Prof. Werner CEUSTERS, MD

1. VUB Leerstoel 2009-2010Theme: Ontology for Ontologies, theory and applicationsOntologies in healthcare and the vision of personalized medicineMay 19, 2010; 17h00-19h00Vrije Universiteit Brussel, Pleinlaan 2, 1050 BrusselsRoom D2.01 Prof. Werner CEUSTERS, MD Ontology Research Group, Center of Excellence in Bioinformatics and Life Sciences and Department of Psychiatry, University at Buffalo, NY, USA

2. Knowledge Representation Informatics Linguistics Ontology Philosophy Computational Linguistics Realism-Based Ontology Medical Natural Language Understanding Electronic Health Records Translational Research Referent Tracking Medicine Pharmacogenomics Performing Arts Defense & Intelligence Biology Pharmacology Context of this lecture series

3. Today’s topic • May 19: ontologies in healthcare and the vision of personalized medicine • Open Biomedical Ontologies Foundry • Example ontologies for eHealth • An ontologist’s view on data models Realism-Based Ontology Electronic Health Records Translational Research Referent Tracking Medicine Pharmacogenomics Biology Pharmacology

4. Data, information andwhat it is about

5. Better care Better information A general belief:

6. Being better informed Better care Better information ‘Information’ versus ‘informing’

7. A general belief: Being better informed • Concerns primarily the delivery ofinformation: Being better informed Better Better care information

8. pretty well covered long way to go A general belief: Being better informed • Concerns primarily the delivery of information: • Timely, • Where required (e.g. bed-side computing), • What is permitted, • What is needed. • Involves: • Connecting systems, • Making systems interoperable: • Syntactically, • Semantically.

9. data organization model development further R&D (instrument and study optimization) add verify use Δ= outcome Generic beliefs application Today’s data generation and use observation & measurement

10. data organization observation & measurement diagnosis add verify use Δ= outcome Generic beliefs treatment Example 1: clinician

11. data organization hypothesis further R&D (instrument and study optimization) add verify use Δ= outcome Generic beliefs Example 2: researcher observation & measurement

12. data organization model development further R&D (instrument and study optimization) add verify use Δ= outcome Generic beliefs application Example 3: device manufacturer / supplier observation & measurement

13. data organization data organization window dressing Δ= outcome add verify use Generic beliefs influence Slightly different: payer / health plan model development $

14. Patient-specific information Scientific “knowledge” “Better Information” must cover … • EHR-EMR-ENR-… • PHR • Various modality related databases • Lab, imaging, … • Textbooks • Classification systems • Terminologies • Ontologies 1 3 2

15. Means to structure the available information Key question: on what should the structure be based ?

16. What is the structure based on ? (1) • Classification systems: on ‘properties’ of patients which are of importance for the purposes the system has been designed http://www.who.int/classifications/en/

17. What is the structure based on ? (2) • Terminologies: • on ‘concepts’ • But terminologists fail to give a good answer on what a concept is

18. What is the structure based on ? (3) • Ontologies (mainstream view): • on ‘concepts’ • when designed by terminologists • on ‘classes’ • when designed by software engineers and computer scientists • a class is a construct that is used as a blueprint to create objects of that class.? • a class is a cohesive package that consists of a particular kind of metadata. ?? • a class usually represents a noun, such as a person??? http://en.wikipedia.org/wiki/Class_(computer_science)

19. Patients become victims of bad IT design • ‘The Data Model That Nearly Killed Me’: • Joe Bugajski, http://tiny.cc/S1HWo • “If data cannot be made reliably available across silos in a single EHR, then this data cannot be made reliably available to a huge, heterogeneous collection of networked systems.” • ‘Are Health IT designers, testers and purchasers trying to kill people?’ • Scot M. Silverstein, http://tiny.cc/CKIW1

20. Our view: on realism-based ontology ! • In philosophy: • Ontology(no plural) is the study of what entities exist and how they relate to each other; • In computer science and (biomedical informatics) applications: • An ontology(plural: ontologies) is a shared and agreed upon conceptualization of a domain; • Our ‘realist’ view within the Ontology Research Group combines the two: • We use realism, a specific theory of ontology, as the basis for building high quality ontologies, using reality as benchmark.

21. OBO and OBO-Foundry A reaction to inadequacy

22. US National Centers for Biomedical Computing

24. OBO Website

26. The OBO Foundry • a family of interoperable biomedical reference ontologies built around the Gene Ontology at its core and using the same principles • a modular annotation catalogue of English phrases • each module created by experts from the corresponding scientific community • http://obofoundry.org

27. OBO Foundry principles (1) • The ontology must be open and available to be used by all without any constraint other than • (a) its origin must be acknowledged and • (b) it is not to be altered and subsequently redistributed under the original name or with the same identifiers. • The ontology is in, or can be expressed in, a common shared syntax. This may be either the OBO syntax, extensions of this syntax, or OWL. • Each Foundry ontology should be built on the basis of BFO top-level distinctions • cave: OWL-DL is not capable of representing all BFO aspects

28. OBO Foundry principles (2) • The ontologies have a unique identifier space within the OBO Foundry. • The source of a representational unit (RU) from any ontology can be immediately identified by the prefix of the identifier of each term. • The ontology provider has procedures for identifying distinct successive versions. • The ontology has a clearly specified and clearly delineated content. • The ontology must be orthogonal to other ontologies already lodged within OBO. • community acceptance of a single ontology for one domain

29. OBO Foundry principles (3) • The ontologies include textual definitions for all RUs. • RUs should be defined so that their precise meaning within the context of a particular ontology is clear to a human reader. • Textual definitions will use the genus-species form: An A =def. a B which Cs, where B is the parent of the defined term A and C is the defining characteristic of those Bs which are also As. • The ontology uses relations which are unambiguously defined following the pattern of definitions laid down in the OBO Relation Ontology. • The ontology is well documented. • The ontology has a plurality of independent users. • The ontology will be developed collaboratively with other OBO Foundry members.

