title: Evaluation of a two-step iterative resampling procedure for internal validation of genome-wide association studies.
abstract: Genome-wide association studies (GWAS) have successfully identified many common genetic variants associated with complex diseases over the past decade. The 'gold standard' method for validating the top single nucleotide polymorphisms (SNPs) identified in GWAS is to independently replicate the findings in similar or diverse large-scale external cohorts. However, for rare diseases, it can be difficult to find an external validation cohort within a reasonable timeframe. In such situations, resampling methods, such as the two-step iterative resampling (TSIR) approach have been used to identify SNPs associated with the outcome of interest. However, the TSIR approach involves choosing several parameters in each step, which can influence the performance of the approach. In this paper, we undertook extensive simulation studies to assess the effect of choice of different parameters on the type I error and power for both binary and continuous phenotypes and also compared the TSIR approach with the traditional one-stage (OS) and two-stage (TS) GWAS analysis. We illustrate the usefulness of the TSIR approach by applying it to a GWAS of childhood cancer survivors. Our results indicate that the TSIR approach with an at least 70:30 split and a cutoff of discovering and replicating SNPs at least 20 times in 100 replications provides conservative type I error control and has near 'optimal' power for internally validated SNPs. Its performance is comparable with the TS GWAS for which an external validation cohort is available with only slight reduction in power in some situations. It has almost the same power as OS GWAS with conservative type I error which leads to fewer false positive findings. TSIR is a powerful and efficient method for identifying and internally validating SNPs for GWAS when independent cohorts for external validation may not be available.
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Guolian
authors.initials: G
authors.lastname: Kang
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Wilson
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Ness
authors.affiliation: Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Robison
authors.affiliation: Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Hudson
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Deo Kumar
authors.initials: DK
authors.lastname: Srivastava
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008297:Male; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018401:Sample Size