Disease Ontology Workshop: The Ontology of Diagnosis (in progress)

1. Disease Ontology WorkshopThe Ontology of Diagnosis(to be quoted as work in progress)Baltimore, MD, USA. November 7, 2006 Werner CEUSTERS Center of Excellence in Bioinformatics and Life Sciences Department of Psychiatry, University at Buffalo, NY, USA National Center for Biomedical Ontology http://www.org.buffalo.edu/RTU

2. Outline • Background notions on ontology. • What is a diagnosis ? • What is a disease ? • Diagnostic decision making from an ontological and epistemological perspective. • The impact of change on making diagnoses. • (if enough time) Tracking changes in representations.

3. Part 1: Background Reality, ontologies, views, …

4. A realist view of the world • 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

5. Three levels of reality • The world exists ‘as it is’ prior to a cognitive agent’s perception thereof; • Cognitive agents build up ‘in their minds’ cognitive representations of the world; • To make these representations publicly accessible in some enduring fashion, they create representational artifacts that are fixed in some medium. 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

6. Representational artifacts • Ideally built out of representational units and relationships that mirror the entities and their relationships in reality.

7. An example: Referent TrackingNow! That should clear up a few things around here ! • Purpose: • explicitreference to the concrete individual entities relevant to the accurate description of each patient’s condition, therapies, outcomes, ... • Method: • Introduce an Instance Unique Identifier(IUI) for each relevant particular (individual) entity Ceusters W, Smith B. Strategies for Referent Tracking in Electronic Health Records. J Biomed Inform. 2006 Jun;39(3):362-78.

8. instance-of at t1 inst-of at t2 #1 #10 person instance-ofat t1 inst-of at t2 #2 #20 liver instance-of at t1 inst-of at t2 #3 #30 tumor instance-of at t1 inst-of at t2 #4 #40 treating clinic #5 #5 instance-of at t1 inst-of at t2 device #6 #6 From non-formalized to formalized repositories through Referent Tracking ‘John Doe’s liver tumor was treated with RPCI’s irradiation device’ ‘John Doe’s ‘John Smith’s liver liver tumor tumor was treated was treated with with RPCI’s RPCI’s irradiation device’ irradiation device’

9. Repository – Ontology “collaboration”

10. Ontology of Biomedical Reality (under development) pathological anatomical structure caused by caused by pathological formation disease isa isa tumor aberrant DNA molecule Liver cell adenoma isa Hepatocellular carcinoma hepatoblastoma

11. Part 2: What is a diagnosis ?

12. instance-of at t caused by #105 Making a diagnosis (naive view)

13. Towards the full picture (1) • Level of biomedical reality: • Persons, diseases, pathological structures and formations,... do exist as particulars (p, d, ps, pf, ... ) and universals (P, D, PS, PF, ...), and are related in specific ways prior to our perception; • Biomedical reality changes: • d’s, p’s, ... come and go; D’s, P’s, ... only come (?) • Level of biomedical science and case perception: • Mirrors reality only partially • Evolves over time towards better understanding

14. Towards the full picture (2) • Level of concretizations • Mirrors biomedical science and case perception only partially • Editing mistakes • Leaving out diseases or pathological behaviours for non-biomedical reasons • Smoking • Adding non-pathological behaviour as a disease • homosexuality

15. My working definition of ‘diagnosis’ Any configuration of representational units which is believed to mirror the portion of reality consisting of an organism’s disease and the relationships this disease enjoys with the entities that caused the disease or influence its course, whereby some part of this configuration of representational units refers to the universal of which that disease is believed to be an instance, or the defined class of which it is believed to be a member.

16. defined class instance-of at t instance-of at t “lung inflammation” BTW: universal versus defined class universal

17. A configuration of representational units; Believed to mirror the person’s disease; Believed to mirror the disease’s cause; Refers to the universal of which the disease is believed to be an instance. Disease isa A well-formed diagnosis of ‘pneumococal pneumonia’ Pneumococcal pneumonia Instance-of at t1 #78 John’s portion of pneumococs #56 John’s Pneumonia caused by

18. Disease Portion of pneumococs caused by isa isa Instance-of at t1 Pneumococcal pneumonia Pneumonia Instance-of at t1 Instance-of at t1 caused by caused by #78 #56 #56 #78 Some motivations and consequences (1) • No use of debatable or ambiguous notions such as proposition, statement, assertion, fact, ... • The same diagnosis can be expressed in various forms.