30. OBO Foundry principles (4) • Single is_a inheritance: ontologies will distinguish a backbone ('asserted') is_a hierarchy subject to the principle of single inheritance (each term in the ontology has maximally one is_a parent in this asserted hierarchy). • Instantiability: RUs in an ontology should correspond to instances in reality.

31. Idea grew out of the Gene Ontology what cellular component? what molecular function? what biological process? 33

32. OBO Foundry ontologies in BFO-dress 34

33. Ontology Scope URL Custodians Cell Ontology (CL) cell types from prokaryotes to mammals obo.sourceforge.net/cgi- bin/detail.cgi?cell Jonathan Bard, Michael Ashburner, Oliver Hofman Chemical Entities of Bio- logical Interest (ChEBI) molecular entities ebi.ac.uk/chebi Paula Dematos, Rafael Alcantara Common Anatomy Refer- ence Ontology (CARO) anatomical structures in human and model organisms (under development) Melissa Haendel, Terry Hayamizu, Cornelius Rosse, David Sutherland, Foundational Model of Anatomy (FMA) structure of the human body fma.biostr.washington. edu JLV Mejino Jr., Cornelius Rosse Functional Genomics Investigation Ontology (FuGO) design, protocol, data instrumentation, and analysis fugo.sf.net FuGO Working Group Gene Ontology (GO) cellular components, molecular functions, biological processes www.geneontology.org Gene Ontology Consortium Phenotypic Quality Ontology (PaTO) qualities of biomedical entities obo.sourceforge.net/cgi -bin/ detail.cgi? attribute_and_value Michael Ashburner, Suzanna Lewis, Georgios Gkoutos Protein Ontology (PrO) protein types and modifications (under development) Protein Ontology Consortium Relation Ontology (RO) relations obo.sf.net/relationship Barry Smith, Chris Mungall RNA Ontology (RnaO) three-dimensional RNA structures (under development) RNA Ontology Consortium Sequence Ontology (SO) properties and features of nucleic sequences song.sf.net Karen Eilbeck http://ontologist.com 35

34. Ontology of General Medical Science First ontology in which the L1/L2/L3 distinction is used

35. Remember Basic Formal Ontology • The world consists of • entities that are • Either particulars or universals; • Either occurrents or continuants; • Either dependent or independent; and, • relationships between these entities of the form • <particular , universal> e.g. is-instance-of, • <particular , particular> e.g. is-member-of • <universal , universal> e.g. isa (is-subtype-of) Smith B, Kusnierczyk W, Schober D, Ceusters W. Towards a Reference Terminology for Ontology Research and Development in the Biomedical Domain. Proceedings of KR-MED 2006, November 8, 2006, Baltimore MD, USA

36. Basic BFO distinctions universals Continuant Occurrent process, event Independent Continuant thing Dependent Continuant quality .... ..... ....... particulars

37. Basic BFO distinctions universals has_participant Continuant Occurrent process, event isa isa Independent Continuant ~ thing Dependent Continuant inheres_in instance_of (at t) .... ..... ....... particulars

38. BFO Top-Level Ontology (partial) Continuant Occurrent (always dependent on one or more independent continuants) Spatial Region Independent Continuant Dependent Continuant SDC GDC Process Temporal Region Quality Realizable Information Content Entity Role Disposition Functioning Function

39. Representational units in various • forms about (1), (2) or (3) (2) Cognitive entities which are our beliefs about (1) (1) Entities with objective existence which are not about anything Three levels of reality in Realist Ontology Terminology Realist Ontology Representation and Reference representational units cognitive units communicative units universals particulars First Order Reality

40. Universals and Defined Classes Unconstrained reasoning HUMAN BEING extension_of at t instance_of at t E: all human beings at t DC-x: patients at t subclass_of at t I-y OWL-DL reasoning class_member_of at t class_member_of at t

41. Goal of OGMS • To be a consistent, logical and extensible framework (ontology) for the representation of • features of disease • clinical processes • results

42. Motivation • Clarity about: • disease etiology and progression • disease and the diagnostic process • phenotype and signs/symptoms

43. Approach • 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 participates_in recognized_as

44. Cirrhosis - environmental exposure • Symptoms & Signs • used_in • Interpretive process • produces • Hypothesis - rule out cirrhosis • suggests • Laboratory tests • produces • Test results – documentation of 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

45. 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 But the disorder also induces normal physiological processes (immune response) that can result 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 – documentation of elevated serum antibody titers • used_in • Interpretive process • produces • Result - diagnosis that patient X has a disorder that bears the disease flu

46. 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

47. HNPCC - genetic pre-disposition hereditary non-polyposis colorectal cancer • 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) – to acquire non-polyposis colon cancer

48. Big Picture

49. Primitive Terms • ‘bodily feature’ – may denote a physical component, a bodily quality, or a bodily process.

50. Independent continuant Quality Process do not have corresponding universals isa isa isa isa Fever Edema Rash Tremor extension_of There are way more sorts of classes than universals