Werner CEUSTERS, MD Center of Excellence in Bioinformatics and Life Sciences

1. Grand Rounds, PsychiatryAdvancing Translational Researchin Psychiatry throughRealism-based OntologyUVM College of Medicine - Department of Psychiatry Fletcher Allen Health CareBurlington, VT, USA,August 15, 2008 Werner CEUSTERS, MD Center of Excellence in Bioinformatics and Life Sciences

2. 1959 - 2008 Short personal history 1977 2006 2004 1989 1992 2002 1995 1998 1993

3. Past work and research in Psychiatry • 1990-1991 Head of Department of Neuropsychiatry, Military Hospital Soest, Germany. • 1990-1993 Consultant in Medical Informatics, Department of Psychiatry, University Hospital of Ghent. • 1990 Egmond Prize for Medical Informatics (1990) (for automated observation scale for psychiatric in-patients). • 1990 Dutch and Belgian Medical Informatics Conference Prize of the Belgian Society for Medical Informatics (for best paper and presentation). • 1991-1992 Member, Belgian Ministry of Health Working Group on the Registration of Psychiatric Patients. • 1991-1999 Neuropsychiatrist, Queen Astrid Military Hospital of Brussels. • 1994-1998 Member, Mental Health Standards Working Group of WHO, Division of Mental Health. • Ceusters W, Van de Wiele L, Van Moffaert M. Therapeutical value of an automated observation scale for psychiatric inpatients, in MIC-Proceedings 1990, Noordwijkerhout, The Netherlands, Nov 9-10, 1990;:212-23. • Ceusters W, De Cuypere G, Jannes C, Hoes M, Pluymakers J. Rational and efficient use of computers in psychiatry: the AMDP as a European standard for psychiatric record systems ? in: Proc MIC 1991, Willems JL (ed.), 1991;:117-126. • Ceusters W, Smith B. Referent Tracking for Treatment Optimisation in Schizophrenic Patients. Journal of Web Semantics 4(3) 2006:229-36;

4. Ongoing Research in Psychiatry • ‘UB Task Force for ontology-based IT support for large scale field studies in Psychiatry’ • Sponsor: John R. Oishei Foundation ($148,328) • Specific aims: • to assess the functional and technical requirements to be fulfilled by a data management system able to do justice to both the dimensional and categorical approach in psychiatric diagnosis; • to design an implementation and funding plan for the technical infrastructure to be built in order to support data collection and analyses in large-scale field studies in psychiatry, and; • to initiate the collaborations needed to deliver data collection and analyses services to provide the answers to the questions raised in the DSM-V research agenda.

5. What has this research to do with translational medicine ?

6. Presentation overview • Some key aspects of Translational Research • Philosophy & Psychiatry • Ontology & Informatics • Connecting the dots: a holistic approach to Evidence Based Medicine (in Vermont)

7. I. Translational Research What is it ?

8. Translational Research • Research in which ideas, insights, and discoveries generated through basic scientific inquiry are applied to the treatment or prevention of human disease. • Two categories: • T1: from ‘bench to bedside’ • T2: from bedside to community: enhance adoption of effective programs and practices

9. Further distinctions translation to humans translation to patients translation to practice Westfall, J. M. et al. JAMA 2007;297:403-406.

10. Translational Research & NIMH • Division of Developmental Translational Research • promotes an integrated program of research across basic behavioral/psychological processes, environmental processes, brain development, pediatric psychopathology and therapeutic interventions. • Division of Adult Translational Research and Treatment Development • understanding the pathophysiology of mental illness and hastening the translation of behavioral science and neuroscience advances into innovations in clinical care. • Geriatric Translational Neuroscience Program • Geriatric Translational Behavioral Science Program

11. Translational psychiatry behavior cognitive functionings Cellular events • Forward translational psychiatry: • attempts to explain how neuronal activity, beginning at the molecular level, 'translates' to elicitation of behavior • Reverse translational psychiatry: • attempts to determine the molecular underpinnings that contribute to the expression of abnormal behavior.