19. Some motivations and consequences (2) • A diagnosis can be of level 2 or level 3, i.e. either in the mind of a cognitive agent, or in some physical form. • Allows for a clean interpretation of assertions of the sort ‘these patients have the same diagnosis’:  The configuration of representational units is such that the parts which do not refer to the particulars related to the respective patients, refer to the same portion of reality.

20. Distinct but similar diagnoses Pneumococcal pneumonia Instance-of at t1 Instance-of at t2 #78 John’s portion of pneumococs #56 John’s Pneumonia #956 Bob’s pneumonia #2087 Bob’s portion of pneumococs caused by caused by

21. Some motivations and consequences (3) • Allows evenly clean interpretations for the wealth of ‘modified’ diagnoses: • With respect to the author of the representation: • ‘nursing diagnosis’, ‘referral diagnosis’ • When created: • ‘post-operative diagnosis’, ‘admitting diagnosis’, ‘final diagnosis’ • Degree of the belief: • ‘uncertain diagnosis’, ‘preliminary diagnosis’

22. But the definition requires working out: • At the level of biomedical reality: • What is a disease ? • What are the entities that cause a specific disease to exist or influence its course ? • What are the relationships between these entities and the disease ? • At the level of representational artifacts: • How do they relate to reality ? • How keeping track of changes in reality ?

23. Part 3: What is a disease ?

24. Latest WHO definition • A disease is: • an interconnected set of one or more dysfunctions in one or more body systems including: • a pattern of signs, symptoms and findings (symptomatology - manifestations) • a pattern or patterns of development over time (course and outcome) • a common underlying causal mechanism (etiology) • linking to underling genetic factors (genotypes, phenotypes and endophenotypes) and to interacting environmental factors • and possibly: to a pattern or patterns of response to interventions (treatment response).

25. Latest WHO definition • A disease is: • an interconnected set of one or more dysfunctions in one or more body systems including: • a pattern of signs, symptoms and findings (symptomatology - manifestations) • a pattern or patterns of development over time (course and outcome) • a common underlying causal mechanism (etiology) • linking to underling genetic factors (genotypes, phenotypes and endophenotypes) and to interacting environmental factors • and possibly: to a pattern or patterns of response to interventions (treatment response). I assume ... ‘of one single person’.

26. Latest WHO definition • A disease is: • an interconnected set of one or more dysfunctions in one or more body systems including: • a pattern of signs, symptoms and findings (symptomatology - manifestations) • a pattern or patterns of development over time (course and outcome) • a common underlying causal mechanism (etiology) • linking to underling genetic factors (genotypes, phenotypes and endophenotypes) and to interacting environmental factors • and possibly: to a pattern or patterns of response to interventions (treatment response). What is referred to by ‘dysfunction’ ? - A non-canonical functioning ? - A functioning which may lead to harming the diseased person ?

27. Latest WHO definition • A disease is: • an interconnected set of one or more dysfunctions in one or more body systems including: • a pattern of signs, symptoms and findings (symptomatology - manifestations) • a pattern or patterns of development over time (course and outcome) • a common underlying causal mechanism (etiology) • linking to underling genetic factors (genotypes, phenotypes and endophenotypes) and to interacting environmental factors • and possibly: to a pattern or patterns of response to interventions (treatment response). Is not an ontological entity but a representational entity. Better: a disease involves one or more ... But then it is left open what a disease IS !

28. Latest WHO definition • A disease is: • an interconnected set of one or more dysfunctions in one or more body systems including: • a pattern of signs, symptoms and findings (symptomatology - manifestations) • a pattern or patterns of development over time (course and outcome) • a common underlying causal mechanism (etiology) • linking to underling genetic factors (genotypes, phenotypes and endophenotypes) and to interacting environmental factors • and possibly: to a pattern or patterns of response to interventions (treatment response). Or: the processual entity composed of the dysfunctionings ...

