title: Two-Stage sampling designs for gene association studies.
abstract: We consider two-stage case-control designs for testing associations between single nucleotide polymorphisms (SNPs) and disease, in which a subsample of subjects is used to select a panel of "tagging" SNPs that will be considered in the main study. We propose a pseudolikelihood [Pepe and Flemming, 1991: JASA 86:108-113] that combines the information from both the main study and the substudy to test the association with any polymorphism in the original set. SNP-tagging [Chapman et al., 2003: Hum Hered 56:18-31] and haplotype-tagging [Stram et al., 2003a; Hum Hered 55:27-36] approaches are compared. We show that the cost-efficiency of such a design for estimating the relative risk associated with the causal polymorphism can be considerably better than for a single-stage design, even if the causal polymorphism is not included in the tag-SNP set. We also consider the optimal selection of cases and controls in such designs and the relative efficiency for estimating the location of a causal variant in linkage disequilibrium mapping. Nevertheless, as the cost of high-volume genotyping plummets and haplotype tagging information from the International HapMap project [Gibbs et al., 2003; Nature 426:789-796] rapidly accumulates in public databases, such two-stage designs may soon become unnecessary.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9011, USA. dthomas@usc.edu
authors.forename: Duncan
authors.initials: D
authors.lastname: Thomas
authors.forename: Rongrong
authors.initials: R
authors.lastname: Xie
authors.forename: Mulugeta
authors.initials: M
authors.lastname: Gebregziabher
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005828:Genetics, Population; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012107:Research Design