POET: A Powerful and Efficient Poisson Exact Test for Rare Variant Association Studies

Music City Center 

Rare variant association studies are inherently challenging due to the sparse nature of variants and high computational demands of large-scale datasets analysis. We introduce POET (Poisson Exact Test), a novel statistical framework specifically designed for rare variant analysis in case-control studies. POET simplifies testing by requiring only summary-level carrier counts and allele frequencies as inputs. Extensive simulations show that POET outperforms Fisher's exact test in power while controlling the false discovery rate (FDR). It is also more computationally efficient than regression-based methods. Applied to whole-exome sequencing data from approximately 400K UK Biobank European participants, POET identified five significant genes (BRCA2, CHEK2, PALB2, BRCA1, ATM) for Breast Cancer and four (CHEK2, ATM, BRCA2, RNF212) for Prostate Cancer (FDR<0.05). These results are comparable to the genes identified using the SKAT-O method in GENEBASS. By combining minimal data requirements with computational efficiency, POET is a scalable and powerful tool for large biobank studies, particularly in cloud computing scenarios, adding a valuable option to the rare variant analysis toolkit.

Rare Variant Association Studies

Whole Exome Sequencing

UK Biobank 

Section on Statistics in Genomics and Genetics