1. Towards an Ontological Treatment of Disease and Diagnosis Barry Smith New York State Center of Excellence in Bioinformatics and Life Sciences University at Buffalo http://ontology.buffalo.edu/smith 1

2. Anders Grimsmo, “Patients, diagnoses and processes in general practice in the Nordic countries. An attempt to make data from computerised medical records available for comparable statistics” Scandinavian Journal of Primary Health Care, 2001  “The major obstacle to extracting more epidemiological data from computerised medical records is caused by information in the databases not being uniquely linked to episodes of care.” http://ontology.buffalo.edu/smith 2

3. What is to be linked with what? What is information in the databases about? To answer this question (to assign numbers to discrete entities), we need a good ontology of the care domain, including episodes of care on the one hand and entities on the side of the patient on the other. http://ontology.buffalo.edu/smith 3

4. and we need to take account of context – of multiple diseases – of the patient’s style of life – of the patient’s environment – of specific aspects of the presentation http://ontology.buffalo.edu/smith 4

5. we do this by paying attention to natural language but the more we succeed in this, the more difficult it is to aggregate the data disease of UMLSitis http://ontology.buffalo.edu/smith 5

6. New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U 6

7. New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U 7

8. New York State Center of Excellence in Bioinformatics & Life Sciences R T U New York State Center of Excellence in Bioinformatics & Life Sciences R T U OBO Foundry 8

9. 9

10. 10 with acknowledgements to NLM: 1R21LM009824-01A1 Confusion of disease with diagnosis

11. 11 with acknowledgements to NLM: 1R21LM009824-01A1 Buffalo Longitudinal Cancer Data Even with the best of intentions, and even if we just use one coding system, results are not always what they seem Problem of SNOMEDitis

12. Why does SNOMED change so much? 12

13. 13 with acknowledgements to NLM: 1R21LM009824-01A1 SNOMED CT: Anaplasma marginale (organism)

14. 14 infectious agent is_a navigational concept with acknowledgements to Werner Ceusters NLM: 1R21LM009824-01A1

15. 15 infectious agent is_a navigational concept

16. 16 with acknowledgements to NLM: 1R21LM009824-01A1

17. 17 with acknowledgements to NLM: 1R21LM009824-01A1

18. 18 with acknowledgements to NLM: 1R21LM009824-01A1

19. 19 with acknowledgements to NLM: 1R21LM009824-01A1

20. 20

21. Why does SNOMED change so much? Problems with ‘concept’  no real coherence as to what SNOMED is representing 21

22. Why does SNOMED change so much? No proper hierarchy (of more and less general) Confusion of disorders (continuants) with etiological and diagnostic processes (occurrents) and of both with information entities (‘findings’) Confusion of ‘disorders’ with ‘morphological abnormalities’ 22

23. SNOMED CT 128477000 Abscess (disorder) 44132006 Abscess (morphologic abnormality) 23

24. Epistemology and Time (from Bill Hogan) According to SNOMED-CT User Guide (p. 42): Concepts in [the Clinical Finding] hierarchy represent the result of a clinical observation, assessment, or judgment, and include both normal and abnormal clinical states. So, does a date/time associated with a ‘finding’ refer to: –Date/time that the observation, assessment, or judgment occurred and thus the result was obtained –Date/time that the entity (that was found) began to exist –Date/time that entity (that was found) began to manifest in symptoms, signs, etc.

25. Epistemology and Combinatorial Explosion Epistaxis/nosebleed –Epistaxis (disorder) –Nosebleed/epistaxis symptom (finding) –On examination - epistaxis (disorder) –Has nosebleeds - epistaxis (disorder) –Evidence of recent epistaxis (finding) from Bill Hogan

26. Epistemology and Combinatorial Explosion Rash –Cutaneous eruption (morphologic abnormality), with synonym Rash –Eruption of skin (disorder), with synonym Rash –Complaining of a rash (finding) –On examination - a rash (finding) Dry skin –Dry skin (finding) –Complaining of dry skin (finding) –On examination - dry skin (finding) –Dry skin dermatitis (disorder) from Bill Hogan

