1. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Showcase Lecture Series: "Ontology, Bioinformatics and the Life Sciences" Ontology and the Future of Psychiatric Diagnosis Buffalo, NY, USA, Thursday October 19th, 2006 Werner CEUSTERS Center of Excellence in Bioinformatics and Life Sciences Department of Psychiatry National Center for Biomedical Ontology University at Buffalo, NY, USA

2. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Ontology and Psychiatry Ontology: –(roughly) the branch of philosophy that deals with what exists and with how the entities that exist relate to each other. –representing reality in IT systems Psychiatry: –(roughly) the branch of medicine that deals with the diagnosis, treatment, and prevention of mental and emotional disorders. Ontology applied to psychiatry: –Studying the nature of mental disorders and their place in pathological anatomy and pathophysiology; –Finding better ways to build IT systems to support the practice of psychiatry.

3. New York State Center of Excellence in Bioinformatics & Life Sciences R T U This could then be a very short presentation Their answer: –‘there are no biological abnormalities responsible for so-called mental illness, mental disease, or mental disorder, therefore mental illness has no biological existence. – Perhaps more importantly, however, mental illness also has no non-biological existence, – except in the sense that the term is used to indicate disapproval of some aspect of a person's mentality.’ Lawrence Stevens, J.D, 1999 The Antipsychiatry Coalition Their question: Does Mental Illness Exist?

4. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Their argument is based on the (narrow ?) definitions for disease. Most attempts refer to bodily issues: –STEDMAN (27th edition): An interruption, cessation, or disorder of body function, system, or organ. Syn: illness, morbus, sickness A morbid entity characterized usually by at least two of these criteria: recognized etiologic agent(s), identifiable group of signs and symptoms, or consistent anatomic alterations. –DORLAND any deviation from or interruption of the normal structure or function of a part, organ, or system of the body as manifested by characteristic symptoms and signs; the etiology, pathology, and prognosis may be known or unknown.

5. New York State Center of Excellence in Bioinformatics & Life Sciences R T U ‘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.

6. New York State Center of Excellence in Bioinformatics & Life Sciences R T U 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).

7. New York State Center of Excellence in Bioinformatics & Life Sciences R T U WHO constitution The State Parties to this Constitution declare, in conformity with the Charter of the United Nations, that the following principles are basic to the happiness, harmonious relations and security of all peoples: –Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity. –…

8. New York State Center of Excellence in Bioinformatics & Life Sciences R T U The “Myth of Mental Illness” “I maintain –that the mind is not the brain, –that mental functions are not reducible to brain functions, and –that mental diseases are not brain diseases, –indeed, that mental diseases are not diseases at all. When I assert the latter, I do not imply that distressing personal experiences and deviant behaviors do not exist. Anxiety, depression, and conflict do exist--in fact, are intrinsic to the human condition-- but they are not diseases in the pathological sense.” Thomas S. Szasz (MD), Mental Disorders Are Not Diseases. USA Today (Magazine) January 2000

9. New York State Center of Excellence in Bioinformatics & Life Sciences R T U The old debate on the “body-mind problem”… Dualistic views in Philosophy of Mind: –asserts the separate existence of mind and body –comes in various flavours: Ontological dualism –Substance dualism –Property dualism –Predicate dualism Interaction dualism Monistic views in Philosophy of Mind: Behaviourism Identity theory Functionalism Non-reductive physicalism …

10. New York State Center of Excellence in Bioinformatics & Life Sciences R T U … and its impact on Psychiatry Mental health professionals continue to employ a mind-brain dichotomy when reasoning about clinical cases. The more a behavioral problem is seen as originating in “psychological” processes, the more a patient tends to be viewed as responsible and blameworthy for his or her symptoms; conversely, the more behaviors are attributed to neurobiological causes, the less likely patients are to be viewed as responsible and blameworthy. Miresco MJ, Kirmayer LJ. The Persistence of Mind-Brain Dualism in Psychiatric Reasoning About Clinical Scenarios. Am J Psychiatry 2006; 163:913–918 But: Conducted in one institution Based on a questionnaire with voluntary submission Thus risk for major bias

11. New York State Center of Excellence in Bioinformatics & Life Sciences R T U A parallel: the ‘categorical – dimensional’ debate on the classification of mental disorders Rough distinction: –“Categorical”: ‘mental disorders’ can be classified as single, discrete and mutually exclusive types, of which a particular patient does or does not exhibit an instance. –“Dimensional”: any particular ‘mental disorder’ in a patient is an instance of just one single type and differences between cases are a matter of ‘scale’. ‘Rough’, because –the literature is huge and vague –descriptions are (philosophically) very incoherent

12. New York State Center of Excellence in Bioinformatics & Life Sciences R T U The categorical view Recognizes various mental disorder types Accepts that disorders are manifested through signs and symptoms, either ‘marker’ or ‘constitutional’ Provides diagnostic criteria to guide the clinician in making a diagnosis.

13. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Evolution of the DSM (1) Psychodynamic period: I and II, 1952-1980 –no sharp distinction between normal and abnormal. –psychosis / neurosis scale –all disorders viewed as reactions (leading to behavior) to environmental events, –everyone is more or less abnormal, –inclusion in the manual presumes abnormality. DSM-II contained “homosexuality” as mental disorder which was removed in 1973 by vote.

14. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Evolution of the DSM (2) Adoption of biomedical model: III, IV 1980 - –Clear distinction between normal/abnormal –Introduction of diagnostic criteria –Latest version is from 2000 DSM-V: foreseen for 2011

15. New York State Center of Excellence in Bioinformatics & Life Sciences R T U An example: Anxiety Disorders Acute Stress Disorder Agoraphobia Generalized Anxiety Disorder Obsessive-Compulsive Disorder Panic Disorder Posttraumatic Stress Disorder Separation Anxiety Disorder Social Phobia Specific Phobia

16. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Example of diagnostic criteria Severe and sustained impairment in social interaction The development of restricted, repetitive patterns of behaviour, interests, and activities. The disturbance must cause clinically significant impairment in social, occupational, or other important areas of functioning. In contrast to Autistic Disorder, there are no clinically significant delays in language (eg: single words are used by age 2 years, communicative phrases are used by age 3 years). There are no clinically significant delays in cognitive development or in the development of age-appropriate self-help skills, adaptive behaviour (other than in social interaction), and curiosity about the environment in childhood. The diagnosis is not given if the criteria are met for any other specific Pervasive Developmental Disorder or for Schizophrenia. Asperger Syndrome

17. New York State Center of Excellence in Bioinformatics & Life Sciences R T U ‘Making’ a DSM diagnosis Axis I: major mental disorders, developmental disorders and learning disabilities Axis II: underlying pervasive or personality conditions, as well as mental retardation Axis III: any nonpsychiatric medical condition ("somatic") Axis IV: social functioning and impact of symptoms Axis V: Global Assessment of Functioning (on a scale from 100 to 0)

18. New York State Center of Excellence in Bioinformatics & Life Sciences R T U By the way: frequent terminological confusions ‘Diseases and diagnoses are the principal ways in which illnesses are classified and quantified, and are vital in determining how clinicians organize health care.’ Ann Fam Med 1(1):44-51, 2003. ‘MedDRA […] is a standardized dictionary of medical terminology [ … which …] includes terminology for symptoms, signs, diseases and diagnoses.’ Medical Dictionary for Regulatory Activities

19. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Disease/disorder in SNOMED-CT

20. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Algorithmic approach (e.g. DSM-IVPC)

21. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Sometimes not really useful

22. New York State Center of Excellence in Bioinformatics & Life Sciences R T U DSM under fire (1) severely ill inpatients often meet criteria for more than one DSM-IV personality disorder  suggests a high rate of co-morbidity, however in absence of any medical or etiologic reason for such a situation many outpatients do not meet the criteria for any of the specific categories identified in DSM-IV; patients with the same categorical diagnosis often vary substantially with respect to which diagnostic criteria were used to make the diagnosis, so that two patients with the same diagnosis can manifest very different signs and symptoms;

23. New York State Center of Excellence in Bioinformatics & Life Sciences R T U DSM under fire (2) frequent revision of the diagnostic thresholds separating what is normal from what is disordered  it is as if given disorders would appear and disappear in course of time; a number of the diagnostic categories mentioned in DSM-IV lack any developing scientific base for an understanding of the corresponding disorder types

24. New York State Center of Excellence in Bioinformatics & Life Sciences R T U The Dimensional Approach (1) Mental processes and behavior follow traits/phenomena which are to be seen as continuous variables along continua on which all members of the population can be located. These continua extend to both normal and pathological phenotypes. These traits are on a par with properties such as temperature, weight, …  Homo sapiens is not further subdivided in subspecies according to weight, temperature, …

25. New York State Center of Excellence in Bioinformatics & Life Sciences R T U The Dimensional Approach (2) “Diagnostic categories defined by their syndromes should be regarded as valid only if they have been shown to be discrete entities with natural boundaries that separate them from other disorders.” “there is no empirical evidence for natural boundaries between major syndromes” … “the categorical approach is fundamentally flawed” Kendell R, Jablensky A. Distinguishing between the validity and utility of psychiatric diagnoses. Am J Psychiatry 2003; 160:4–12. Cloninger CR: A new conceptual paradigm from genetics and psychobiology for the science of mental health. Aust N Z J Psychiatry 33:174–186, 1999.

26. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Is there empirical evidence for this boundary ? And if not, do these mountains exist ?

27. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Then also these guys would be from the same species W.N. Kellogg, L.A. Kellogg. The Ape and The Child; A Comparative Study of the Environmental Influence Upon Early Behavior. Hafner Publishing Company, New York and London, 1967.

28. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Attempts to resolve the problem (1) Mental disorders as ‘practical kinds’ –‘stable patterns that can be identified with varying levels of reliability and validity’ and which are justified by their usefulness for specific purposes – such as giving an appropriate treatment Zachar, P. 2000b. Psychiatric disorders are not natural kinds. Philosophy, Psychiatry and Psychology 7:167–94.

29. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Basis: ‘epistemic value commitments’ ‘values involved in making and advancing epistemologically-relevant claims, such as scientific ones’: Coherence Consistency Comprehensiveness Fecundity Simplicity Instrumental efficacy Originality Relevance Precision JZ. Sadler. Epistemic Value Commitments in the Debate over Categorical vs. Dimensional Personality Diagnosis. Philosophy, Psychiatry, & Psychology 3.3 (1996) 203-222

30. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Attempts to resolve the problem (2) Non-arbitrary basis for drawing a categorical distinction This basis is an objective discontinuity The discontinuity is sharp and binary The discontinuity is constituted by an ‘essence’ No Yes Non-kind No Yes Practical kind No Yes Fuzzy kind No Yes Discrete kind Natural kind Haslam N. Kinds of Kinds: A Conceptual Taxonomy of Psychiatric Categories. Philosophy, Psychiatry, & Psychology, 9 (2002), 203-218 ‘severity’ ‘neuroticism’ ‘essential hypertension’ ‘depression’ ‘borderline personality’ ‘melancholia’‘Williams syndrome’

31. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Williams Syndrome www.thefencingpost.com/mary/www.williams.ngo.hu/ medgen.genetics.utah.ed u/.../pages/williams.htm http://www.williams-syndrome.org/ Williams Syndrome (WS) is a rare genetic disorder characterized by mild to moderate mental retardation or learning difficulties, a distinctive facial appearance, and a unique personality that combines overfriendliness and high levels of empathy with anxiety.

32. New York State Center of Excellence in Bioinformatics & Life Sciences R T U DSM-IV-TR currently plays it both ways “In DSM-IV, there is no assumption that each category of mental disorder is a completely discrete entity with absolute boundaries dividing it from other mental disorders or from no mental disorder” “DSM-IV is a categorical classification that divides mental disorders into types based on criterion sets with defining features” Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [DSM-IV-TR]; AmericanPsychiatric Association [APA], 2000, p. xxxi).

33. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Some desiderata: 1.generate acceptable definitions for mental disorder; disease and illness; 2.provide a framework for validating the correctness of assignments of instances to disorder categories; 3.provide assessment of the arguments to the effect that a dimensional view is needed in addition to the categorical view; 4.reduce the discrepancies between DSM-V and ICD-11; 5.ensure that DSM-V can be used cross-culturally; 6.ensure that DSM-V can be used in non-psychiatric settings. Kupfer DJ, First MB, Regier DA (eds.) A Research Agenda for DSM-V. American Psychiatric Association 2002. … but asks for research in preparation of DSM-V

34. New York State Center of Excellence in Bioinformatics & Life Sciences R T U to establish, among many other things, –under which circumstances one or the other of the two views should be adopted, –the categories which will then need to be recognized, and –the thresholds for associated criteria. The proposed research is to be based on large scale cross-cultural clinical, genetic, pathophysiologic, etiologic and outcome assessments, … but asks for research in preparation of DSM-V and thus requires the collection of vast amounts of data of diverse sorts.

35. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Our proposal 1.Address the theoretical issues in the research agenda within the framework of 1.Basic Formal Ontology 2.Granular Partition Theory 3.as they are applied in the Ontology of Biomedical Reality. 2.Use Referent Tracking for keeping track of the instance data that will be generated when carrying out the field studies.

36. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Applicability criteria give mental health patients the best possible care in spite of ongoing changes and controversies in psychiatry, allow health care workers to remain faithful to their existing beliefs as concerns mental disorders as long as these beliefs do not stand in conflict with accumulated evidence, minimize the burden of carrying out the data collection, especially when the data are to be collected by clinicians not directly involved in the studies, ensure that the data remain useful even when research questions change, and satisfy privacy and security issues as expressed in HIPAA rules and other provisions.

37. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Basic Formal Ontology (BFO) Based on philosophical realism –acknowledge only those entities which exist in biological reality, –reject all those types of putative negative entities – absences, non-existents, possibilia, and the like – which are postulated merely as artifacts of specific logical or computational frameworks. –BFO can accept the existence of processes such as ‘developing peer relationships’ or ‘seeking to share enjoyment’, but not the ‘existence’ of absences thereof which are two criteria for autistic disorder. Fundamental distinctions: –Particulars (p) / universals (u) –Continuants / occurrents –Dependent / independent entities –3 major sorts of relations: Grenon P, Smith B, Goldberg L. Biodynamic ontology: applying BFO in the biomedical domain. In DM Pisanelli (ed.), Ontologies in Medicine, Amsterdam: IOS Press, 2004, p. 20-38.

38. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Granular Partition Theory A highly general framework for understanding the ways in which, when cataloguing, classifying, mapping or diagnosing a certain portion of reality, we divide up or partition this reality at one or more levels of granularity. Applied in a calculus for quality assurance in evolving ontologies and data-repositories by distinguishing: (1) the level of reality (2) the cognitive representations of this reality (3) the publicly accessible concretizations of these cognitive representations in artifacts of various sorts. Bittner T, Smith, B. A taxonomy of granular partitions, in D Montello (ed.), Spatial Information Theory. (Lecture Notes in Computer Science 2205), 28–43. Ceusters W, Smith B. A Realism-Based Approach to the Evolution of Biomedical Ontologies. Forthcoming in Proceedings of AMIA 2006, Washington DC, November 11-15, 2006.

39. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Purpose: –explicit reference 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 Referent Tracking Ceusters W, Smith B. Strategies for Referent Tracking in Electronic Health Records. J Biomed Inform. 2006 Jun;39(3):362-78.

40. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Essentials of Referent Tracking Generation of universally unique identifiers; deciding what particulars should receive a IUI; finding out whether or not a particular has already been assigned a IUI (each particular should receive maximally one IUI); using IUIs in the EHR, i.e. issues concerning the syntax and semantics of statements containing IUIs; determining the truth values of statements in which IUIs are used; correcting errors in the assignment of IUIs.

41. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Work in progress Required (core) ontological entities –For sure: normal anatomical structure, pathological anatomical structure, pathological formation, organismal process, pathological process, disease, course of disease, clinical picture –Probably: behavioural process, behavioural quality, cognitive process, sign, symptom

42. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Some temptative definitions (1) ‘pathological process’: –an organismal process that contributes to the dysfunctioning of an anatomical structure within the same organism. ‘disease’: –a disposition which, when realized, affects the well- being of the organism or any of its parts. this entity is NOT what usually is referred to by the term ‘disease’ in general medical language.

43. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Some temptative definitions (2) ‘course of disease’: –the process composed of pathological processes that realize the disease. ‘clinical picture’: –the unit, comparable to physical-behavioural units in which organisms behave, formed by the course of the disease and the anatomical structures and pathological formations that participate in the pathological processes, and, by its nature, has both temporal and spatial parts.

44. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Beliefs about the relevant portion of reality (1) P1.A particular person may exhibit parts of a clinical picture. –Most relevant in the domain of psychiatry are pathological behavioural or cognitive processes such as tics, confabulations, perseverations and abnormal thought formations. P2.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. –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.

45. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Beliefs about the relevant portion of reality (2) P3.A particular disease exists in a particular person before a particular clinical picture is present in that person. P4.There can be no clinical picture without a disease. P5.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.

46. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Beliefs about the relevant portion of reality (3) P6.The course of some particular disease may lead to other particular diseases of the same or different disease types in a particular person. P7.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. …

47. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Application in preparation of DSM-V (1) For each ‘mental disorder’ –Express the criteria in terms of the core ontological entities and their possible co-occurrence in concrete cases For each particular case (‘disorder in patient’) –Describe the case using the core ontological entities and their actual co-occurrence, i.e. Assign IUIs Express in RT-formalism

48. New York State Center of Excellence in Bioinformatics & Life Sciences R T U Application in preparation of DSM-V (2) Create an adequate IT infrastructure: –For case registration: RTU-based electronic patient record –For data collection: RTU back-end Use the DSM-criteria as hypotheses that need to be validated on the basis of the data collected, and adjust when needed.