1. 1 Semantic Network (SN) and Biomedical Ontology Barry Smith Department of Philosophy, University at Buffalo Institute for Formal Ontology and Medical Information Science ifomis.org

2. 2 Assumption SN is designed to support automatic reasoning involving multiple UMLS source terminologies Conclusion: Relations in SN are very important

3. 3 Inheritance Body part, Organ or Organ Component location_of Biologic Function Therefore Body Part, Organ or Organ Component location_of Disease or Syndrome Alexa: “We can sometimes infer... you have to bring some medical knowledge to bear”

4. 4 Part_of as a relation between classes is more problematic than is standardly supposed testis part_of human being ? heart part_of human being ?

5. 5 Dr Humphreys: SN lists “possible significant relations”

6. 6 What we need for automatic inference is uniformly (necessarily) significant relations A is_a B Every instance of A is an instance of B

7. 7 What we need for automatic inference is uniformly (necessarily) significant relations A is_a B Every instance of A is an instance of B We hope all is_a relations are exceptionless in this sense

8. 8 Some non-is_a relations are exceptionless in this sense Fully formed anatomical structure contains body substance

9. 9 But most are not Bacterium causes Experimental Model of Disease Experimental Model of Disease affects Fungus Experimental model of disease is_a Pathologic Function

10. 10 Bacterium causes Experimental Model of Disease causes – Brings about a condition or an effect. Implied here is that an agent, such as for example, a pharmacologic substance or an organism, has brought about the effect. This includes induces, effects, evokes, and etiology.

11. 11 GALEN: Vomitus contains carrot Gene Ontology: Menopause part_of Death HL7: Individual Allele is_a Act of Observation

12. 12 Thesis: Biomedical ontology integration will never be achieved through integration of meanings or concepts in people’s heads the problem is precisely that different user communities use different concepts

13. 13 Promise of evidence-based medicine in the genomics era: integrating biomedical terminologies with EHR data  need facility for dealing with time and instances (particulars, actual cases) with this tumor here and now in this breast...

14. 14 Move from associative relations between meanings to strictly defined relations between the entities themselves See: Smith, Ceusters, Klagges, Köhler, Kumar, Lomax, Mungall, Neuhaus, Rector, Rosse “Relations in Biomedical Ontologies” Genome Biology, in press

15. 15 Clear instructions Fewer mistakes

16. 16 Key idea To define ontological relations like SN’s part_of, contains, adjacent-to we need also to take account of instances and time (= link to Electronic Health Record)

17. 17 Kinds of relations : is_a, part_of,... : this explosion instance_of the class explosion : Mary’s heart part_of Mary

18. 18 Kinds of relations : is_a, part_of,... : this explosion instance_of the class explosion : Mary’s heart part_of Mary = instance-level part_of is a primitive (you can’t define everything, on pain of circularity)

19. 19 part_of A part_of B =def. for all a and all t, if a is an instance of A at time t, then there is some instance b of B such that a is an instance-level part_of b at t ALL-SOME STRUCTURE

20. 20 part_of A part_of B =def. for all a and all t, if a is an instance of A at time t, then there is some instance b of B such that a is an instance-level part_of b at t ALL-SOME STRUCTURE

21. 21 testis part_of human being - NO human testis part_of human being - YES human ovary part_of human being - YES

22. 22 transformation_of c at t 1 C c at t C 1 time same instance mature RNA transformation_of pre-RNA fetus transformation_of embryo adult transformation_of child

23. 23 transformation_of C 2 transformation_of C 1 =def. any instance of C 2 was at some earlier time an instance of C 1

24. 24 Note the problem of inverses here Not every child becomes transformed into an adult

25. 25 The Granularity Gulf as an obstacle to reasoning most existing data-sources are of fixed, single granularity many (all?) clinical phenomena cross granularities

26. 26 C c at t c at t 1 C 1 embryological development

27. 27 C c at t c at t 1 C 1 tumor development

28. 28 Advantages of the methodology of enforcing commonly accepted coherent definitions promote quality assurance (better coding) guarantee automatic reasoning across ontologies and across data at different granularities, from molecule to clinic yields direct connection to times and instances in EHR