27. Similar problems with HL7 with UMLS with ICD 10, 11 with ICPC ? 27

28. 28

29. 29

30. An Alternative: Basic Formal Ontology  360 BC: Aristotle’s Metaphysics  1879: Invention of modern logic (Boole, Frege)  1920:The problem of the Unity of Science (Logical Positivism)  1940Birth of computing (Turing) http://ontology.buffalo.edu/smith 30

31. Ontology Timeline  1970: AI, Robotics (J. McCarthy, P. Hayes)  1980:KIF: Knowledge Interchange Format  1990: Description Logics  2000: Semantic Web (OWL), Protégé  2007: National Center for Biomedical Ontology (NCBO) Bioportal http://ontology.buffalo.edu/smith 31

32. Uses of ‘ontology’ in PubMed abstracts 32

33. Biomedical Ontology in PubMed

34. By far the most successful: GO (Gene Ontology) 34

35. Ontology Timeline  1990: Human Genome Project  1999: The Gene Ontology (GO) – Model Organism Research  2005: The Open Biomedical Ontologies (OBO) Foundry  2010: Ontology for General Medical Science http://ontology.buffalo.edu/smith 35

36. The GO is a controlled vocabulary for use in annotating data  multi-species, multi-disciplinary, open source  contributing to the cumulativity of scientific results obtained by distinct research communities  compare use of kilograms, meters, seconds … in formulating experimental results 36

37. NIH Mandates for Data Sharing Organizations such as the NIH now require use of common standards in a way that will ensure that the results obtained through funded research are more easily accessible to external groups. ODR will be created in such a way that its use will address the new NIH mandates. It will designed also to allow information presented in its terms to be usable in satisfying other regulatory purposes—such as submissions to FDA. http://ontology.buffalo.edu/smith 37

38. GO provides answers to three types of questions: for each gene product (protein...)  in what parts of the cell has it been identified? Cell Constituent Ontology  exercising what types of molecular functions? Molecular Function Ontology  with what types of biological processes? Biological Process Ontology 38

39. 39

40. 40

41. = part_of = subtype_of Gene Product Associations 41

42. $100 mill. invested in literature curation using GO  over 11 million annotations relating gene products described in the UniProt, Ensembl and other databases to terms in the GO  ontologies provide the basis for capturing biological theories in computable form  in contrast to terminologies and thesauri – which focus on socially diverse uses of language – the GO method focuses on commonly shared results of basic biological science 42

43. A new kind of biological research based on analysis and comparison of the massive quantities of annotations linking ontology terms to raw data, including genomic data, clinical data, public health data What 10 years ago took multiple groups of researchers months of data comparison effort, can now be performed in milliseconds 43

45. The GO covers only generic (‘normal’) biological entities of three sorts: – cellular components – molecular functions – biological processes It does not provide representations of diseases, symptoms, genetic abnormalities … How to extend the GO methodology to other domains of biology and medicine? 45

46. RELATION TO TIME GRANULARITY CONTINUANTOCCURRENT INDEPENDENTDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Biological Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function (GO) MOLECULE Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Molecular Process (GO) The Open Biomedical Ontologies (OBO) Foundry 46

47. all follow the same principles to ensure interoperability – GO Gene Ontology – ChEBI Chemical Ontology – PRO Protein Ontology – CL Cell Ontology –... – OGMS Ontology for General Medical Science OBO Foundry ontologies 47

48. Basic Formal Ontology: GO at a high level http://ontology.buffalo.edu/smith 48

49. Basic Formal Ontology (BFO) A simple top-level ontology to support information integration in scientific research No abstracta Nothing propositional Clear hierarchy No overlap with domain ontologies No confusion of ontology with epistemology No confusion of terms with what terms represent in reality 49

50. Basic Formal Ontology Continuant Occurrent (Process, Event) Independent Continuant Dependent Continuant http://ifomis.uni-saarland.de/bfo/ 50

51. BFO and the 3 Gene Ontologies (GO) Continuant Occurrent Independent Continuant Dependent Continuant Cell Component Biological Process Molecular Function Kumar A., Smith B, Borgelt C. Dependence relationships between Gene Ontology terms based on TIGR gene product annotations. CompuTerm 2004, 31-38. Bada M, Hunter L. Enrichment of OBO Ontologies. J Biomed Inform. 2006 Jul 26 51

