PMC:4572492 / 11206-13304 JSONTXT

{"project":"2_test","denotations":[{"id":"26140448-22466613-2053694","span":{"begin":489,"end":490},"obj":"22466613"}],"text":"Joint Location-Scale Testing Procedure for Gene-Set Analysis\nThe chosen JLS test statistic (e.g., WF) for single-SNP analysis can then be used for implementing gene-based, gene-set, or pathway analysis in a direct fashion.\nAssume that J SNPs have been annotated to a gene or gene-set of interest. For each SNP j, the JLS-Fisher test statistic (e.g., WF,j) is first obtained and then the association evidence can be aggregated across the SNPs by considering, for example, the sum statistic,5 ∑jWF,j. To account for LD between SNPs, the overall association evidence can be evaluated by a phenotype-permutation approach where the empirical p value is the proportion of K permutation replicates with sum statistics more extreme than the observed value. Because this multivariate method analyzes all J SNPs simultaneously, the number of permutations need not be exceedingly large and K = 10,000 provides accurate estimates for p values in the range of 0.05. If multiple genes or gene-sets are of interest, more replicates would be required to adjust for the corresponding number of hypothesis tests.\nTo compare strength of association evidence between sets of variants within the same gene or across different genes, an extension of the gene-set approach can be implemented. Sum statistics are obtained as previously described for each group of variants, then calibrated by the respective number of variants. The difference between the two proportional sum statistics is the test statistic of interest,DF=1J∑jWF,j−1K∑kWF,k,where the j = 1,…,J and k = 1,…,K subscripts index the competing sets of variants, and the F subscript indicates that the variant-specific joint location-scale statistics are obtained by Fisher’s method (although other methods of combining such as minP could be used as well). The significance of DF can be evaluated with the phenotype-permutation approach as described above.\nIn all applications, genotypes were coded additively (G = 0, 1 or 2), and for X chromosome SNPs, female and male genotypes were analyzed together and coded as G = 0, 1, or 2 and G = 0 or 2, respectively."}