presents an exemplary database upon which immunologic data mining was performed according to the techniques of the present invention, and summarizes interesting and illustrative results form that exercise.
• a variety of business and commercial methods are described in which information from the assay panels as stored in the database and further processed can be used to increase business efficiencies, create new markets and opportunities, and/or provide useful tools for research and development.
• Fig. 1 depicts an exemplary process flow according to an exemplary embodiment of the present invention.
• an assay or panel of assays can be conducted on a biological sample, e.g., blood, urine, etc., which has been taken from an individual.
• a biological sample e.g., blood, urine, etc.
• Such individual can simple be an individual or he or she can be a member of a population or sub-population whose immunologic informatics are of use to some entity or enterprise.
• the individual could be an insured of a health insurance company that is using the techniques of the present invention to efficiently manage the healthcare of its insureds so as to minimize costs.
• such an individual could be an immigrant whose vaccination history is unknown but whose immune status is of interest to his new country's immigration service.
• Such exemplary embodiments are described more fully below in Section III.
• the results of the assay or assays conducted at 101 can be obtained, and at 103 there can be an optional step of analyzing the assay results locally.
• assays can be conducted and read in a variety of assay reading devices. There are many assays available using known techniques. Some of them are more sophisticated and some less sophisticated.
• an assay reading device can, for example, obtain results at 102, store those results and analyze them locally, for example, in a processor communicably connected to the assay reading device. Alternatively, if only raw assay results are obtained from a less sophisticated technology, those results can, for example, be sent over a data network and stored in a database record.
• the results can be analyzed by accessing the particular record associated with the particular individual to whom the assay panel or panels were administered at a given time.
• Such analysis can involve a variety of algorithms ranging from a simplistic look at quantity of antibodies per defined unit of blood or other bodily fluid, or it can also, for example, include a complex analysis where a variety of assay results are input and combined in linear and non-linear ways to produce some metric of immunologic significance.
• Such algorithms are described more fully below in Section IL
• recommendations can be generated.
• Such recommendations can include, for example, that the individual obtain one or more vaccines, that the individual be administered prophylactic therapies to boost his or her immune system, or that the individual be administered gene therapy to correct the genetic defect which places him or her at risk of communicating a certain disease or condition, to name a few.
• Fig. 2 is an exemplary generalized system diagram which correlates to the generalized method depicted in Fig. 1. With reference to Fig. 2, there can be seen a number of assay devices 201.
• These assay devices include one or more assay panels which have been conducted with respect to an individual or individuals and for which results have been obtained.
• the results obtained from the assay devices can, as described in connection with the generalized method in Fig. 1, be locally analyzed at each assay device, provided that such assay device has a data processor and memory and the results can be stored locally at the assay device.
• the assay device results can, for example, be communicated over a data network 202 to a central processor 204 and stored in a central database 203.
• the central processor 204 can access the records which it has received and analyze them by implementing a number of analytic algorithms as described more fully below.
• Central processor 204 based on its analysis, can generate recommendations based on decision trees and criteria embedded in the various analytic algorithms it implements. These recommendations can be displayed locally at the central processor at display 205 and can there be printed in a tangible medium for distribution to interested persons. Alternatively, the central processor 204 can, for example, send the results of its analysis over a data network to various users who can access the results at user terminals 210.
• Fig. 2A presents an alternative generalized system diagram similar to Fig. 2.
• the business rules database 220 communicably connected to central processor 204.
• the central processor can implement algorithms to operate on stored assay data which can, for example, also take as inputs various business rules in generating a decision regarding a recommendation.
• an exemplary embodiment of the present invention can be utilized to help a health insurance underwriter manage its population of insureds. There can, for example, be an annual or semi-annual requirement of all insureds to have assays for various immunological components conducted on their blood or other bodily fluids.
• an insurance company can determine whether a particular insured is susceptible to one or more given diseases or other ailments which would result in increased expenditures for medical treatment. The insurance company could then decide if it was not more economical to require the insured to undergo certain prophylactic treatments, such as, for example, vaccines or immune system boosting therapies, etc., where the cost of such prophylactic therapies is less than, as determined by some user determined factor, the expected exposure for medical care if the insured contracts one or more of the diseases or ailments to which he or she is susceptible.
• prophylactic treatments such as, for example, vaccines or immune system boosting therapies, etc.
• Fig. 2B presents an alternative generalized system diagram similar to Figs. 2 A and 2B.
• a hypothesis and rules database 250 communicably connected to central processor 204.
• a central processor can, for example, implement data mining algorithms to operate on stored immunologic and background data to find a set of correlations.
• data mining algorithms can for example, be used to corroborate known or expected relationships, such as, for example, a correlation in antibody levels for measles, mumps and rubella in persons born in the United States after 1960, where the three vaccines were given simultaneously.
• an interesting follow-up would be to track if the rates of antibody levels for each of these three diseases change in the individual at a similar or a different rate, and if different, determine why.
• such data mining algorithms can be used to find counter-intuitive, or generally unknowns connections between variables or fields in the database.
• intelligence in an exemplary system can be used to automatically generate a set of hypotheses to explain such correlations (or, if known, any follow-up data related thereto, as described above) and proceed to test the viability of each hypothesis using the data in the database. Or, alternatively, such intelligence can inform a user that additional data is needed to vet a hypothesis.
• an exemplary system can, for example, also take as inputs various business rules in generating a decision regarding a recommendation.
• an exemplary embodiment of the present invention can be utilized to help a health insurance underwriter manage its population of insureds.
• There can, for example, be an annual or semi-annual requirement of all insureds to have assays for various immunological components conducted on their blood or other bodily fluids.
• an insurance company can determine whether a particular insured is susceptible to one or more given diseases or other ailments which would result in increased expenditures for medical treatment.
• the insurance company could then decide if it was not more economical to require the insured to undergo certain prophylactic treatments, such as, for example, vaccines or immune system boosting therapies, etc., where the cost of such prophylactic therapies is less than, as determined by some user determined factor, the expected exposure for medical care if the insured contracts one or more of the diseases or ailments to which he or she is susceptible.
• certain prophylactic treatments such as, for example, vaccines or immune system boosting therapies, etc.
• the present invention is, inter alia, concerned with assessing the "protective immune status” or “immunologic status” of an individual or population.
• a “protective immune status” is understood to be represented by an array of detectable components (phenotypic and/or genotypic) of an immune system (adaptive and/or innate) that comprise its protective capacity against harmful substances and/or cells (such as, for example, microorganisms or cancer).
• Such components can, for example, consist of genes as well as gene products.
• Genes can include, for example, those which encode immunologic receptors (such as, for example, toll-like receptors ("TLR"s) and chemoattractant receptors) as well as effector molecules ⁇ such as, for example, cytokines and chemokines) which may also, for example, exist as genetic polymorphisms capable of deleterious and/or beneficial effects.
• Gene products can include, for example, antibodies, complements, cytokines, chemokines, chemoattractant receptors, TLRs, lectins, and other immune-related ligands. Harmful substances can consist of, for example, chemicals and/or toxins originating from the environment, microorganisms, or one's self.
• diagnostic information is acquired from an individual regarding his or her immune status, this information can be, for example, added to a system database.
• a system database can contain, for example, not only the results of ImrnunoScore diagnostic testing but a wide variety of demographic data and patient history information as well.
• Such a system database can, for example, be used to record adverse events occurring coincident with immunizations.
• Such information can be invaluable to, for example, the ACIP for making recommendations regarding immunization scheduling, as well as help discover unsuspected patterns and correlations relevant to immune status and immune response.
• ImmunoScore diagnostic testing can be, for example, tailored to meet an individual's specific immunization status needs.
• each individual can, for example, receive their own personal ImmunoScore card that they could carry with them to health care office visits, and the database information can be easily transferable in the ever-increasingly likely event that they change physicians or other primary health care providers.
• ImmunoScore data, analysis of such data and relevant database information can, for example, be stored as part of a person's totality of health information and medical records, in electronic formats such as, for example, entries in electronic health information databases, or computer chips embedded in, for For economy of description, most of the references cited herein are provided in full citation in Appendix A to the Immunologic Informatics Patent. Throughout the text citations are made to author and year of publication alone.
• ImmunoScore diagnostic testing is envisioned to be done on a small assay device or testing instrument that can be located, for example, in a doctor's office.
• the testing can be done, for example, with a sample of an individual's whole blood, plasma, serum, saliva, milk, semen, tears, or urine.
• the sample can be obtained by a finger prick, heel stick, ear stick, other skin prick, capillary draw, venous draw, or an arterial draw.
• the instrument can, for example, take assay panels and the patient sample. Patient information can also be input.
• the resulting information can be, for example, displayed to a user, printed, stored in a removal medium, stored in the instrument, and/or transmitted (wired or wireless) to other devices such as via an intranet, a VPN or the Internet, for example.
• Electrochemiluminescent (ECL) assay techniques are an improvement over chemiluminescent techniques. They can, for example, provide a sensitive and precise measurement of the presence and concentration of an analyte of interest.
• the incubated sample is exposed to a voltammetric working electrode in order to trigger luminescence.
• electrochemiluminescence is triggered by a voltage impressed on the working electrode at a particular time and in a particular manner.
• the light produced by the label is measured and indicates the presence or quantity of the analyte.
• Amplification techniques for nucleic acids may be combined with the above assay techniques.
• US patent 6,048,687 discloses how NASBA can be combined with an ECL technique
• US patent 6,174,709 discloses how PCR can be combined with an ECL technique.
• the disclosures of the aforesaid patents are also hereby incorporated herein by reference.
• An assay instrument can, for example, be, or be similar to, the BioVeris Corporation MlR or MlM instruments with an added sample processing front end. Aspects of these instruments are disclosed in pending US patent application numbers 10/600,165 and 10/841,569, each under common assignment herewith. The disclosures of these patent applications are hereby incorporated herein by reference.
• an assay instrument can include, for example, amplification techniques such as PCR or NASBA.
• the instrument can use fluorescence, chemiluminescence, or ECL assay techniques.
• multiple measurements can be done simultaneously; in other exemplary embodiments of the present invention, multiple measurements can be done sequentially.
• an assay instrument can, for example, contain self-test and/or self-calibration components.
• a sample can be added to an assay panel, and the combination then inserted into the test instrument, as shown in Fig. 3.
• the sample and assay panel can be separately inserted into the test instrument, as shown, for example, in Fig. 4.
• entries to an exemplary master ImmunoScore database can be, for example, coded so as to protect patient confidentiality.
• a patient could, however, be able to learn from their physician in real time, for example, which vaccines he or she might need to ensure protection from vaccine-preventable illnesses.
• the physician can, for example, offer the vaccine. or other therapy, during the same visit, or shortly thereafter. Any possible adverse effects from any delivered vaccinations could be subsequently entered into an ImmunoScore database and that information could be shared with the ACIP or other agencies or bodies, as described more fully below.
• the actual assays can be performed, for example, based upon the needs of the individual or individuals being examined. Age, occupation, travel plans, immigration status, military status, and previous health status can all be considered prior to initiation of ImmunoScore diagnostic analyses in exemplary embodiments.
• the following exemplary broad categories can, for example, be utilized as focal points for test panels:
• Complement-deficient individuals e.g. meningococcal disease susceptibility
• b. Genetically identified e.g. HLA haplotype, sepsis susceptibility
• an ImmunoScore vaccine diagnostic surveillance system can not only aid in increasing vaccine coverage, but can also, for example, add increased surveillance of the level of immune response and duration of protection thereof for a wide variety of recommended vaccines.
• an antibody titer to a specific agent is determined to not meet the recognized level of a correlate of protection by an exemplary ImmunoScore analysis, and that titer is easily boosted by vaccination, then that individual would likely be more easily convinced of the need for protective immunization. Not only would this diagnostic tool prove extremely beneficial to the individual, but data added to an IrnmunoScore database can be collected regarding immune correlates of protection for very large populations. Demographic assessments can also be compiled from the database, leading to, for example, new discoveries regarding possible age-related or ethnic responses to immunizations and/or other immune status issues.
• targeted panels ot immune status assays can be defined.
• Such exemplary targeted panels can be organized, for example, into two broad -groups, college students and adults.
• three exemplary panels were defined: (a) a Meningococcal diagnostic panel, (b) a panel designed to measure the residual immunity induced by childhood vaccines, and (c) a panel directed to measuring immunity from common sexually transmitted diseases.
• exemplary panels were defined directed to the following groups or categories: (a) military personnel, (b) travelers, (c) adults-general immune status, (d) health care workers, (e) bioterrorism, (f) chronic disease, (g) Th-1-Th2 diagnostic panel, and (h) immigrants and internationally adopted children.
• aggregations of one or more panels can be defined for various purposes. These can be referred to, for example, as ImmunoScore "superpanels.”
• a primary school panel can be defined, to be administered upon a child's entry into grammar school. Such a panel could include, for example, a persistent immunity to childhood vaccines assay panel.
• a middle school student superpanel can be defined as well.
• Such a superpanel can include, for example, a persistent immunity to childhood vaccines panel and a sexually transmitted disease panel.
• Another exemplary superpanel could be defined for women of childbearing years. Such an exemplary superpanel can include, for example, a newly defined women of childbearing years panel, a persistent immunity induced by childhood vaccines panel, and a sexually transmitted disease panel.
• the following tests can be included in a meningococcal diagnostic panel: 1. Antibody (Ig) to (4 tests):
• GYMP Group Y Meningococcal Polysaccharide
• results from an exemplary meningococcal diagnostic panel can be analyzed as follows:
• Serum Ig levels for vaccine-preventable serogroups (A, C, Y, and W- 135) of N. meningitidis can be assessed. An Ig level exceeding 2.0 ⁇ g/mL of all four serogroups would be presumptive of protection in an otherwise healthy individual. There would be no immediate recommendation for meningococcal vaccination in these individuals.
• the ImmunoScore meningococcal diagnostic panel can prevent over-immunization with the polysaccharide formulation by first measuring immune status vis- ⁇ -vis menigococcal disease prior to simply vaccinating following a standard schedule. Immunization with Group C conjugate vaccine overcomes the hyporesponsiveness, but is not yet approved in the United States.
• the following tests can, for example, be used for ImmunoScore measurement of immunity to STDs:
• Antibodies to Chlamydia - IgG, IgA, and IgM (3) Antibodies to HSV - IgG to HSV l and HSV-2 (2) DNA analyses of HPV types — particular emphasis on high-risk Antibody to N. gonorrhoeae (1) T-cell related response to t. pallidum
• ImmuhoScore database can generate correlate of protection information for all diseases. As vaccines are developed, Imm ⁇ noScore diagnoses can be designed to examine antibody and other related immune responses to vaccine components.
• the following tests for measurement of immunity to childhood vaccines can be included in an exemplary ImmunoScore panel directed to college students, or in other exemplary embodiments, to adults in general:
• Antibody to HBs (1) Antibody to diphtheria toxin (1) Antibody to tetanus toxin (1) .
• Antibodies to poliovirus serotypes Pi, P2, and P3 (3) Antibody to measles (1) Antibody to mumps (1) Antibody to rubella (1) Antibody to varicella (1) Antibody to pneumococcal serotypes (7)
• the following exemplary analyses and recommendations can, for example, be made:
• the current indication for partial protection from diphtheria disease is an anti-diphtheria toxin antibody concentration between 0.01 and 0.1 IU/mL. Protection is considered to be complete above 0.1 IU/mL (Plotkin, 2002).
• ImmunoScore diagnostics can recommend a booster dose if antibody concentration were to fall below 0.1 IU/mL.
• the ImmunoScore database can shed further light in the future as to the true protective level of anti-diphtheria toxin antibody.
• the current indication for partial protection from tetanus disease is an anti-tetanus toxin antibody concentration between 0.01 and 0.1 IU/mL. Protection is considered to be complete above 0.1 IU/mL (Plotkin, 2002). ImmunoScore diagnostics can recommend a booster dose if antibody concentration were to fall below 0.1 IU/mL. The ImmunoScore database can shed further light in the future as to the true protective level of anti-tetanus toxin antibody.
• ImmunoScore diagnostics for this population can, for example, best be served in data acquisition and correlation to incidence of disease. There is not yet an adult pertussis vaccine, but development proceeds along those lines.
• the ImmunoScore diagnostic application can be beneficial in exemplary embodiments to ACIP for vaccine recommendations. Testing four components for pertussis disease would lend weight to the accumulated data.
• Serum antibody levels > 120 mIU are considered to be completely protective against measles infection (Plotkin, 2001). Vaccination can be considered for individuals whose antibody titers fall below this level.
• An ImmunoScore diagnostic recommendation can, for example, initially be for a boost if antibody levels fell below 1.0 ⁇ g/mL, and then the database analyses can be able to shape future recommendations.
• military personnel can have specific vaccination needs as outlined in Table 3 below depending on their assignments and type of deployment. Specific branches of the service may also have specific vaccination needs and permutations of the basic diagnostic panels. Thus, in exemplary embodiments, military personnel can be administered one or more of the following tests:
• an ImmunoScore diagnostic panel can, for example, be extremely flexible at adding new diagnostic tests for vaccines under development.
• Adenovirus vaccine is not currently given to military recruits, but infection with adenovirus remains a concern. Development and use of adenovirus vaccines are likely in the future and an exemplary ImmunoScore diagnostic application can require an updated assay format over the currently accepted neutralizing antibody assay.
• an exemplary ImmunoScore diagnostic application can require an updated assay format over the currently accepted neutralizing antibody assay.
• serological correlates of protection to inhalation anthrax are being developed in animal models.
• ImmunoScore diagnostics can, for example, measure level of serum IgG to protective antigen (PA) and the ImmunoScore database can, for example, thus build serologic correlates of protection in humans.
• PA protective antigen
• Immunity to cholera is currently not completely understood. However, ImmunoScore diagnostics can focus first on levels of anti-LPS IgG, and further attempt to build meaning into the database correlates of protection.
• ImmunoScore diagnostics can, for example, monitor serum antibody levels to current plague vaccine components and be able to adapt to any new vaccine configurations.
• ImmunoScore database can, for example, compile immune response data and be correlate the relevant antibody levels to levels of protection.
• Immune memory after smallpox vaccination is a valuable benchmark for understanding the kinetics and longevity of B cell memory in the absence of re-exposure to antigen, since immunization of the U.S. population was stopped in 1972 and smallpox disease was declared eradicated worldwide in 1980.
• Immune memory to smallpox is a useful benchmark both for understanding the longevity and the stability of immune memory in the absence of re-stimulation. Circulating antibody persists for over 50 years.
• ImmunoScore diagnostics can, in exemplary embodiments of the present invention, measure antibody to smallpox. Correlates of protection can, for example, be generated from analyses of the ImmunoScore database.
• the human protective response to vaccination against Lyme disease is purely a serum- mediated antibody response. Individuals are generally considered protected with antibody levels against OspA greater than 1100 IU. Subjects with less antibody titers less than 1100 would, in exemplary embodiments of the present invention, be recommended to have a booster vaccination.
• an ImmunoScore traveler's assay panel can, for example, include the following:
• Antibody to rabies (1) other rabies related cytokine assays (as necessary) Antibody to Typhoid fever (1) Antibody to yellow fever (1) Antibody to diphtheria toxin (1) Antibody to tetanus toxin (1) Pertusis antibodies (4):
• Antibodies to poliovirus serotypes Pl, P2, and P3 (3) Antibody to measles (1) Antibody to mumps (1) Antibody to rubella (1)
• recommendations for use of a ImmunoScore diagnostic panel for analytes specific to travelers can include all of the uses of the results of the Meningococcal Diagnostic Panel tests, as described above. Additionally, the following recommendations/conclusions can be implemented:
• the protective level of antibody to hepatitis A has been established to be approximately 10 mlU/mL if that concentration is maintained for a two month period, although some individuals may be protected at much lower concentrations (Conrad and Lemon, 1987). An individual that had less than 10 mlU/mL of antibody to hepatitis A can be recommended for vaccination.
• Current analyses of antibody levels to Japanese Encephalitis consist of neutralization assays. These assays would need to be refined for IminunoScore diagnostic applications.
• an ImmunoScore database can catalog antibody levels in anticipation of establishing future serologic correlates of protection.
• ImmunoScore diagnostic assays can include at the very least antibody levels to G envelope protein and can also measure relevant cytokines to assess serological correlates of protection.
• ImmunoScore diagnostic analysis can thus, in exemplary embodiments of the present invention, focus on antibody to Vi capsular polysaccharide. ImmunoScore data analyses can create necessary correlates of protection against typhoid fever disease.
• ImmunoScore diagnostic analysis can recommend that an individual with antibody titer below 0.7 IU be boosted. 14. ImmunoScore Measurement of Immunity in Health Care Workers
• the judicious application of ImmunoScore diagnostics to the needs of health-care workers can assure that these individuals will be appropriately immunized and protected from both becoming infected and spreading infection.
• the Centers for Disease Control (CDC) has recommended various immunizing agents for health-care workers.
• Hepatitis B virus (HBV) infection is the major infectious health hazard for health-care personnel. Data indicate that 5-10% of HBV-infected workers become chronically infected. Individuals with chronic HBV infection are at risk for chronic liver disease and are potentially infectious throughout their lifetimes. The risk of acquiring HBV infection from occupational exposures is dependent on the frequency of percutaneous and permucosal exposures to blood or body fluids containing blood. Depending on the tasks he or she performs, any health-care or public safety worker may be at high risk for HBV exposure. Workers performing tasks involving exposure to blood or blood-containing body fluids should be vaccinated. For public safety workers whose exposure to blood is infrequent, timely post-exposure prophylaxis may be considered, rather than routine pre-exposure vaccination.
• Pre-vaccination serologic screening for prior infection is not currently indicated for persons being vaccinated because of occupational risk.
• Post- vaccination testing for antibody to hepatitis B surface antigen response is indicated for health-care workers who have blood or patient contact and are at ongoing risk for injuries with sharp instruments or needlesticks. Knowledge of antibody response aids in determining appropriate post-exposure prophylaxis.
• Vaccine-induced antibodies to HBV decline gradually over time, and ⁇ 60% of persons who initially respond to vaccination will lose detectable antibodies over 12 years (Stevens, et al. 1992). Studies among adults have demonstrated that, despite declining serum levels of antibody, vaccine-induced immunity continues to prevent clinical disease or detectable viremic HBV infection (Hadler, et al. 1992).
• Asymptomatic HBV infections have been detected in vaccinated individuals by means of serologic testing for antibody to hepatitis B core antigen. However, these infections also provide lasting immunity and are not associated with HBV-related chronic liver disease.
• influenza outbreaks During community influenza outbreaks, admitting patients infected with influenza to hospitals has led to nosocomial transmission of the disease (Balkovic, et al. 1980), including transmission from staff to patients. Transmission of influenza among medical staff causes absenteeism and considerable disruption of health care. In addition, influenza outbreaks have caused morbidity and mortality in nursing homes. Because there is a recommendation for an annual influenza vaccination for health-care workers, it is unlikely that there would be an ImmunoScore diagnostic application for flu. The only potential here would be to -correlate vaccination and protection in a multitude of individuals working in the health-care field.
• Measles vaccination is contraindicated in pregnant and immunocompromised individuals, including HIV-infected persons who have evidence of severe immunosuppression. Measles is also contraindicated following recent administration of immune globulin.
• an IrnmunoScore diagnostic panel would be a useful application for health-care workers. These vaccines are available as monovalent or trivalent combinations. Lack of protective levels of antibody to any one of the components could be ameliorated by vaccination. In addition, health-care workers would again provide a large population to add an exemplary IrnmunoScore database. Nosocomial transmission of varicella zoster virus (VZV) is well recognized. Sources for nosocomial exposure of patients and staff have included patients, hospital staff, and visitors who are infected with either varicella (chickenpox) or zoster (shingles).
• VZV varicella zoster virus
• a reliable history of chickenpox is a valid measure of VZV immunity.
• Serologic tests have been used to assess the accuracy of reported histories of chickenpox. Among adults, 97-99% of individuals with a positive history of varicella are seropositive. In addition, the majority of adults with negative or uncertain histories are seropositive (range 71-93%). Persons who do not have a history of varicella, or whose history is uncertain can be considered susceptible, and can be tested serologically by ImmunoScore diagnostic methodology to determine their immune status. In health-care institutions, serologic screening of personnel who have a negative or uncertain history of varicella is likely to be cost effective (CDC, 1996). If susceptible health-care workers are exposed to varicella, they are potentially infective 10-21 days after exposure.
• VZIG varicella zoster immune globulin
• Varicella virus vaccine protects approximately 70-90% of recipients against infection and 95% of recipients against severe disease for at least 7-10 years after vaccination. Significant protection is long-lasting. Breakthrough infections have occurred among vaccinees after exposure to natural varicella virus. Estimates of vaccine efficacy and persistence in vaccinees are based on research conducted before widespread use of varicella vaccine began to influence the prevalence of natural VZV infection. Therefore, the extent to which boosting from exposure to natural virus increases the protection provided by vaccination remains unclear. Whether longer term immunity may wane as the circulation of natural VZV decreases also is unknown.
• the CDC recommends that vaccination should be considered for unvaccinated health-care workers who lack documented immunity if they are exposed to varicella.
• individuals vaccinated after an exposure should be managed in the manner recommended for unvaccinated persons.
• the ImmunoScore diagnostic assay for varicella would be a valuable assessment tool prior to initiation of vaccination of individuals uncertain of their immune status or disease history.
• Bacille Calraette-Gu ⁇ rin (BCG) vaccine has not been recommended for general uses because the population risk for infection with Mycobacterium tuberculosis (TB) is low and the protective efficacy of BCG vaccine uncertain.
• BCG vaccination may contribute to the prevention and control of TB when other strategies are inadequate.
• the fundamental strategies for the prevention and control of TB include:
• BCG vaccination may complicate preventive therapy because of difficulties in distinguishing tuberculin skin test responses caused by infection with M tuberculosis from those caused by the immune response to vaccination.
• Hepatitis C virus is the etiologic agent in most cases of parenterally transmitted non-A, non-B hepatitis in the United States. CDC estimates that the annual number of newly acquired HCV infections has ranged from 180,000 in 1984 to 28,000 in 1995. Of these, and estimated 2- 4% occurred among health-care personnel who were occupationally exposed to bleed. At least 85% of individuals who contract HCV infection become chronically infected, and chronic hepatitis develops in an average of 70% of all HCV-infected individuals (Shakil, et al. 1995).
• HCV non-structural 3
• Occupational risk may be high, but protection via active or passive immunization is not available (i.e. pertussis), or
• Vaccines are available but are not routinely recommended for all health-care workers or are recommended only in certain situations (i.e. vaccinia and meningococcal vaccines).
• Occupational exposure generally does not increase health-care worker's risk for hepatitis A virus (HAV) infection.
• HAV hepatitis A virus
• nosocomial HAV transmission is rare.
• Outbreaks caused by transmission of HAV to neonatal intensive care unit staff by infants infected through transfused blood have occasionally been observed (Rosenblum, et al. 1991).
• Transmission of HAV from adult patients to health-care workers is usually associated with fecal incontinence in the patients.
• most patients hospitalized with hepatitis A are admitted after onset of jaundice, when they are beyond the point of peak infectivity (Goodman, 1985).
• Serologic surveys among many types of health-care workers have not identified an elevated prevalence of HAV infection compared with other occupational populations.
• hepatitis A administration of immune globulin (IG) and hepatitis A vaccine.
• IG immune globulin
• hepatitis A vaccine administration of immune globulin (IG) and hepatitis A vaccine.
• IG immune globulin
• hepatitis A vaccine administration of immune globulin (IG) and hepatitis A vaccine.
• IG immune globulin
• hepatitis A vaccines There are two inactivated hepatitis A vaccines currently available in the United States. The duration of clinical protection has not yet been established.
• An ImmunoScore database built from surveillance of health-care workers can thus be instrumental in the determination of the duration of clinical protection of each of these vaccines.
• Nosocomial transmission of Neisseria meningitidis is uncommon.
• direct contact with respiratory secretions of infected persons e.g. during mouth to mouth resuscitation
• meningococcal respiratory infections are rare
• health-care workers may be at increased risk for meningococcal infection if exposed to N. meningitidis- infected patients with active productive coughs.
• Health-care workers can decrease the risk for infection by adhering to precautions to prevent exposure to respiratory droplets.
• Post-exposure prophylaxis is advised for individuals who have had intensive, unprotected contact with infected patients (e.g. intubating, resuscitating, or closely examining the oropharynx of patients).
• Antimicrobial prophylaxis can eradicate carriage of N. Meningitidis and prevent infections in individuals who have unprotected exposure to patients with meningococcal infections.
• the serogroups A and C vaccines which have demonstrated estimated efficacies of 85-100% in older children and adults, are useful for control of epidemics.
• the decision to implement mass vaccination to prevent serogroup C meningococcal disease depends on whether the occurrence of more than one case of the disease represents an outbreak or an unusual clustering of endemic meningococcal disease.
• Surveillance for serogroup C disease and calculation of attack rates can be used to identify outbreaks and determine whether use of meningococcal vaccine is warranted.
• the meningococcal diagnostic panel of the ImmunoScore diagnostic application would be a useful tool to monitor health-care workers, and to also identify health-care workers at increased risk for meningococcal disease.
• Pertussis is highly contagious. Secondary attack rates among susceptible household contacts exceed 80% (Mortimer, 1990). Transmission occurs by direct contact with respiratory secretions or large aerosol droplets from the respiratory tract of infected persons. The incubation period is generally 7-10 days. The period of communicability starts with the onset of the catarrhal stage and extends into the paroxysmal stage. Vaccinated adolescents and adults, whose immunity wanes 5-10 years after the last dose of vaccine (usually administered at age 4-6 years), are an important source of pertussis infection for susceptible infants. The disease can be transmitted from adult patients to close contacts, especially unvaccinated children. Such transmission may occur in households and hospitals.
• Pertussis transmission in health-care settings involves diagnosis and early treatment of clinical cases, respiratory isolation of infectious patients who are hospitalized, exclusion from work of staff who are infectious, and post-exposure prophylaxis. Early diagnosis of pertussis, before secondary transmission occurs, is difficult because the disease is highly communicable during the catarrhal stage, when symptoms are still non-specific. Pertussis should be one of the differential diagnoses for any patient with an acute cough illness of > 7 days duration without another apparent cause, particularly if characterized by paroxysms of coughing, post-tussive vomiting, whoop, or apnea (CDC, 1997). Health-care settings would be the ideal placement for ImmunoScore diagnostic assays for pertussis. Periodic measurement of the level of pertussis antibody in health-care workers could become part of routine screening to protect both the health-care worker and the patient populations.
• acellular pertussis vaccine is immunogenic in adults, but does not increase risk for adverse events when administered with tetanus and diphtheria (Td) toxoids, as compared with the administration of Td alone (Edwards, et al. 1993). If acellular pertussis vaccines are licensed for use in adults in the future, booster doses of adult formulations of acellular pertussis vaccines may be recommended to prevent the occurrence and spread of the disease in adults, including healthcare workers.
• Td diphtheria
• acellular pertussis vaccines combined with diphtheria and tetanus toxoids will need to be reformulated for use in adults, because all infant formulations contain more diphtheria toxoid than is recommended for individuals aged > 7 years.
• Recommendations regarding routine vaccination of adults will require additional studies (e.g. studies of the incidence, severity, and cost of pertussis among adults; studies of the efficacy and safety of adult formulations of DTaP; and studies of the effectiveness and cost-effectiveness of a strategy of adult vaccination, particularly for health-care workers).
• an LnrnunoScore diagnostic assay for pertussis and the patient database can be a valuable tool for evaluating the need and the effectiveness of the vaccine application.
• Smallpox is spread most efficiently in droplets or aerosols from the oropharynx of infected individuals. Smallpox also can be spread by direct contact with infected lesions or with clothing or bed linens contaminated with the virus. After the incubation period of 7 to 17 days, the period of infectivity begins as an exanthema and rash characterized by maculae progressing to papules, vesicles, and pustules all in the same stage, developing first on the face and extremities. Patients remain contagious until the scabs have been shed. Most patients are sick enough during the prodromal period to be confined to bed by the time the rash develops. For this reason, household contacts, hospital workers, and other health-care professionals are the most likely individuals to develop secondary cases.
• Immunization causes a local infection that is pruritic and uncomfortable. Fever, malaise, and regional lymphadenitis often occur about a week after immunization. The site of immunization develops a papule that matures into a pustule and then a scab that separates by about the third week after immunization. Re-immunization typically causes a milder lesion that develops more quickly. Occasionally, satellite or distant pustules develop when a vaccine recipient scratches the pustule and auto inoculates the virus at another site.
• a major reason not to initiate universal immunization in the absence of actual cases of smallpox besides the limited availability of vaccine is the risk of serious complications of immunization. Severe complications of immunization include death, post-vaccinal encephalitis, progressive vaccinia, eczema vaccinatum, generalized rash, and accidental inoculation to the face, eye or other sites.
• Smallpox vaccine has been known for decades to produce significant adverse effects, especially with immunocompromised individuals. In patients with chronic skin conditions, smallpox vaccine can cause a severe, sometimes fatal dermatologic involvement termed eczema vaccinatum.
• Atopic dermatitis is the most common disorder associated with severe eczema vaccinatum, and people with this disorder may be susceptible even if the skin disorder is in remission. Even unimmunized susceptible individuals can have such reactions if the virus spreads to them from those who have been immunized.
• Smallpox vaccine is not recommended for people with eczema or other exfoliative skin disorders, for pregnant women, or for people with immunodeficiencies, whether primary or secondary.
• Atopic dermatitis a genetically based immune abnormality, occurs within the first five years of life and affects 15% of the population.
• vaccine In the event of a known bioterrorist release of the smallpox virus, vaccine would be administered to exposed individuals. If vaccine is given within 3 to 4 days of exposure, immunity can develop before the disease occurs, and this would be expected to prevent or ameliorated the severity of the disease. Post-exposure immunization is recommended for persons who have had face-to- face, household contact with or have been in proximity to a person who has active smallpox skin lesions, persons who have been involved in the care of such an individual, and persons exposed in any way to laboratory specimens or bedding from an infected patient. Such a plan (referred to as a "ring vaccination" program) would allow the most effective use of available stocks of vaccine while exposing a minimal number of individuals to the risks of immunization.
• Variola virus as an agent of bioterrorism has been discussed widely, but the difficulty of introducing the virus into the population and the limited effects of doing so have persuaded most public health authorities that the chances of a smallpox outbreak are very small. Because of the known adverse effects of smallpox immunization, the large number of immunocompromised people in the population, and the currently limited supplies of vaccine and IG, all stockpiled vaccine is considered an investigational agent and is available for use by public health authorities only.
• the major proposed strategies for smallpox immunization in the face of a bioterrorism threat include mass immunization, voluntary immunization, and ring vaccination or "surveillance and containment.”
• the proponents of mass immunization claim it to be the strategy that would most effectively prevent spread of disease. They also postulate that a bioterrorist would be unlikely to introduce variola into a well immunized population.
• Those who favor voluntary immunization feel that each individual should be allowed to weigh the pros and cons of immunization and act according to his or her own analysis (Bicknell, 2002). Unfortunately, much of the population is not familiar with the problems and complications of vaccinia immunization.
• the ring vaccination strategy is supported by the American Academy of Pediatrics (AAP), which considers this option to be the best approach at present (AAP, 2002).
• the AAP supports the current CDC recommendation of the strategy known as ring vaccination, also referred to as surveillance and containment.
• ring vaccination also referred to as surveillance and containment.
• This strategy can control a localized outbreak with minimal exposure of vulnerable populations to the complications of immunization.
• the ring strategy is based on the knowledge that vaccination can prevent or ameliorate disease severity if given within 3 to 4 days of initial exposure and can decrease symptoms if given within the first week of exposure.
• Immunizing and monitoring a ring of people around each infected individual and his or her contacts would help protect those at the greatest risk of contracting the disease and form a buffer of immune individuals to prevent the spread of disease.
• the AAP supports the opinion of the ACIP that it is desirable to have patients with smallpox cared for by persons who have been immunized.
• national, state-based, and local teams of health-care professionals who already have been immunized will be trained in all aspects of smallpox investigation and care and will be available to go immediately to the site of a suspected or proven smallpox case. With teams available in every state, approximately 10,000 to 20,000 carefully screened individuals will receive smallpox vaccination.
• an ImmunoScore diagnostic evaluation can be used to assess an individual health-care worker's immune status with regards to these, or other, as may be appropriate, infectious diseases.
• steroid therapy usually does not contraindicate administration of live virus vaccines such as MMR and its component vaccines when therapy is a) short term ( ⁇ 14 days) low to moderate dose; b) low to moderate dose administered daily or on alternate days; c) long-term alternate day treatment with short-acting preparations; d) maintenance physiologic doses (replacement therapy); or e) administered topically (skin or eyes) by aerosol, or by intraarticular, bursal, or tendon injection.
• steroid dose that is equivalent to or greater than a prednisone dose of 20 mg per day sufficiently immunosuppressive to cause concern about the safety of administering live virus vaccines.
• Individuals who have received prolonged or extensive topical, aerosol, or other local corticosteroid therapy should not receive MMR or its component vaccines, and varicella vaccine for at least one month after one month after cessation of therapy.
• ImmunoScore diagnostic analyses and database for immunocompromised health-care workers can be used for assessing these workers and in monitoring them following corticosteroid therapy for levels of immune response.
• HIV-infected individuals have suboptimal immunologip responses to vaccines.
• the response to both live and killed antigens may decrease as the disease progresses (Vardinon, et al. 1990).
• Administration of higher doses of vaccine or more frequent boosters to HIV-infected persons may be considered.
• recommendations cannot be made at this time (CDC, 1997).
• MMR. vaccine is recommended for all asymptomatic HIV-infected health-care workers who do not have evidence of severe immunosuppression.
• an ImmunoScore diagnostic panel can be in place in health-care settings for the routine monitoring of health-care professionals.
• Such an ImmunoScore database can combine information obtained from immune status of health-care workers with that of other segments of the population. The panel can be a valuable tool for the health-care industry and hopefully reduce the burden of vaccine-preventable nosocomial illnesses.
• diseases for which vaccination should be considered include tuberculosis (pretty much as a last resort), hepatitis A, pertussis, meningococcal disease, typhoid fever, and vaccinia.
• tetanus diphtheria
• pneumococcal disease Other vaccine-preventable diseases for which protection should be maintained include tetanus, diphtheria, and pneumococcal disease.
• Levels of antibodies can be monitored periodically by ImmunoScore diagnostic immune status assays.
• the overall immune health could be measured initially using the meningococcal diagnostic panel.
• a typhoid fever antibody assay could also be developed for health-care professionals.
• a hepatitis C antibody assay can also need to be established. There is as yet no vaccine for hepatitis C, but an HCV infection presents a risk of nosocomial infections.
• ImrnunoScore diagnostic analysis can include measurement of as yet undetermined cellular components important to controlling TB infection.
• the CDC has outlined the following steps for preparation for terrorist attacks using biological agents:
• the planning group assembled by the CDC categorized biological agents according to their perceived level of threat.
• the first of these are Category A agents.
• These high-priority agents include organisms that pose a risk to national security because they:
• Category A agents include:
• filoviruses • filoviruses: o Ebola hemorrhagic fever o Marburg hemorrhagic fever
• Bacillus anthracis the causative agent of anthrax. Infection, usually by spores, is introduced through scratches or abrasions of the skin, inhalation, eating insufficiently cooked infected meat, or by the bites of flies. Anthrax spores may remain stable for decades or can be produced, weaponized, and delivered as a wet or dry aerosol cloud.
• Bacillus anthracis is detectable by Gram stain of the blood, blood culture on routine media, and by ELISA, but often not until later in the course of the illness. Approximately 50% of the cases are accompanied by hemorrhagic meningitis, and therefore organisms may also be identified in cerebrospinal fluid (Bush, et al. 2001). Only vegetative encapsulated bacilli are present during infection. Spores are not found within the body unless the bacilli are exposed to ambient air. Toxin production parallels the appearance of bacilli in the blood, and tests are available to rapidly detect the toxin. With the appearance of symptoms, the white blood cell count becomes elevated and remains so until death. The primary cause of morbidity and mortality is believed to be the extreme toxin load generated by the organism.
• Smallpox is caused by the Variola virus. There are no non-human reservoirs for smallpox and no human carriers. The disease has survived throughout history through continual person-to- person transmission. Smallpox was probably responsible for more than 100 million deaths during the 20 th century alone.
• Smallpox is perhaps the most feared of potential biological warfare agents.
• Vaccines are in short supply; however, the Federal government has entered into contracts to rectify this.
• the smallpox virion is readily transmitted from person to person by way of respiratory particles. Virions can also remain viable on fomites for up to one week. The virus initially replicates in respiratory tract epithelial cells then migrates to regional lymph nodes.
• a massive asymptomatic viremia ensues three to four days later and may result in focal infections involving lymphoid tissues, skin, intestines, lungs, kidneys, or brain (Henderson, et al. 1999).
• Initial - symptoms resemble an acute viral illness.
• a second viremia lasting two to five days, results in high fevers, malaise, headache, backache, rigors, and vomiting.
• the patient may develop delirium.
• a rash typically develops within 48 hours, beginning in the mouth, and heralds the onset of viral shedding.
• the rash rapidly spreads to the hands and forearms followed by the legs and trunk.
• the rash becomes distinctive when the lesions become pustular.
• Viral shedding and secondary infection cases may occur from the onset of rash until scabs have separated (Henderson, et al. 1999). Death usually occurs late in the first week or during the second week of the illness and is caused by the toxemia induced by the overwhelming viremia.
• the rash may resemble chickenpox.
• the rash of smallpox develops synchronously, in contrast to the asynchronous development observed with varicella.
• the rash of smallpox is concentrated on the face and extremities, as opposed to on the trunk as occurs in chickenpox (Henderson, 1999)
• Initial diagnosis will likely be clinical, based on the characteristic rash.
• Diseases with similar skin manifestations must be considered in the differential diagnosis, including cutaneous lues (syphilis), meningococcemia, acute leukemia, or drug toxicity. Laboratory confirmation is extremely important, as a single case of smallpox must be treated as an international public health emergency.
• Smallpox can be confirmed through clinical presentation and identification of the virion particles on electron microscopy of vesicular fluid, although this only confirms presence of an orthopox virus. Further classification of the orthopox virus requires cell culture or growth on chorioallantoic egg membrane. ImmunoScore diagnostic analysis can be used to identify levels of smallpox antibody in sera of individuals. In addition, ImmunoScore database analyses could be performed on larger numbers of individuals to track the longevity of serum antibody to smallpox.
• Yersinia pestis a gram-negative bacillus, has tormented civilization throughout history.
• the Byzantine Empire recorded a sixth century pandemic, and the Black Death killed millions of people throughout 14 th century Europe.
• the most recent pandemic originated in China and spread worldwide at the turn of the 20 th century.
• Plague is a zoonosis with a rodent host and a flea vector.
• the vector is not essential, however, and direct host-to-host transmission can occur by way of an infectious aerosol.
• a bite from an infected flea causes an infection in the lymphatic system leading to the bubonic form of the disease.
• Inhalation of aerosolized bacillus preferred for deliberate dissemination, results in a primary pulmonary infection, known as pneumonic plague.
• the disease is rapidly fatal in the absence of prompt antibiotic treatment and may result in secondary contagion spread.
• Modern efforts to weaponize Y. pestis were begun by the Japanese during World War II, but dissemination attempts were met with limited success. Infected fleas were bred by the billions and then released over northern Chinese cities that had not previously recorded plague casualties.
• Serum antibody to Fraction I capsular antigen is correlated with resistance to Y. pestis infection in experimental animals.
• PHA passive hemagglutination
• Tularemia is a small aerobic, non-motile, gram- negative, cocco-bacillus.
• Tularemia is a zoonotic disease that humans may acquire after skin or mucous membrane contact with tissues or body fluids of infected animals, or from bites of infected ticks, deerflies, or mosquitoes. Less commonly, inhalation of contaminated dusts or ingestion of contaminated foods or water may produce clinical disease. Respiratory exposure by aerosol would typically cause typhoidal or pneumonic tularemia.
• F. tularensis remains viable for weeks in water, soil, carcasses, hides, and for years in frozen meat. Resistant for months to temperatures of freezing and below, it is easily killed by heat and disinfectants (Evans and Friedlander, 1997).
• Francisella tularensis was weaponized by the United States in the 1950s and 1960s during the U.S. offensive biowarfare program. Other countries are suspected to have weaponized this agent. This organism could potentially be stabilized for weaponization by an adversary and produced in a wet or dried form for delivery against U.S. forces or as a weapon of terror. Onset of disease is usually acute and occurs after an incubation period that ranges from 1 to 21 days. In humans, as few as 10 to 50 organisms may cause disease if inhaled or injected intradermally (McCrumb, et al. 1957). AU ages are susceptible, and recovery is generally followed by permanent immunity.
• Typhoidal tularemia occurs mainly after inhalation of infectious aerosols, but can also occur after intradermal or gastrointestinal challenge.
• F. tularensis would most likely be delivered as an aerosol if used as a weapon and would primarily cause typhoidal tularemia that manifests as fever, prostration, and weight loss.
• Pneumonia may be severe and fulminant.
• Respiratory symptoms and a cough may also be present.
• Case fatality rates may be greater than the 1-3% seen with appropriately treated natural disease. Case fatality rates are approximately 35% in untreated naturally acquired typhoidal cases (Darling, et al. 2002). Similar to many bacterial and viral diseases, early symptoms of exposure to F. tularensis are fairly generic and nonspecific, making differential diagnosis difficult.
• a live vaccine strain (LVS) tularemia vaccine is under IND status in a protocol at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), and is available only for at-risk U.S. military personnel. It is administered by scarification. Despite the increased risk of a bioterror threat felt after September 11, further vaccine development for tularemia remains slow. The projected date of a new licensed vaccine in the United States is not until 2009 (Nierengarten and Lutwick, 2002). There is some confusion over which arm of the immune system should be targeted. New lots of LVS produced in the United States show immunogenicity in human volunteers, producing both brisk cell-mediated and humoral immune responses. ImmunoScore diagnostic analysis can be applied in this setting to monitor the response to vaccines in clinical trials and follow the duration of the immune response. In addition, cellular components of the immune system can also be tracked, for example, through compilation of information added to an ImmunoScore database.
• the viral hemorrhagic fevers are caused by a diverse group of RNA viruses in four separate families: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. All have lipid envelopes, limited geographic ranges, are highly infectious by way of the aerosol route ⁇ except Dengue), and are believed to have animal reservoirs with arthropod vectors. Terrorist groups have attempted to weaponize agents from this class (Cams, 2001). Each disease is characterized by its own unique characteristics, but all have a final common pathway of diffuse hemorrhage and bleeding diathesis.
• Yellow fever and dengue are probably the archetypical diseases of this group, but are not considered significant biological warfare threat agents.
• Hantavirus (Bunyaviridae) is enzootic in rodents. West Africa's Lassa fever and Argentine, Venezuelan hemorrhagic fevers (Arenaviridae) are also enzootic in rodents within their respective areas.
• the most publicized viral hemorrhagic fevers are the Ebola and Marburg (Filoviridae) viruses. These viruses produce grotesquely lethal diseases. The reservoir and natural transmission of Ebola and Marburg are unknown but they are readily transmissible by infected blood and tissue.
• Aerosols may be formed naturally when infectious body fluids are expelled or in the case of hantavirus when rodent feces and urine are resuspended by movement in the area. Laboratory cultures can yield sufficient concentrations of organisms to provide a credible terrorist weapon if disseminated as an aerosol (Darling, et al. 2002).
• Clostridium botulinum is a gram-positive, spore-forming anaerobic bacillus found in soil around the world. Botulism is the syndrome caused by botulinum toxin produced by this bacterium. Cases have historically been categorized according to transmission as food-borne illness (from ingestion of the toxin in home-canned goods, poorly heated vegetables, or meats), wound botulism (secondary to soil-contaminated wounds, drug abuse, and C-section deliveries), and infantile illness (from ingestion of spores) (Arnon, et al. 2001).
• Botulinum toxin is one of the most toxic substances known (Middlebrook and Franz, 1998). Seven distinct types of toxin exist, identified by antigenicity and referred to as types A-G. Botulinum toxin could be used to sabotage food supplies, although a more likely scenario would involve dissemination as an aerosol. During the Gulf War, Iraq produced 20,000 L of botulinum toxin, 12,000 L of which were used in field testing and to fill warheads (Zilinskas, 1997). Despite the efforts to produce an effective botulinum toxin weapon, most authorities agree that it is unlikely this toxin could ever be effectively deployed as a weapon of mass destruction.
• Aerosol delivery over a battlefield or a defined geographic region populated by civilians would require a precisely orchestrated effort.
• Large quantities of toxin would have to be delivered to the area at the optimum time because botulinum toxin quickly degrades in the environment.
• Even municipal water reservoirs are most likely safe from contamination by terrorist actions because literally ton quantities would be necessary because of the effects of dilution.
• botulism intoxication In the emergency setting the diagnosis of botulism intoxication will be clinical. An influx of patients with descending muscle paralysis and bulbar findings may herald a bioterrorist event or a natural outbreak of food-borne botulism. No routine laboratory tests will aid in the diagnosis.
• the toxin may be detected by assays of serum or gastric contents.
• Antitoxin may prevent progression or shorten the course of the illness.
• a pentavalent toxoid of Clostridium botulinum toxin types A, B, C, D, and E is available as an IND product for pre-exposure prophylaxis.
• ImmunoScore analyses can be useful in examining response to the prophylactic vaccine as well as in following the duration of protection.
• the Category B agents are the second highest priority and they include those agents that:
• Category B agents include: Coxiella burnetti (Q fever) Brucella species Burkholderia mallei alphaviruses ricin toxin from Ricinus communis (castor beans) epsilon toxin of Clostridium perfringens Staphylococcus enterotoxin B Salmonella species Shigella dysenteriae Escherichia coli O157:H7 Vibrio cholerae Cryptosporidium parvum
• Category C agents include: Nipah virus hantaviruses tickborne hemorrhagic fever viruses tickborne encephalitis viruses yellow fever multidrug-resistant tuberculosis
• an ImmunoScore diagnostic platform can be constructed so as to be able to grow with the needs of bioterror agent analyses. As new agents arise, diagnostic testing can available to test for immune responses to such agents as well as any vaccines that have been or will be developed.
• Chronic diseases take a huge toll. In the United States, more than 70% of all deaths are due to one or more chronic diseases, and more than 90 million people suffer daily. Even diseases not typically associated with pathogens may have underlying infectious causes. Of the eight million new cases of cancer in the world each year, one million are attributable to a known infectious agent.
• Helicobacter pylori is a gram-negative bacterium that causes a lifelong infection in over half of the world's human population. Without specific antimicrobial treatment, all infected individuals exhibit chronic gastric inflammation, and a small percentage will develop peptic ulcers and gastric adenocarcinoma or mucosa associated lymphoid tissue lymphoma. In response to infection, the host launches a vigorous immune response, including the mucosal infiltration of neutrophils, lymphocytes, and macrophages. This immune response is insufficient for clearance of the bacterium, suggesting the H. pylori is capable of evading host immune responses.
• Infection with H. pylori induces apoptosis in macrophages, disrupts phagosome maturation, and disrupts cytokine signaling. Induction of macrophage apoptosis may represent a mechanism by which H. pylori usurps the host immune response to establish a chronic infection in humans.
• Atherosclerosis Many individuals with atherosclerosis lack identifiable traditional risk factors (smoking, diet and exercise, hypercholesterolemia, hypertension, diabetes, and genetic factors). Atherogenic processes resemble many aspects of chronic inflammation, a response that may be promoted by microorganisms. Both Chlamydia pneumoniae and cytomegalovirus (CMY) are widely distributed, can infect blood vessel walls, and exhibit persistence, latency, and recurrence of infection.
• CRIS cytomegalovirus
• H. pylori and Herpes Simplex Virus (HSV) antibody levels have also been associated with cardiovascular disease.
• Mycobacterial disease shares interesting connections to heart disease. Not only is tuberculosis the only microorganism to depend on cholesterol for its pathogenesis, but CDC maps for cardiovascular disease bear a striking similarity to those of State and regional tuberculosis cases.
• Present day markers suggested as indicators for heart disease susceptibility such as C-reactive protein (CRP), interleukin-6, and homocysteine are all similarly elevated in tuberculosis.
• Group A streptococci are important human pathogens which cause a variety of pyrogenic infections that can be mild (e.g. pharyngitis, impetigo) to extremely severe (cellulites, necrotizing fasciitis, septicemia, pneumonia and streptococcal toxic shock syndrome).
• Molecular mimicry between streptococcal and heart components has been proposed as the triggering factor leading to autoimmunity in rheumatic heart disease.
• HSV Herpes Simplex Virus
• HSV ocular infection is the leading cause of infectious corneal blindness in the United States.
• HSV-I shedding is associated with reduced hospital survival in patients receiving assisted ventilation in intensive care units.
• the virus spreads to and enters sensory neurons, where it establishes a latent infection.
• Latent infection forms a reservoir of virus for recurrent infection, disease, and transmission to other individuals.
• HSV-I is usually associated with primary infections of the orofacial area and latent infections of the trigeminal ganglion.
• HSV-2 is usually associated with genital infections and latent infection in sacral ganglia.
• HPV Human papillomavirus
• HPV Human papillomavirus
• Most HPV infections are benign - plantar and palmar warts, common warts, and flat warts. Strains that target the face make skin cancer more likely. Other strains that grow primarily in the lining of the mouth produce small elevated nodules that can develop into fatal squamous cell cancers.
• Cervical cancer is the third most common cancer in women in the United States. The magnitude of the association between HPV and cervical squamous cell carcinoma is higher than that for the association between smoking and lung cancer. HPV has been implicated in 99.7% of cervical squamous cell cancer cases world wide.
• Pseudomonas aeruginosa is classified as an opportunistic pathogen, primarily infecting individuals who are immunocompromised, such as patients with cancer or AIDS. Cystic fibrosis (CF) almost always leads to chronic airway infection with P. aeruginosa. Despite advances in antibiotic therapy, after chronic infection, rapid deterioration in lung function occurs, increasing morbidity and mortality. Chronic P. aeruginosa airway infections remain the primary cause of morbidity and mortality in the CF population. Young children with CF may be infected as -early as 6 months of age and P. aeruginosa becomes chronic in the first decade of life with pulmonary exacerbations increasing in frequency. A pulmonary infection with P. aeruginosa is characterized by a strong recruitment of neutrophils and significant inflammation in the lung parenchyma, which results in extensive damage to the lung tissue through the action of neutrophil enzymes and oxidants.
• Tuberculosis has been declared a global emergency. Pulmonary TB is the second leading cause of mortality from infectious disease world wide, with 8 million new cases and 2 million deaths due to TB each year. There is an urgent need for rapid, cost-effective, and accurate methods for the diagnosis of TB. A serologic test is attractive because it would be relatively rapid and would not require sputum expectoration. Challenges for the development of effective serologic tests include:
• Lyme disease is a troubling chronic infection. Infection of humans by Borrelia burgodorferi results in a spectrum of clinical illnesses. Earliest symptoms may include a typical or atypical rash, followed by flu-like illness. As the disease progresses, other neurologic and musculoskeletal symptoms and signs may develop. The pathophysiology of the chronic symptoms is not well understood, with hypotheses ranging from persisting infection to autoimmunity to a combination of the two. The diagnosis of chronic Lyme disease has been made difficult because of several factors. The multi-symptom complex consisting of fatigue, musculoskeletal pains and neurocognitive dysfunction cannot be distinguished from disorders that have been termed fibromyalgia, chronic fatigue and Gulf War syndrome.
• Hepatitis C virus is a small RNA virus that chronically infects 170-350 million people world wide. Of those acutely infected, only 15% recover, while the remaining 85% succumb to chronic hepatitis. Up to 20% of the individuals with chronic hepatitis C progress to cirrhosis and these patients are at greater risk of developing hepatocellular carcinoma. Extensive studies have been carried out in the past decade in order to find immunodominant HCV peptides and there are many peptides capable of inducing cellular immune responses. None of these, however, has proven to be clinically effective in preventing HCV disease. Although interferon and other agents are effective for eliminating HCV in certain patients, they are too expensive for the majority of HCV patients in most countries.
• Epstein-Barr Virus is a B-lymphotropic human herpesvirus, and like other herpesviruses, establishes a lifelong presence in the host. The virus infects the vast majority of the world's adult population and is well known for its association with a broad spectrum of benign and malignant diseases including:
• Respiratory tract infections caused by viruses, Chlamydia, and Mycoplasma have been implicated in the pathogenesis of asthma.
• Viruses have been demonstrated to be associated with asthma epidemiologically in at least two ways. During infancy, certain viruses have been implicated as potentially being responsible for the inception of the asthmatic phenotype.
• viral upper respiratory tract infections play a significant role in producing acute exacerbations of airway obstruction that may result in frequent outpatient visits or hospitalizations.
• microorganisms are implicated in the initiation and/or progression of chronic illnesses. There are other effects of carriage of these microorganisms on the immune system (e.g. cytokines, cellular responses, effector molecules). Monitoring of antibody responses and plasma cytokine levels merit serious consideration for ImmunoScore diagnostic analyses in exemplary embodiments of the present invention.
• Th1-Th2 Paradigm Lymphocytes are the effector cells of acquired (or adaptive) immunity, originating as bone marrow stem cells that undergo hematopoiesis. A portion of these lymphocytes migrate to the thymus to undergo further differentiation and maturation to become T cells, which can be divided into subsets based on physical markers or surface receptors (e.g., CD4, CD8, and either ⁇ or ⁇ T cell receptor), representing a generally irreversible genetic commitment (for review, see Kidd P, 2003; Pier GB et al., 2004). Other subsets have been defined by functional properties that may be environmentally altered; e.g., expression of different cytokines, which are chemicals used for cell-to-cell communication.
• cytokines which are chemicals used for cell-to-cell communication.
• ThI and Th2 T helper cell subsets
• Fig. 41 shows some of the complex interactions between the polarized ThI and Th2 responses.
• Thl-Th2 paradigm the cytokines secreted by the Th cells will feedback and reinforce the particular clonal phenotype from which they originated (e.g., IL-4 for ThI vs.
• Fig. 4 J shows the complex balance between ThI and Th2 cells as dictated by the ThI -Th2 paradigm regarding disease.
• the ThI cell (with its associated cytokines: INF- ⁇ , TNF- ⁇ , IL-2, IL- 12) is biased towards the cell-mediated side of immunity, effective against intracellular parasites, and its downregulation of Th2 can provide relief from allergic reactions due to IgE; but detrimental effects may result in autoimmunity and graft rejection.
• the Th2 cell (with its associated cytokines: IL-4, IL-5, 11-6, IL-IO, IL-13) favors humoral (antibody) immunity, providing an effective correlate of protection for most vaccines, and its downregulation of ThI can result in some benefit of tolerance to prevent cellular autoimmune reactions; but certain harmful characteristics related to IgE-based allergies and autoimmunity may result.
• ThI- Th2 polarization in mice with discrete cytokine profiles has given way to a more flexible continuum of responses in humans, where the functionality of Th cells may be more variable and not necessarily locked into a single type for subsequent generations (Kelso A, Groves P, 1997; Kelso A et al., 1999; Doyle AG et al., 1999; Fitzpatrick DR at al., 1999).
• Thl-Th2 paradigm has provided valuable insight into the nature and treatment/prevention of infectious diseases and immunologic disorders (e.g., allergies and autoimmunity).
• Fig. 4K shows a more comprehensive picture of immune regulation with additional cell types. From this figure, one can see additional T regulator cells which contribute to the paradigm by providing suppressor functions (e.g., NKT, CD45RB 10 , CIM + CTXUS + ), including some that are antigen-specific (e.g., Th3, TrI), thereby preventing autoimmune diseases.
• suppressor functions e.g., NKT, CD45RB 10 , CIM + CTXUS +
• T F H nonpolarized effector T cell
• T F H follicular helper T cell
• Cytokine secretion and regulatory functions are not restricted to just lymphocytes or lymphoid cells, but these activities are also provided by and impact myeloid ceils (also originating from stem cells through hematopoiesis), including neutrophils, eosinophils, basophils, mast cells, dendritic cells, monocytes, and macrophages.
• Figs. 4L show more of these interactions (left panel) as well as differentiation among different cell types (right panel), including antibody-producing B cells, antigen presenting cells (APC), and natural killer cells (NK).
• APC antigen presenting cells
• NK natural killer cells
• T cells and other effector cells find their way into specific tissue where needed and interact with each other in spatial and temporal patterns by way of secreted chemokines (chemotactic cytokines) and chemokine receptors expressed on their surfaces. T cells interact with eosinophils, mast cells, and basophils during allergic reactions, or with macrophages and neutrophils for delayed-type hypersensitivity reactions (Sallusto F et al., 2000).
• ThI vs. Th2 Specific disease states have been identified that are associated with, and possibly result from, an imbalance of the immune regulatory process already described.
• Atopy (familial allergy) in humans was shown to be characterized by a Th2 profile in whole blood cell culture, where high levels of IL-4 and low levels of IFN- ⁇ were observed for CD4 + T cells, but the Th2 deviation in atopic asthma showed high levels of IFN- ⁇ for CD8 + T cells (Magnan AO et al., 2000).
• IL-4 was used therapeutically to ameliorate the clinical disease in mice that were experimentally given an autoimmune disease, allergic encephalomyelitis, switching the ThI cells to Th2 cells (Racke MK et al., 1994).
• Th polarization status In order to diagnose or predict an immunologic disease and/or provide therapy or prophylaxis, the Th polarization status must be determined; this should also be applied to measure susceptibility to infectious and neoplastic diseases. Th status is measurable in terms of cytokine profiles (House RV, 1999; Harber M et al., 2000; House RV, 2001), chemokine / chemoattractant receptors (Sallusto et al., 1998; Syrbe U et al., 1999; Sallusto et al., 2000; Kaplan AP, 2001; Cosmi L et al., 2001), specific effector cell products (Venge P et al, 1999; Venge P, 2004), or gene expression profiles (Rogge L, 2002). Table 8 below shows how the cytokines and chemokine/chemoattractant receptors can, for example, be aligned within the ThI- Th2 paradigm for an exemplary diagnostic panel according to an exemplary embodiment of the present
• Bioassays require living material to induce proliferation, maintain viability, stimulate migration, induce a secondary function, or inhibit a function.
• Immunoassays are commonly the enzyme-linked immunosorbent assay (ELISA) or the radioimmunoassay (RIA); the ELISA is most often used, being a colorimetric antibody-based assay.
• ELISA enzyme-linked immunosorbent assay
• RIA radioimmunoassay
• ELISA radioimmunoassay
• Molecular biological methods usually employ the polymerase chain reaction (PCR), or reverse transcriptase PCR (RT-PCR) to measure the rnRNA representing a particular cytokine.
• PCR polymerase chain reaction
• RT-PCR reverse transcriptase PCR
• combinations of these assays can used for improved results concerning a particular application (House RV, 2001); e.g., RT-PCR ELISA, where the RT-PCR amplifies the message and the ELISA detects the result; in situ hybridization, where genetic material is detected with labeled antibodies; ELISPOT assay, where cytokines are detected from single cells by ELISA and molecular methodology; and cytokine immunotrapping assay, a capture ELISA where cytokine antibodies are used to capture cytokines expressed from isolated cells for analysis.
• RT-PCR ELISA where the RT-PCR amplifies the message and the ELISA detects the result
• in situ hybridization where genetic material is detected with labeled antibodies
• ELISPOT assay where cytokines are detected from single cells by ELISA and molecular methodology
• cytokine immunotrapping assay a capture ELISA where cytokine antibodies are used to capture cytokines expressed from isolated cells for analysis.
• chemokine receptors Over 60 chemokine receptors have been identified (Pier GB et al., 2004), but only a few are preferentially expressed by specific Th clones (Sallusto et al., 2000) as indicated in a previous table. These receptors may appear as cell surface-bound and in soluble forms. Bioassays and immunoassays can measure soluble receptors, but flow cytometry and in situ hybridization would be more appropriate for surface-bound receptors (House RV, 2001). Effector cells, such as eosinophils, release different cytotoxic products upon activation during allergic inflammation (Venge P, 2004).
• ECP eosinophil cationic protein
• EPO eosinophil peroxidase
• EPX/EDN eosinophil protein X / eosinophil-derived neurotoxin
• ECP eosinophil cationic protein
• EPO eosinophil peroxidase
• EPX/EDN eosinophil protein X / eosinophil-derived neurotoxin
• ECP may be measured in serum, plasma, sputum, or saliva as an indicator of eosinophil granulocyte activity and turnover in the allergic or asthmatic patient (Venge P et al., 1999; Bjork A et al., 2000; Venge P, 2004).
• EPX/EDN may be measured in urine as another noninvasive way of monitoring eosinophil-related allergic inflammation (Venge P, 2004). Elevated urine levels of EPX/EDN have been shown in atopic dermatitis (Breuer K et al., 2001) and have also been predictive of asthma development in children (Oymar K, 2001).
• the gene expression of these substances can also be evaluated, deriving gene expression profiles to correlate with the ThI -Th2 paradigm (Rogge L, 2002).
• Oligonucleotide microarrays have been used to assess human gene expression with a transcript level display capacity of 6000 human genes. From purified and stimulated ThI and Th2 cells, ' 215 genes were found to be differentially expressed at a 95% confidence level (Rogge L, 2002). These results were also confirmed by RT- PCR for 28 out of 29 genes.
• ThI cell-mediated response In the event of a microbial or cancerous attack, the type of immune response will usually dictate the outcome. It is generally considered that a ThI cell-mediated response would be desirable against viruses, intracellular bacteria, fungi, parasites, and cancer, while a Th2 humoral response might work better for most mucosal and extracellular bacterial infections; however, this is really an over-simplification for a complex area fraught with conflicting scenarios (for review, see Lucey DR, 1996).
• humoral antibody responses are often established as measurements of potency or correlates of protection for vaccines, even against viruses, such as poliovirus (Fox JP, 1984; SaIk J, 1984; Sutter RW et al., 1995), and intracellular bacteria, such as Salmonella typhi (Klugman KP et al., 1996; Tacket CO et al., 2004). It is clear that 2 distinct mechanisms of protection (humoral vs. cell-mediated) can occur against the same disease (Kaul D, Ogra PL, 1998; Tacket CO et al., 2004).
• ThI- Th2 Due to the complexity of pathogenesis, with different stages of infection and transmission, it is likely that a balance of ThI and Th2 is required to enable either part to play a role as needed. Nonetheless, it appears that a simple ThI- Th2 paradigm does apply to certain organisms, such as Mycobacterium tuberculosis, during a natural infection (Ki dd P, 2003). Epidemiological studies have shown that ThI -mediated (IFN- ⁇ , IL- 12) protection is essential for protection against tuberculosis, and Th2 predominance leads to severe disease that is often fatal (Newport MJ et al., 1996; Lienhardt C et al., 2002).
• ThI -Th2 paradigm It is probable that people who are predisposed to only one side of the ThI -Th2 paradigm would be at a disadvantage in terms of options available in response to disease.
• infectious and neoplastic diseases in relation to ThI and Th2 profiles see Lucey DR et al., 1996.
• Th1-Th2 and Immunologic Diseases Allergy/Atopy and Autoimmunity/Inflammatory Disease
• the nature of the immune response is first influenced by the specific signals that are involved in the early recruitment of immune components to the site of inflammation (Cookson, 2004). As different pattern-recognition receptors can signal through different pathways, different pathogens or antigens can induce different immune responses (Palaniyar, et al. 2002). Second, the nature of the local immune response might also be strongly influenced by tissue-specific facors, and it has been suggested that the epithelial cells, in general, tend to initiate Th2 rather then ThI -type responses (Matzinger, 2002). In addition, there is evidence that dendritic cells from airways • encourage Th2-cell development by default (Stumbles, et al. 1998), and that the induction of Th2 or ThI type responses by dendritic cells depends on the stimulus with which they are activated (Mazzoni and Segal, 2004).
• ThI-Th2 paradigm of atopic disease The perception that specific early signals induced by different infections (or damage by different proteins or other entities) might modify the nature of the subsequent immune response has implications for the ThI -Th2 paradigm of atopic disease.
• One important issue is the timing of establishment of the Th2-cell bias: on the one hand, ThI- or Th2-cell responses to allergens might be fixed at the time of first exposure in early childhood, and the bias might be subsequently manipulated by bacterial and other adjuvants.
• ThI- or Th2-cell responses might develop as a consequence of activation of particular patter-recognition receptors by particular pattern-associated molecular patterns (PAMPs) that are present in allergens (Cookson, 2004).
• PAMPs pattern-associated molecular patterns
• Allergy or atopy usually involves Th2 predominance, particularly related to IgE antibodies which attach to basophils and mast cells and cause the release of mediators such as histamine, leukotrienes, and prostaglandins (Kidd P, 2003).
• Th2 predominance particularly related to IgE antibodies which attach to basophils and mast cells and cause the release of mediators such as histamine, leukotrienes, and prostaglandins
• IL-4 Th2
• cytokines Secrist H et al., 1993
• ThI IL-12
• ThI cell responses This raises the possiblity that manipulation of the immune system in early life could result in persistent ThI or Th2 type responses. If this is the case, vaccination to induce ThI cell responses might be effective against asthma and other allergic disorders (Holt, 1994).
• ThI cell responses might be effective against asthma and other allergic disorders (Holt, 1994).
• ThI cell deviation theory it has been proposed that lack of normal microbial exposure leads to reduced activity of regulatory T cells rather than Th2 cell deviation (Romagnani, 2004).
• Asthma is an inflammatory condition, both atopic and nonatopic, that is generally Th2 (IL-4) dominant (Larche M, 2003). Asthma has now reached epidemic proportions, with more than 10% of children being affected in many westernized societies (Cookson, 2004). Allergen injections have been used effectively as immunotherapy in IgE-mediated disease (Abramson MJ et aL, 1995).
• IL- 13 polymorphism influences mucus production as well as serum IgE levels through a receptor encoded by the polymorphic IL-4R (Ober, et al. 2000).
• FCERIB variants modify the activity of Fc ⁇ RI on mast cells, possibly by modulating the level of expression of the receptor on the cell surface (Donnadieu, et al. 2003).
• a receptor expressed by T cells for the key mast cell signalling factor prostanoid DP has also been reported to be associated with asthma (Oguma, et al. 2004).
• asthma susceptibility genes include the pattern-recognition receptors of the innate immune system, which are expressed by dendritic cells and other cells, and recognize specific microbial components and activate innate immune responses (Cookson, 2004). Polymorphism in CD 14, Toll-like receptor 2 (TLR2), nucleotide-binding oligomerization domain 2 (NOD2, or alternatively CARD 15), and T-cell immunoglobulin domain and mucin domain 1 have all been shown to influence asthma susceptibility (Baldini, et al. 1999; Eder, et al. 2004; Kabesch, et al.
• tumor-necrosis factor (Moffatt and Cookson, 1997), which encodes a potent pro-inflammatory cytokine that is released by many cells, including airway epithelial cells and transforming growth factor- ⁇ (Pulleyn, et al. 2001), which is an important local regulator of epithelial inflammation.
• Atopic dermatitis can involve a mixture of ThI and Th2 states, depending on the type or stage of disease.
• the acute disease is usually Th2 (IL.-4), while the chronic disease may show more ThI (IL-12) cytokines (Singh VK et al., 1999). Further studies indicate that the initial phase of disease is Th2, while ThI may appear later (Bohm I, Bauer R, 1997).
• Alternative mechanisms for bacterial products to modify the risk of atopic diseases include the enhancement of an effective airway barrier by the induction of mucus production through IL- 13 stimulation (Kuperman, et al. 2002), or the induction of sufficient polyclonal IgA or IgE to provide nonspecific protection against allergens. Additionally, a protective role by microorganisms might follow the acquisition of distinct commensal or symbiotic organisms. Once an individual's commensal microflora is established in the first year of life, it remains relatively stable (Hooper and Gordon, 2001). Substantial differences have been observed in the intestinal microflora between neighboring countires with a different prevalence of atopic disease (Sepp, et al.
• RA Rheumatoid arthritis
• ThI-driven IFN- ⁇
• Th2 IL-4, IL-10
• pregnancy which seems to have a Th2 bias, appears to ameliorate the progression of RA, providing indirect evidence of the role of ThI in RA (Da Silva JA, Spector TD, 1992).
• MS Multiple sclerosis
• ThI ThI -driven IL-12, IFN- ⁇
• Kidd P 2003
• this may be a complication of the role of regulatory T cells (Tr) secreting cytokines (IL-10) to normally downregulate the ThI cells (Bettelli E et al., 1998).
• Type 1 diabetes is an autoimmune disease that may be ThI dominant. Data available thus far in human diseases favor a prevalent ThI lyrnphokine profile in target organs of patients with organ- specific autoimmunity. Adjuvant therapy with BCG injections seems to benefit patients and nonobese diabetic mice by raising Th2 (IL-4) cytokine levels (Singh VK et al., 1999). However, administration of Th2 cells to nonobese diabetic mice can worsen the disease, if the recipient mice are immunocompromised (Pakala, et al. 1997).
• Miscarriage might be the result of an autoimmune response to the fetus during pregnancy, where the normally Th2 (IL-3, IL-4, IL-10) dominance during pregnancy has shifted to a ThI state (IL-2, IFN- ⁇ , TNF- ⁇ ), allowing the maternal cell-mediated response to be directed towards the paternal antigens of the fetus (Chaouat G et al., 2004). While the simplicity of the Thl-Th2 paradigm applied to pregnancy is being questioned, particularly in terms of potential therapy and the inability to generalize across all individuals, there may still be a Th2 bias for normal pregnancies (Chaouat G et al., 2004).
• Systemic lupus erythematosus is a chronic, recurrent, potentially fatal multisystem inflammatory disorder that typically shows anti-nuclear and other autoantibodies, with elevated ThI (IL-2, IFN- ⁇ ) and Th2 (IL-4) cytokines (Kidd P, 2003).
• ThI IL-2, IFN- ⁇
• IL-4 Th2
• Patients with arthritis have higher ThI cytokine levels, while those with CNS involvement have higher Th2 cytokine levels (Chang DM et al., 2002).
• C4A and C4B are responsible for different individuals in a population, two to seven (possibly eight) C4 genes may be present in a diploid genome, leading to a 3- to 5- fold variation in plasma C4 protein concentrations and the presence of multiple allotypes (Yang, et al. 2003).
• C4A and C4B are responsible for the roles of C4A and C4B in immunoclearance, memory, and effector functions of the humoral immune response, it is not unexpected that a deficiency of C4A or C4B is frequently associated with infectious and/or autoimmune diseases (Yang, et al. 2004b).
• PDCDl programmed cell death gene 1
• SNP single-nucleotide polymorphism
• Fibrotic disease involving tissue fibrosis (scarring), is the result of a ThI -Th2 imbalance during wound healing in response to chronic inflammation, and is responsible for an estimated 45% of U.S. deaths (Wynn TA, 2004).
• Th2 IL-4, IL-5, IL-13
• ThI IFN- ⁇ , IL-12
• tissue remodeling permanent scar tissue
• the CDC states that doses of measles-containing vaccine administered prior to the first birthday should not be counted as part of the series (CDC, 2002). They also state that serological testing for IgG antibody to MMR vaccine viruses can be considered if the individual lacks the appropriate paperwork. A child whose record indicates receipt of measles or measles-rubella vaccine at age > 1 year and who has protective antibody levels against measles and rubella should receive a single dose of MMR as age appropriate to ensure protection against mumps.
• poliovirus vaccine the CDC suggests that the "simplest approach" is to revaccinate immigrants with IPV according to the U.S. schedule (CDC, 2002). They also state that children appropriately vaccinated with three doses of oral polio vaccine (OPV) in economically developing countries might have suboptimal seroconversion.
• OOV oral polio vaccine
• serologic testing for neutralizing antibody to poliovirus types 1, 2, and 3 can be obtained commercially and at certain state health department laboratories. Incorporation of poliovirus assays into ImmunoPrint diagnostics would enable immigration authorities to screen individuals for seroconversion to poliovirus types 1, 2, and 3. Recommended immunization boosters could then be followed through with in timely fashion.
• Vaccination providers can re-vaccinate a child with DTaP vaccine without regard to recorded doses; however, one concern regarding this approach is that data indicate increased rates of local adverse reactions after the fourth and fifth doses of DTP or DTaP. If a re- vaccination approach is adopted and a severe local reaction occurs, serologic testing for specific IgG antibody to tetanus and diphtheria toxins can be measured by ImmunoPrint analyses before administering additional doses. Protective concentration indicates that further doses are unnecessary and subsequent vaccination should occur as age-appropriate. There is, as yet, no serologic correlate of protection for pertussis. The lack of a serologic correlate of protection is one area where application of the ImmunoPrint database would be of great value.
• Hib Haemophilus influenzae type B
• the ACIP recommends serologic testing for hepatitis B surface antigen (HBsAg) for international adoptees (CDC, 2002). Children determined to be HBsAg positive should be monitored for the development of liver disease. Household members of HBsAg-positive children should be vaccinated.
• the current recommendation from the ACIP states that a child whose records indicate receipt of > 3 doses of vaccine can be considered protected and additional doses of vaccine are not needed if > 1 doses were administered at > 6 months of age. Those who have received ⁇ 3 doses should complete the series at the recommended intervals (CDC, 2002). This rather complicated recommendation depending on accurate record-keeping could be replaced with ImmunoPrint diagnostic testing. A positive anti-HBsAg IgG antibody would be indicative of protection in these individuals.
• Varicella vaccine is not administered in the majority of countries.
• the ACIP recommends that a child who lacks a reliable medical history regarding prior varicella disease should be vaccinated as age-appropriate (CDC, 1996).
• a well-timed ImmunoScore diagnostic assay can, in exemplary embodiments of the present invention, remove speculation from the vaccination protocol.
• Pneumococcal conjugate and pneumococcal polysaccharide vaccines are not administered in the majority of countries.
• the CDC recommends that vaccines should be administered as age- appropriate or as indicated by the presence of underlying medical conditions (CDC, 2002). ImmunoPrint diagnostic analysis could be used to point out the need for vaccination in immigrating individuals.
• Each country may have needs for assessing the immune status of immigrants that may not necessarily coincide with the U.S. requirements as previously outlined.
• Greenaway et al. (2004) have embarked on a mission to assess the immune status of immigrants in the Montreal area of Canada, with initial emphasis on 5 different infectious agents: hepatitis A, measles, mumps, rubella, and varicella (Greenaway CA, Boivin JF, Dongier P, Miller MA, Schwartzman K. Susceptibility to vaccine-preventable diseases in newly arrived immigrants.
• diagnostic panels may be expanded where appropriate to represent additional infectious agents that are listed for selected immunization.
• diagnostic subpanels can be developed to accommodate the needs for different researchers where there is an interest to follow up on particular infectious agents in a region where there may be new or ongoing outbreaks of disease.
• VPD vaccine preventable diseases
• varicella and rubella vaccines are not routinely administered in many countries, and this has therefore resulted in an over representation of immigrants in outbreaks of varicella and rubella in areas where these vaccines already exist.
• Tuberculosis is another disease that may be of considerable importance to monitor, not necessarily for immune status, but for active infection, particularly in immigrant populations. It is estimated that one third of the global population is infected with TB. Due to improved laboratory services during the 1990s, there has been a resumption of an overall decline in U.S. cases of TB. Nonetheless, the CDC states, "TB continues to pose substantial social, public health, and economic costs.” (Centers for Disease Control and Prevention. National plan for reliable tuberculosis laboratory services using a systems approach: recommendations from CDC and the Association of Public Health Laboratories Task Force on Tuberculosis Laboratory Services. MMWR 2005;54[No. RR-6]: 1-12).
• the BCG vaccine currently licensed for TB, is not recommended for routine use in the U.S. because of questionable efficacy; however, there are other countries that routinely use this vaccine.
• the United Kingdom, in 2005 announced that, after 50 years, it is dropping its school TB vaccination program for young teenagers, in favor of targeting infants in ethnic populations that are at greater risk (Celia Hall, Medical Editor, Chat Group Limited, July 7, 2005). For example, they have indicated that the case rate in whites is 3.6 per 100,000, while the rate in Africans is 279.8 per 100,000, and the rate in Indian, Pakistani, and Bangladeshi people is 126.7. New immigrants from countries with high TB incidence would also be targeted for vaccinations. It is possible that a diagnostic panel which includes TB would prove useful for screening these populations.
• a TB diagnostic could be included in the subpanel proposed for Canada, or used as a separate diagnostic, as a follow-up to the Greenaway et al. study. It is possible to use specific antibody detection- to distinguish active TB infections from non-active or non-TB (Tong M et al. 2005. J Immunol Methods. 301:154-63). In this case, specific TB antigens, particularly those of a carbohydrate nature, may be selected for inclusion in the proposed diagnostic panels to identify people with active TB infections in need of treatment.
• Antibodies directed against self antigens and tissues are known as autoantibodies. These autoantibodies can be expressed years or decades before the autoimmunity causes clinical disease. The clinical disease arises when the autoantibodies cause so much damage that the afflicted individuals begin to show symptoms. For example, antibodies attacking self nuclear antigens cause glomeruloneprhtis and vasculitis as symptoms of systemic lupus erythematosus; and antibodies to myelin basic protein and myeling oligodendrocyte glycoprotein eventually cause brain invasion by CD4 + T cells in multiple sclerosis. ImmunoScore technology may one day allow physicians to screen a healthy person's blood for autoantibodies years prior to causing disease, and thereby, enable a physician to recommend a course of treatment to delay, or even perhaps prevent, the manifestation of clinical disease.
• Elements that have been proposed to be of importance in the course of this disease include mannose-binding lectin polymorphisms; expression of apolipoprotein E (apo-E) isoform; levels of cytokines IFN- ⁇ , IL-6, and TNF- ⁇ ; levels of serum proteins including apo A-IV, haptoglobin, transthyretin, and fibrinogen; antibodies to GDla/GdlB complex, LM-I, and GMl; HLA haplotype; and even exposure to vaccine antigens. Detection of susceptible genes would not necessarily reveal when (or even if) an individual would be stricken with an autoimmune disease. Detection of specific antibodies with the ImmunoScore Autoimmune Disease detection panel would signal that a disease-causing process was already underway.