29. 29 Automatic reasoning non-is_a relations are all-some relations A R B =def for all instances a of A there is some instance b of B such that a r b where r is some instance-level relation If you know A R B, and you know that a is an instance of A, then you know that there is some instance b of B and inheritance is unrestrained (exceptionless) if you know B R C you can reason with this instance b to infer that there is some C, and so on

30. 30 Conclusions for SN Remove the merely ‘possibly significant relations’ (these are less than facts) Reform definitions (remove circularity) Remove those relations, such as prevents which cannot be given a coherent instance-based all-some definition Reform treatment of inverses

31. 31 prevents Definition: Stops, hinders or eliminates an action or condition. Inverse: prevented_by contraception prevents pregnancy pregnancy prevented_by contraception

32. 32 Better treatment of prevention contraception causes prevention_of_pregnancy

33. 33 Reform treatment of inverses adjacent_to – “Close to, near or abutting another physical unit with no other structure of the same kind intervening. This includes adjoins, abuts, is contiguous to, is juxtaposed, and is close to.” Inverse: adjacent_to

34. 34 Adjacent_to is not its own inverse nuclear membrane adjacent_to cytoplasm BUT NOT: cytoplasm adjacent_to nuclear membrane ovary adjacent_to parietal pelvic peritoneum BUT NOT: parietal pelvic peritoneum adjacent_to ovary

35. 35 Better treatment of inverses Use preceded_by not precedes as primary relation preceded_by supports inheritance (supports automatic reasoning) embryological development precedes birth NOT EXCEPTIONLESS

36. 36 If NLM does not reform SN in something like this way, then someone else will build a competitor to integrate the UMLS for purposes of automatic reasoning and integration across granularities

37. 37 http://ifomis.org The End

38. 38 Human-Caused Phenomenon or Process (Environmental Effect of Humans): Phenomenon and Process put together

39. 39 Entity Event Activity Phenomenon or Process Physical Object Conceptual Entity UMLS Semantic Types

40. 40

41. 41 gene part_of cell component body system conceptual_part_of fully formed anatomical structure

42. 42 conceptual entity idea or concept functional concept body system

43. 43 But: Gene or Genome is defined as: “A specific sequence … of nucleotides along a molecule of DNA or RNA …” and nucleotide sequence is_a conceptual entity

44. 44 entity physical conceptual object entity idea or concept functional concept body system confusion of entity and concept

45. 45 Functional Concept: Body system is_a Functional Concept. but: Concepts do not perform functions or have physical parts.

46. 46 This: is not a concept

47. 47 UMLS-SN Semantic Relation produces Definition: Brings forth, generates or creates. Inverse: produced_by artificial insemination produces pregnancy pregnancy produced by artificial insemination

48. 48 Definitions conceptual_part_of – Conceptually a portion, division, or component of some larger whole. should not be circular

49. 49 part_of – “Composes, with one or more other physical units, some larger whole. This includes component of, division of, portion of, fragment of, section of, and layer of.” Inverse: has-part contains – “Holds or is the receptacle for fluids or other substances. This includes is filled with, holds, and is occupied by.” Inverse: contained_in consists_of – “Is structurally made up of in whole or in part of some material or matter. This includes composed of, made of, and formed of.” Inverse: constitutes connected_to – “Directly attached to another physical unit as tendons are connected to muscles. This includes attached to and anchored to.” Inverse: connected_to interconnects – “Serves to link or join together two or more other physical units. This includes joins, links, conjoins, articulates, separates, and bridges.” Inverse: interconnected by branch_of – “Arises from the division of. For example, the arborization of arteries.” Inverse: has_branch

50. 50 tributary_of – “Merges with. For example, the confluence of veins.” Inverse: has_tributary ingrediant_of – “Is a component of, as in a constituent of a preparation.” Inverse: has_ingredient physically_related_to – “Related by virtue of some physical attribute or characteristic.” Inverse: physically_related_to

