title: Statistical power considerations in genotype-based recall randomized controlled trials.
abstract: 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.
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden.
authors.forename: Naeimeh
authors.initials: N
authors.lastname: Atabaki-Pasdar
authors.affiliation: Department of Astronomy and Theoretical Physics, Computational Biology and Biological Physics Unit, Lund University, Lund, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Ohlsson
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shungin
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden.
authors.forename: Azra
authors.initials: A
authors.lastname: Kurbasic
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Division of Cardiovascular &Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden.
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden.|Department of Public Health &Clinical Medicine, Umeå University, Umeå, Sweden.|Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000517:prevention & control*; D015444:Exercise; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008687:Metformin / Q000627:therapeutic use*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D018401:Sample Size
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; D008687:Metformin