Vanderbilt University General Clinical Research Center

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

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

11. 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 Patient-Oriented Research:The Old Paradigm

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

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

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

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) 2nd 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 • Diagnostic Tool • Indicator of Disease • Disease Staging Tool • 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: • A normal biologic process • A pathogenic process • Response to intervention

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

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

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

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

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: • A normal biologic process • A pathogenic process • Response to intervention

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

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