52. Benefits of coordination No need to reinvent the wheel Can profit from lessons learned through mistakes and through criticism Can more easily reuse what is made by others Modular organization and incremental testing 52

53. Users of BFO NCI BiomedGT SNOMED CT Ontology for General Medical Science (OGMS) ACGT Clinical Genomics Trials on Cancer – Master Ontology / Formbuilder (Case Report Forms for Cancer Clinical Trials) 53

54. Users of BFO MediCognos / Microsoft Healthvault Cleveland Clinic Semantic Database in Cardiothoracic Surgery Major Histocompatibility Complex (MHC) Ontology (NIAID) Neuroscience Information Framework Standard (NIFSTD) and Constituent Ontologies 54

55. Users of BFO Interdisciplinary Prostate Ontology (IPO) Nanoparticle Ontology (NPO): Ontology for Cancer Nanotechnology Research Neural Electromagnetic Ontologies (NEMO) ChemAxiom – Ontology for Chemistry Ontology for Risks Against Patient Safety (RAPS/REMINE) (EU FP7) IDO Infectious Disease Ontology (NIAID) 55

56. Infectious Disease Ontology Consortium MITRE, Mount Sinai, UTSouthwestern – Influenza IMBB/VectorBase – Vector borne diseases (A. gambiae, A. aegypti, I. scapularis, C. pipiens, P. humanus) Colorado State University – Dengue Fever Duke University – Tuberculosis, Staph. aureus Case Western Reserve – Infective Endocarditis University of Michigan – Brucellosis 56

57. GO Gene Ontology CL Cell Ontology SO Sequence Ontology ChEBI Chemical Ontology PATO Phenotype (Quality) Ontology FMA Foundational Model of Anatomy ChEBI Chemical Entities of Biological Interest CARO Common Anatomy Reference Ontology PRO Protein Ontology Infectious Disease Ontology Plant Ontology Environment Ontology Ontology for Biomedical Investigations RNA Ontology The OBO Foundry 57

58. RELATION TO TIME GRANULARITY CONTINUANTOCCURRENT INDEPENDENTDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Biological Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function (GO) MOLECULE Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Molecular Process (GO) The Open Biomedical Ontologies (OBO) Foundry 58

59. CONTINUANTOCCURRENT INDEPENDENTDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Organism-Level Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function (GO) Cellular Process (GO) MOLECULE Molecule (ChEBI, SO, RNAO, PRO) Molecular Function (GO) Molecular Process (GO) rationale of OBO Foundry coverage (homesteading principle) GRANULARITY RELATION TO TIME 59

60. OBO Foundry organized in terms of Basic Formal Ontology Methodology of downward population Each Foundry ontology can be seen as an extension of a single upper level ontology (BFO) 60

61. Example: The Cell Ontology

62. Ontology for General Medical Science BFO-based ontology for clinical medicine Continuant Occurrent Independent Continuant Dependent Continuant Anatomical Component + Disorder Pathological Process + Clinical Encounter Disease + Bodily Quality 62

63. Continuant Independent Continuant Dependent Continuant.......... QualityDisposition 63

64. Realizable dependent continuants plan function role disposition capability tendency continuants 64

65. Their realizations execution expression exercise realization application course occurrents 65

66. Continuant Independent Continuant Dependent Continuant.......... Non-realizable Dependent Continuant (quality) Realizable Dependent Continuant (function, role, disposition) 66

67. realization depends_on realizable Continuant Occurrent Independent Continuant bearer Dependent Continuant disposition................ 67 Process of realization

68. Specific Dependence on the instance level a depends_on b =def. a is necessarily such that if b ceases to exist than a ceases to exist on the type level A specifically_depends_on B =def. for every instance a of A, there is some instance b of B such that a depends_on b. 68

69. depends_on Continuant Occurrent process, event Independent Continuant thing Dependent Continuant quality................ temperature depends on bearer 69

70. this particular case of redness (of a particular fly eye) the universal red instantiates an instance of eye (in a particular fly) the universal eye instantiates depends_on 70

