Formal Principles for Biomedical Ontologies

1. VR

2. Formal Principles for Biomedical Ontologies Barry Smith http://ifomis.de

3. Three levels of ontology http:// ifomis.de

4. Three levels of ontology • formal (top-level) ontology dealing with categories employed in every domain: • object, event, whole, part, instance, class • 2) domain ontology, applies top-level system to a particular domain • cell, gene, drug, disease, therapy • 3) terminology-based ontology • large, lower-level system • Dupuytren’s disease of palm, nodules with no contracture http:// ifomis.de

5. Three levels of ontology • formal (top-level) ontology dealing with categories employed in every domain: • object, event, whole, part, instance, class • 2) domain ontology, applies top-level system to a particular domain • cell, gene, drug, disease, therapy • 3) terminology-based ontology • large, lower-level system • Dupuytren’s disease of palm, nodules with no contracture http:// ifomis.de

6. Three levels of ontology • formal (top-level) ontology dealing with categories employed in every domain: • object, event, whole, part, instance, class • 2) domain ontology, applies top-level system to a particular domain • cell, gene, drug, disease, therapy • 3) terminology-based ontology • large, lower-level system • Dupuytren’s disease of palm, nodules with no contracture http:// ifomis.de

7. Compare: • pure mathematics (re-usable theories of structures such as order, set, function, mapping) • applied mathematics, applications of these theories = re-using the same definitions, theorems, proofs in new application domains • physical chemistry, biophysics, etc. = adding detail http:// ifomis.de

8. Three levels of biomedical ontology ????? • formal (top-level) ontology = • medical ontology has nothing like the technology of re-usable definitions, theorems and proofs provided by pure mathematics • 2) domain ontology • = UMLS Semantic Network, GALEN CORE • 3) terminology-based ontology • = UMLS, SNOMED-CT, GALEN, FMA http:// ifomis.de

9. Description Logic , Protégé, • and other tools for supporting automatic reasoning do not fill this gap • they do not provide theories of classes, functions, processes, etc. • rather: successful coding in a DL-framework presupposes that such theories have already been applied in the very construction of the terminology-based ontology http:// ifomis.de

10. IFOMIS • Institute for Formal Ontology and Medical Information Science, • mission: • use basic principles of philosophical ontology, traditional theories of classification and definition for quality assurance and alignment of biomedical ontologies http:// ifomis.de

11. Strategy • Part 1: Survey of GO • Part 2: Provide principles for building biomedical ontologies derived from formal (top-level) ontology, and illustrate how they can help in quality assurance of terminology-based ontologies like GO • Part 3: Show how it can be done right http:// ifomis.de

12. Part One Survey of GO http:// ifomis.de

13. GO is three ontologies • cellular components • molecular functions • biological processes • December 16, 2003: • 1372 component terms • 7271 function terms • 8069 process terms http:// ifomis.de

14. GO an impressive achievement • used by over 20 genome database and many other groups in academia and industry • successful methodology, much imitated • now part of OBO (open biological ontologies) consortium • Here I focus on problems / errors • GO here is just an example http:// ifomis.de

15. Primary aim of GO not rigorous definition and principled classification but rather: providing a practically useful framework for keeping track of the biological annotations that are applied to gene products http:// ifomis.de

16. Each of GO’s ontologies • is organized in a graph-theoretical structure involving two sorts of links or edges: • is-a • (epithelial cell differentiation is-a cell differentiation) • part-of • (axonemal microtubule part-of axoneme) http:// ifomis.de

17. This graph-theoretic architecture • to designed to help humans, who can use the graphs to locate the features and attributes they are addressing in their work and thus to determine the designated terms for these features and attributes within GO’s ‘controlled vocabulary.’ http:// ifomis.de

18. GO’s three ontologies • When a gene is identified, three important types of questions need to be addressed: Where is it located in the cell? What functions does it have on the molecular level? And to what biological processes do these functions contribute? http:// ifomis.de

19. molecular functions biological processes cellular constituents GO’s three ontologies http:// ifomis.de

20. The Cellular Component Ontology (counterpart of anatomy) • consists of terms such as flagellum, chromosome, ferritin, extracellular matrix and virion • Cellular components are physical and measurable entities. They are, in the terminology of philosophical ontology, objects or things(independent continuants). They endure self-identically through time while undergoing changes of various sorts • Cellular component embraces also the extracellular environment of cells and cells themselves http:// ifomis.de

21. No organisms • GO does not include terms for specific organisms, not even for single-celled organisms http:// ifomis.de

22. The Molecular Function Ontology • molecular function = the action characteristic of a gene product. • Actions such as ice nucleation or protein stabilization do not endure but rather occur. http:// ifomis.de

23. The Molecular Function Ontology • Originally included terms such as anti-coagulant (defined as: ‘a substance that retards or prevents coagulation’) and enzyme (defined as: ‘a substance … that catalyzes’) • These refer neither to functions nor to actions but rather to components. http:// ifomis.de

24. The Molecular Activity Ontology • Confusion remedied to a degree by policy change of March 2003: ‘All GO molecular function term names [with the exception of the parent term molecular function and of the whole node binding] are to be appended with the word “activity”.’ http:// ifomis.de

