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Statistical power considerations in genotype-based recall randomized controlled trials

Author:
  • Naeimeh Atabaki-Pasdar
  • Mattias Ohlsson
  • Dmitry Shungin
  • Azra Kurbasic
  • Erik Ingelsson
  • Ewan R. Pearson
  • Ashfaq Ali
  • Paul W. Franks
Publishing year: 2016-11-25
Language: English
Publication/Series: Scientific Reports
Volume: 6
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

Randomized controlled trials (RCT) are often underpowered for validating gene-treatment interactions. Using published data from the Diabetes Prevention Program (DPP), we examined power in conventional and genotype-based recall (GBR) trials. We calculated sample size and statistical power for gene-metformin interactions (vs. placebo) using incidence rates, gene-drug interaction effect estimates and allele frequencies reported in the DPP for the rs8065082 SLC47A1 variant, a metformin transported encoding locus. We then calculated statistical power for interactions between genetic risk scores (GRS), metformin treatment and intensive lifestyle intervention (ILI) given a range of sampling frames, clinical trial sample sizes, interaction effect estimates, and allele frequencies; outcomes were type 2 diabetes incidence (time-to-event) and change in small LDL particles (continuous outcome). Thereafter, we compared two recruitment frameworks: GBR (participants recruited from the extremes of a GRS distribution) and conventional sampling (participants recruited without explicit emphasis on genetic characteristics). We further examined the influence of outcome measurement error on statistical power. Under most simulated scenarios, GBR trials have substantially higher power to observe gene-drug and gene-lifestyle interactions than same-sized conventional RCTs. GBR trials are becoming popular for validation of gene-treatment interactions; our analyses illustrate the strengths and weaknesses of this design.

Keywords

  • Medical Genetics
  • Probability Theory and Statistics

Other

Published
  • Genetic and Molecular Epidemiology
  • ISSN: 2045-2322
Paul Franks
E-mail: paul.franks [at] med.lu.se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49

60-12-021

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Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00