71. the particular case of redness (of a particular fly eye) red instantiates an instance of an eye (in a particular fly) eye instantiates depends on coloranatomical structure is_a 71

72. portion of water this portion of H 2 0 72 portion of ice portion of liquid water portion of gas instantiates at t 1 instantiates at t 2 instantiates at t 3 Phase transitions

73. human John (exists continuously) 73 embryofetusadultneonateinfantchild instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 instantiates at t 6 in nature, no sharp boundaries here

74. temperature John’s temperature (exists continuously) 74 37ºC37.1ºC37.5ºC37.2ºC37.3ºC37.4ºC instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 instantiates at t 6 in nature, no sharp boundaries here

75. coronary heart disease John’s coronary heart disease (exists continuously) 75 asymptomatic (‘silent’) infarction early lesions and small fibrous plaques stable angina surface disruption of plaque unstable angina instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 time

76. OGMS Ontology for General Medical Science http://code.google.com/p/ogms/ 76

77. OGMS: The Big Picture 77

78. depends_on Continuant Occurrent process Independent Continuant thing Dependent Continuant quality................ temperature depends on bearer 78

79. Generically Dependent Continuants Generically Dependent Continuant Information Object Gene Sequence if one bearer ceases to exist, then the entity can survive, because there are other bearers (copyability) the pdf file on my laptop the DNA (sequence) in this chromosome 79

80. Continuant Occurrent Independent Continuant Specifically Dependent Continuant Quality Disposition Functioning Function Generically Dependent Continuant Realizable Role Information Artifact Sequence…

81. 81

82. Realizable dependent continuants Role: nurse role, pathogen role, food role Disposition: fragility, virulence, susceptibility, genetic disposition to disease X Function: to pump (of the heart), to unlock (of the key) 82

83. Role (Externally-Grounded Realizable Entity) role =def. a realizable entity which exists because the bearer is in some special physical, social, or institutional set of circumstances in which the bearer does not have to be, and is not such that, if it ceases to exist, then the physical make-up of the bearer is thereby changed. 83

84. Disposition (Internally-Grounded Realizable Entity) disposition =def. a realizable entity which if it ceases to exist, then its bearer is physically changed, and whose realization occurs when this bearer is in some special physical circumstances, in virtue of the bearer’s physical make-up 84

85. Function (A Disposition Designed or Selected For) function =def. a disposition that exists in virtue of the bearer’s physical make-up,, and this physical make-up is something the bearer possesses because it came into being, either through evolution (in the case of natural biological entities) or through intentional design (in the case of artifacts), in order to realize processes of a certain kind. 85

86. Four distinct classificatory tasks 1.of people (patients, carriers, …) 2.of diseases (cases, instances, problems, …) 3.of courses of disease (symptoms, treatments…) 4.of representations (records, observations, data, diagnoses…) ICD confuses 1. & 2. HL7, most standard terminologies, confuse 2. and 4 86

87. Four distinct BFO categories 1.person (patient, carrier, …) – independent continuant 2.disease (case, instance, problem, …) – specifically dependent continuant 3.course of disease (symptom, treatment…) – occurrent 4.representation (record, datum, diagnosis…) – generically dependent continuant 87

88. Four distinct BFO categories 1.people (patients, carriers, …) – independent continuants 2.disease (case, instance, problem, condition …) – disposition 3.course of disease (symptom, episode, outbreak …) – realization of dispositions 4.representations (records, data, diagnoses…) – generically dependent continuants 88

89. Disposition (potentiality) A disposition is a realizable entity which is such that, if it ceases to exist, then its bearer is physically changed, whose realization occurs, in virtue of the bearer’s physical make-up, when this bearer is in some special physical circumstances 89

90. Disorder independent continuant that is part of an organism that deviates from the canonical anatomy of the organism in a way that gives rise to pathological processes 90

91. Disorder serves as the bearer of a disposition to pathological processes A part of the body that typically gets larger over time 91

92. Disease course the totality of all disease processes through which a given disease instance is realized. multiple disease courses will be associated with the same disorder type, for example in reflection of the presence or absence of pharmaceutical or other interventions, of differences in environmental influence, and so forth.

