1. Vanderbilt University General Clinical Research Center

2. So you want to be a clinical investigator David Robertson

3. Kinds of Clinical Research Human gene function Human cell function Clinical pathophysiology Clinical pharmacology (therapeutics) Clinical trials Outcomes Epidemiology

4. Patient Oriented Research Human gene function Human cell function Clinical pathophysiology Clinical pharmacology (therapeutics) Clinical trials Outcomes

5. Interdependency Preclinical (Bench) Research –Reductionist Clinical Research –Integrative The interdependency is now absolute Bench research is the lingua franca Epidemiology

8. Aphorisms You have to take care of yourself Enjoy writing grant proposals Select a mentor who is successful and who fights for proteges Help your mentor succeed; you may get his/her job Never do something that might be wrong: in research there may be no second chance; in clinical research there is usually no second chance

9. GENOME PROTEOME PHYSIOME/ INTERMEDIATE PHENOTYPE CLINICAL RESEARCH: OLD PARADIGM

10. Intermediate Phenotype (Physiome or Phenome) Physiology Visualization (PET, fMRI,…) Physiological Assay (BME instruments) Analytical Assay (chemical, proteome)

11. Patient-Oriented Research: The Old Paradigm Homogeneity Norm Phenotype-Driven Aim: Intermediate Phenotype Few Patients Relatively Data-Poor Hypertension High Blood Pressure Plasma Renin Activity Levels Maybe 6-20 Simple Statistics

12. GENOME PROTEOME PHYSIOME/ INTERMEDIATE PHENOTYPE CLINICAL RESEARCH: NEW PARADIGM

13. Patient-Oriented Research: The New Paradigm Heterogeneity Intermediate Phenotype-Driven Aim: Genotype Many Patients Relatively Data-Rich Non-Modulators RBF Angiotensin Dependence Polymorphism Familial Subgroups Complex Statistics

14. GENOME PROTEOME PHYSIOME/ INTERMEDIATE PHENOTYPE CLINICAL RESEARCH: NEXT PARADIGM ENVIRONOME

15. Be a great physician Study your patients Study your books Study your journals Study OMIM + links

16. Study your patients 2000 patients during residency Listen to your patients’ observations Master each H&P finding Rationalize each lab abnormality Maintain access to all 2000 H&Ps and summaries: they are your magnum opus Reexamine them each decade

17. Maintain a targeted practice Focus on one lifetime clinical area Choose that area with care Limit your practice to that area * Limit your practice to 10% effort * Manage all aspects of their care Look for heterogeneity Think laterally about your patients * may be difficult to do in 2003

18. Guides for Master Clinicians P. A. Tumulty: The Effective Clinician D. W. Cathell: The Physician Himself J. M. Orient: Sapira’s Art and Science of Bedside Diagnosis

19. Develop Good Habits Make your tasks educational Be competent; know your methodology Remember that a scientific career is a pleasure but also a business

20. Career Advice: The Far Side C. J. Sindermann, Winning the Games Scientists Play (Cambridge: Perseus) 2 nd edition. 2001 Richard J. Johns, How to Swim with Sharks, Trans Assoc Am Physicians. 1975; 88: 44- 54.

21. Periodicals for Master Clinicians New England Journal of Medicine Journal of Clinical Investigation Nature, Science, Cell The New York Times Consider The National Enquirer

22. At any given moment, have … 6 projects in planning 4 projects in process 2 projects in press ….Victor A. McKusick, Advice to Housemen, 1964

23. Education Medical Scientist Training Program Clinical Scholars Training Program Master’s in Clinical Investigation –Genetics –Human Physiology –Biostatistics and Study Design –Bioinformatics

24. Professional Organizations Association of American Physicians (AAP) American Society for Clinical Investigation (ASCI) American Federation for Medical Research (AFMR) Association for Patient-Oriented Research (APOR)

25. Practicing Clinical Research Be a clear thinker Hypothesis-testing is the liturgy of POR Understand “biomarkers”

26. Biomarker 1)Diagnostic Tool 2)Indicator of Disease 3)Disease Staging Tool 4)Tool to Monitor Intervention

27. Clinical Endpoint A variable that reflects how a patient feels, functions, or survives.

28. Surrogate Endpoint A Biomarker intended to substitute for a clinical endpoint

29. The Perfect Surrogate THERAPY SURROGATE CLINICAL ENDPOINT

30. Vanderbilt University General Clinical Research Center

31. Inpatient Facilities Room and board Specialized equipment Nursing support Nutritional planning/analysis Patient recruitment assistance

32. Outpatient Facilities Examining rooms Physiological laboratories Specialized equipment Nursing support Patient recruitment assistance

33. General GCRC Services Nursing support Nutritional manipulation Core laboratory tests Study subject recruitment Patient ancillary tests –Chemistry –Imaging

34. Nutrition Services to Investigators planning/calculating research diets assessing dietary intake inpatient metabolic diets outpatient dietary recalls dietary records food frequency questionnaires analyzing dietary information monitoring compliance

35. Core Laboratory DNA isolation Energy balance Mass spectrometry Biochemical tests Sleep studies/EEG

39. Informatics/Computing Data management services Biomedical engineering support –BP; oximetry; sleep; hyperemia, etc. Statistical software Data storage Presentation hardware

40. GCRC The GCRC must not be the Jurassic Park of the Biomedical Research Archipelago APOR: average age 46 years SFN: average age 32 years

41. So you want to be a clinical investigator Patients Physiology Genetics Mice

42. Biological Marker (Biomarker) Objectively measured characteristic: 1)A normal biologic process 2)A pathogenic process 3)Response to intervention

43. GENOME PROTEOME ENVIRONOME INTERMEDIATE PHENOTYPE LANDSCAPE OF PATIENT-ORIENTED RESEARCH

44. Patient-Oriented Research: The Old Paradigm Phenotype-Driven Aim: Intermediate Phenotype Relatively Data-Poor

45. Genome and Environome: New POR Paradigm Genome Intermediate Phenotype Environome

46. Genome and Environome: Old POR Paradigm Genome Intermediate Phenotype Environome

47. Patient-Oriented Research Patient/Physician In the Same Room At the Same Time And Both Are Alive

48. Biological Marker (Biomarker) Objectively measured characteristic: 1)A normal biologic process 2)A pathogenic process 3)Response to intervention

49. GENOME PROTEOME ENVIRONOME INTERMEDIATE PHENOTYPE LANDSCAPE OF PATIENT-ORIENTED RESEARCH

50. Patient-Oriented Research: The Old Paradigm Phenotype-Driven Aim: Intermediate Phenotype Relatively Data-Poor

51. Genome and Environome: New POR Paradigm Genome Intermediate Phenotype Environome

52. Genome and Environome: Old POR Paradigm Genome Intermediate Phenotype Environome