Robust and Adaptive Non-Parametric Tests for Detecting General Distributional Shifts in Gene Expression.

Differential expression analysis is crucial in genomics, yet existing methods primarily focus on detecting mean shifts. Variance shifts in gene expression are well-documented in studies of cellular signaling pathways, and more recently they have characterized aging, thus motivating the need for flexible detection approaches that include tests of expression variance changes. In this work, we present QRscore (Quantile Rank Score), a general method for detecting distributional shifts in gene expression by extending the Mann-Whitney test into a flexible family of rank-based tests. Here, we focus on implementing QRscore to detect shifts in mean and variance in gene expression, using weights designed from negative binomial (NB) and zero-inflated negative binomial (ZINB) models to combine the strengths of parametric and non-parametric approaches. We show through simulations that QRscore not only achieves high statistical power while controlling the false discovery rate (FDR), but also outperforms existing methods in detecting variance shifts and mean shifts. Applying QRscore to bulk RNA-seq data from the Genotype-Tissue Expression (GTEx) project, we identified numerous differentially dispersed genes and differentially expressed genes across 33 tissues. Notably, many genes have significant variance shifts but non-significant mean shifts. QRscore augments the genome bioinformatics toolkit by offering a powerful and flexible approach for differential expression analysis. QRscore is available in R, at https://github.com/songlab-cal/QRscore.