• Fig.5B depicts exemplary process flow in which one or more exemplary ImmunoScore autoimmune panels can be used.
• healthy patients can, for example, be screened at regular intervals for antibodies or other markers known to be indicative of autoimmune disease (as described below) at, for example, their physician's office.
• Women and patients with a family history of autoimmune disease can, for example, be scheduled for more regular ImmunoScore Autoimmune Disease diagnostic screenings.
• the patient's HLA type can also, for example, be a useful input to the appropriate diagnostic determination.
• an individual patient's rise and fall of relevant antibody populations could be followed and stored in an ImmunoScore Database (sometimes referred to herein as an "ImmunoScoreKeeper"). If it happened, such as at 5B30, that a patient's antibody levels were not a cause for concern, that patient's data could be maintained in the autoimmune disease. Most chronic diseases, however, arise from a complex interplay between environmental influences and multiple genes that each make a small contribution to the course of the disease. Many factors apparently play an as yet completely undefined role in the expression of Guillain-Barre syndrome.
• Elements that have been proposed to be of importance in the course of this disease include mannose-binding lectin polymorphisms; expression of apolipoprotein E ⁇ apo-E) isoform; levels of cytokines IFN- ⁇ , IL-6, and TNF- ⁇ ; levels of serum proteins including apo A-IV, haptoglobin, transthyretin, and fibrinogen; antibodies to GDla/GdlB complex, LM-I, and GMl ; HLA haplotype; and even exposure to vaccine antigens. Detection of susceptible genes would not necessarily reveal when (or even if) an individual would be stricken with an autoimmune disease. Detection of specific antibodies with the ImmunoScore Autoimmune Disease detection panel would signal that a disease-causing process was already underway.
• Fig. 5B depicts exemplary process flow in which one or more -exemplary ImmunoScore autoimmune panels can be used.
• healthy patients can, for example, be screened at regular intervals for antibodies or other markers known to be indicative of autoimmune disease (as described below) at, for example, their physician's office.
• Women and patients with a family history of autoimmune disease can, for example, be scheduled for more regular ImmunoScore Autoimmune Disease diagnostic screenings.
• the patient's HLA type can also, for example, be a useful input to the appropriate diagnostic determination.
• an individual patient's rise and fall of relevant antibody populations could be followed and stored in an ImmunoScore Database (sometimes referred to herein as an "ImmunoScoreKeeper"). If it happened, such as at 5B30, that a patient's antibody levels were not a cause for concern, that patient's data could be maintained in the database and referred to by researchers as well as that patient's physician(s) at subsequent visits. In addition, this information might be of use to insurance providers and health maintenance organizations for statistical analyses.
• a therapeutic course of action involving treatment with appropriate pharmaceuticals, or perhaps other suggested therapies including dietary modifications or similar recommendations can be implemented.
• the patient can be regularly screened for any change in the antibody or marker levels, as shown at 5B40.
• Such an early indication of autoimmune disease might be helpful to the insurance industry and the treatment prior to chronic disease would be more cost-effective to both the patient and the insurance provider.
• Therapies considered experimental can, for example, be monitored by researchers with regular ImmunoScore Autoimmune Disease diagnostic measurements during the course of the experimental treatments). Efficacy of drugs or behavior modifications could thereby be monitored before the disease outbreaks became full blown. The presence of predictive antibodies would not mean that a patient would get definitely sick, but would -give a percentage risk of autoimmune disease developing over some years or months.
• ImmunoScore Diagnostic screening which can, for example, accelerate the development of such treatments.
• HSCT autologous hemopoietic stem cell transplantation
• autoimmune T cells found abnormal in several autoimmune diseases, have been proposed as central to achieve long-term remissions.
• Mesenchymal stem cells of bone marrow origin have more recently been shown not only to be able to differentiate into multiple tissues, but also to exert a potent antiproliferative effect that results in the inhibition of immune responses an prolonged survival of hematopoietic stem cells.
• all of these potential resources clearly need to be investigated at the preclinical level but support a great deal of enthusiasm for cell therapy of autoimmune diseases (Dazzi, et al. 2007).
• autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body.
• the many diseases called autoimmune are either systemic (involving many body organs) or organ specific.
• the immune system may initiate an attack on self because the normal controlling mechanisms of the immune system are impaired, because a host response to an extrinsic immunogen, such as a virus, fails to distinguish between normal tissue and the object of the attack (cross-reactivity), or because immunogenic tissues, normally hidden from the immune system, are made visible to the immune system (loss of tolerance). Any or all of these mechanisms may occur in human autoimmune disease (Lockshin, 2001). Differences among authors among their definitions of autoimmunity cause published lists of autoimmune diseases to differ.
• autoimmune diseases primarily affect women. In humans, severity of illness does not differ between men and women. Men and women respond similarly to infection and vaccination, which suggests that the intrinsic differences in immune response between the sexes do not account for differences in disease frequency. In autoimmune-like illnesses caused by recognized environmental agents, sex discrepancy is usually explained by differences in exposure. Endogenous hormones are not a likely explanation for sex discrepancy; hormones could have an effect if the effect is a threshold rather than quantitative. X and Y chromosomal differences have not been studied in depth. Other possibilities to explain sex discrepancy include chronobiologic difference and various other biologies, such and pregnancy and menstruation, in which men differ from women (Lockshin, 2006).
• T-cell mediated autoimmune diseases the presence of serum antibodies can predate the onset of disease, and be predictive of the development of clinical symptoms.
• ADEM Acute disseminated encephalomyelitis
• ADEM Acute disseminated encephalomyelitis
• ADEM Acute disseminated encephalomyelitis
• ADEM is a monophasic autoimmune demyelinating disease of the central nervous system that typically follows a febrile infection or a vaccination. Children are predominantly affected. A plethora of viral and bacterial pathogens and a number of vaccinations have been associated with ADEM. Experimental animal studies indicate that both primary and secondary autoimmune responses contribute to central nervous system inflammation and subsequent demyelination. The clinical diagnosis of ADEM is strongly suggested by a close temporal relationship between an infectious incident or an immunization and the onset of leukoencephalopathic neurological symptoms (Menge, et al. 2005).
• Addison's disease about 7 in 10 cases are due to an autoimmune disease.
• auto-immune Addison's disease antibodies are made which attach to cells in the adrenal cortex. These destroy the cells which make Cortisol and aldosterone.
• Patients with autoimmune Addison's disease are prone to develop other autoimmune manifestations.
• An increased prevalence of celiac disease (CD) has recently been demonstrated in Northern European patients with AAD.
• patients with AAD there is a high prevalence of both CD and IgA deficiency. Consequently, it is important to screen for CD with tissue transglutaminase autoantibodies of the IgA class and for IgA levels (Betterle, et al. 2006).
• Ankylosing spondylitis is JL chronic, progressive autoimmune disease characterized by arthritis, inflammation, and eventual immobility of a number of joints.
• the disease usually involves the spine and surrounding spinal structures and usually begins between the ages of fifteen and thirty-five years and affects young white males three times as frequently as females.
• Some patients of this debilitating disease have antibodies to the bacterium Klebsiella. This micro-organism apparently has some antigenicity which causes the body to make antibodies which in turn attack the lower spine and cause ankylosing spondylitis.
• Antiphospholipid antibody syndrome affects blood-clotting process - causes blood clots to form in veins and/or arteries.
• Antiphospholipid antibody syndrome There are three primary classes of antibodies associated with the antiphospholipid antibody syndrome: 1) anticardiolipin antibodies, 2) the lupus anticoagulant and 3) antibodies directed against specific molecules including a molecule known as beta-2-gIycoprotein 1. (University of Illinois - Urbana/Champaign. Carle Cancer Center. Hematology Resource Page http://www- admin.med.uiuc.edu/hematology/PtAPS.htm).
• Aplastic anemia may be caused by autoimmune attack on the bone marrow, slowing or shutting down production of new blood cells.
• Some acquired aplastic anemia (AA) results from immune-mediated destruction of hematopoietic stem cells.
• Cytokine gene polymorphisms are implicated in controlling cytokine production and increasing the susceptibility to some autoimmune diseases (Gidvani, et al. 2007).
• Autoimmune hepatitis caused by attack on the liver by body's immune system. The disease is usually quite serious and, if not treated, gets worse over time. It's usually chronic, meaning it can last for years, and can lead to cirrhosis (scarring and hardening) of the liver and eventually liver failure. Autoimmune hepatitis is classified as -either type I or II. Type I is the most common form in North America. It occurs at any age and is more common among women than men. About half of those with type I have other autoimmune disorders, such as type 1 diabetes, proliferative glomerulonephritis, thyroiditis, Graves' disease, Sjogren's syndrome, autoimmune anemia, and ulcerative colitis.
• Type II autoimmune hepatitis is less common, typically affecting girls ages 2 to 14, although adults can have it too (National Institute of Diabetes and Digestive and Kidney Diseases, NIH. h11p://digestive.niddk.iiih.gov/ddiseases/pubs/autoi ⁇ imvmehep/index.htm ).
• Coeliac disease characterized by chronic inflammation of the proximal portion of the small intestine.
• people with celiac disease eat foods or use products containing gluten, their immune system responds by damaging the small intestine.
• the villi lining the small intestine are damaged or destroyed (National Institute of Diabetes and Digestive and Kidney Diseases,
• Crohn's disease form of inflammatory bowel disease characterized by chronic inflammation of the intestinal tract - major symptoms include abdominal pain and diarrhea.
• the new treatment is an antibody designed to disable interleukin-12 (IL- 12), an immune system protein involved in inflammation. People with Crohn's produce excess IL-12.
• IL- 12 interleukin-12
• Diabetes mellitus characterized by a deficiency or absence of insulin production (Type I) — often the consequence of autoimmune attack on the insulin-producing beta cells in the islets of Langerhans of the pancreas.
• LADA latent Autoimmune Diabetes of Adulthood
• type 1.5 diabetes a slowly progressive form of type 1 diabetes mellitus.
• Patients are often diagnosed as type II diabetes, but have positive pancreatic islet antibodies, especially to glutamic acid decarboxylase (GAD). They do not immediately require insulin for treatment, are often not overweight, and have little or no resistance to insulin (Johns Hopkins).
• Grave's disease most common form of hyperthyroidism — caused by anti-thyroid antibodies that have the effect of stimulating the thyroid into overproduction of thyroid hormone. Grave's disease is an autoimmune disorder in which antibodies to the thyrotropin receptor result in constitutive activation of the receptor and increased levels of thyroid hormone. ThI and Th2-like cytokines are also involved in the pathogenesis of Graves' disease (Molnar, 2007).
• Guillain-Barr ⁇ syndrome an acquired immune-mediated inflammatory disorder of the peripheral nervous system — also called acute inflammatory demyelinating polyneuropathy, acute idiopathic polyradiculoneuritis, acute idopathic polyneuritis, and Landry's ascending paralysis.
• GRS Guillain-Barr ⁇ syndrome
• the virus has changed the nature of cells in the nervous system ⁇ o that the immune system treats them as foreign cells. It is also possible that the virus makes the immune system itself less discriminating about what cells it recognises as its own, allowing some of the immune cells, such as certain kinds of lymphocytes and macrophages, to attack the myelin.
• Sensitized T lymphocytes cooperate with B lymphocytes to produce antibodies against components of the myelin sheath and may contribute to destruction of the myelin.
• Bots are investigating these and other possibilities to find why the immune system goes awry in Guillain-Barre syndrome and other autoimmune diseases.
• the cause and course of Guillain-Barr ⁇ syndrome is an active area of neurological investigation, incorporating the cooperative efforts of neurological scientists, immunologists. and virologists (National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/gbs/gbs.htm).
• Hashimoto's disease common form of hypothyroidism — characterized by initial inflammation of the thyroid, and later dysfunction and goiter — there are several characteristic antibodies (e.g., anti-thyroglobulin).
• susceptibility genes for autoimmune thyroiditis In addition to the classical major histocompatibility complex class II genes and cytotoxic T cell antigen-4, new studies have appeared on CD40 the protein tyrosine phosphatase-22. Too much iodine increases the incidence of Hashimoto's thyroiditis, perhaps by augmenting the antigenicity of thyroglobulin.
• T regulatory cells, Toll-like receptors and presentation of lipid antigens by CDl molecules are new areas of basic immunological investigation that have been applied to autoimmune thyroiditis (Caturegli, et al. 2007).
• Idiopathic thrombocytopenic purpura an autoimmune disease where the body produces anti-platelet antibodies resulting in a low platelet count.
• Immune thrombocytopenic purpura is classified as primary or as secondary to an underlying disorder and as acute (of six months or less in duration) or chronic.
• thirty-seven patients wilh idiopathic thrombocytopenic purpura (ITP) were treated with a standard Helicobacter pylori eradication regimen irrespective of H. pylori infection. Their results indicate that platelet recovery results from the disappearance of H. pylori itself, and is mediated, in part, through suppression of anti-platelet autoantibody production (Asahi, et al. 2006).
• MS Multiple sclerosis
• MOG myelin oligodendrocyte glycoprotein
• MBP myelin basic protein
• Opsoclonus myoclonus syndrome a neurological disorder — result of autoimmune attack on the nervous system - symptoms include opsoclonus, myoclonus, ataxia, intention tremor dysphasia, dysarthria, mutism, hypotonia, lethargy, irritability, or malaise.
• opsoclonus-myoclonus OM
• no specific autoantigen has been identified.
• a group found frequent and heterogeneous immunity to neuronal autoantigens without a single specific antibody marker of OM (Bataller, et al. 2003).
• Optic neuritis inflammation of the optic nerve that may cause a complete or partial loss of vision.
• Patients with optic neuritis had more anti-myelin basic protein and anti-proteolipid protein antibodies than did control subjects ⁇ Sellebj erg, et al. 1995). Since high concentrations of GQIb gangliosides are known to be present in the human optic nerve and anti-GQlb antibodies can cross the blood-brain barrier, the optic disc oedema in [a] patient could represent an anti-GQlb IgM complement mediated inflammatory demyelination (Chan, 2003).
• Ord's thyroiditis similar to Hashimoto's disease, except the thyroid is reduced in size.
• Pemphigus an autoimmune disorder that causes blistering and raw sores on skin and mucous membranes. Patients with pemphigus develop antibodies that bind to the keratinocyte cell surface, the site of primary pathology (Payne, et al.2005).
• Pernicious anemia - autoimmune disorder characterized by anemia due to maladsorption of vitamin B 12.
• the best tests for diagnosing pernicious anemia are the vitamin B12 level, folic acid level, methylmalonic (MMA) level, and antibody tests for antibodies to intrinsic factor and parietal cells. Levels of MMA are elevated in both serum and urine before levels of vitamin B 12 become abnormally decreased or symptoms of deficiency appear. The blood test for MMA is considered superior to the urine measurement (Greenwood and Sentry, 2007).
• PBC pyruvate dehydrogenase complex
• the pathogenetic mechanism is believed to be caused by a defect in immunologic tolerance, resulting in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. This leads to ductulopenia and persistent cholestasis, by developing end-stage hepatic-cell failure (Reshetnyak, 2006).
• Rheumatoid arthritis a heterogeneous autoimmune disorder wherein the immune system attacks the bone joints.
• CCP anti-cyclic citrullinated peptide
• Reiter's syndrome autoimmune attack on various body systems in response to a bacterial infection and the body's confusion over the HLA-B27 marker.
• Other polymorphic determinants of MHC class I antigens might play a critical role in the pathogenesis of Reiter's syndrome (Shimamoto, et al.2000).
• Sjogren's syndrome autoimmune disorder in which immune cells attack and destroy the exocrine glands that produce tears and saliva.
• Antibody self-reactivities include anti-fodrine and anti-salivary duct antibodies, rheumatoid factor, especially of the IgA isotype, and anti- nuclear antibodies, most notably anti-Ro/SSA and anti-La/SSB antibodies (Youinou, et al. 2005).
• Systemic lupus erythematosus a chronic autoimmune disease wherein the immune system becomes hyperactive and attacks normal tissue - this results in inflammation an brings about symptoms.
• About 90% of people who have lupus are young women in their late teens to 30s, but children (mostly girls) and older men and women can also be affected.
• the number and variety of antibodies that can appear in lupus are greater than those in any other disorder.
• These antibodies which are the underlying physiologic problem in lupus, along with other unknown factors, determine which symptoms develop. However, the levels of these antibodies may not always be proportional to the person's symptoms.
• Laboratory tests can help doctors confirm the diagnosis.
• a blood test can detect antinuclear antibodies, which are present in almost all people who have lupus ( http://www.merck.com/mmhe/secO5/chO68/chO68b.htmlX
• Temporal arteritis also known as giant cell arteritis - inflammation of blood vessels - most commonly the large and medium arteries of the head. Anticardiolipin antibody levels predict flares and relapses in patients with giant-cell (temporal) arteritis (Kerleau, et al. 1994).
• Warm autoimmune hemolytic anemia characterized by IgM attack against red blood cells. In the warm antibody type, the autoantibodies attach to and destroy red blood cells at temperatures equal to or in excess of normal body temperature.
• Warm AIHA was the most common type of acquired immune hemolytic anemia; it comprised 64 of the 100 patients, whereas 26 patients showed a cold AIHA (Vaglio, et al. 2007).
• ANCAs antineutrophil cytoplasmic antibodies
• Behcet's disease multi-system condition where the immune system produces inflammation in bodily tissues, primarily causing vasculitis. Behcet's is one of the few forms of vasculitis in which there is a known genetic predisposition. The presence of the gene HLA- B51 is a risk factor for this disease. However, it must be emphasized that presence of the gene in and of itself is not enough to cause Behcet's: many people possess the gene, but relatively few develop Behcet's rhttp://vasculitis.med.ihu.edu/tvpesof/behcets.html).
• Chagas disease believed in the chronic phase to be result from homology of a Trypanosoma cruzi antigen to body tissue — resulting in a delayed autoimmune reaction leading to Chagasic cardiopathy (cardiomegaly), volvulus or constipation, and ultimately, death. Chagas disease afflicts about 30% of the 20 million people infected with T. cruzi in South America (Marin-Neto, et al. 2007).
• Chronic fatigue syndrome a disorder whose primary symptom is usually intense fatigue — likely has multiple causes - some maintain that autoimmune damage to the brain stem is the principal mechanism in a significant subset of cases.
• Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions.
• VIP vasoactive intestinal peptide
• PACAP pituitary adenylate activating polypeptide
• Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition (Staines, 2004).
• Dysautonomia - malfunction of the autonomic nervous system including such disorders as postural orthostatic tachycardia syndrome.
• Post-viral autoimmune damage appears to be a frequent cause.
• Acute autonomic neuropathy can affect parasympathetic, sympathetic, and enteric nerves or neurons and is associated with antibodies to ganglionic nicotinic acetylcholine receptors. These antibodies appear to be causative based on a rabbit immunization model and serum transfer studies from patients and animals (Etienne and Weimer, 2006).
• Endometriosis common medical condition wherein the tissue lining the uterus is found outside the uterus, typically affecting other organs in the pelvis - can lead to serious health problems, primarily pain and infertility.
• Endometriosis and polycystic ovary syndrome (PCOS) are associated with higher values of anti-FSH-immunoglobulin (Ig)A, anti-V14D- IgA, and endometriosis with anti-Vl 4D-IgG.
• Hydradenitis suppurativa rare skin disease in which apocrine sweat glands become severely inflamed. A reduction in the percentage of NK cells over time and a lower monocyte response to triggering by bacterial components is observed in patients with hidradenitis suppurativa. Further research is needed to clarify if these changes are connected to an autoimmune mechanism in the pathogenesis of hidradenitis suppurativa (Giamarellos- Bourboulis, et al. 2007).
• Interstitial cystitis a urinary bladder disease characterized by any of the following symptoms — pelvic pain, urinary frequency, urgency, pain with sexual intercourse, and pain with urination.
• Interstitial cystitis (IC) has been deemed by some authors as a local manifestation of a systemic disease, particularly one of the autoimmune disorders (Porru, et al. 2005).
• cytokeratin 10 present in synovial microvascular endothelium, as a target ligand and a putative autoantigen in chronic, antibiotic treatment- resistant Lyme arthritis. Furthermore, there is cross-reactivity between cytokeratin 10 and a prominent B. burgdorferi Ag, outer surface protein A. Release of the self protein in the context of inflammation-induced tissue injury and the resulting in situ response to it could set in motion a feed-forward loop, which amplifies the inflammatory process, thereby rendering it chronic and self-perpetuating, even in the absence of the inciting pathogen (Ghosh, et al. 2006).
• Neuromyotonia spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin. It develops as a result of both acquired and hereditary diseases. The acquired form is more frequent and is usually caused by antibodies against neuromuscular junction. About 40% of patients with acquired neuromyotonia will have detectable voltage-gated potassium-channel antibodies. Clinical, electrophysiological and immunological measurements are important in defining the phenotype of neuromyotonia, and other, milder forms of peripheral nerve hyperexcitability (Madd ⁇ son, 2006).
