title: Application of family-based tests of association for rare variants to pathways.
abstract: Pathway analysis approaches for sequence data typically either operate in a single stage (all variants within all genes in the pathway are combined into a single, very large set of variants that can then be analyzed using standard "gene-based" test statistics) or in 2-stages (gene-based p values are computed for all genes in the pathway, and then the gene-based p values are combined into a single pathway p value). To date, little consideration has been given to the performance of gene-based tests (typically designed for a smaller number of single-nucleotide variants [SNVs]) when the number of SNVs in the gene or in the pathway is very large and the genotypes come from sequence data organized in large pedigrees. We consider recently proposed gene-based tests for rare variants from complex pedigrees that test for association between a large set of SNVs and a qualitative phenotype of interest (1-stage analyses) as well as 2-stage approaches. We find that many of these methods show inflated type I errors when the number of SNVs in the gene or the pathway is large (>200 SNVs) and when using standard approaches to estimate the genotype covariance matrix. Alternative methods are needed when testing very large sets of SNVs in 1-stage approaches.
authors.affiliation: Department of Mathematics and Statistics, Grinnell College, 1115 8th Ave, Grinnell, IA 50112, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Greco
authors.affiliation: Division of Biostatistics, UC Berkeley, 367 Evans Hall, Berkeley, CA 94720, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Luedtke
authors.affiliation: Department of Statistics, Baylor University, 1511 S. 5th St, Waco, TX 76798, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Hainline
authors.affiliation: Department of Biostatistics, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Alvarez
authors.affiliation: Department of Mathematics, Loyola University Chicago, 1052 W Loyola Ave, Chicago, IL 60660, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Beck
authors.affiliation: Department of Mathematics, Statistics and Computer Science, 498 4th Ave. NE, Dordt College, Sioux Center, IA 51250, USA.
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Tintle