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

1. Grand Rounds, Department of PsychiatryAdvancing Translational Researchin Psychiatry throughRealism-based Ontology andReferent TrackingBuffalo, NY,February 13, 2009 Werner CEUSTERS, MD Center of Excellence in Bioinformatics and Life Sciences Department of Psychiatry, SUNY at Buffalo

2. Presentation overview • Some key aspects of Translational Research • Philosophy & Psychiatry • Ontology & Informatics • Referent Tracking • Summary

3. ‘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 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.

4. I. Translational Research What is it ?

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

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

7. 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.

8. 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.

9. 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 • …

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

11. With the sad result … • Why most published research findings are false. Ioannidis JPA (2005). PLoS Med 2(8): e124. • Institute for Clinical Research and Health Policy Studies, Department of Medicine, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts. • Why Current Publication Practices May Distort Science. Young NS, Ioannidis JPA, Al-Ubaydli O (2008, October 7) PLoS Med 5(10): e201. doi:10.1371/journal.pmed.0050201. • Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland,

12. Key question: Why is this ?

13. ‘The spectrum of the Health Sciences’ Turning data in knowledge http://www.uvm.edu/~ccts

14. ? What is missing here ? Turning data in knowledge http://www.uvm.edu/~ccts

15. Source of all data Reality !

16. data organization model development further R&D (instrument and study optimization) add verify use Δ= outcome Generic beliefs application Today’s data generation and use observation & measurement

17. representation reality Key components data information generates generates generates influences • Players • HIT • Outcomes knowledge hypotheses about

18. Current deficiencies • At the level of reality: • Desired outcomes different for distinct players • Competing interests • Multitude of HIT applications and paradigms • At the level of representations: • Variety of formats • Silo formation • Doubtful semantics • In their interplay: • Very poor provenance or history keeping • No formal link with that what the data are about • Low quality

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

20. Most importantly: a misunderstanding about what it is to define something ! • e.g.: ‘The symptoms of ASD [Autism Spectrum Disorders ] appear before age three, by definition, …’ Autism Spectrum Disorders (ASD) Services Roadmap Presented to Interagency Autism Coordinating Committee May 16, 2005 http://iacc.hhs.gov/reports/2005/services-subcommittee-report-may16.shtml

21. Realism-based Ontology Major problems Solutions • A mismatch between what is - and has been - the case in reality, and representations thereof in: • (generic) Knowledge repositories, and • (specific) Data and Information repositories. • An inadequate integration of a) and b). P h i l o s o p h y H I T Philosophical realism Referent Tracking

22. II. Philosophy & Psychiatry

23. Also sprach … • “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

24. Ontology • Ontology: • (roughly) the branch of philosophy that deals with what exists and with how the entities that exist relate to each other. • a method for representing reality in IT systems • Such a representation is an ontology

25. ‘Ontology’ in PubMed

26. 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. • a method for 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.

27. TheAntipsychiatryCoalition 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

28. 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

29. 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

30. The categorical approach 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.

31. 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.

33. Attempts to resolve the problem • 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.

34. 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

35. III. Ontology and Informatics

36. 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?

37. 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

38. 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.

39. 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

40. Representation and the three levels Level 1, 2 or 3 Level 2 or 3 Level 3 Level 1 unique identifiers

41. The distinction helps to solve puzzles • On September 9th, 1935, Carl Austin Weiss shot Senator Huey Long in the Louisiana State Capitol with a .35 calibre pistol. Long died from this wound thirty hours later on September 10th. Weiss, on the other hand, received between thirty-two and sixty .44 and .45 calibre hollow point bullets from Long's agitated bodyguards and died immediately. Sorensen, R., 1985, "Self-Deception and Scattered Events", Mind, 94: 64-69. • Questions: • Did Weiss kill Senator Long ? • If so, when did he kill him ? It’s all in ‘definitions’

42. What does it mean ‘to define something’ ? Autism Spectrum Disorder ‘ASD’ ‘Autism Spectrum Disorder’

43. What does it mean ‘to define something’ ? Under what circumstances am I allowed in my community to use the word ‘ASD’ to denote some thing in reality ? Autism Spectrum Disorder ‘ASD’ ‘Autism Spectrum Disorder’

44. What does it mean ‘to define something’ ? • What are the essential characteristics that distinguish ASD from other things ? Autism Spectrum Disorder ‘ASD’ ‘Autism Spectrum Disorder’

45. What does it mean ‘to define something’ ? • How to determine whether the thing from which this boy suffers is an ASD ? Autism Spectrum Disorder ‘ASD’ ‘Autism Spectrum Disorder’

46. generic specific Human understanding and communication First-order reality How can we know what ASD ‘really’ is ? ‘ASD’ ASD ‘ASD’

47. generic specific Human understanding and communication First-order reality In what way do the corner-denotations interact ? Scientific discovery ‘ASD’ ASD Case study Convention Convention ‘ASD’ Convention

48. Basic Formal Ontology Continuant Occurrent (always dependent on one or more independent continuants) Spatial Region Independent Continuant Dependent Continuant Role Function Quality Propensity Process Temporal Region

49. GRANULARITY Open Biomedical Ontology Foundry RELATION TO TIME

50. Referent Tracking