• Psoriasis a skin disorder in which rapidly-multiplying skin cells produce itchy, scaly inflamed patches on the skin.
• Psoriasis is a common chronic inflammatory skin disease, the study of which might also be of considerable value to the understanding of other inflammatory and autoimmune-type diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and diabetes mellitus.
• T cells and dendritic cells have a central role in psoriasis (Boyman, et al. 2007).
• Sarcoidosis disease wherein granulomas can form anywhere in the body, but particularly in the lungs.
• Various autoimmune diseases have been reported to occur in patients with sarcoidosis (Takahashi, et al. 2006).
• the prevalence of Chlamydophila pneumon ⁇ ae-specific antibodies in bronchoalveolar lavage fluids was significantly higher in sarcoidosis patients for IgG and IgA (IgG: 74.4%; IgA: 46.2%) compared to controls (IgG: 14.7%; IgA: 14.7%) (Gaede, et al. 2002).
• Schizophrenia - mental disease characterized by impairments in the perception or expression of reality and by significant social or occupational dysfunction.
• Initial investigations of the possible interaction between schizophrenia and the immune system began in the early 1900s and have proceeded in a rather halting fashion because of the methodological challenges faced by investigators.
• a confluence of recent data suggests that activation of the inflammatory response system, the cellular immune system, and the humoral immune system may be present in some patients with schizophrenia.
• ISome of the most compelling data support the hypothesis that minor levels of immune activation may be associated with acute psychotic exacerbations.
• a second body of evidence suggests that some individuals with schizophrenia may have chronic, evolving autoimmune processes (Rapaport and Delrahim, 2001).
• Scleroderma chronic disease characterized by excessive deposits of collagen. Progressive systemic scleroderma can be fatal —the local type of the disease is not serious. Autoantibodies to centromeric proteins are commonly found in sera of limited scleroderma and other rheumatic disease patients. Utilizing samples from 263 anti-centromere immunofluorescence positive patients, 93.5% were found to have anti-CENP-A reactivity and 95.4% had anti-CENP-B reactivity by ELISA. Very few patient samples exclusively targeted CENP-A (2.7%) or CENP-B (4.2%) (Akbarali, et al. 2006).
• Ulcerative colitis an inflammatory disease of the bowel that usually affects the distal end of the large intestine and rectum.
• Complement activation observed in relation to epithelium- bound IgGl in ulcerative colitis indicates that the surface epithelium is subjected to immunological attack by an autoimmune reaction.
• Comparison of identical twins, discordant with regard to ulcerative colitis suggests that the markedly skewed local IgGl response seen in this IBD entity may be genetically determined (Brandtzaeg, et al. 2006).
• IL-23 is essential for manifestation of chronic intestinal inflammation (Yen, et al. 2006).
• MBL Mannose binding lectin
• ImmunoScore assays for autoimmunity can include dozens of screening tests run on individual patients from "cradle to grave.” Ideally, individuals would first be screened at the time of entry to the public school system to obtain baseline measurements. Those individuals with ImmunoScores of concern or familial history of autoimmune disease can be screened more frequently than other individuals as they aged. At the time of college entry/high school graduation, it would be more imperative to screen everyone for an adult baseline ImmunoScore for autoimmune disease predictability. The timing of the screening can, for example, thereby precede development of most autoimmune diseases in susceptible patients.
• An exemplary autoimmune baseline screening panel follows. This screening can be performed on the young adult population. Females, particularly with a family history of autoimmune disease should be screened more regularly than males. Pregnant females could routinely be screened during pregnancy to monitor any possible onset of autoimmune symptoms. Males could again be screened at the 50 year old checkup as a means of gathering another appropriate time-point to their personal ImmunoScore record. In exemplary embodiments of the present invention, some or all of the following assays can be included in an ImrnunoScore Autoimmune Screening/Diagnostic Panel:
• MOG myelin oligodendrocyte glycoprotein
• coli antibody (anti-OmpC) anti-glutamic acid decarboxylase antibody (GADA) o particularly anti-65 kDa isoform anti-protein tyrosine phosphatase-like molecule antibody (IA-2A) anti-glomerular basement membrane (GBM) antibody anti-neutrophil cytoplasmic antigens (ANCA) anti-GDI a/GDlb complex antibody anti-LMl antibody anti-GMl antibody anti-thyroglobulin antibody anti-nuclear antibodies (ANA) o lupus anticoagulant (LA) antibody o anti-phospholipid (aPL) o anti-SS/A antibody o anti-SS/B antibody o anti-Sm antibody o anti-RNP antibody o anti-Jol antibody o anti-Scl-70 antibody o anti-dsDNA antibody o anti-Centromere B antibody o anti-Histone antibody anti-alphallbbeta 3 IgM anti-acetylcholine receptor (anti-ACh
• anti-BP 230 (bullous pemphigoid antigen 1) anti-intrinsic factor antibody anti-parietal cell antibodies anti-mitochondrial antibodies o in particular, anti-E2 component of pyruvate dehydrogenase complex (PDC) antibody anti-cyclic citrullinated peptide (CCP) antibody anti-heat shock protein (HSP) 65 antibody anti-HSP 90 antibody anti-DnaJ antibody anti-BiP antibody anti-heterogeneous nuclear RNP A2/B1 antibody anti-heterogeneous nuclear RNP D antibody anti-annexin V antibody anti-calpastatin antibody anti-type II collagen antibody anti-glucose-6-phosphate (GPI) antibody anti-elongation factor anti-human cartilage gp39 antibody anti-CMamydia antibodies anti-La/SSB antibody anti-fodrine antibody anti-salivary duct antibodies anti-Red Blood Cell (RBC) IgM anti-neutrophil cytoplasmic antibodies anti-thyroid micro
• Interleukin-1 ⁇ (IL- l ⁇ )
• Interferon ⁇ IFN- ⁇
• TLR Toll-like Receptor
• IRP immune risk phenotype
• Lifelong and chronic antigenic load may represent the major driving force for immunosenescence, which impacts on human lifespan by reducing the number of virgin antigen- non experienced T cells, and results in their replacement by expanded clones of antigen- experienced effector and memory T cells which display a late differentiation phenotype.
• the T cell population shifts to a lower ratio of na ⁇ ve cells to memory cells, the thymus releases fewer na ⁇ ve T cells with age and those T cells remaining, especially the CD8 + subset, also show increased oligoclonality with age.
• the repertoire of cells available to respond to antigenic challenge from previously encountered pathogens shrinks.
• CMV-specific T cells A high number of CD8 + cells are found to be specific for a single CMV epitope (Pawelec, et al. 2005; Pawelec, et al. 2004).
• the accumulation of CMV-specific T cells has been observed to reduce T cell immunity toward EBV infection (Khan, et al. 2004) and influenza vaccination (Trzonkowski, et al.2003).
• Functional analyses performed with T cells from nonagenarians demonstrated that they were characterized by decreased functional capacity when compared with similar cells isolated from middle aged individuals (Hadrup, et al.2006). This suggests that increased numbers of CMV-specific T cells could be the result of a compensatory mechanism enabling control of CMV despite lower functional capacity (Hadrup, et al. 2006).
• the biology of CMV infection in humans can be conceptualized as an evolutionary "negotiated" balance between viral mechanisms of pathogenesis, persistence, and immune evasion and the host cellular immune response (Sylwester, et al. 2005).
• CMV-specific CD8 + T cells One of the immunodominant viral antigens recognized by CMV-specific CD8 + T cells is derived from the 65-kDa phosphoprotein (pp65) .
• Samples from octogenarian and nonagenarian populations revealed that a large number of CD8 + CD28 " cells were specific for the pp65 antigen. These findings imply a co-dominant role of CMV as a cause for a compromised immunity in old age (Vasto, et al. 2007).
• a second immunodominant antigen is the IE-I antigen. Epitope specificity and immunodominance of CD8 T cells against IE-I and pp65 are comparable in acute infection and long-term memory often with marked focusing of responses that are probably established very early on.
• the mutation accumulation theory of senescence postulates that there are numerous loci subject to mutation to deleterious alleles, whose effects on survival or other components of fitness are restricted to narrow bands of ages (Rose, 1991). The equilibrium frequencies of such deleterious alleles will be higher the later in life in which they act (Charlesworth, 1994).
• the alternative path involves antagonistic pleiotropy, according to which genes that increase early performance are likely to become established in a population even if they have adverse effects on later performance (Williams, 1957; Rose, 1991).
• Antagonistic nleiotronv was orieinallv defined as meanins oooosite effects of the same allele at different aces (Williams, 1957).
• Antagonistic pleiotropy in evolutionary theory usually refers to opposite effects of a genotype on fecundity and survival. The existence of trade-offs between these two components of Darwinian fitness was proposed to explain the evolution of senescence and the maintenance, via the creation of the heterozygous advantage, of polymorphism at loci involved in the determination of both traits (Kirkwood and Rose, 1991).
• antagonistic pleiotropy involved instead, relative survival values of a genotype at different ages (Toupance, et al. 1998).
• the two theories are not mutually exclusive* and modeling exercises have examined the validity of each (Charlesworth and Hughes, 1996).
• An example of antagonistic pleiotropy would be the high expression of testosterone in a male gorilla, which could lead to increased aggression and strength that would allow the male to become dominant and mate more frequently, but may eventually lead to a shortened lifespan ⁇ iue to increased atherosclerosis.
• Recent studies at the molecular level have suggested that cellular senescence may be antagonistically pleiotropic because it prevents tumorigenesis, but also contributes to organismic aging (Troen, 2003).
• Tumor progression is a complex process that depends on interactions between tumor cells and host cells.
• the inflammatory aspect of the host response is of particular interest because it includes the release of pro-inflammatory cytokines, some of which may promote tumor growth and hence influence survival.
• Some kinds of solid tumors are likely affected by regulatory cytokine genotypes.
• pro-inflammatory genotypes characterized by a low IL-IO or a high IL-6 producer seem to be associated with a worse clinical outcome (Caruso, et al. 2004).
• recent evidence has linked IL-10 and IL-6 cytokine polymorphisms to longevity.
• Caretaker tumor suppressor genes prevent cancer by protecting the .genome from mutations. They generally act by preventing DNA damage or optimizing DNA repair. In addition to preventing cancer, genes that help maintain genomic integrity also prevent or retard the development of other aging phenotypes and age-related pathologies (Hasty, et al. 2003).
• Gatekeeper tumor suppressors by contrast, prevent cancer by acting on intact cells — specifically, mitotic cells that are at risk for neoplastic transformation. Gatekeepers can virtually eliminate potential cancer cells by inducing programmed cell death (apoptosis).
• senescent cells can create a tissue environment that synergizes with oncogenic mutations to promote the progression of age-related cancers (Krtolica and Campisi, 2003).
• the recent evidence indicates that cellular senescence may be an example of evolutionary antagonistic pleiotropy.
• a major difference between microbial pathogens and tumors as potential vaccine targets is that cancer cells are derived from the host, and most of their macromolecules are normal self- antigens present in normal cells. To take advantage of the immune system's specificity, antigens must be found that clearly mark the cancer cells as different from host cells. An area generating much interest is the possibility of overcoming mechanisms that downregulate or attenuate the immune response, as is depicted in Fig.
• Fig. 5D (Berzofsky, et al. 2004b). With refemce thereto, Fig. 5D illustrates negative regulation of tumor immunosurveillance and antitumor immune responses.
• Fig. 5D(A) depicts CD4 + CD25 + T regulatory cells, induced by peptide presented by class II MHC molecules in the presence of IL-2, may inhibit induction of effector CD4 + or CD8 + T cells by a contact-dependent mechanism, possibly involving cell surface and/or secreted TGF- ⁇ , and Fig.
• 5D(B) illustrates how CD4 + NKT cells may be induced by tumor glycolipid presented by CDId to secrete IL-13, which stimulates Gr-I + CDl lb + myeloid cells to produce TGF- ⁇ , which inhibits induction of CD8 + CTLs mediating tumor immunosurveillance. TGF- ⁇ may also inhibit CD4+ T cells (not shown).
• Blockade of other mechanisms can improve immunosurveillance and the response to vaccines.
• Other suppressor or negative regulatory cells have been described in other contexts, but not as well study in the context of cancer (Berzofsky, et al.). Such mechanisms may have evolved to reduce inflammation and immunopathology or to prevent autoimmunity. Tumors have co-opted these mechanisms to evade immunosurveillance.
• CMV seropositivity appears to be one of the driving forces for induction of CD8 T cell clonality, this is not currently detectable in the middle-age population (Hadrup, et al. 2006).
• the influence of CMV on clonality only becomes relevant at a detectable level in the elderly.
• Superior detection capabilities available through the ImmunoScore technology might lead to earlier detection of possible immune depletion as individuals pass through middle age.
• ImmunoScore technology by its nature of compiling individual patient data would offer the opportunity for longitudinal design of research studies.
• the longitudinal design is a superior alternative to the cross-sectional method for conducting ageing research, but it has seldom -been used due to extensive costs as studies are currently conducted.
• the ImmunoScore svstem would naturally build a longitudinal component into patient care at no increased initial cost.
• the database would yield important insights into ageing and all its implications at a lower cost and dramatically improve healthcare.
• Immunogenetic components can, for example, be monitored using unique technology designed to investigate single nucleotide polymorphisms (SNPs) rapidly and those data could be stored in the ImmunoScore central database. Additionally, social and environmental factors can be part of the ImmunoScore demographic data collected at routine patient visits to then * physicians. The accumulation of these data on the ImmunoScore database would yield potential relationships regarding environmental and social factors to the IRP.
• SNPs single nucleotide polymorphisms
• ImmunoScore can, for example, track treatments and even shed light on when such treatments should commence in the life of the afflicted individuals.
• CMV CMV Vaccine and Vaccines against Chronic Viral Infections and Cancer.
• CMV was ranked in the highest of five tiers by the Institute of Medicine in the United States as a potentially cost-saving vaccine target (Stratton, et al. 2000).
• CMV is acquired earlier in life in developing countries and among the lower socioeconomic strata of the developed countries (Stagno and Cloud, 1990).
• seroepidemiology of CMV was examined in Australia (Seale, et al.2006).
• the pattern of age- specific seroprevalence of CMV antibody as provided in Fig. 5C, closely matched the pattern found from analysis of the exemplary CIP database described in Section II, below.
• CMV seroprevalence studies conducted around the world revealed that residents of developing countries have higher rates of CMV seropositivity than those of developed countries (Enright and Prober, 2004).
• the potential benefits of a CMV vaccine would include reduced transmision to pregnant women and less CMV disease due to primary infection or reactivation in organ transplant recipients and the immunosuppressed (Griffiths, et al. 2000). It is possible that the development of a vaccine that is effective against viruses that cause chronic infection may require consideration of a paradigm different than those previously used for organisms causing acute infection (Berzofsky et al.2004). In most cases of chronic viral infection, the immune response to the natural infection is not sufficient to eradicate that infection.
• a middle school superpanel can, for example, comprise the following exemplary panels:
• an ImmunoScore STD diagnostic panel would thus be to recommend treatments, track immunological response or provide other analyses, and not be used to recommend a vaccine or track the persistence of immunity conferred by it.
• an exemplary ImmunoScore database can, for example, generate correlates of protection information for all disease-causing organisms.
• ImmunoScore diagnoses could, for example, be designed to examine antibody and other related immune responses to vaccine components.
• Chlamydia trachomatis infection is the most commonly reported sexually transmitted disease in the United States, with the highest rates among adolescent females and young women. Because up to 70% of chlamydial infections in women are asymptomatic, routine screening and treatment of infected persons is essential to prevent pelvic inflammatory disease, infertility, ectopic pregnancy, and perinatal infections.
• USPSTF U.S. Preventive Services Task Force
• Herpes simplex virus type 2 (HSV-2) is the primary cause of genital herpes, a common sexually transmitted disease with at least 40 to 60 million infected individuals in the U. S. Medically serious complications of HSV are rare but constitute a significant burden, given the high rates of HSV seropositivity in the population. Many prophylactic and therapeutic vaccination approaches have been explored for the prevention or treatment of HSV infection. Infection induces both humoral and T-cell immunity. Vaccine candidates for HSV-2 infection include subunit vaccines, killed and live attenuated virus vaccines, and viral DNA vaccines.
• HPV Human papillomaviruses
• Cervical cancer is the second leading cause of cancer death among women worldwide, and more than 99% of cervical cancers contain HPV, particularly the high-risk HRP type 16 (HPV- 16).
• HPV- 16 Two HPV oncoproteins, E6 and E7, are consistently expressed in HPV-associated cancer cells and are responsible for their malignant transformation. These oncogenic proteins represent ideal target antigens for developing vaccines and immunotherapeutic strategies against HPV-associated neoplasms. More than 10,000 American women a year are diagnosed with cancer or precancerous cells caused by HPV, and 3,700 of them will die. Eighty times that number will die worldwide. An effective vaccine could prevent nearly all of those deaths. The CDC is currently considering an HPV vaccine for all children aged 12 years. A positive recommendation by the ACIP could start states thinking of requiring the vaccine for entry into middle school.
• Neisseria gonorrhoeae the causative agent or gonorrhea
• gonorrhea is one of the most common sexually transmitted pathogens worldwide. Although a robust inflammatory response ensues during symptomatic infection, no apparent protective immunity is developed following infection, as shown in a male human challenge study and by the high incidence of recidivism among patients attending sexually transmitted disease clinics. The search for a vaccine against gonorrhea has been largely disappointing. In human vaccine trials, partially lysed gonococci, purified pilin, and purified porin were shown to be immunogenic, but all failed to elicit protection upon subsequent natural exposure.
• the lack of protective immunity is likely due, in part, to the capacity of many gonococcal surface antigens to undergo high-frequency phase and antigenic variation.
• Individuals infected with Treponema pallidum subsp. pallidum develop specific immune responses that are able to clear millions of treponemes from sites of primary and secondary syphilis.
• humans develop robust immune responses against T. pallidum, they can be infected multiple times.
• the response is a T-cell mediated delayed-type hypersensitivity response in which T cells infiltrate syphilitic lesions and activate macrophages to phagocytose antibody-opsonized treponemes.
• T. pallidum repeat protein K (TprK) is a strong candidate for a treponemal factor involved in immune evasion.
• Epitope mapping studies revealed that, during experimental infection, T cells are directed to the conserved regions of TprK, while the antibodies are directed to the variable regions.
• HIV human immunodeficiency virus
• an effective HIV-I vaccine must be capable of inducing neutralizing antibodies as well as strong cell-mediated immune responses in outbred populations.
• GBS Group B Streptococci
• Urinary tract infections are a leading cause of morbidity and mortality and health care expenditures in persons of all ages. Sexually active young women are disproportionately affected, but several other populations, including elderly persons and those undergoing genitourinary instrumentation and catheterization, are also at risk. UTIs are the leading cause of gram-negative bacteremia (Orenstein and Wong, 1999).
• Lymphocytes are the effector cells of acquired immunity. There are two T helper subsets, ThI and Th2, based on two distinct cytokine profiles that resulted in the overall regulation of the immune response.
• the ThI cell (with its associated cytokines: INF- ⁇ , TNF- ⁇ , IL-2, IL- 12) is biased towards the cell-mediated side of immunity, effective against intracellular parasites, and its down regulation of Th2 can provide relief from allergic reactions due to IgE; but detrimental effects may result in autoimmunity and graft rejection.
• the Th2 cell (with its associated cytokines IL-4, IL-5, IL-6, IL-IO, IL-13) favors humoral immunity, providing an effective correlate of protection for most vaccines, and its down regulation of ThI can result in some benefit of tolerance to prevent cellular autoimmune reactions; but certain harmful characteristics related to IgE- based allergies and autoimmunity may result.
• the Th polarization status In order to diagnose or predict an immunologic disease and/or provide therapy or prophylaxis, the Th polarization status must be determined; this should also be applied to measure susceptibility to infectious and neoplastic diseases. Th status is measurable in terms of cytokine profiles, chemokine/chemoattractant receptors, specific effector cell products, or gene expression profiles.
• An exemplary diagnostic panel is described in the table below:
• CMV Cytomegalovirus
• Laboratory testing for antibody to CMV can be performed to determine if a woman already had a CMV infection.
• a Women of Child-Bearing Years ImmunoScore superpanel can be defined as follows.
• Pregnancy test (1) A pregnancy test is critical to making the correct decisions regarding administration of vaccines to women of this age group. There are, of course, other considerations here, but the status of the woman in question regarding pregnancy must be resolved in order to make accurate therapeutic decisions.
• the physician(s) of women of child bearing years need to be aware of the recommendations of the CDC regarding immunizing pregnant women and the risks of immunization vs. the risks of foregoing immunizations.