29. Latest WHO definition • A disease is: • an interconnected set of one or more dysfunctions in one or more body systems including: • a pattern of signs, symptoms and findings (symptomatology - manifestations) • a pattern or patterns of development over time (course and outcome) • a common underlying causal mechanism (etiology) • linking to underling genetic factors (genotypes, phenotypes and endophenotypes) and to interacting environmental factors • and possibly: to a pattern or patterns of response to interventions (treatment response). Violates the principle of the a priori reality: diseases would only exist if we look for them.

30. ‘Ontology inspired’ definition • An organism (or part of an organism) is diseased if and only if • it includes among its parts pathological anatomical structures which compromise the organism’s physiological processes to the degree that they give rise to symptoms and signs. • An anatomical structure is pathological whenever: • it has come into being as a result of changes in some pre-existing canonical anatomical structure • through processes other than the expression of the normal complement of genes of an organism of the given type, and • is predisposed to have health-related consequences for the organism in question manifested by symptoms and signs. Smith B, Kumar A, Ceusters W, Rosse C. On carcinomas and other pathological entities. Comparative and Functional Genomics, Volume 6, Issue 7-8 (October - December 2005), p 379-387.

31. Some origines of pathological structures • At molecular level • Defective piece of DNA (“gene”) • Transcription mistakes or mutations • Random event • Environmental effect (radiation, chemical, virusses...) • Results in cellular dysfunction or structural damage • At higher levels of granularity • Traumatic  Results in cellular, organ or system damage

32. ‘Ontology inspired’ definition • An organism (or part of an organism) is diseased if and only if • it includes among its parts pathological anatomical structures which compromise the organism’s physiological processes to the degree that they give rise to symptoms and signs. • An anatomical structure is pathological whenever: • it has come into being as a result of changes in some pre-existing canonical anatomical structure • through processes other than the expression of the normal complement of genes of an organism of the given type, and • is predisposed to have health-related consequences for the organism in question manifested by symptoms and signs. A clever trick for not having us to commit at that time what a disease IS. Smith B, Kumar A, Ceusters W, Rosse C. On carcinomas and other pathological entities. Comparative and Functional Genomics, Volume 6, Issue 7-8 (October - December 2005), p 379-387.

33. 1st tentative definition of disease a disposition which, when realized, has health-related consequences for the well-being of the organism or any of its parts.

34. Somewhat problematic • Notion of “well-being” easily leads into circularity when associated with ‘non-diseased’. • ‘having health-related consequences’ may also be positive. • It says very little about the nature of the disposition.

35. 2nd tentative definition of disease A disease is a disposition acquired by a relatively isolated causal system (RICS) to have its external membrane or covering damaged through the coming into existence of a pathological structure.

36. An entity is a relatively isolated causal system iff (1) • The entity has an external boundary which is established via a physical covering or membrane which extends continuously across all or almost all of its surface. • The events transpiring within the entity have characteristic magnitudes which either fall or fall not within a certain spectrum of allowed values. The latter are distinguished by the fact that they will, in cumulation, lead to the entity’s ceasing to exist. Barry Smith and Berit Brogaard. Sixteen Days. Journal of Medicine and Philosophy 2003, Vol. 28, No. 1, pp. 45–78

37. An entity is a relatively isolated causal system iff (2) • The external membrane or covering serves as a shield to protect the entity from those causal influences deriving from its exterior which are likely to give rise to events which are outside its spectrum of allowed values. • The entity contains within itself its own mechanisms which are able to maintain (or, in cases of disturbance, to re-establish) sequences of events falling within the spectrum of allowed values. The entity also contains within itself mechanisms for reconstituting or replacing its external membrane or covering in case of damage. Barry Smith and Berit Brogaard. Sixteen Days. Journal of Medicine and Philosophy 2003, Vol. 28, No. 1, pp. 45–78

38. Entities qualifying as relatively isolated causal system • Organisms • Human beings • Unicellular organisms • ... • Certain parts of organisms • Cells • Organ systems • Some organs • Maximal portions of tissues Opens the possibility for an entity to be a disease of a body part without being a disease of the organism of which that body part is a part, yet being a disease in that organism.

