2. Building a Suite of Biomedical Ontologies Barry Smith 1

3. Problems with UMLS-style approaches let a million ontologies bloom, each one close to the terminological habits of its authors in concordance with the “not invented here” syndrome then map these ontologies, and use these mappings to integrate your different pots of data 2

4. Mappings are hard They create an N 2 problem; are fragile, and expensive to maintain Need new authorities to maintain(one for each pair of mapped ontologies), yielding new risk of forking – who will police the mappings? The goal should be to minimize the need for mappings, by avoiding redundancy in the first place – one ontology for each domain Invest resources in disjoint ontology modules which work well together – reduce need for mappings to minimum possible 3

5. How to do it right? how create an incremental, evolutionary process, where what is good survives, and what is bad fails where the number of ontologies needing to be used together is small – integration = addition where these ontologies are stable by creating a scenario in which people will find it profitable to reuse ontologies, terminologies and coding systems which have been tried and tested 4

6. Modularity modularity ensures annotations can be additive division of labor amongst domain experts high value of training in any given module lessons learned in one module can benefit work on other modules incentivization of those responsible for individual modules 5

7. Reasons why GO has been successful It is a system for prospective standardization built with coherent top level but with content contributed and monitored by domain specialists Based on community consensus Updated every night Clear versioning principles ensure backwards compatibility; prior annotations do not lose their value Initially low-tech to encourage users, with movement to more powerful formal approaches (including OWL-DL – though still proceeding caution) 6

8. GO has learned the lessons of successful cooperation Clear documentation The terms chosen are already familiar Fully open source (allows thorough testing in manifold combinations with other ontologies) Subjected to considerable third-party critique Tracker for user input and help desk with rapid turnaround 7

9. GO has been amazingly successful in overcoming the data balkanization problem but it covers only generic biological entities of three sorts: – cellular components – molecular functions – biological processes no diseases, symptoms, disease biomarkers, protein interactions, experimental processes … 8

10. How create a disease ontology? One option: a flat list One option: template approach – Cancer – Infectious Disease – Diabetes – Autoimmune Disease To make this work: think very hard about what a disease is 9

11. Aristotelian definitions To define a term ‘A’ in an ontology identify the parent term ‘B’ and start your definition: An A is a B which … Cs …. A = species B = genus C = differentia 10

12. Cancer disease is a disease which … Genetic disease is a disease which … Infectious disease is a disease which … 11

13. Information Artifact Ontology (IAO) Ontology for Biomedical Investigations (OBI) Ontology of General Medical Science (OGMS) Basic Formal Ontology (BFO) 12

14. Anatomy Ontology (FMA*, CARO) Environment Ontology (EnvO) Infectious Disease Ontology (IDO*) Biological Process Ontology (GO*) Cell Ontology (CL) Cellular Component Ontology (FMA*, GO*) Phenotypic Quality Ontology (PaTO) Subcellular Anatomy Ontology (SAO) Sequence Ontology (SO*) Molecular Function (GO*) Protein Ontology (PRO*) OBO Foundry Modular Organization top level mid-level domain level Information Artifact Ontology (IAO) Ontology for Biomedical Investigations (OBI) Ontology of General Medical Science (OGMS) Basic Formal Ontology (BFO) 13

15. Ontology for General Medical Science http://code.google.com/p/ogms/ (OBO) http://purl.obolibrary.org/obo/ogms.obo (OWL) http://purl.obolibrary.org/obo/ogms.owl 14

16. OGMS-based initiatives Vital Signs Ontology (VSO) EHR / Demographics Ontology Infectious Disease Ontology (IDO) Psychology Ontology (PSY) Emotion Ontology (PSY-EM) … Genetic Disease Ontology Cancer Ontology 15

17. BFO: the very top Continuant Occurrent (Process, Event) Independent Continuant Dependent Continuant 16

18. 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) 17

19. BFO & GO continuant occurrent biological processes independent continuant cellular component dependent continuant molecular function 18

20. Basic Formal Ontology Continuant Occurrent process, event Independent Continuant thing Dependent Continuant quality................ types instances 19

21. Experience with BFO in building ontologies provides a community of skilled ontology developers and users (user group has 120 members) associated logical tools documentation for different types of users a methodology for building conformant ontologies by starting with BFO and populating downwards 20

22. Example: The Cell Ontology

23. How to build an ontology import BFO into ontology editor such as Protégé work with domain experts to create an initial mid- level classification find ~50 most commonly used terms corresponding to types in reality arrange these terms into an informal is_a hierarchy according to this universality principle A is_a B  every instance of A is an instance of B fill in missing terms to give a complete hierarchy (leave it to domain experts to populate the lower levels of the hierarchy) 22

24. Basic Formal Ontology continuant occurrent independent continuant dependent continuant organism 23

25. Continuants continue to exist through time, preserving their identity while undergoing different sorts of changes independent continuants – objects, things,... dependent continuants – qualities, attributes, shapes, potentialities... 24

26. Occurrents processes, events, happenings –your life –this process of accelerated cell division 25

27. Qualities temperature blood pressure mass... are continuants they exist through time while undergoing changes 26

28. Qualities temperature / blood pressure / mass... are dimensions of variation within the structure of the entity a quality is something which can change while its bearer remains one and the same 27

