Transcript So you want to be a clinical investigator

Vanderbilt University
General Clinical Research Center
So you want to be a clinical
investigator
David Robertson
Kinds of Clinical Research
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Human gene function
Human cell function
Clinical pathophysiology
Clinical pharmacology (therapeutics)
Clinical trials
Outcomes
Epidemiology
Patient Oriented Research
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Human gene function
Human cell function
Clinical pathophysiology
Clinical pharmacology (therapeutics)
Clinical trials
Outcomes
Interdependency
• Preclinical (Bench) Research
– Reductionist
• Clinical Research
– Integrative
• The interdependency is now absolute
• Bench research is the lingua franca
• Epidemiology
Current NIH-Funded Clinical Research
at Vanderbilt by Category
Molecular
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Outcome
26
Cellular
25
Clinical Trials
15
Clinical
Therapeutics
15
Clinical
Pathophysiol.
42
Epidemiology
12
Current NIH-Funded Clinical Research
at Vanderbilt by Category
Molecular
26
Outcome
26
Cellular
25
Clinical Trials
15
Clinical
Therapeutics
15
Clinical
Pathophysiol.
42
Epidemiology
12
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
CLINICAL RESEARCH: OLD PARADIGM
PHENOTYPE
PHYSIOME/
INTERMEDIATE
PHENOTYPE
PROTEOME
GENOME
Intermediate Phenotype
(Physiome or Phenome)
• Physiology Visualization (PET, fMRI,…)
• Physiological Assay (BME instruments)
• Analytical Assay (chemical, proteome)
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
CLINICAL RESEARCH: NEW PARADIGM
PHENOTYPE
PHYSIOME/
INTERMEDIATE
PHENOTYPE
PROTEOME
GENOME
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
CLINICAL RESEARCH: NEXT PARADIGM
PHENOTYPE
PHYSIOME/
INTERMEDIATE
PHENOTYPE
ENVIRONOME
PROTEOME
GENOME
Be a great physician
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Study your patients
Study your books
Study your journals
Study OMIM + links
Study your patients
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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
Maintain a targeted practice
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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
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
Develop Good Habits
• Make your tasks educational
• Be competent; know your methodology
• Remember that a scientific career is a
pleasure but also a business
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: 4454.
Periodicals for Master Clinicians
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New England Journal of Medicine
Journal of Clinical Investigation
Nature, Science, Cell
The New York Times
Consider The National Enquirer
At any given moment, have …
• 6 projects in planning
• 4 projects in process
• 2 projects in press
….Victor A. McKusick, Advice to Housemen, 1964
Education
• Medical Scientist Training Program
• Clinical Scholars Training Program
• Master’s in Clinical Investigation
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Genetics
Human Physiology
Biostatistics and Study Design
Bioinformatics
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)
Practicing Clinical Research
• Be a clear thinker
• Hypothesis-testing is the liturgy of POR
• Understand “biomarkers”
Biomarker
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Diagnostic Tool
Indicator of Disease
Disease Staging Tool
Tool to Monitor Intervention
Clinical Endpoint
A variable that reflects
how a patient
feels, functions, or survives.
Surrogate Endpoint
A Biomarker intended to substitute
for a clinical endpoint
The Perfect Surrogate
THERAPY
SURROGATE
CLINICAL
ENDPOINT
Vanderbilt University
General Clinical Research Center
Inpatient Facilities
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Room and board
Specialized equipment
Nursing support
Nutritional planning/analysis
Patient recruitment assistance
Outpatient Facilities
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Examining rooms
Physiological laboratories
Specialized equipment
Nursing support
Patient recruitment assistance
General GCRC Services
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Nursing support
Nutritional manipulation
Core laboratory tests
Study subject recruitment
Patient ancillary tests
– Chemistry
– Imaging
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
Core Laboratory
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DNA isolation
Energy balance
Mass spectrometry
Biochemical tests
Sleep studies/EEG
Informatics/Computing
• Data management services
• Biomedical engineering support
– BP; oximetry; sleep; hyperemia, etc.
• Statistical software
• Data storage
• Presentation hardware
GCRC
• The GCRC must not be the Jurassic Park of
the Biomedical Research Archipelago
• APOR:
• SFN:
average age 46 years
average age 32 years
So you want to be a clinical
investigator
Patients
Physiology
Genetics
Mice
Biological Marker (Biomarker)
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Objectively measured characteristic:
1) A normal biologic process
2) A pathogenic process
3) Response to intervention
LANDSCAPE OF PATIENT-ORIENTED RESEARCH
PHENOTYPE
ENVIRONOME
INTERMEDIATE
PHENOTYPE
PROTEOME
GENOME
Patient-Oriented Research:
The Old Paradigm
• Phenotype-Driven
• Aim: Intermediate Phenotype
• Relatively Data-Poor
Genome and Environome:
New POR Paradigm
Phenotype
Environome
Intermediate
Phenotype
Genome
Genome and Environome:
Old POR Paradigm
Phenotype
Environome
Intermediate
Phenotype
Genome
Patient-Oriented Research
Patient/Physician
In the Same Room
At the Same Time
And Both Are Alive
Biological Marker (Biomarker)
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Objectively measured characteristic:
1) A normal biologic process
2) A pathogenic process
3) Response to intervention
LANDSCAPE OF PATIENT-ORIENTED RESEARCH
PHENOTYPE
ENVIRONOME
INTERMEDIATE
PHENOTYPE
PROTEOME
GENOME
Patient-Oriented Research:
The Old Paradigm
• Phenotype-Driven
• Aim: Intermediate Phenotype
• Relatively Data-Poor
Genome and Environome:
New POR Paradigm
Phenotype
Environome
Intermediate
Phenotype
Genome
Genome and Environome:
Old POR Paradigm
Phenotype
Environome
Intermediate
Phenotype
Genome