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We will implement three burden tests.
We will implement three burden tests.
# First, a Variable Threshold Combined Multivariate and Collapsing count method (described in this publication [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032073/ VTCMC]), where the number of rare alleles is counted in each gene, then the gene is tested for association. The threshold for what variants are considered "rare" (MAF < .05? MAF < .01?) is set adaptively such that the result minimizes the p-value obtained.
# First, a Variable Threshold Combined Multivariate and Collapsing count method ([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032073/ VTCMC]), where the number of rare alleles is counted in each gene, then the gene is tested for association. The threshold for what variants are considered "rare" (MAF < .05? MAF < .01?) is set adaptively such that the result minimizes the p-value obtained.
# Second, we will use SKAT (described in this publication [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135811/ SKAT]) for all rare variants (MAF < .05) within a gene. SKAT allows for variants with opposite directions of effect within the same gene, whereas the variable threshold combined multivariate and collapsing method does not.
# Second, we will use SKAT ([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135811/ SKAT]) for all rare variants (MAF < .05) within a gene. SKAT allows for variants with opposite directions of effect within the same gene, whereas the variable threshold combined multivariate and collapsing method does not.
# Third, we will use a burden test developed by Madsen and Browning ([http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000384 M-B]) where the number of rare alleles is counted in each gene, then the gene is tested for association, but alleles in the count are weighted by the inverse of the MAF. Thus rarer alleles are given more weight than common allele.
# Third, we will use a burden test developed by Madsen and Browning ([http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000384 M-B]) where the number of rare alleles is counted in each gene, then the gene is tested for association, but alleles in the count are weighted by the inverse of the MAF. Thus rarer alleles are given more weight than common allele.