51. 51 connected_to and connects not clearly defined ingrediant_of doesn’t fit

52. 52 temporally_related_to – (co-occurs_with; precedes): The relevant definitions are as follows: precedes – “Occurs earlier in time. This includes antedates, comes before, is in advance of, predates, and is prior to.” Inverse: follows co-occurs_with – “Occurs at the same time as, together with, or jointly. This includes is co-incident with, is concurrent with, is contemporaneous with, accompanies, coexists with, and is concomitant with.” Inverse: co- occurs_with temporally_related_to – “Related in time by preceding, co- occuring with, or following.” Inverse: temporally_related_to

53. 53 Too unspecific. KIF annotations? affects – (interacts_with; disrupts; prevents; complicates; manages; treats): The relevant definitions are as follows: interacts_with – “Acts, functions, or operates together with.” Inverse: interacts_with disrupts – “Alters or influences an already existing condition, state, or situation. Produces a negative effect on.” Inverse: disrupted_by prevents – “Stops, hinders or eliminates an action or condition.” Inverse: prevented_by complicates – “Causes to become more severe or complex or results in adverse effects.” Inverse: complicated_by manages – “Administers, or contributes to the care of an individual or group of individuals.” Inverse: managed_by treats – “Applies a remedy with the object of effecting a cure or managing a condition.” Inverse: treated_by affects – “Produces a direct effect on. Implied here is the altering or influencing of an existing condition, state, situation, or entity. This includes has a role in, alters, influences, predisposes, catalyzes, stimulates, regulates, depresses, impedes, enhances, contributes to, leads to, and modifies.” Inverse: affected_by

54. 54 interacts_with need not be affects occurs_in – (process_of): The relevant definitions are as follows: process_of – “Action, function, or state of.” Inverse: has_process occurs_in – “Takes place in or happens under given conditions, circumstances, or time periods, or in a given location or population. This includes appears in, transpires, comes about, is present in, and exists in.” Inverse: has_occurrence

55. 55 No reason why one is a subclass of the other brings_about – (produces, causes): The relevant definitions are as follows: produces – “Brings forth, generates or creates. This includes yields, secretes, emits, biosynthesizes, generates, releases, discharges, and creates.” Inverse: produced_by causes – “Brings about a condition or an effect. Implied here is that an agent, such as for example, a pharmacologic substance or an organism, has brought about the effect. This includes induces, effects, evokes, and etiology.” Inverse: caused_by brings_about – “Acts on or influences an entity.” Inverse: brought_about_by performs – (carries_out, practices, exhibits): The relevant definitions are as follows:

56. 56 carries_out – “Executes a function or performs a procedure or activity. This includes transacts, operates on, handles, and executes.” Inverse: carried_out_by practices – “Performs habitually or customarily.” Inverse: practiced_by exhibits – “Shows or demonstrates.” Inverse: exhibited_by performs – “Executes, accomplishes, or achieves an activity.” Inverse: performed_by Difference between “performs” and “carries out” unclear

57. 57 functionally_related_to – (manifestation_of; affects; occurs_in; uses; indicates; result_of; brings_about; performs): The relevant definitions are as follows: manifestation_of – “That part of a phenomenon which is directly observable or concretely or visibly expressed, or which gives evidence to the underlying process. This includes expression of, display of, and exhibition of.” Inverse: has_manifestation uses – “Employs in the carrying out of some activity. This includes applies, utilizes, employs, and avails.” Inverse: used_by indicates – “Gives evidence for the presence at some time of an entity or process.” Inverse: indicated_by result_of – “The condition, product, or state occurring as a consequence, effect, or conclusion of an activity or process. This includes product of, effect of, sequel of, outcome of, culmination of, and completion of.” Inverse: has_result functionally_related_to – “Related by the carrying out of some function or activity. ” Inverse: functionally_related_to

58. 58 analyzes – (assesses_effect_of): The relevant definitions are as follows: assesses_effect_of – “Analyzes the influence or consequences of the function or action of.” Inverse: assessed_for_effect_by analyzes – “Studies or examines using established quantitative or qualitative methods. ” Inverse: analyzed_by conceptually_related_to – (property_of; conceptual_part_of; evaluation_of; measures; diagnoses; issue_in; derivative_of; developmental_form_of; degree_of; measurement_of; method_of; analyzes): The relevant definitions are as follows:

