Vanderbilt University General Clinical Research Center

So you want to be a clinical investigator

David Robertson

Kinds of Clinical Research

• Human gene function

• Human cell function

• Clinical pathophysiology

• Clinical pharmacology (therapeutics)

• Clinical trials

• Outcomes

• Epidemiology

Patient Oriented Research

• 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

Molecular26

Epidemiology12

Clinical Pathophysiol.

42

Outcome26

Cellular25

Clinical Therapeutics

15

Clinical Trials15

Current NIH-Funded Clinical Research at Vanderbilt by Category

Molecular26

Epidemiology12

Clinical Pathophysiol.

42

Outcome26

Cellular25

Clinical Therapeutics

15

Clinical Trials15

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

GENOME

PROTEOME

PHYSIOME/INTERMEDIATE

PHENOTYPE

PHENOTYPE

CLINICAL RESEARCH: OLD PARADIGM

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

GENOME

PROTEOME

PHYSIOME/INTERMEDIATE

PHENOTYPE

PHENOTYPE

CLINICAL RESEARCH: NEW PARADIGM

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

GENOME

PROTEOME

PHYSIOME/INTERMEDIATE

PHENOTYPE

PHENOTYPE

CLINICAL RESEARCH: NEXT PARADIGM

ENVIRONOME

Be a great physician

• Study your patients

• Study your books

• Study your journals

• Study OMIM + links

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

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

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: 44-54.

Periodicals for Master Clinicians

• 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– 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

1) Diagnostic Tool

2) Indicator of Disease

3) Disease Staging Tool

4) Tool to Monitor Intervention

Clinical Endpoint

A variable that reflects how a patientfeels, functions, or survives.

Surrogate Endpoint

A Biomarker intended to substitutefor a clinical endpoint

The Perfect Surrogate

THERAPY

SURROGATE

CLINICALENDPOINT

Vanderbilt University General Clinical Research Center

Inpatient Facilities

• Room and board

• Specialized equipment

• Nursing support

• Nutritional planning/analysis

• Patient recruitment assistance

Outpatient Facilities

• Examining rooms

• Physiological laboratories

• Specialized equipment

• Nursing support

• Patient recruitment assistance

General GCRC Services

• 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

• 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: average age 46 years

• SFN: average age 32 years

So you want to be a clinical investigator

Patients

Physiology

Genetics

Mice

Biological Marker (Biomarker)

• Objectively measured characteristic:1) A normal biologic process

2) A pathogenic process

3) Response to intervention

GENOME

PROTEOME

ENVIRONOME INTERMEDIATEPHENOTYPE

PHENOTYPE

LANDSCAPE OF PATIENT-ORIENTED RESEARCH

Patient-Oriented Research:The Old Paradigm

• Phenotype-Driven

• Aim: Intermediate Phenotype

• Relatively Data-Poor

Genome and Environome:New POR Paradigm

Genome

IntermediatePhenotype

Phenotype

Environome

Genome and Environome:Old POR Paradigm

Genome

IntermediatePhenotype

Phenotype

Environome

Patient-Oriented Research

Patient/PhysicianIn the Same RoomAt the Same TimeAnd Both Are Alive

Biological Marker (Biomarker)

• Objectively measured characteristic:1) A normal biologic process

2) A pathogenic process

3) Response to intervention

GENOME

PROTEOME

ENVIRONOME INTERMEDIATEPHENOTYPE

PHENOTYPE

LANDSCAPE OF PATIENT-ORIENTED RESEARCH

Patient-Oriented Research:The Old Paradigm

• Phenotype-Driven

• Aim: Intermediate Phenotype

• Relatively Data-Poor

Genome and Environome:New POR Paradigm

Genome

IntermediatePhenotype

Phenotype

Environome

Genome and Environome:Old POR Paradigm

Genome

IntermediatePhenotype

Phenotype

Environome