• physicians should be aware that following appropriate immunization protocols and assuring a competent immune status is extremely important for women of child-bearing years.
• the results of immunologic and other assays of an individual together with additional medical, lifestyle, environmental and other demographic information can be collected at the same time as, or derived from, the collected data, and can, for example, be stored in a system database.
• a system database can, for example, serve as an electronic record of immune status and other data over a period of time, both for individuals as well as for populations or sub-populations, as described below.
• such a database can be augmented with information regarding diagnoses received, treatments administered, pharmaceuticals prescribed, costs of medical services perfomed, insurance re-imbursements, metrics as to the efficacy of treatments and/or pharmaceuticals administered, as well other relevant information to facilitate evaluation of the efficacy and efficiency of medical services rendered, as described more fully below.
• Data can, for example, be -stored in an electronic database using standard techniques as are l ⁇ iown in the art.
• An example of data which can be stored and the manner in which it can be stored is next described. It is understood that this example is not intended to preclude the storage of additional collected or derived data as may prove useful for the purposes of trending, data mining, evaluation or diagnostic improvement, as described below, or as may be needed in or useful to any of the exemplary applications described in Section III below.
• an exemplary system can record a unique assay ID, which can incorporate, for example, among other information, an identifier for the assay instrument.
• This DD can be unique over the universe of instruments, ensuring that when data is aggregated into a central system no two assay result records will have the same identifier.
• GUID Globally Unique Identifier
• Each record can include the time and date that the assay was performed, stored to a time resolution of, for example, one second.
• time resolution of, for example, one second.
• standard means of storing time and date information in a database One simple means is, for example, to record the number of seconds from an arbitrary start time, such as, for example, January 1 st , 1900 at midnight.
• Each record can, for example, also include an indication of the location where the sample was processed. This can include, for example, an identifier of the instrument used, as well as real- world location information, such as, for example, the name and address of the facility where the instrument has been installed.
• the aforementioned exemplary fields comprise identification information which is important to maintain for all samples.
• information about the sample and patient can be stored in the database as well.
• Patient information can, for example, be stored in a form which is separate from the bulk of the data, and referenced by a data link.
• Patient information which can include, for example, name, social security number, birth date or other information (such as is described below in detail), can be maintained with emphasis on security standards are known in the art.
• the storage of identifiable individual patient information in a separate virtual location from the remaining data can help to maintain such a high level of security.
• a system can, for each assay result, also store an identifier indicating exactly which assay was performed on the sample. This can indicate not only the analyte to be determined, but also information regarding the production of the reagents used in the assay. This information can be used to distinguish between, and compensate for, for example, lot-to-lot variations in assay manufacture. It can also allow for converting different assays for the same analyte into a normalized value, so that trends across geography as well as time can be obtained.
• the measurement of an immune response to a particular disease or other analyte can involve the collection of a large quantity of low level data generated by an instrument.
• an instrument can measure the light emitted from the electrochemiluminescence over some time period as well as other information such as voltages and currents used to induce the electrochemiluminescence and the temperature near the electrodes through which the electrical energy is delivered to drive the electrochemiluminescent reaction. From this "raw data" and possibly instrument calibration information, a single number, for example, can be computed to represent an ECL signal for that measurement.
• Additional information can be computed from the raw data and instrument calibration information that indicates the quality of the ECL signal, for example, whether the instrument was operating in an appropriate environmental condition, whether sample was present, or whether the instrument was operating as expected.
• the raw data and such derived data can, for example, be stored in an exemplary ImmunoScore system database.
• the size of the storage required for this raw data can varv deoendine upon the resolution at which the data is captured. It is possible that a finer-grained resolution, resulting in a larger data storage requirement, will yield more useful analysis for some assays rather than others.
• Storage of both the raw data and the derived values can be done, for example, using industry-standard methods for the persistence of floating point numbers. For example, four (4) bytes of storage, yielding approximately six (6) significant digits, can be used for each stored value.
• the quantity of greatest interest in an assay is the concentration of the analyte under evaluation.
• This concentration can be determined by converting a computed ECL signal to a concentration. This conversion can be done, for example, by backfitting the ECL signal through a calibration curve that relates ECL signal to analyte concentration. In general, such a calibration curve can vary from assay to assay, and can change over time for a given assay as that assay is refined.
• Calibration curves enable both interpolation and extrapolation of ECL signal measurements for samples with known analyte concentrations for ECL signal measurements of samples of unknown amounts of analyte.
• the form of the mathematical functions used in a curve fit can, for example, make assumptions regarding the continuity and/or smoothness of the underlying relation such as through interpolating the measurements with functions such as piecewise constant, piecewise linear, cubic spline, or for example, by throughfitting all the data with linear, quadratic, cubic, or quartic polynomials.
• parameters can be computed by minimizing an error function such as, for example, least squares ⁇ e.g., Press et al.
• the form of the mathematical function may make assumptions about the assay mechanism, such as a one site saturation, two site saturation, one site saturation with nonspecific binding, two site saturations with nonspecific binding, a sigmoidal dose response curve with or without a variable slope, one-site competition, two-site competition, or a four-parameter logistic.
• Generation of a calibration curve entails selecting the form of the mathematical function and then fitting the parameters of the function with measurements.
• the measurements can, for example, be done on the test instrument or can be done in whole or in part elsewhere (e.g. , at the place the assay is manufactured).
• the measurements can either perfectly constrain or over-constrain the mathematical function.
• model parameters can be computed by minimizing an error function such as least squares.
• the computed model parameters can be associated with each measurement of the analyte.
• the association for each measurement can be a link to the calibration data rather than the calibration data itself.
• Instruments can be re-calibrated at any time, such as, for example, on a weekly basis or with every measurement. The quality of the calibration can also be assessed, for example, through the running of controls or by computing the residual error from an overconstrained curve fit.
• a calculated concentration can be stored by the system.
• This can be, in exemplary embodiments of the present invention, the primary input to analysis recommendation algorithms employed by the remainder of the system. It is noted that not all assays will result in a quantitative concentration. For example, some assays, due to the shape of their calibration curve, may yield two different concentrations for the same measured signal. Such assays are said to "hook.” In such cases the most an exemplary system can store is an indicator that the measured concentration is above a certain level, the lower of the two returned calculated values. Other assays, for various reasons, may return only qualitative results rather than true quantitative results. In all cases, a system database can be capable of storing and retrieving the result.
• the result of an assay can be stored not as a simple floating point number, but as a complex object which can take into account the various scenarios described above.
• Such an object can have, for example, several fields of its own.
• a compressed version of the database can, in exemplary embodiments of the present invention, consist of only the initial ID information, patient ID information, test ID information, and the calculated concentration of analyte. This is a minimal set of data which can prove productive for data mining and trending analysis, as detailed below.
• the additional data described herein can, for example, be used to enhance the value of this analysis.
• Algorithms encoded or implemented or implemented in an exemplary system can be used, for example, to determine a recommendation for action. This recommendation can be based upon a calculated concentration of, for example, antibody response. Other information can also be considered, including, for example, the results of other assays upon the same sample within a given assay panel.
• a final recommendation can be stored in the database.
• a system database can, for example, also store the "reasoning" behind the recommendation, allowing a human to later query the database to determine why a given course of action was recommended. Given that the number of recommended courses of action can be broad, these actions can be categorized and encoded. For example, a recommendation to administer a particular vaccination may be encoded with one byte to indicate "give vaccination” and two additional bytes to indicate the particular vaccination that is warranted. A field for comments can also be included, to allow the capture of the system's reasoning — in this case, an explanation of how algorithms and rules were applied to determine the stated conclusion.
• a system database can be implemented, for example, as a shared resource spread over multiple computer platforms. For purposes of trending and analysis, it may be necessary to accumulate the data from a large number of systems into a central repository as depicted in Figs. 2, or, for example, in the case of having only decentralized information, by using a mechanism or process to locate and query the distributed sources.
• the individual databases can therefore require the capability to link up with a defined central database and upload their contents. This can occur on a periodic basis, or as may be triggered by a user of the system. Additionally, there can be multiple central servers, so that a given enterprise may choose to aggregate their data at any level. Unique IDs associated with sample and panel records can serve to allow for the combination of data from disparate sources without data "collision.”
• the linkage between local databases and a central database can be implemented, for example, across a local area network (LAN), a private data network, a VPN, an intranet or across the Internet. It is also possible to link databases on a periodic basis using physical media, such as CD-ROMs.
• various users such as, for example, health care providers, individuals, insurance executives, consumers of research services, health care management personnel, etc., can access an exemplary system via a web based interface across a local area network (LAN), a private data network, a VPN, an intranet or across the Internet.
• each data record can, for example, be identified with a particular individual or patient and a particular time and date, it becomes possible to perform trending analysis of a patient' s-(or a population's) ImmunoScore profile over time.
• an individual's absolute measured value of an analyte is not as important as the trending of that value over a time.
• Some individuals may have naturally low or naturally high values which are not best measured against a statistical mean for their demographic population, but rather against that individual's own measured history.
• each patient can, for example, also be placed within certain demographic categories. It can be useful to compare a patient's measured ImmunoScore profile against the corresponding profile for the demographic groups to which he or she belongs. Deviation from the measured means for a demographic slice of the population can prove more meaningful than can a comparison to a total threshold.
• collected data can be used to continually modify the demographic profile averages known to the system, taking care to not pollute the system with outlying data points. For example, it may prove useful to produce separate ImmunoScore demographic profiles for patients who are known to have experienced vaccinations versus those for whom there is no known immunization record.
• Such an immunization record can be inferred and reconstructed, as in the provision of ImmunoScore services to national immigration services
• Trending information in a demographic profile can also be useful. For example, tracking an indication of a typical person (e.g., mean, median, or mode), or an indication of the spread amongst people (e.g., standard deviation, interquartile range, or range) over time can enable an exemplary system to assess the relationship between immune status indicia and external factors, such as, for example, seasonal effects. Eating habits, sleeping habits, time aboard ship, etc. can be found to affect immune status in groups where these external factors are partially controllable (such as, for example, in military personnel). Comparing immune status indicators of differing demographic profiles can have important epidemiological significance.
• a database system was constructed to serve as a testbed for the exercise of the business models described below.
• Such an exemplary database system was used to demonstrate the tools and techniques that might be used in a full scale system according to the present invention. Accordingly, a large data set was constructed using statistical techniques. The data was produced according to match existing knowledge about the distribution of immune response values among the general population.
• the exemplary database system has two primary components. These two components represent the algorithmically interesting sections that can be, for example, present in a full-scale operational system according to an embodiment of the present invention. Such a full system could, for example, contain other modules as well, along the lines of industry standard large scale database systems. Such an exemplary system is depicted in Fig. 5 and is next generally described.
• an exemplary system architecture can be constructed.
• the exemplary system architecture can be, for example, divided into two sub-systems, one relatively local to "point of care" or locations where the individuals or patients whose immune status is to be analyzed are located.
• the other subsystem can be in a central location where complex data mining and analysis can occur.
• an upper portion of the figure contains components which can be located at the point of care and a lower portion of the figure contains components which can be, for example, located at a system central location.
• the point of care is divided from the central location in the figure by a double dotted and dashed line for ease of identification.
• Instruments 505 which are devices which can read immunologic assays. Instruments 505 yield Assay Results 506. Assay Results 506, along with Doctor's Observations 503, Patient History 502 and Demographic Information 501 regarding the individual or patient can all be stored in Local PatientEvent Database 510. Database 510 can be , for example, an online transaction processing database. Because the point of care sub-system is generally directed to generating a recommendation in a relatively short time, there are two pathways to Diagnostic Module 515. Diagnostic Module 515 applies algorithmic rules to the assay results to determine a proper course of treatment or action based on current readings and optionally on past history.
• Diagnostic Module 515 can implement algorithms having other inputs besides the current Assay Results 506, such as, for example, Demographic Information 501, Patient History 502, and Doctor's Observations 503 (understood to include any observations by any health care provider, or the like, in a general sense) which can be stored in Local PatientEvent Database 510.
• the central location sub-system could be mirrored in a number of distributed central location subsystems, the point of care sub-system is contemplated to take data from numerous instruments and in fact have numerous local patient event databases in those locales. In short, the point of care sub-system is found wherever potential customers or patients are found. It is noted that there can be a myriad of such locations, given the various and sundry applications and business models that exemplary embodiments of the present invention contemplate.
• Central PatientEvent Database 520 can, for example, also be an online transaction processing database or OLTP. It is contemplated that this database can, for example, periodically load data to an online analytic processing database, or OLAP in the form of PatientEvent Database 530.
• PatientEvent Database 530 can be, for example, adapted to provide inputs to complicated algorithms dealing with data mining and pattern detection, as next described.
• PatientEvent Database 530 can, for example, reside on a central server and utilize a data warehouse approach. There can be a variety of connections to PatientEvent Database 530 such as, for example, a Query Module 531, a Data Mining Module 532 and a Pattern Detection Module 533.
• Query Module 531 can be, for example, an interface by which a user can interactively search for information in database 530.
• Query Module 531 can also access Central PatientEvent Database 520 implement a variety of operations on the data there as well.
• Data Mining Module 532 can be an interface by which a user can interactively use OLAP tools to finds trends and summaries in the stored data.
• Pattern Detection Module 533 can be a program module which can be used to automatically search for patterns or other "hidden" correlations between various data points in a database. It is contemplated that in exemplary embodiments of the present invention Pattern Detection Module 533 can regularly sort through all of the stored data looking for patterns using various algorithms. Some of such algorithms can, for example, articulate some hunch or a correlative assumption provided by a panel of immunological experts for which they do not have hard data. Pattern Detection Module 533 is thus an important feature in exemplary embodiments of the present invention. Additional exemplary databases which Patter Detection Module 533 can utilize are described below in connection with Fig. 5A. The exemplary system depicted in Fig.
• Diagnostic Module 515 A first module of interest is termed Diagnostic Module 515.
• the function of this software module is to input a set of assay results 506 obtained through measurements by instruments 505, and to make one or more recommendations 516 based upon the analysis of assay results 506.
• Diagnostic Module 515 can be designed in such a way that additional assay panels can be slotted into an existing system as they are developed.
• Some exemplary algorithms used to make recommendations as a function of assay results are described in more detail below, including descriptions both of algorithms used in the exemplary database as well as additional algorithms that could be implemented in various exemplary embodiments of the present invention.
• Diagnostic Module 515 can rest upon a Local Database 510 containing Assay Results 506 obtained from Instruments 505. These results are pertinent to an individual patient.
• Local Database 510 can also, for example, contain background medical history 502 for that patient, demographic information 501 pertinent to the patient, and a summary of other medical observations 503 made by medical professionals or persons fulfilling a similar function.
• Local Database 510 can also, for example, contain statistical information obtained from a larger central database, as described below.
• a second exemplary module of interest is Data Mining Module 532.
• Diagnostic Module 515 is intended for the analysis of a particular individual's data at a particular point in time
• Data Mining module 532 can, for example, look at a broader range of data collected from many individuals over a range, or interval, of time. Through analysis of this collected data a system can, for example, be used to support various business methods and other applications by deducing trends and patterns within an immunological landscape. A particular result could be fed back into the Diagnostic Module's algorithms, improving their effectiveness bv providing additional specificity with regard to an individual's background, possibly in terms of background or demographic information such as, for example, gender, racial background, geographic origin, lifestyle, economic circumstances social circumstances, or age.
• Fig. 5 While the Diagnostic Module's functionalities are primarily local in nature and patient-specific, the Data Mining Module's functionalities are primarily central, and system-wide. As noted, this structure is reflected in the division of Fig. 5 into two zones, the "Point of Care” zone, shown at the top of the figure, and the "Central Location” zone, shown at the bottom of the figure.
• Data Mining Module 532 depends upon the existence of a large central database containing records from a wide variety of individuals over a long span of time.
• the local databases described above can, for example, exist in a federated state with the central database, uploading their information on a regular basis, where this information can, for example, be integrated into the full system.
• Patterns can be detected within the data in an exemplary database which are related to demographic and other non-immunologic information such as, for example, gender, age, ethnicity, geographic origin, employment, etc. These patterns may not be obvious until large numbers of individuals are assessed, using a computer that can be by nature much more efficient, unbiased, and precise in pattern recognition.
• new correlates can, for example, can be established, and old correlates can be changed.
• a serum antibody concentration of 2 micrograms per ml should be used to represent a threshold of protection against meningococcal disease, so that anyone with less antibody would be recommended for immunization.
• this threshold value should be reduced or raised for given individuals, depending on, for example, age or ethnic background, or some other undefined parameter.
• an ethnicity evaluation could lead to the discovery of a specific biological or genetic marker.
• Hib antibodies may vary with different individuals, where the same antibody concentration may not possess the same level of bacteriocidal activity due to differences in antibody avidity.
• Hib polysaccharides were shown to be poorly immunogenic in children less than 2 years of age (Granoff DM, 1985, J Pediatr 107:330-36).
• ethnicity it has been shown from previous studies that Eskimos and Apaches are more susceptible to Hib meningitis because they possess a less effective antibody repertoire to the Hib polysaccharide capsule, based on the presence or absence of certain variable region genes used in the production of the polysaccharide-specific antibodies.
• HLA haplotypes have also been correlated with the susceptibility to certain infections, as well as the unresponsiveness to certain vaccines.
• certain HLA antigens appear to be correlated with chronic hepatitis B virus (HBV) infections and HBV vaccine nonresponsiveness.
• HBV chronic hepatitis B virus
• subpopulations can be identified, initially by ethnicity, then later by genetics, to evolve a more specific and appropriate diagnostic outcome.
• BiDilTM is an orally administered, nitric oxide-enhancing drug that was shown to have clearly different effects on blacks versus whites in clinical trials, where the "differences may be related to environmental, social, lifestyle, or genetic factors or to interactions among all of these.” (see http://www.fda.gov/fdac/features/2005/505_BiDil.html).
• data mining can, for example, be used to observe and identify these kinds of effects and correlations, and then be later used to determine the specific underlying mechanisms.
• Data mining can also be used, for example, to change or reverse previously held dogma(s) concerning long-term protection from vaccination.
• immunity resulting from the smallpox vaccine used extensively during the previous century, was originally thought to last for less than a decade.
• Recent analyses however, have shown that "more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox.” (Hammarlund E et al., 2003, Nature Medicine 9: 1131-37).
• a system similar to that depicted in Fig. 5 was built using standard software development tools and packages.
• the algorithms were encoded using the XML data description language.
• the engine for executing the algorithms was built using the Java programming language.
• An Oracle database was used for data storage and data mining querying.
• Excel spreadsheets were used for data construction and analysis. Details of the construction are given below.
• Diagnostic Module 515 forms the heart of an exemplary ImmunoScore decision system.
• the diagnostic module exists to provide relevant information and/or to suggest courses of recommended action (for various purposes, depending upon the application; see Section III below) based upon an individual's immune status, as measured by instrumentation or obtained from elsewhere, in combination with other supporting data. There are many different ways that such a determination could be made. Next described are some exemplary algorithms that were used in the example system as well as other exemplary decision support algorithms which could be implemented using the same techniques.
• One essential function of a diagnostic module can be, for example, to assist a medical or other professional in making decisions regarding which actions to take with a specific individual, making use of data regarding that person's immune status.
• an individual's immune status can be determined by conducting a panel of assays, each of which assays can produce an element of data.
• assays can produce an element of data.
• information presumed to be obtainable through such assays is summarized in Fig. 6. It should be noted that in practice some of this information may not yet be obtainable, although it is expected that assays could be developed along the lines of existing tests in order to complete this spectrum.
• a diagnostic module can make use of other information specific to the patient being examined. This information falls into two principal categories: demographic information 3 such as, for example, age and gender, and patient medical history. Most demographic information can be simply expressed in a database. Patient medical history is more problematic, although there are many existing healthcare database systems which do this adequately. The difficulty with patient medical history, however, is in devising algorithms which can make use of this qualitative data. It is expected that particular care can be taken to use algorithmic techniques which have proven adept in dealing with inconsistent or unreliable data, such as, for example, neural networks, described in greater detail below. This is due to the inherent unreliability of self-reported medical history data, along with the historic problems found in the transfer of medical records. If a system with built-in reliability checks is implemented, then it can be possible to rely more strongly upon historical data.
• the exemplary system described below can store both demographic and past medical history information for individual patients, but does not make use of these factors in performing diagnostic assessments or recommendations of courses of action.
• the algorithms implemented can easily be extended into these realms once more information becomes available.
• the output of Diagnostic Module 515 can be, for example, a series of recommendations.
• a recommendation is simply defined as any discernible bit of data which might be of interest to a medical professional, health care or life insurer, medical services analyst, researcher or other user of the present invention in determining a given course of action.