59. 59 property_of – “Characteristic of, or quality of.” Inverse: has_property conceptual_part_of – “Conceptually a portion, division, or component of some larger whole.” Inverse: has_conceptual_part evaluation_of – “Judgment of the value or degree of some attribute or process.” Inverse: has_evaluation measures – “Ascertains or marks the dimensions, quantity, degree, or capacity of.” Inverse: measured_by diagnoses – “Distinguishes or identifies the nature or characteristics of.” Inverse: diagnosed_by issue_in – “Is an issue in or a point of discussion, study, debate, or dispute.” Inverse: has_issue derivative_of – “In chemistry, a substance structurally related to another or that can be made from the other substance. This is used only for structural relationships. This does not include functional relationships such as metabolite of, by product of, nor analog of.” Inverse: has_derivative developmental_form_of – “An earlier stage in the individual maturation of.” Inverse: has_developmental_form degree_of – “The relative intensity of a process or the relative intensity or amount of a quality or attribute.” Inverse: has_degree measurement_of – “The dimension, quantity, or capacity determined by measuring.” Inverse: has_measurement method_of – “The manner and sequence of events in performing an act or procedure.” Inverse: has_method conceptually_related_to – “Related by some abstract concept, thought, or idea.” Inverse: conceptually_related_to

60. 60 spatially_related_to – (location_of; adjacent_to; surrounds; traverses): The relevant definitions are as follows: location_of – “The position, site, or region of an entity or the site of a process.” Inverse: has_location adjacent_to – “Close to, near or abutting another physical unit with no other structure of the same kind intervening. This includes adjoins, abuts, is contiguous to, is juxtaposed, and is close to.” Inverse: adjacent_to surrounds – “Establishes the boundaries for, or defines the limits of another physical structure. This includes limits, bounds, confines, encloses, and circumscribes.” Inverse: surrounded_by traverses – “Crosses or extends across another physical structure or area. This includes crosses over and crosses through.” Inverse: traversed_by spatially_related_to – “Related by place or region.” Inverse: spatially_related_to associated_with – (physically_related_to, temporally_related_to, functionally_related_to, conceptually_related_to, spatially_related_to): associated_with is defined as “has a significant or salient relationship to.” Inverse: associated_with Discussion The inclusion of the opposition Chemical Viewed Structurally and Chemical Viewed Functionally raises the suggestion that SN might be better interpreted as clas ‑ sifying not entities but rather the concepts we have of such entities. The concepts we use when referring to chemicals can after all be divided quite naturally un ‑ der these two headings. Then, however, the root nodes of SN should be not: Entity and Event, but rather: Entity Concept and Event Concept, and the latter should themselves be re-assigned to the position of daughters of a new root Concept. A restructuring along these lines would how ‑ ever in other ways conflict radically with SN’s current architecture. Above all, it would con ‑ tradict the fact that Idea or Concept is already itself a subnode of Conceptual Entity. It would also contradict explicit statements to the effect that SN is ‘an upper-level ontology … in which all concepts are given a consistent and semantically coherent representation’. [7] Conclusion A number of proposals have been advanced to increase SN’s effectiveness as a terminology integration platform that can support enhanced reasoning and information retrieval. Thus [8] argues that UMLS lacks the requisite granularity, semantic types and relationships for comprehensively and consistently representing anatomical concepts in machine readable form. [9] and [10] propose enhancing the efficiency of UMLS-based reasoning systems via a clustering of SN nodes to yield more coarse-grained partitions of the network. Our proposal is that SN’s power to support terminology-based reasoning can be enhanced through a reclassification along the lines sketched in the above. As an example of how such a reclassification would support inferences currently blocked, consider the way in which SN currently views tissues and cells as physical parts of organs, but views these organs themselves as mere conceptual parts of body systems, which are in turn conceptual parts of fully-formed anatomical structures, which are in turn physical parts of organisms. When we reclassify Body System as a Physical Entity, there is no longer a need for the distinction between conceptual and physical part-of relations. Reasoning systems can thus exploit the full power of mereology, including the rules governing transitivity of part-of.