93. Where does Mount Everest begin and end? Cf. Barry Smith and David M. Mark, “Do Mountains Exist?”, Environment and Planning B, 30, 2003. 93

94. The Big Picture 94

95. A disease is a disposition rooted in a physical disorder in the organism and realized in pathological processes. etiological process produces disorder bears disposition realized_in pathological process produces abnormal bodily features recognized_as signs & symptomsinterpretive process produces diagnosis used_in 95

96. Elucidation of Primitive Terms ‘bodily feature’ - an abbreviation for a physical component, a bodily quality, or a bodily process. disposition - an attribute describing the propensity to initiate certain specific sorts of processes when certain conditions are satisfied. clinically abnormal - some bodily feature that (1) is not part of the life plan for an organism of the relevant type (unlike aging or pregnancy), (2) is causally linked to an elevated risk either of pain or other feelings of illness, or of death or dysfunction, and (3) is such that the elevated risk exceeds a certain threshold level.* *Compare: baldness 96

97. Definitions - Foundational Terms Disorder =def. – A causally linked combination of physical components that is clinically abnormal. Pathological Process =def. – A bodily process that is a manifestation of a disorder and is clinically abnormal. Disease =def. – A disposition (i) to undergo pathological processes that (ii) exists in an organism because of one or more disorders in that organism. 97

98. Influenza - infectious Etiological process - infection of airway epithelial cells with influenza virus produces Disorder - viable cells with influenza virus bears Disposition (disease) - flu realized_in Pathological process - acute inflammation produces Abnormal bodily features recognized_as Symptoms - weakness, dizziness Signs - fever Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out influenza suggests Laboratory tests produces Test results - elevated serum antibody titers used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease flu But the disorder also induces normal physiological processes (immune response) that can results in the elimination of the disorder (transient disease course). 98

99. Huntington’s Disease - genetic Etiological process - inheritance of >39 CAG repeats in the HTT gene produces Disorder - chromosome 4 with abnormal mHTT bears Disposition (disease) - Huntington’s disease realized_in Pathological process - accumulation of mHTT protein fragments, abnormal transcription regulation, neuronal cell death in striatum produces Abnormal bodily features recognized_as Symptoms - anxiety, depression Signs - difficulties in speaking and swallowing Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out Huntington’s suggests Laboratory tests produces Test results - molecular detection of the HTT gene with >39CAG repeats used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease Huntington’s disease 99

100. HNPCC - genetic pre-disposition Etiological process - inheritance of a mutant mismatch repair gene produces Disorder - chromosome 3 with abnormal hMLH1 bears Disposition (disease) - Lynch syndrome realized_in Pathological process - abnormal repair of DNA mismatches produces Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2) bears Disposition (disease) - non-polyposis colon cancer realized in Symptoms (including pain) 100

101. Dispositions and Predispositions All diseases are dispositions; not all dispositions are diseases. A predisposition is a disposition to acquire a disposition. Predisposition to Disease of Type X =def. – A disposition in an organism that constitutes an increased risk of the organism’s subsequently developing the disease X. HNPCC is caused by a disorder (mutation) in a DNA mismatch repair gene that disposes to the acquisition of additional mutations from defective DNA repair processes, and thus is a predisposition to the development of colon cancer. 101

102. Cirrhosis - environmental exposure Etiological process - phenobarbitol- induced hepatic cell death – produces Disorder - necrotic liver – bears Disposition (disease) - cirrhosis – realized_in Pathological process - abnormal tissue repair with cell proliferation and fibrosis that exceed a certain threshold; hypoxia-induced cell death – produces Abnormal bodily features – recognized_as Symptoms - fatigue, anorexia Signs - jaundice, splenomegaly Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out cirrhosis suggests Laboratory tests produces Test results - elevated liver enzymes in serum used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease cirrhosis

103. Systemic arterial hypertension Etiological process – abnormal reabsorption of NaCl by the kidney – produces Disorder – abnormally large scattered molecular aggregate of salt in the blood – bears Disposition (disease) - hypertension – realized_in Pathological process – exertion of abnormal pressure against arterial wall – produces Abnormal bodily features – recognized_as Symptoms - Signs – elevated blood pressure Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out hypertension suggests Laboratory tests produces Test results - used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease hypertension

