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GENETICS by lonyoo

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									Taking Research and Development to the Clinic: Issues for Physicians
AAAS/FDLI Colloquium I Diagnostics and Diagnoses Paths to Personalized Medicine Howard Levy, MD, PhD Johns Hopkins University
June 1, 2009

What is Personalized Medicine?
• Biomarkers and genetic tests
• Customization of medical care to the individual patient • All aspects of care—not just biomarkers, not just genetics

Challenges & Opportunities
Self-evident truths: • Physicians want to help patients • Time & resources are scarce
Can biomarkers improve both?

Using a Biomarker
• • • • • Select a test Order a test Get it paid for Get it done Receive result • Understand result • Archive result • Access result (now & future) • Apply result in clinical care

Clinical Utility
Does the biomarker improve clinical care? • Pharmacogenetics • Predictive testing • Faster or more precise diagnostics

Clinical Utility
What are the costs? • Financial • Time/Resources • Social/Ethical/Legal • Medical (incorrect conclusions) • Psychological

Pharmacogenetics
• The right drug • At the right time • In the right dose
• ↑ Efficacy • ↓ Adverse events

Warfarin Dosing
• Fixed-dose • Clinical algorithm (weight, age, sex)
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This is personalized medicine! PGx explains ~40% of dose variability Clinical + PGx explains ~54% of variability

• Pharmacogenetic (VKORC1 & CYP2C9)
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Int’l Warfarin PGx Consortium

N Engl J Med 360(8):753-764 February 19, 2009

Warfarin PGx Clinical Utility
Likely to achieve therapeutic dose faster Relatively easy to order & receive results Often covered by 3rd parties Algorithm freely available • Improved efficacy & fewer adverse events?
 

Seems likely Still being studied

Warfarin PGx Clinical Utility
Limitations: • Needs to be done promptly at initiation of therapy • ~45% of dose variability unexplained • Environmental factors remain important

Drug Metabolism: CYP450
• • • • >50% of all drugs Prodrug  Active Drug Active  Inactive Relevant Factors:
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Other drugs Diet & environment Genetic variants

CYP450 PGx Clinical Utility
• • • • Genetic testing is available Is PGx testing better than trial & error? Drug choice & dosing recommendations? What if there are no alternatives?
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Psychological distress Relative risk Genetic determinism

Genetic Determinism
Belief that clinical outcomes are inexorably defined by genetic factors Ignores:
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Genetic/epigenetic modifiers Environmental modifiers Variable expression Reduced penetrance

Predictive Testing
“It’s tough to make predictions, especially about the future”
-Dan Quayle, Casey Stengel, et al.

“The future ain’t what it used to be”
-Yogi Berra

Genetic Risk Assessment
• Family History  Varies over time • DNA variants  Stable over time  Relative risk

GWAS: Genome-Wide
Association Studies
• Really BIG case-control study
 

1000’s of subjects 500,000 to 1,000,000 SNPs

• Power to detect small effect sizes • Subject to same errors & biases as any other epidemiologic study

CAD Risk Assessment: Gene ↔ Environment
• Smoking, HTN, DM, etc: OR ≈ 10-20 • SNPs: OR ≈ 1.2-2.0 (usually 1.2-1.3) • Family History: intermediate

Heritability
• Proportion of disease predisposition that is due to inherited factors
SNPs—small amount  Other heritable factors (DNA & Non-DNA variants)


• Current tests assess only a small portion of heritability

Analytical & Clinical Validity
• Is the test accurate? • Does the biomarker correlate clinically (retrospective vs. prospective study)? • How are results of multiple tests combined?
• Validity is often assumed when test is offered clinically.

The Fallacy of Genetic Determinism Positive tests ≠ Disease Negative tests ≠ Health

Clinical Utility of Genetic Testing for Common Disease?
• • • • • What do the results mean? Small effect size Environmental factors Fallacy of genetic determinism Undue anxiety/false reassurance?

Clinical Utility of Genetic Testing for Common Disease?
• Modify therapy to reduce risk? • Motivation to change behavior?
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Smoking, exercise & diet campaigns Does the Personalized Medicine model work?

Clinical Utility of Genetic Testing for Common Disease?
• • • • Cost Large amounts of clinical data Paucity of tools to integrate data Uncertain plan of action

• May be appropriate for some patients

PM Opportunities
• • • • • • Improved diagnostics Improved therapeutics Improved health maintenance More efficient use of time Lower health care costs Patient & physician satisfaction

PM Challenges
Clinician Education
• • • • • Test indications Test validity Result interpretation Clinical utility Integration into clinical care

Clinician Education
• • • •

Learning Preferences Clinically relevant Just in time (point of care) Fast (<2 minutes) Increasingly Internet-based
o

• 2 sources (authority vs. accuracy)

• GeneFacts

PM Challenges
Test Validity
• Transparency


Providers lack time & knowledge to evaluate Slows progress, limits access, ↑ cost

• Regulation


• Paternalism vs. Autonomy

PM Challenges
Test Ordering & Payment
• • • • Facilitating ordering the correct test DTC testing vs. physician gatekeeper 3rd party payers Paternalism vs. Autonomy

PM Challenges
Receiving, Archiving and Accessing Results
• EHRs
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Can also prompt provider to order/use tests

• PHRs • Information sharing between providers
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Does the data already exist?

• Privacy & Security

PM Challenges
Clinical Utility
• Better assessment of health factors
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Genetic Environmental

• Better tools to combine environment, family history & biomarkers • Studies of actual clinical outcomes (Hype  Hope  Reality)

The Art of Medicine
• Evidence-based medicine
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Based on population studies Autonomous Variably reliable Ever-changing environment Requires knowing & monitoring the patient and therapy at the individual level

• Individual people
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• Personalized Medicine
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