title: Evaluating rare variants under two-stage design.
abstract: Current genome-wide association studies (GWAS) focusing on relatively common single-nucleotide polymorphisms (SNPs) usually adopt a cost-effective multi-staged design in which a proportion of the total samples are genotyped using a commercial SNP array with a reasonably good coverage of the whole genome at the initial stage, and a list of promising SNPs are further genotyped and evaluated on the remaining samples at the second stage. This staged design in principal can also be used for the study of rare genetic variants at the genome-wide scale, but the statistical methods developed for evaluating the relatively common SNPs under the staged design are not appropriate for rare variants due to the invalidity of large sample theorems. Here, we develop a new statistical framework that aims to evaluate rare variants under two-staged (or multi-staged) design. By extensive computer simulations, we evaluate the empirical type I error rate and power of the proposed procedures. A real example from two recent case-control rheumatoid arthritis genetic association studies is also used to demonstrate the performances of the proposed methods.
authors.affiliation: Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, People's Republic of China. liqz@amss.ac.cn
authors.forename: Qizhai
authors.initials: Q
authors.lastname: Li
authors.forename: Dongdong
authors.initials: D
authors.lastname: Pan
authors.forename: Weihua
authors.initials: W
authors.lastname: Yue
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
mesh_terms: D000465:Algorithms; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics; D016022:Case-Control Studies; D003198:Computer Simulation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results