104. Type 2 Diabetes Mellitus Etiological process – – produces Disorder – abnormal pancreatic beta cells and abnormal muscle/fat cells – bears Disposition (disease) – diabetes mellitus – realized_in Pathological processes – diminished insulin production, diminished muscle/fat uptake of glucose – produces Abnormal bodily features – recognized_as Symptoms – polydipsia, polyuria, polyphagia, blurred vision Signs – elevated blood glucose and hemoglobin A1c Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out diabetes mellitus suggests Laboratory tests – fasting serum blood glucose, oral glucose challenge test, and/or blood hemoglobin A1c produces Test results - used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease type 2 diabetes mellitus

105. Type 1 hypersensitivity to penicillin Etiological process – sensitizing of mast cells and basophils during exposure to penicillin-class substance – produces Disorder – mast cells and basophils with epitope-specific IgE bound to Fc epsilon receptor I – bears Disposition (disease) – type I hypersensitivity – realized_in Pathological process – type I hypersensitivity reaction – produces Abnormal bodily features – recognized_as Symptoms – pruritis, shortness of breath Signs – rash, urticaria, anaphylaxis Symptoms & Signs used_in Interpretive process produces Hypothesis - suggests Laboratory tests – produces Test results – occasionally, skin testing used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease type 1 hypersensitivity to penicillin

106. Next steps in OGMS classification of distinct types of disease courses for instances of each disease type –in different typical environments –with and without treatment –with treatment plan that is or is not realized by the patient –where the disease exists in combination with other diseases

107. Next steps in OGMS modify the Big Picture to take account of differences between primary care and specialist care

108. The Big Picture 108

109. Definitions - Clinical Evaluation Terms Sign =def. – A bodily feature of a patient that is observed in a physical examination and is deemed by the clinician to be of clinical significance. (Objectively observable features) Symptom =def. – An experienced bodily feature of a patient that is observed by and observable only by the patient and is of the type that can be hypothesized by a patient to be a realization of a disease. (A restricted family of phenomena including pain, nausea, anger, drowsiness, which are of their nature experienced in the first person) Symptoms are subjective. But this does not mean that there is no objective fact of the matter whether a given symptom exists 109

110. Definition: Etiology Etiological Process =def. – A process in an organism that leads to a subsequent disorder. Example: toxic chemical exposure resulting in a mutation in the genomic DNA of a cell; infection of a human with a pathogenic virus; inheritance of two defective copies of a metabolic gene The etiological process creates the physical basis of that disposition to pathological processes which is the disease. 110

111. Definitions - Diagnosis Clinical Picture =def. – A representation of a clinical phenotype that is inferred from the combination of laboratory, image and clinical findings about a given patient. Diagnosis =def. – A conclusion of an interpretive process that has as input a clinical picture of a given patient and as output an assertion to the effect that the patient has a disease of such and such a type. 111

112. Definitions - Qualities Manifestation of a Disease =def. – A bodily feature of a patient that is (a) a deviation from clinical normality that exists in virtue of the realization of a disease and (b) is observable. Observability includes observable through elicitation of response or through the use of special instruments. Preclinical Manifestation of a Disease =def. – A manifestation of a disease that exists prior to its becoming detectable in a clinical history taking or physical examination. Clinical Manifestation of a Disease =def. – A manifestation of a disease that is detectable in a clinical history taking or physical examination. Phenotype =def. – A (combination of) bodily feature(s) of an organism determined by the interaction of its genetic make-up and environment. Clinical Phenotype =def. – A clinically abnormal phenotype. 112

113. For an ontology to succeed,  potential users should be incentivized to use it,  it should be populated using the terms that they need and using definitions that conform to their understanding of these terms  it should be easily correctable in light of new research discoveries  it should enable the data annotated in its terms to be easily integrated with legacy data from related fields  it should be easily extendable to new kinds of data. http://ontology.buffalo.edu/smith 113

114. A new kind of Electronic Health Record resting on the use of the same (public domain) ontologies in mapping proprietary EHR vocabularies to yield patient data annotated in consistent ways that support 114  integrated care and continuity of care  comparison and integration for diagnosis and meta-analysis  secondary uses for research