29. A Chart representing how John’s temperature changes 28

30. A Chart representing how John’s temperature changes 29

31. John’s temperature, the temperature he has throughout his entire life, cycles through different determinate temperatures from one time to the next John’s temperature in thus changing, exerts an influence on other dimensions of variation in the physiology of the organism through time 30

32. BFO: The Very Top continuant independent continuant dependent continuant quality occurrent temperature 31

33. Blinding Flash of the Obvious independent continuant dependent continuant quality temperature types instances organism John John’s temperature 32

34. Blinding Flash of the Obvious independent continuant dependent continuant quality temperature types instances organism John John’s temperature 33

35. Blinding Flash of the Obvious temperature types instances organism John John’s temperature. inheres_in 34

36. temperature types instances John’s temperature 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 35

37. human types instances John 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 36

38. whole plant continuants occurrents 37 zygote pro- embryo mature whole plant globular embryo bilateral embryo... becomes reproductively able fertili- zation first cell division

39. child transformation_of fetus 38

40. Temperature subtypes Development-stage subtypes are threshold divisions (hence we do not have sharp boundaries, and we have a certain degree of choice, e.g. in how many subtypes to distinguish, though not in their ordering) 39

41. independent continuant dependent continuant quality temperature types instances organism John John’s temperature 40

42. independent continuant dependent continuant quality temperature organism John John’s temperature occurrent process course of temperature changes John’s temperature history 41

43. independent continuant dependent continuant quality temperature organism John John’s temperature occurrent process life of an organism John’s life 42

44. BFO: The Very Top continuantoccurrent independent continuant dependent continuant qualitydisposition 43

45. BFO: The Very Top continuant independent continuant dependent continuant quality function role disposition occurrent 44

46. disposition - of a glass vase, to shatter if dropped - of a human, to eat - of a banana, to ripen - of John, to lose hair 45

47. disposition if it ceases to exist, then its bearer and/or its immediate surrounding environment is physically changed its realization occurs when its bearer is in some special physical circumstances its realization is what it is in virtue of the bearer’s physical make-up 46

48. function - of liver: to store glycogen - of birth canal: to enable transport - of eye: to see - of mitochondrion: to produce ATP not optional; reflection of physical makeup of bearer; subtype of disposition 47

49. independent continuant dependent continuant function to see eye John’s eye function of John’s eye: to see occurrent process process of seeing John seeing 48

50. OGMS Ontology for General Medical Science http://code.google.com/p/ogms 49

51. Physical Disorder 50

52. :. Physical Disorder – independent continuant fiat object part A causally linked combination of physical components of the extended organism that is clinically abnormal. 51

53. Clinically abnormal –(1) not part of the life plan for an organism of the relevant type (unlike aging or pregnancy), –(2) causally linked to an elevated risk either of pain or other feelings of illness, or of death or dysfunction, and –(3) such that the elevated risk exceeds a certain threshold level.* *Compare: baldness 52

54. Big Picture 53

55. Pathological Process =def. A bodily process that is a manifestation of a disorder and is clinically abnormal. Disease =def. – A disposition to undergo pathological processes that exists in an organism because of one or more disorders in that organism. 54

56. 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, enlarged spleen 55

57. Dispositions and Predispositions All diseases are dispositions; not all dispositions are diseases. Predisposition to Disease =def. – A disposition in an organism that constitutes an increased risk of the organism’s subsequently developing some disease. 56

58. 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) 57

59. Huntington’s Disease – genetic 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 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 58

60. 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 59

61. 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 - headaches, dizziness 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 60

62. 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 61

63. 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 62

64. 63

65. Disease vs. Disease course Disease =def. – A disposition to undergo pathological processes that exists in an organism because of one or more disorders in that organism. Disease course =def. – The aggregate of processes in which a disease disposition is realized. 64

66. coronary heart disease John’s coronary heart disease disease associated with asymptomatic (‘silent’) infarction disease associated with early lesions and small fibrous plaques stable angina disease associated with 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 65

67. independent continuant dependent continuant disposition disease disorder John’s disordered heart John’s coronary heart disease occurrent process course of disease course of John’s disease 66

68. OGMSIDO Independent Continuant Disorder Infectious disorder Dependent Continuant Disease Predisposition to disease Infectious disease Protective resistance OccurrentDisease course Infectious disease course Examples of ontology terms

69. IDO (Infectious Disease Ontology) Core Follows GO strategy of providing a canonical ontology of what is involved in every infectious disease – host, pathogen, vector, virulence, vaccine, transmission – accompanied by IDO Extensions for specific diseases, pathogens and vectors Provides common terminology resources and tested common guidelines for a vast array of different disease communities 68

70. 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 Cleveland Clinic – Infective Endocarditis University of Michigan – Brucellosis Duke University, University at Buffalo – HIV 69

71. 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 70

72. Influenza – disease course 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 71 The disorder also induces normal physiological processes (immune response) that can results in the elimination of the disorder (transient disease course).

73. Big Picture 72