Vanderbilt University General Clinical Research Center
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Transcript of Vanderbilt University General Clinical Research Center
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Vanderbilt University General Clinical Research Center
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So you want to be a clinical investigator
David Robertson
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Kinds of Clinical Research
• Human gene function
• Human cell function
• Clinical pathophysiology
• Clinical pharmacology (therapeutics)
• Clinical trials
• Outcomes
• Epidemiology
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Patient Oriented Research
• Human gene function
• Human cell function
• Clinical pathophysiology
• Clinical pharmacology (therapeutics)
• Clinical trials
• Outcomes
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Interdependency
• Preclinical (Bench) Research– Reductionist
• Clinical Research– Integrative
• The interdependency is now absolute
• Bench research is the lingua franca
• Epidemiology
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Current NIH-Funded Clinical Research at Vanderbilt by Category
Molecular26
Epidemiology12
Clinical Pathophysiol.
42
Outcome26
Cellular25
Clinical Therapeutics
15
Clinical Trials15
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Current NIH-Funded Clinical Research at Vanderbilt by Category
Molecular26
Epidemiology12
Clinical Pathophysiol.
42
Outcome26
Cellular25
Clinical Therapeutics
15
Clinical Trials15
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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
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GENOME
PROTEOME
PHYSIOME/INTERMEDIATE
PHENOTYPE
PHENOTYPE
CLINICAL RESEARCH: OLD PARADIGM
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Intermediate Phenotype(Physiome or Phenome)
• Physiology Visualization (PET, fMRI,…)
• Physiological Assay (BME instruments)
• Analytical Assay (chemical, proteome)
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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
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GENOME
PROTEOME
PHYSIOME/INTERMEDIATE
PHENOTYPE
PHENOTYPE
CLINICAL RESEARCH: NEW PARADIGM
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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
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GENOME
PROTEOME
PHYSIOME/INTERMEDIATE
PHENOTYPE
PHENOTYPE
CLINICAL RESEARCH: NEXT PARADIGM
ENVIRONOME
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Be a great physician
• Study your patients
• Study your books
• Study your journals
• Study OMIM + links
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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
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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
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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
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Develop Good Habits
• Make your tasks educational
• Be competent; know your methodology
• Remember that a scientific career is a pleasure but also a business
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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.
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Periodicals for Master Clinicians
• New England Journal of Medicine
• Journal of Clinical Investigation
• Nature, Science, Cell
• The New York Times
• Consider The National Enquirer
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At any given moment, have …
• 6 projects in planning
• 4 projects in process
• 2 projects in press
….Victor A. McKusick, Advice to Housemen, 1964
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Education
• Medical Scientist Training Program
• Clinical Scholars Training Program
• Master’s in Clinical Investigation– Genetics– Human Physiology– Biostatistics and Study Design– Bioinformatics
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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)
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Practicing Clinical Research
• Be a clear thinker
• Hypothesis-testing is the liturgy of POR
• Understand “biomarkers”
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Biomarker
1) Diagnostic Tool
2) Indicator of Disease
3) Disease Staging Tool
4) Tool to Monitor Intervention
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Clinical Endpoint
A variable that reflects how a patientfeels, functions, or survives.
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Surrogate Endpoint
A Biomarker intended to substitutefor a clinical endpoint
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The Perfect Surrogate
THERAPY
SURROGATE
CLINICALENDPOINT
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Vanderbilt University General Clinical Research Center
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Inpatient Facilities
• Room and board
• Specialized equipment
• Nursing support
• Nutritional planning/analysis
• Patient recruitment assistance
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Outpatient Facilities
• Examining rooms
• Physiological laboratories
• Specialized equipment
• Nursing support
• Patient recruitment assistance
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General GCRC Services
• Nursing support
• Nutritional manipulation
• Core laboratory tests
• Study subject recruitment
• Patient ancillary tests– Chemistry– Imaging
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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
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Core Laboratory
• DNA isolation
• Energy balance
• Mass spectrometry
• Biochemical tests
• Sleep studies/EEG
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Informatics/Computing
• Data management services
• Biomedical engineering support– BP; oximetry; sleep; hyperemia, etc.
• Statistical software
• Data storage
• Presentation hardware
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GCRC
• The GCRC must not be the Jurassic Park of the Biomedical Research Archipelago
• APOR: average age 46 years
• SFN: average age 32 years
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So you want to be a clinical investigator
Patients
Physiology
Genetics
Mice
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Biological Marker (Biomarker)
• Objectively measured characteristic:1) A normal biologic process
2) A pathogenic process
3) Response to intervention
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GENOME
PROTEOME
ENVIRONOME INTERMEDIATEPHENOTYPE
PHENOTYPE
LANDSCAPE OF PATIENT-ORIENTED RESEARCH
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Patient-Oriented Research:The Old Paradigm
• Phenotype-Driven
• Aim: Intermediate Phenotype
• Relatively Data-Poor
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Genome and Environome:New POR Paradigm
Genome
IntermediatePhenotype
Phenotype
Environome
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Genome and Environome:Old POR Paradigm
Genome
IntermediatePhenotype
Phenotype
Environome
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Patient-Oriented Research
Patient/PhysicianIn the Same RoomAt the Same TimeAnd Both Are Alive
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Biological Marker (Biomarker)
• Objectively measured characteristic:1) A normal biologic process
2) A pathogenic process
3) Response to intervention
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GENOME
PROTEOME
ENVIRONOME INTERMEDIATEPHENOTYPE
PHENOTYPE
LANDSCAPE OF PATIENT-ORIENTED RESEARCH
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Patient-Oriented Research:The Old Paradigm
• Phenotype-Driven
• Aim: Intermediate Phenotype
• Relatively Data-Poor
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Genome and Environome:New POR Paradigm
Genome
IntermediatePhenotype
Phenotype
Environome
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Genome and Environome:Old POR Paradigm
Genome
IntermediatePhenotype
Phenotype
Environome