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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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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CLINICAL RESEARCH OLD PARADIGM
PHENOTYPE
PHYSIOME/ INTERMEDIATE PHENOTYPE
PROTEOME
GENOME
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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 ResearchThe 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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CLINICAL RESEARCH NEW PARADIGM
PHENOTYPE
PHYSIOME/ INTERMEDIATE PHENOTYPE
PROTEOME
GENOME
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Patient-Oriented ResearchThe 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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CLINICAL RESEARCH NEXT PARADIGM
PHENOTYPE
ENVIRONOME
PHYSIOME/ INTERMEDIATE PHENOTYPE
PROTEOME
GENOME
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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 HP finding
• Rationalize each lab abnormality
• Maintain access to all 2000 HPs 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 Sapiras 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
• Masters 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 patient feels,
functions, or survives.
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Surrogate Endpoint
A Biomarker intended to substitute for a
clinical endpoint
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The Perfect Surrogate
THERAPY
SURROGATE
CLINICAL ENDPOINT
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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
• A normal biologic process
• A pathogenic process
• Response to intervention

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LANDSCAPE OF PATIENT-ORIENTED RESEARCH
PHENOTYPE
ENVIRONOME
INTERMEDIATE PHENOTYPE
PROTEOME
GENOME
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Patient-Oriented ResearchThe Old Paradigm

• Phenotype-Driven
• Aim Intermediate Phenotype
• Relatively Data-Poor

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Genome and EnvironomeNew POR Paradigm
Phenotype
Environome
Intermediate Phenotype
Genome
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Genome and EnvironomeOld POR Paradigm
Phenotype
Environome
Intermediate Phenotype
Genome
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Patient-Oriented Research
Patient/Physician In the Same Room At the Same
Time And Both Are Alive
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Biological Marker (Biomarker)

• Objectively measured characteristic
• A normal biologic process
• A pathogenic process
• Response to intervention

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LANDSCAPE OF PATIENT-ORIENTED RESEARCH
PHENOTYPE
ENVIRONOME
INTERMEDIATE PHENOTYPE
PROTEOME
GENOME
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Patient-Oriented ResearchThe Old Paradigm

• Phenotype-Driven
• Aim Intermediate Phenotype
• Relatively Data-Poor

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Genome and EnvironomeNew POR Paradigm
Phenotype
Environome
Intermediate Phenotype
Genome
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Genome and EnvironomeOld POR Paradigm
Phenotype
Environome
Intermediate Phenotype
Genome