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Genotype-based risk and pharmacogenetic sampling in clinical trials

Academic Article
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Overview

authors

  • Schork, Nicholas
  • Topol, Eric

publication date

  • 2010

journal

  • Journal of Biopharmaceutical Statistics  Journal

abstract

  • A number of recent genome-wide association (GWA) studies have identified unequivocal statistical associations between inherited genetic variations, mostly single-nucleotide polymorphisms (SNPs), and common complex diseases such as diabetes, cardiovascular disease, and obesity. Genotyping individuals for these variations has the potential to help redefine how pharmacologic agents undergo clinical development. By identifying carriers of known genomic variants that contribute to susceptibility, a high-risk population can be defined, as well as individuals with potential for a better response to a drug. We evaluated the potential utility that selecting individuals for a trial on the basis of genotypes identified in contemporary GWA studies would have had on recently described clinical trials. We pursued this by constraining both the risks of a disease outcome associated with particular genotypes and overall drug responses to those actually observed in genetic association and clinical trial studies, respectively. We pursued these evaluations in the context of clinical trials investigating drugs for macular degeneration, obesity, heart disease, type II diabetes, prostate cancer, and Alzheimer's disease. We show that the increase in incidence of outcomes in trials restricted to individuals with specific genotypic profiles can result in substantial reductions in requisite sample sizes for such trials. In addition, we also derive realistic bounds for samples sizes for clinical trials investigating pharmacogenetic effects that leverage genetic variations identified in recent association studies.

subject areas

  • Alzheimer Disease
  • Clinical Trials as Topic
  • Data Interpretation, Statistical
  • Diabetes Mellitus, Type 2
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Heart Diseases
  • Humans
  • Macular Degeneration
  • Male
  • Models, Statistical
  • Obesity
  • Pharmacogenetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms
  • Risk Assessment
  • Risk Factors
  • Sample Size
  • Treatment Outcome
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Research

keywords

  • DNA sequencing
  • Drug validation
  • Polymorphism
  • Study design
  • Translational medicine
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Identity

PubMed Central ID

  • PMC2892229

International Standard Serial Number (ISSN)

  • 1054-3406

Digital Object Identifier (DOI)

  • 10.1080/10543400903572779

PubMed ID

  • 20309761
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Additional Document Info

start page

  • 315

end page

  • 333

volume

  • 20

issue

  • 2

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