BFO and Disease Barry Smith Milan, September 4, 2009

1. BFO and Disease Barry Smith Milan, September 4, 2009

2. BFO A simple top-level ontology to support information integration in scientific research No abstracta Nothing propositional No overlap with domain ontologies (for society, for information, …) – built by populating downwards

3. Blinding Flash of the Obvious Continuant Occurrent (Process, Event) Independent Continuant Dependent Continuant http://ifomis.uni-saarland.de/bfo/

4. PT Particular ED Endurant PD Perdurant Q Quality AB Abstract PED Physical Endurant NPED Non-physical Endurant AS Arbitrary Sum EV Event STV Stative TQ Temporal Quality PQ Physical Quality AQ Abstract Quality … Fact Set R Region M Amount of Matter F Feature POB Physical Object … NPOB Non-physical Object ACH Achievement ACC Accomplishment ST State PRO Process TL Temporal Location … … SL Spatial Location … TR Temporal Region PR Physical Region AR Abstract Region … … … … … T Time Interval … S Space Region … APO Agentive Physical Object NAPO Non-agentive Physical Object MOB Mental Object SOB Social Object ASO Agentive Social Object NASO Non-agentive Social Object SAG Social Agent SC Society DOLCE taxonomy

5. PT Particular ED Endurant PD Perdurant Q Quality AB Abstract PED Physical Endurant NPED Non-physical Endurant AS Arbitrary Sum EV Event STV Stative TQ Temporal Quality PQ Physical Quality AQ Abstract Quality … Fact Set R Region M Amount of Matter F Feature POB Physical Object … NPOB Non-physical Object ACH Achievement ACC Accomplishment ST State PRO Process TL Temporal Location … … SL Spatial Location … TR Temporal Region PR Physical Region AR Abstract Region … … … … … T Time Interval … S Space Region … APO Agentive Physical Object NAPO Non-agentive Physical Object MOB Mental Object SOB Social Object ASO Agentive Social Object NASO Non-agentive Social Object SAG Social Agent SC Society DOLCE taxonomy

6. Example: The Cell Ontology

7. Benefits of coordination No need to reinvent the wheel Can profit from lessons learned through mistakes made by others Can more easily reuse what is made by others Can more easily inspect and criticize results of others’ work (PATO) Leads to innovations (e.g. Mireot) in strategies for combining ontologies

8. 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)

9. 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

10. 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)

11. IDO 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 – Brucilosis

12. The Open Biomedical Ontologies (OBO) Foundry

13. The OBO Foundry Initial Candidate Members • 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

14. The OBO Foundry Under development • Disease Ontology • Infectious Disease Ontology • Mammalian Phenotype Ontology • Plant Trait Ontology • Environment Ontology • Ontology for Biomedical Investigations • Behavior Ontology • RNA Ontology  

15. E N V I R O N M E N T

16. RELATION TO TIME GRANULARITY rationale of OBO Foundry coverage (homesteading principle)

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

18. BFO and the 3 Gene Ontologies (GO) Continuant Occurrent biological process Independent Continuant Dependent Continuant cell component 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

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

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

21. Their realizations execution expression exercise realization application course occurrents

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

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

24. Specific Dependence on the instance level adepends_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.

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

26. Specifically dependent continuants • the quality of whiteness of this cheese • your role as lecturer • the disposition of this patient to experience diarrhea

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

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

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

30. Specifically Dependent Continuants Specifically Dependent Continuant if the bearer ceases to exist, then its quality, function, role ceases to exist the color of my skin the function of my heart to pump blood my weight Quality, Pattern Realizable Dependent Continuant

31. Generically Dependent Continuants 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 Generically Dependent Continuant Information Object Gene Sequence

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

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

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

35. Disposition Internally-Grounded Realizable Entity 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

36. Disorder person – independent continuant objects fiat object part object aggregate

37. Disorder A fiat object part of an organism which serves as the bearer of a disposition of a certain sort This fiat object may have no determinate boundaries (compare: Downtown Santa Barbara)

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

39. Big Picture (with thanks to Richard Scheuermann)

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

41. 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

42. 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.

43. Dispositions and Predispositions • All diseases are dispositions; not all dispositions are diseases. • A predisposition is 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.

44. 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. – A 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

45. Cirrhosis - environmental exposure • 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 • 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

46. But the disorder also induces normal physiological processes (immune response) that can results in the elimination of the disorder (transient disease course). Influenza - infectious • 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 • 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

47. Huntington’s Disease - genetic • 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 • 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

48. 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)

49. 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.

50. 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.