We compare and contrast case-only designs for detecting gene gene (G G) interaction in rheumatoid arthritis (RA) using the genome-wide data provided by Genetic Analysis Workshop 16 Problem 1. can involve utilization of the whole sample or just the cases, and associated tests are derived theoretically on the basis of underlying models of disease penetrance. The power of a test to detect an interaction depends on the size of the detectable effect, the Leflunomide manufacture sample size and composition, and the suitability of the test as it relates to the true underlying model. In this study, we seek to compare and contrast how association findings can vary as a result of the different regression models applied to detect G G interaction in the case-only sample. Motivated by differences in the magnitude of genetic effects associated with rheumatoid arthritis (RA) observed at genes PTPN22, CTLA4, and PADI4 across samples of common ancestry , we concentrate on interactions between each of these genes and a genome-wide subset of markers selected to be in approximate linkage equilibrium using the genome-wide data provided by Genetic Analysis Workshop 16 (GAW16) Problem 1. Specifically we propose to compare case-only designs that test for single-nucleotide polymorphism (SNP)-by-SNP interactions in RA between alleles at loci in candidate genes PTPN22, PADI4, and CTLA4, each known to have a previous putative marginal association with RA, and alleles at a selected subset of markers in the GAW16 data from the North American Rheumatoid Arthritis Consortium (NARAC). Assuming that the genes being studied are not in linkage disequilibrium, case-only designs are a valid approach for the detection of G G interaction and provide increased statistical efficiency over case-control analyses . Yang et al. demonstrated their results assuming binary genotype variables; here we consider case-only designs that allow for disease susceptibility genes with multiple genetic variants. Methods Materials The data set for these interaction studies of RA were provided as part of GAW16 Problem 1. The case-control data set included 868 cases and 1194 controls genotyped with the Illumina 550 k chip (531,689 SNPs). All samples were retained after checks for contamination and relatedness. 496,578 SNPs (93.4%) passed our quality control filters. Of these, 21,959 have a study-wide minor-allele frequency (MAF) less than 1% and were excluded from the analysis. armadillo Of the remaining 447,619 SNPs, 6 were on PTPN22, 7 were on PADI4, and 2 were Leflunomide manufacture on CTLA4; these 17 SNPs in candidate genes are referred to as the gene SNPs. A subset of 81,596 SNPs with pairwise linkage equilibrium r2 < 0.2 was created by considering all pairs of retained SNPS in sliding windows of size 50; these SNPS are referred to as the equilibrium SNPs. Leflunomide manufacture Additional phenotype data including sex, shared epitope alleles, anti-cyclic citrullinated peptide (CCP) and rheumatoid factor were available for both cases and controls. Models We consider a binary trait that is influenced by two bi-allelic disease susceptibility loci F and G according to a model of joint locus effects. Here we assume F denotes a candidate gene SNP and G denotes an equilibrium SNP. We test Leflunomide manufacture for G G interaction between gene and equilibrium SNPs using tests based on logistic, proportional odds, and multinomial generalized linear regression models. For each model, there are two regressions: first F is modelled as the outcome variable and G the predictor, then vice versa. The outcome variable Leflunomide manufacture is categorized appropriately according to the relevant model: a binary categorization for the logistic model, an ordinal categorization for the proportional odds model, and a nominal categorization for the multinomial model. The predictor variable is categorized as an ordinal variable in all the regressions. Table ?Table11 summarizes the generalized linear regression models considered. Each model generates a likelihood and G G test of.