• a common recommendation could be, for example, to recommend a particular vaccination, to conclude whether the individual is in an overall sense healthy, to conclude that certain potential hypotheses need further data to be fully explored, to tag the individual as being potentially immunosenescent, or to grant a health insurance credit or debit relative to a health insurance policy or HMO membership fee.
• a recommendation not to vaccinate to reduce the over-vaccination of the populace.
• a Diagnostic Module Oan be capable of producing a set of recommendations for each analysis. For example, it might recommend that both vaccine V be administered and that the individual be retested in three weeks to monitor his or her response to such vaccine.
• an exemplary Diagnostic Module can, for example, also provide a confidence level, which is a measure of the system's support for any given conclusion. A user can take this confidence level into account when deciding upon a course of action. A course of action with a low confidence level but a high financial cost, for example, could be delayed until additional data could be gathered to more strongly support the course of action.
• a Diagnostic Module can, for example, be constructed in a manner to allow the deployment of many different algorithms within its basic shell.
• an algorithmic approach based upon perceptions was used. This approach is detailed below. Additionally described are alternative algorithmic approaches, each of which has different strengths and weaknesses. It is noted that some of these approaches are realistically infeasible until such time as large-scale data collection of immune status informatics becomes available.
• a perceptron is a simple neural network, a computer science representation based upon an analogy with the operation of human neurons. Perceptrons were invented by Frank Rosenblatt in 1957, and have been used in artificial intelligence research since that time. A perceptron is simplistic, but adequate for the computation of algorithmic diagnostic results within the exemplary system of the invention. More importantly, there is a clear progression between perceptrons and more sophisticated artificial intelligence techniques, which may be of use in more complex embodiments of the invention.
• Figs. 8 and 8 A An example of a perceptron is given in Figs. 8 and 8 A. These networks encode the decision making process for the running of a Meningococcal Diagnostic Panel, as described above. There are seventeen inputs to the algorithm, one for each of the measurements that can be taken in an exemplary meningococcal assay panel. Five inputs are for the meningococcal serogroups, seven for the complement components, and five for the genetic poymorpbisms. There are two output recommendations from this panel Rl 810 (or in Fig. 8A, R2 810) and R3 840. R1/R2 is a recommendation to vaccinate an individual with a meningococcal vaccine.
• R3 840 is a recommendation to monitor the individual on a stricter interval schedule than normal, because the individual may be more susceptible to this condition than the average individual in the populace.
• Figs. 8 and 8 A depict the same prerceptron, with different values for the various nodes upon firing.
• a serum IgG level exceeding 2.0 ug/mL for all four serogroups would be presumptive of protection in an otherwise healthy individual, i.e., an individual (i) found not deficient in serum levels of measured complement components, and (ii) having no deleterious genetic polymorphisms as indicated in the CC Test 820 and Genetic Polymorphism Test 830. There would be no immediate recommendation for meningococcal vaccination for these individuals.
• Fig. 8A is similar to Fig. 8, except that it applies a different recommend vaccination rule, R2 at 810, for a different immunological context.
• the perceptron is modified as to values, but the nodes are identical.
• CC Test or the Genetic Poly Test show the person is not normal, one of them will fire, giving a minimal total of 10 at R2. Then, all that is required is for one of the serogroups to be deficient (i.e., ⁇ 5.0 ug/ml) in order for the recommendation at R2 to evaluate to true.
• R3 - Recommend Flagging If the CC Test and the Genetic Poly Test show the person is normal, both of them will fire, giving a minimal total of 2.0. If the total is less than 2.O, R3 fires, they are not normal and the recommendation will be to flag this individual for monitoring.
• an abnormal individual can, for example, be captured in the perceptron of Fig. 8 A and can thus receive no vaccination recommendation from the perceptron of Fig. 8.
• a perceptron operates through software by simulating the "firing" of nodes based upon numerical conditions being met. As each node fires, it can contribute to the firing of other nodes, in some cases positively and in some cases in an inhibitory fashion. The network as a whole has completed execution when the rightmost nodes, representing diagnostic recommendations, have either fired or have come to rest.
• the perceptrons in the exemplary system were encoded manually based upon existing knowledge of diagnostic recommendations in use today.
• Each perceptron can be represented either graphically, as in Fig. 8, or textually, as in Fig. 9.
• Fig. 9 is thus a textual representation of the perceptron network using a language called XML, or extensible Markup Language.
• XML extensible Markup Language
• these XML files can be deployed to the diagnostic module as discrete packets.
• An exemplary Diagnostic Module connected to an instrument, or bank of instruments, could, for example, be configured with only those perceptron algorithms required for that site.
• updated versions of these algorithms could be deployed as the algorithms are improved over time in a continuous process of system learning or iteration.
• knowledge gained through use of the data mining module can be fed back into the individual diagnostic modules, thus improving the accuracy of the entire system.
• a new perceptron algorithm could then be deployed, for example, including the gender of the patient as a new input node, with a link to the vaccination recommendation node.
• a perceptron can include within it a series of weights which can, for example, correspond to the importance of each bit of evidence to the recommendation procedure. Over time these weights can be continually adjusted and redeployed to reflect increased understanding of the role of each of the immunological factors being measured.
• An exemplary system can, for example, include a combination of these approaches in order to come up with the most complete recommendation for a course of action.
• a Diagnostic Module can, for example, be configured to optimize for any one of a number of different criteria. Possible goals can include, for example, optimizing the welfare of the patient, minimizing costs for the patient related to the disease in question, minimizing overall patient healthcare costs, and minimizing life insurance costs.
• the decision algorithm used in the diagnostic module can thus vary depending on how these goals are prioritized.
• a key difference between a system according to the present invention and existing systems is the use of an individual's immune status information and associated data as inputs to the decision procedure. This allows the system to provide more tailored and individualized recommendations instead of relying upon aggregate statistical measures.
• a second key difference is the introduction of historical patient immune status and other data. It is possible, for example, that a given individual's antibody level is below some computed norm, but is in fact high in relation to that individual's past results. This might conventionally be, for example, a contraindication for vaccination, a recommendation which would not be made if the individual's immune status were only to be compared to the population standards.
• an exemplary system can either maintain a central record of the patient's immune status over time, or provide means to allow the portable storage and transfer of this historical record, perhaps under the patient's control.
• Various forms of "smartcard” or electronic storage technologies as are known could be used for this purpose.
• a second type of additional input data relates to demographic information.
• Current decision procedures do little to distinguish treatment recommendations based upon an individual's age, gender or racial background, although it is known that these factors have a considerable effect on the interpretation of immune status information.
• an exemplary system could make use of such demographic information, customizing the diagnostic algorithms to take into account observed patterns. Additional research would be required to deduce these patterns in the population as a whole in order to make reasonable modifications to the decision procedures.
• a clear successor to the perceptron approach could be to extend the system to full neural networks.
• the distinction between perceptrons and more complex neural networks is the incorporation into the latter of feedback links from later nodes to earlier nodes in the network. This not only increases the complexity of the algorithms which can be implemented, but allows for algorithms which improve over time through a learning mechanism.
• Neural networks are a well-established domain of artificial research. The primary impediment to neural networks is that they are difficult to construct by hand.
• a typical neural network is instead evolved through the use of training algorithms. These training algorithms require as input a set of training data.
• the training data could consist of immune status data from a large population of people coupled with data about the eventual onset of diseases in that population.
• neural networks could be constructed which could predict the onset of disease based upon features in an individual's immune status information.
• An advantage to using neural networks is that they could be a simple drop-in replacement to the current Diagnostic Module in terms of inputs and outputs.
• Data Mining Module 4.1 Overview
• the Data Mining Module is the large-scale component of exemplary systems according to the present invention. As noted above, while the Diagnostic Module focuses upon obtaining results specific to a particular individual, the Data Mining Module can be, for example, designed to examine trends in large data sets assembled for many individuals and with many readings per individual. This capability is necessary to support business models in which information is deduced about immune status patterns, as well as to improve the functionality of the Diagnostic Module over time.
• a 'star schema' which is a database layout optimized for online analytical processing. This is a standard concept in data mining. More information about the data storage is given below.
• the sample database was intended to represent actual immune status information which could be collected from a large population over a large span of time.
• the test measurements contained within the database are randomly generated within the constraints detailed below.
• the exemplary database contains three distinct sorts of information.
• the first block of information is individual immune status information.
• the individual is assumed to be a patient in some healthcare context.
• the schema for the patient information table is given in Fig. 12.
• the database contains information on the patient's birthdate, gender, racial background and geographic location. All of this information can potentially be used for data mining efforts related to immune status.
• the database also contains other information strictly for identification purposes, such as name and ID.
• patient information was randomly generated. Gender was split evenly, and geographic placement was divided among four test cities. Racial backgrounds were assigned to match latest U.S. census figures available.
• the second block of information is patient visit information.
• a schema for the patient visit information table is given in Fig. 13. To summarize, this information covers data that could, for example, be collected by a physician at the time of a patient's visit. There can be multiple visit information records for each patient. The majority of this information covers various symptoms present in the patient at the time of the visit.
• This information can be used within the Diagnostic Module, above, as part of an algorithm which takes into account diagnostic information other than the immune status assay results. This information can also be used in data mining to discover correlations between physical symptoms, immune status indicator levels, and subsequent onset of disease.
• the visit information section of the database is also used to store recommendations from the Diagnostic Module.
• symptomatic information was assigned randomly.
• the example Diagnostic Module did not make use of symptomatic information.
• the third block of information is the actual results of immune status assays.
• the exemplary database there are 48 distinct simulated measured quantities, although this can be expanded, for example, to any reasonable number in a straightforward manner.
• the schema for this data block is given in Fig. 14.
• assay test results are generated with care.
• the distribution of antibody levels are randomly generated based upon a log-normal distribution with an average of 50 micrograms per milliliter, as is consistent with measured antibody levels in practice. These values are used as initial baseline levels for the patients in the database. New values are then entered to simulate readings taken at set time intervals in the exemplary patients' lives, as indicated in Fig. 15. At each age, the antibody levels were perturbed using a small normal distribution, to simulate variation in the population over time. Results are biased to match the observed behavior of antibody activity in populations as they age, as shown in Fig. 16. All data in Fig. 16 is from simulated vaccinated patients.
• sample data was produced a population with interesting characteristics that could be highlighted in the data mining module. Although the exact features used may not be strictly representative of the population as a whole, they represent the type of correlation that a system such as this could detect within real patient data. It could easily be imagined, for example, that individuals of a particular racial background might naturally have elevated levels of a particular antibody. The system being described could be used to deduce that fact, which may have implications for the immunological care that such individuals would receive.
• assay results such as antibody levels, such as, for example, "Gcmp AVG” in Fig. 16, may be measured and quantified as units (U) per volume (e.g., ml), where U may be defined as some arbitrary unit of a particular assay for the purpose of relative comparisons. In addition, U may be replaced by a more precise measurement of mass, such as micrograms, where possible and appropriate.
• Antibody activity such as, for example, "Gcmp AVG” in Fig. 16, refers to the functional activity of an antibody, which may consist of, but not necessarily be restricted to, bactericidal or bacterial killing properties. In these specific examples, assay results from individuals may be processed for statistical purposes in the evaluation of a population, as in Fig.
• a database used for data mining can, for example, be accessed in three different modes, as indicated in Fig. 5.
• a first mode can be, for example, an interactive query mode.
• a user can interactively search for results in the database.
• queries might include the retrieval of a single individual's immune status over time, or the comparison of two such individuals, as shown in Fig. 19.
• Queries can be submitted, for example, using either a graphical query tool or through the use of Structured Query Language (SQL), a computer language for the querying of databases.
• SQL Structured Query Language
• An exemplary SQL query is shown in Fig. 19A. Both of these methods of access are well-known in the industry.
• a user can use the query mode via Query Module 531.
• a second exemplary mode is the use of Online Analytical Processing tools, or OLAP tools, to find patterns within the database.
• OLAP tools Online Analytical Processing tools
• a simple example of this is the production of aggregate statistics for subpopulations within the whole.
• a query for correlation coefficients to GCMP levels is restricted to female patients.
• a similar query might look at only patients from a distinct geographical area or racial background.
• Correlation statistics can also be generated, to test hypotheses about possible causal links among measured antibodies, between antibody measurements and physical symptoms, or correlations between any of these and demographic information.
• the utility of such a tool depends directly on the quantity and quality of data that is input into the system.
• a third exemplary mode that is anticipated is the construction of a pattern detection module.
• This can, for example, comprise software programmed to sift through the accumulated immune status and other data and search for patterns that might not be evident to a human observer. It is generally true that there are statistically significant patterns in the underlying data which are too subtle or too complex for simple detection schemes.
• Such an automated detection system can, for example, rely upon one or more of the artificial intelligence pattern recognition techniques as described above and in the standard literature.
• both neural networks and genetic algorithms can, for example, be used to perform this task.
• a user can use the pattern detection mode via Pattern Detection Module 533.
• Fig. 5 A illustrates an alternative exemplary system architecture to that of Fig. 5.
• Fig. 5 A has a few additions, namely, Hypothesis Database 560 and Rules Database 565.
• Hypothesis Database 560 can be used, for example, when pattern detection module 533 discovers a correlation between database variables. When that occurs, a list of such correlations san, for example, be reported to a human expert or group of experts for review. Or, for example, an intelligent system can attempt to recognize the characteristics of such a correlation and associate possible hypotheses to explain it.
• These can be generated, for example, from a Hypothesis Database 560, and the rules by which a given correlation can, for example, be mapped to one or more hypotheses can be stored, for example, in a Rules Database 565.
• an exemplary system itself can go back and mine the data to either rule out, corroborate, or confirm that there is insufficient data to either confirm or rule out, each hypothesis in the set.
• the system can recommend that further information be collected, such as, for example, via additional assay panels known to the system, lab tests, additional patient history items, etc. This process is described in greater detail below.
• Appendix A contains selections (i.e. an initial set of records) from an exemplary database which was used to illustrate various data mining functionalities according to exemplary embodiments of the present invention.
• the database was created from data obtained in interviews with and by performing tests on blood obtained from a number of newly arrived immigrants to Canada under the auspices of Dr. Chris Greenaway (Assistant Professor in the Department of Medicine, McGiIl University, and a staff physician in the Departments of Microbiology and Internal Medicine, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec).
• the database now contains, specifically, the following data:
• Region of Origin being one of:
• Country of origin being one of:
• results of the following assays could be added: Tuberculosis, Avian (H5N1) flu, Pandemic flu (not necessarily H5N1), Chronic infectious diseases other than CMV
• HTLV I Helicobacter pylori
• Lyme disease Tularemia
• Parasite infections Malaria, Strongyloides, Hantavirus, Leishmaniasis, Toxoplasmosis (particularly among pregnant women), Antibody levels to other infectious diseases currently on vaccination schedules: Hib,
• Pneumococcal conjugate vs. PS vaccines
• Meningococcal conjuggate vs. PS vaccines
• Poliovirus Poliovirus
• Traveler's vaccines Japanese encephalitis
• Cholera Yellow fever
• Military-specific vaccines Anthrax, Smallpox, Plague, Rabies; Other infectious agents not currently vaccinated for, including: Staphylococcus aureus, Moraxella catarrhalis.
• non-immunologic data can, for example, also be obtained and stored in an individual's exemplary Immunoscore database record:
• an exemplary database can contain records for various individuals from different countries and locales, being managed under various health care systems, and that various types of assays can be used to obtain assay results.
• the data stored in the database can, for example, be normalized to some database wide standard defined for each data field used in the database, or , for example, can be stored in its original form and any algorithm that seeks to access data first performs normalizing of the various records which are input to that algorithm. It is for the purposes of such normalizing that information regarding assay manufacturer, type, and curve that maps an OD or other assay raw result to IUs Qf an antibody or other measured biochemical needs, in general, to be stored in the database.
• immunologic information stored in an exemplary database can, for example, be analyzed in various ways and related to other variables in the database.
• Three useful examples of such analysis can, for example, include: (1) linear regression analysis on two variables to determine whether a positive or a negative correlation exists; (2) comparison of geometric mean immune values (obtained, for example, as antibody concentration, optical density, etc.) for both genders by geographical regions; and (3) percentage of positive or negative support within a population for one variable with respect to another. Examples of such analyses are described below using data from the CIP database.
• tables of correlation coefficients (r) can, for example, be generated when comparing one particular immunologic variable (such as, for example, varicella antibody optical density) against other disease-related immune measurements, either for both genders together or separately.
• Fig.20 presents the correlation coefficients between Varicella OD and various other variables in the CIP database.
• Fig. 20 presents three tables. The top table is the correlation of Varicella OD with each of nine other variables from the CIP database for all persons in the CIP database.
• the second and third tables present this information segregating males and females.
• r values have been highlighted by shading when they are either > 0.05 or ⁇ -0.05, as a means of readily identifying patterns of relatedness (where
• Varicella optical density is obviously highly positively correlated with Varicella titration dilution, inasmuch as one is calculated from the other, but other relationships also appear, although somewhat less pronounced. If the genders are separated, then the relationships appear even more strongly, as expected, since scatter is thus reduced. From the tables presented in Fig. 20, Measles and Mumps immunity (Dade assay) appear to be slightly correlated with Varicella immunity.
• the r values in the tables can also, for example, be graphed in such a way so as to better visualize any condition patterns, as is shown, for example, in Fig. 2OA. Again, the Measles and Mumps relationship to Varicella stands out above the others (not considering the Varicella titration dilution data, which is obviously correlated to Varicella OD).
• immune data can, for example, be statistically analyzed for the purpose of characterizing populations of different geographical regions, as well as for comparing results across genders.
• Such mean values can thus be graphically compared by gender and region to visualize population dynamics.
• the geometric means of Rubella antibody concentrations for different regions can be ⁇ graphically analyzed by gender, as shown in Fig. 2OB. With reference thereto, a trend can be seen where males have higher antibody levels than females across all populations in the database. It is also apparent that persons from Southeast Asia show a lower antibody level relative to the other regions in this study. To help facilitate this assessment, dotted lines were drawn on Fig.
• exemplary embodiments of the present invention can be directed to health insurance underwriting.
• knowledge of the fact that Southeast Asians tend to be vulnerable to Rubella would indicate that such persons, as a condition of maintaining insured status under a health plan or HMO, could be required to obtain Rubella vaccination.
• a dotted line has been drawn to represent the mean of the means (geometric) from all of the populations, excluding Southeast Asia and East Europe, but combining males and females.
• Another dotted line has been drawn to represent the mean of the means from the excluded populations, except for the Eastern European females, which are noticeably higher in units (and thus lower in antibodies).
• the arrows in Fig. 2OC highlight the differences between (i) the overall population mean of means and the mean for Southease Asians and Eastern EuroDean male*?- anA fi ⁇ fht > overall population mean of means and the unit levels for Eastern European females.
• Hep A reactivity for Southeast Asia and Eastern Europe when compared with other regions; this is especially so among East European females. This may, for example, indicate no vaccination and possibly less exposure, with greater disease susceptibility.
• an adult female from Eastern Europe should have a Hep A vaccination.
• the percentage of a population that demonstrates a positive or negative relationship for one variable with respect to another variable can, for example, be determined and graphically analyzed.
• Rubella antibody levels were measured in females from China, and the results were grouped according to immune status: immune support (protective high antibody level), low level support (equivocal antibody level), or susceptible support (non-immune antibody level).
• immune support protecting high antibody level
• low level support equivocal antibody level
• susceptible support non-immune antibody level
• immune support can also be related to other variables that do not measure immune status, such as, for example, education.
• Fig. 2OF An example of such a correlation analysis is shown in Fig. 2OF.
• the positive and negative Mumps support groups are plotted for Southeast Asia and East Europe with respect to university attendance. From these results it appears that for Southeast Asia, a higher percentage of negative Mumps immune support occurs when there is less university attendance, and in the expected reciprocal way, a higher percentage of positive Mumps immune support occurs with university attendance. For Eastern Europe, however, there is no relationship seen between Mumps immune support and university attendance.
• the data mining examples described above demonstrate the usefulness, in exemplary embodiments of the present invention, of an analysis of relationships among different variables, both immunologic and otherwise in an unbiased mathematical manner.
• Regression analysis can, for example, be performed to just look for correlations at random, but the relationships may be weak and difficult to see.
• population means can be used to detect broad population differences or similarities.
• percentage support analysis between different variables can, for example, allow for a greater focus on specific relationships between different immune status results and other factors that may affect them.
• CMV Cytomegalovirus
• Tetanus Tetanus
• Diphtheria Hepatitis A
• Hepatitis B Hepatitis B
• Fig. 20Gl represents the correlation of CMV with the other immune factors.
• highlighting (color) threshold to + or — 0.1.
• South Asia was the only region that showed no overall correlation for CMV, and males generally showed more correlations than females in other parts of the world.
• Fig. 20G2 Fig. 20G3, and Fig. 20G4

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