25. ‘Function’ = ‘Activity’ • Thus the term ‘structural molecule,’ which is defined as meaning: ‘the action of a molecule that contributes to structural integrity,’ is amended to ‘structural molecule activity’ http:// ifomis.de

26. still problem’s with GO Molecular Function Definitions • anti-coagulant activity (defined as: “a substance that retards or prevents coagulation”) • enzyme activity (defined as: “a substance that catalyzes”) http:// ifomis.de

27. … and there are still problems with Molecular Function terms • GO:0005199: • structural constituent of cell wall http:// ifomis.de

28. structural constituent of cell wall • Definition: The action of a molecule that contributes to the structural integrity of a cell wall. • confuses actions, which GO includes in its function ontology, with constituents, which GO includes in its cellular component ontology http:// ifomis.de

29. extracellular matrix structural constituent • puparial glue (sensu Diptera) • structural constituent of bone • structural constituent of chorion (sensu Insecta) • structural constituent of chromatin • structural constituent of cuticle • structural constituent of cytoskeleton • structural constituent of epidermis • structural constituent of eye lens • structural constituent of muscle • structural constituent of myelin sheath • structural constituent of nuclear pore • structural constituent of peritrophic membrane (sensu Insecta) • structural constituent of ribosome • structural constituent of tooth enamel • structural constituent of vitelline membrane (sensu Insecta) http:// ifomis.de

30. The Biological Process Ontology • biological process: ‘A phenomenon marked by changes that lead to a particular result, mediated by one or more gene products.’ • Examples: • glycolysis, • death, • adult walking behavior • response to blue light http:// ifomis.de

31. Occurrents • Both molecular activity and biological process terms refer to what philosophical ontologists call occurrents • = entities which do not endure through time but rather unfold themselves in successive temporal phases. • Occurrents can be segmented into parts along the temporal dimension. • Continuants exist in toto in every instant at which they exist at all. http:// ifomis.de

32. Molecular functions and biological processes are closely interrelated • E.g. the process anti-apoptosis involves the molecular function apoptosis inhibitor activity. • How can GO express such relations? http:// ifomis.de

33. Are they a matter of granularity? • ‘A biological process is accomplished via one or more ordered assemblies of molecular functions.’ • ??? Molecular activities = building blocks of biologica processes ??? • So: Functions are parts of processes • But no: http:// ifomis.de

34. GO’s three ontologies are separate biological processes molecular functions • No links or edges defined between them cellular constituents http:// ifomis.de

35. Question: • How understand granularity • if not in terms of parthood? http:// ifomis.de

36. Molecular functions • renamed ‘activities’, • because ‘activity’ unlike ‘process’, connotes agency ? • but molecules are not agents • hypothesis: the term ‘function’ was used for the molecular function ontology because the activities in question are functional in relation to the pertinent organism. http:// ifomis.de

37. Functions • A function is functional • = beneficial to the organism • If an organism-part has a function, this is because the functioning of this organism-part is beneficial to the organism • The function of the heart is to pump blood • Not: the function of the hip is to financially support hip-replacement surgeons http:// ifomis.de

38. Some processes are functionings • E.g. pumping blood http:// ifomis.de

39.  Two sorts of processes • Functionings (realizations of functions = beneficial to the organism) • Other processes (e.g. the result of external interventions) • Cf. difference between physiology and pathology http:// ifomis.de

40. GO not clear about this distinction • transport: The directed movement of substances (such as … ions) into, out of, or within a cell • cell growth and/or maintenance: Any process required for the survival and growth of a cell • Synonym: cell physiology • transportis-a cell growth and/or maintenance • but (GO:0019060) viral intracellular protein transport • is-a transport http:// ifomis.de

41. Why do these problems arise? • GO has no clear understanding of the role of temporal relations in organizing an ontology • (thus also no clear understanding of the difference between a function and the activity which is the realization of a function) http:// ifomis.de

42. GO excludes organisms from its scope (they are of the wrong granularity) • Yet each process or function requires some bearer or bearers which it is the process or function of. • Processes are dependent on their bearers • (Theory of dependence vs. independence part of formal ontology) • (Theory of continuants vs. occurrents part of formal ontology) http:// ifomis.de

43. Some formal ontology • Components are independent continuants • Functions are dependent continuants • (the function of an object exists continuously in time, just like the object which has the function; • and it exists even when it is not being exercised) • Processes are (dependent) occurrents http:// ifomis.de

44. More generally: • Continuants can be divided into independent (objects, things, components) and dependent (features, attributes, conditions, functions, roles, qualities …) • All occurrents are dependent entities. • Every occurrent is dependent for its existence on one or more continuants. • A change is always a change in some continuant object. http:// ifomis.de

45. http:// ifomis.de

46. Part Two • Principles of Biomedical Ontologies and their use in quality assurance of terminology-based ontologies http:// ifomis.de

47. Principle of Temporal Coherence • An ontology should rigorously distinguish continuants from occurrents. • (Anatomy is a science of continuants) http:// ifomis.de

48. Principle of Dependence • If an ontology recognizes a dependent entity then it (or a linked ontology) should recognize also the relevant class of bearers • Part of our aim here is to lay down principles which can support such linkability http:// ifomis.de

49. Linking to external ontologies • can also help to link together GO’s own three separate parts http:// ifomis.de

50. GO’s three ontologies biological processes molecular functions  dependent  cellular constituents  independent http:// ifomis.de