In i-GSEA, we implement SNP label permutation instead of phenotype label permutation to analyze SNP P-values and to correct gene and gene set variation and multiply k/K to the ES to get the significance proportion based enrichment score (SPES), where k is the proportion of significant genes of the gene set and K is the proportion of significant genes of the total genes in the GWAS. Here, significant genes are defined as the genes mapped with at least one of the top 5% of all SNPs. Instead of ES which focuses on the total significance coming from either a few or many significant genes, SPES emphasizes on total significance coming from high proportion of significant genes. So, i-GSEA trends to pick up pathways/gene sets including a high proportion of significant genes and is more appropriate for study of the combined effects of possibly modest SNPs/genes in complex disease. This ensures i-GSEA the improved sensitivity.