12. medgen.genetics.utah.edu/.../pages/williams.htm www.thefencingpost.com/mary/ www.williams.ngo.hu/ http://www.williams-syndrome.org/ A key challenge: understanding how disorders at molecular level lead to disorders at mesoscopic level Williams Syndrome: 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. Any ideas about the above ?

13. Difficult process Conflicting outcomes Another key challenge: multi-disciplinaritye.g.: Translational Research and the cause of Alzheimer Disease • mouse genetics • cell biology • animal neuropsychology • protein biochemistry • neuropathology • … Disciplines Hypotheses • ADDL • Amyloid cascade • Alternative amyloid cascade • …

14. Barriers for Translational Research Sung NS et al. Central challenges facing the national clinical research enterprise. JAMA. 2003;289:1278–1287.

15. Common approach: semantic annotation of scientific data Amit Sheth. Semantic Web Technology in Support of Bioinformatics for Glycan Expression. W3C workshop on Semantic Web for Life Sciences, October 28, 2004, Cambridge MA

16. Lost in translation Various reporting formalisms and data formats Various levels of granularity

17. Not the least in … psychiatry BTP: Barriers for translational psychiatry =BTR: barriers for translational researchop?BPR: barriers for psychiatric research BTP = BTR+BPR or BTR*BPR or BTR(BPR) ?

18. II. Philosophy & Psychiatry

19. A little test: who said … • “Too little attention has been paid in psychiatric education and training to the philosophical underpinnings of our field, and we believe that many problems with the way in which psychiatry is both perceived from the outside and practiced from the inside are attributable to a lack of clarity - or simply an absence of thought - on this topic.” Waterman, GS. & Schwartz, RJ. The Mind-Body Problem. Letter to the Editor. Am J Psychiatry 159:878-879, May 2002

20. 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 research in and practice of psychiatry.

21. ‘Ontology’ as the study of what exists • Key questions: • What exists ? • How do things that exist relate to each other ? • Some hypotheses: • An external reality, time, space • Ideas, concepts • Particulars, universals, objects, processes • God • Ontologists from distinct ‘schools’ differ in opinion about the existence of some of the above: • Realism, nominalism, conceptualism, monism, …

22. TheAntipsychiatryCoalition A parallel: some wonder whether ‘mental disorders’ exist • ‘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

23. 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

24. Another 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. DSM • “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

25. DSM under fire • severely ill inpatients often meet criteria for more than one DSM-IV personality disorder; • 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 signs and symptoms; • frequent revision of the diagnostic thresholds separating what is normal from what is disordered; • a number of the diagnostic categories mentioned in DSM-IV lack any developing scientific base for an understanding of the corresponding disorder types.

26. Medical Models and the Dimensions of Categorization • ‘Theories about […] psychiatric disorders […] often contain a range of assumptions about what counts as real, valid, relevant, and useful. They also often assume different notions about the nature of causal processes in psychiatric illness.’ Zachar P, Kendler KS. Psychiatric Disorders: A Conceptual Taxonomy. Am J Psychiatry 2007; 164:557–565

27. But: some dimensionalists also use flawed arguments • “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.

28. Is there empirical evidence for this boundary ? And if not, do these mountains exist ?

29. Key issue: constructs & reality www.perseus.tufts.edu/.../Hpix/1992.06.1227.jpeg mcgonnigle.files.wordpress.com/.../lightning.jpg Just as what used to be seen as Zeus’s thunderbolts can still be lethal, what is currently referred to as mind can certainly be—and clearly is—causally efficacious. Waterman, GS. & Schwartz, RJ. The Mind-Body Problem. Letter to the Editor. Am J Psychiatry 159:878-879, May 2002

30. 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.