39. But the definition requires working out: • At the level of biomedical reality: • What is a disease ? • What are the entities that cause a specific disease to exist or influence its course ? • What are the relationships between these entities and the disease ? • At the level of representational artifacts: • How do they relate to reality ? • How keeping track of changes in reality ?

40. Part 4: Diagnostic decision makingfrom an ontological and epistemological perspective How to come to a diagnosis ?

41. Some common notions given an ontological flavor • Clinical picture: • A spatiotemporal entity • Comparable to a theatre play • Which has temporal parts which form the course of the disease • Which has spatial parts which are the pathological formations and pathological anatomical structures. • Pathological entity: • Any part of a clinical picture. • Pathological process: • an organismal process that contributes to the dysfunctioning of the organism or any of its parts.

42. Disease and course of disease processual entity disposition ? actualized in Joe’s disease Joe’s disease’s course caused by part-of Creations of pathological formations and of pathological anatomical structures in Joe

43. Some counterintuitive aspects (1) • If in a RICS a disposition is realized in such a way that it can’t get that type of disease anymore (because the RICS will certainly die or becomes immune), then the “disease” would have come to an end, but it’s course not. • We tend to say “the disposition for the disease”, while the disposition IS the disease. • Thus perhaps better (?): • ‘Disease’  ‘disease-disposition’ • ‘Course of disease’  ‘disease’

44. Some counterintuitive aspects (2) • The creations of pathological formations and of pathological anatomical structures in Joe lead to new dispositions but are these dispositions distinct diseases ? • A virus enters one cell in Joe  1 disease ? • The virus enters a second cell  2nd disease ? • … But ! 1) The absence of counterintuitive notions associated with colloquial use of the word ‘disease’ is an illusion. They are there, but unnoticed. 2) Word usage is such that language treats disease as continuant.

45. Beliefs about diseases and clinical pictures (1) • A particular person may exhibit particular pathological entities. • A particular clinical picture starts to exist at the time the first pathological process that is a realization of a particular disease starts to exist. • A particular clinical picture ceases to exist when the last pathological process that is a realization of a particular disease comes to an end, and when there are no more pathological formations or pathological anatomical structures that were formed by the course of the disease.

46. Beliefs about the relevant portion of reality (2) • A particular disease exists in a particular person before a particular clinical picture is present in that person. • There can be no clinical picture without a disease. • A person may exhibit different particular diseases during his lifetime, some or all of them of the same disease type, and some or all of them at the same time or during overlapping time spans.

47. Beliefs about diseases and clinical pictures (3) • A clinical picture can continue to exist although its disease ceased to exist: • Remaining scars • Healthy carriers of virusses • Instances of the same disease may lead to non-similar clinical pictures, even in the same person.

48. Beliefs about the relevant portion of reality (4) • The course of some particular disease may lead to other particular diseases of the same or different disease types in a particular person. • Varicella (?) as a child, zoster as an adult • A particular disease of type A in one person may lead to a particular clinical picture of type B, while a particular disease of that same type A in another person may lead to a clinical picture of a totally different type. • …

49. On ‘findings’ and ‘observations’ (1) • A particular pathological entity may at a certain time be undetectable by any observation method or technique available to an observer, including the person exhibiting the pathological entity itself. • A particular observation may produce false results and thus simulate the existence of a pathological entity. • An observer may observe or fail to observe a detectable particular pathological entity.

50. On ‘findings’ and ‘observations’ (2) • When an observer perceives a particular pathological entity, he might judge it • (1) to be an instance of the universal of which it is indeed an instance in reality, • (2) to be an instance of another universal (and thus be in error), or • (3) he might be not able to make an association with any universal at all. • Distinct manifestations of ‘the same type’ may be pathological or not: • Singing naked under the shower versus in front of The White House • ...