Fast effect size shrinkage software for beta-binomial models of allelic imbalance

Abstract

Allelic imbalance occurs when the two alleles of a gene are differentially expressed within a diploid organism, and can indicate important differences in cis-regulation and epigenetic state across the two chromosomes. Because of this, the ability to accurately quantify the proportion at which each allele of a gene is expressed is of great interest to researchers. This becomes challenging in the presence of small read counts and/or sample sizes, which can cause estimates for allelic expression proportions to have high variance. Investigators have traditionally dealt with this problem by filtering out genes with small counts and samples. However, this may inadvertently remove important genes that have truly large allelic imbalances. Another option is to use Bayesian estimators to reduce the variance. To this end, we evaluated the accuracy of three different estimators, the latter two of which are Bayesian shrinkage estimators: maximum likelihood, approximate posterior estimation of GLM coefficients (apeglm) and adaptive shrinkage (ash). We also wrote C++ code to quickly calculate ML and apeglm estimates, and integrated it into the apeglm package. The three methods were evaluated on both simulated and real data. Apeglm consistently performed better than ML according to a variety of criteria, including mean absolute error and concordance at the top. While ash had lower error and greater concordance than ML on the simulations, it also had a tendency to over-shrink large effects, and performed worse on the real data according to error and concordance. Furthermore, when compared to five other packages that also fit beta-binomial models, the apeglm package was substantially faster, making our package useful for quick and reliable analyses of allelic imbalance. Apeglm is available as an R/Bioconductor package at http://bioconductor.org/packages/apeglm.