31. 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

32. No Yes No Yes No Yes No Yes Non-kind Practical kind Fuzzy kind Discrete kind Attempts to resolve the problem (2) Non-arbitrary basis for drawing a categorical distinction Haslam N. Kinds of Kinds: A Conceptual Taxonomy of Psychiatric Categories. Philosophy, Psychiatry, & Psychology, 9 (2002), 203-218 This basis is an objective discontinuity ‘severity’ ‘neuroticism’ The discontinuity is sharp and binary ‘essential hypertension’ ‘depression’ The discontinuity is constituted by an ‘essence’ ‘borderline personality’ Natural kind ‘melancholia’ ‘Williams syndrome’

33. DSM-IV-TR currently plays it both ways • “In DSM-IV, there is no assumption that each category of mental disorderis a completely discrete entity with absolute boundaries dividing it fromother mental disorders or from no mental disorder” • “DSM-IV is a categoricalclassification that divides mental disorders into types based on criterionsets with defining features” Diagnostic and StatisticalManual of Mental Disorders, 4th Edition, Text Revision [DSM-IV-TR]; AmericanPsychiatric Association [APA], 2000, p. xxxi).

34. … but asks for research in preparation of DSM-V • Some desiderata: • generate acceptable definitions for mental disorder; disease and illness; • provide a framework for validating the correctness of assignments of instances to disorder categories; • provide assessment of the arguments to the effect that a dimensional view is needed in addition to the categorical view; • reduce the discrepancies between DSM-V and ICD-11; • ensure that DSM-V can be used cross-culturally; • 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.

35. … but asks for research in preparation of DSM-V • 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, and thus requires the collection of vast amounts of data of diverse sorts.

36. III. Ontology and Informatics

37. Realism Conceptualism Nominalism Universal Concept Collection of particulars yes: in particulars perhaps: in minds no Three major views on reality • Basic questions: • What does a general term such as ‘psychosis’ refer to? • Do generic things exist?

38. Types of realism • Naive realism: • things really are as they seem • Scientific realism: • things really are as science determines (or ultimately will determine) them to be • science discovers objective truths

39. Reality universals particulars Scientific Research (realism-based) William M.K. Trochim. Idea of Construct Validity. Research Method Knowledge Base 2006. http://www.socialresearchmethods.net/kb/considea.php

40. Realism-based ontology • Basic assumptions: • reality exists objectively in itself, i.e. independent of the perceptions or beliefs of cognitive beings; • reality, including its structure, is accessible to us, and can be discovered through (scientific) research; • the quality of an ontology is at least determined by the accuracy with which its structure mimics the pre-existing structure of reality.

41. 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 Representation and Reference representational units cognitive units communicative units universals particulars First Order Reality

42. Realist ontology: a modern version of Alberti’s grid !

43. 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

44. 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.

45. IV. Connecting the dots in Vermont

46. Vermont Health Information Technology Plan • Core objectives for 2007-2012: • increase the amount of health information that exists in electronic form, i.e. in electronic health record systems • achieve a secure electronic health information exchange to achieve the plan’s vision. • empower consumers to take an active role in electronic health information initiatives in Vermont. • enable public health agencies to use HIT to monitor and ensure the public’s health more transparently and quickly

47. Some key choices identified in VHITP • Appropriate national standards for technical, semantic, and process interoperability; • But cave: too many “standards” for semantic interoperability exhibit one or more problems: • very superficial semantics • bad design • no solid foundation (lack a serious benchmark) • not compatible with other standards • A hybrid technology architecture with both centralized and distributed data service components;

48. Adoption ofthe (Chronic) Care Model Wagner EH, Austin BT, Davis C, Hindmarsh M, Schaefer J, Bonomi A. Improving chronic illness care: translating evidence into action. Health Aff (Millwood). 2001;20:64

49. CCM: Clinical Information Systems • Provide reminders for providers and patients • Identify relevant patient subpopulations for proactive care • Facilitate individual patient care planning • Share information with providers and patients • Monitor performance of team and system

50. ACIC 3.5: Clinical Information SystemsScores