title: Pathway analysis by adaptive combination of P-values.
abstract: It is increasingly recognized that pathway analyses-a joint test of association between the outcome and a group of single nucleotide polymorphisms (SNPs) within a biological pathway-could potentially complement single-SNP analysis and provide additional insights for the genetic architecture of complex diseases. Building upon existing P-value combining methods, we propose a class of highly flexible pathway analysis approaches based on an adaptive rank truncated product statistic that can effectively combine evidence of associations over different SNPs and genes within a pathway. The statistical significance of the pathway-level test statistics is evaluated using a highly efficient permutation algorithm that remains computationally feasible irrespective of the size of the pathway and complexity of the underlying test statistics for summarizing SNP- and gene-level associations. We demonstrate through simulation studies that a gene-based analysis that treats the underlying genes, as opposed to the underlying SNPs, as the basic units for hypothesis testing, is a very robust and powerful approach to pathway-based association testing. We also illustrate the advantage of the proposed methods using a study of the association between the nicotinic receptor pathway and cigarette smoking behaviors.
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI, Rockville, Maryland 20892, USA. yuka@mail.nih.gov
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Qizhai
authors.initials: Q
authors.lastname: Li
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rosenberg
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee