FedEdgeR: federated and privacy-preserving edgeR for differential gene expression analysis

Abstract

Motivation: Multi-center RNA-seq studies improve statistical power, but privacy regulations restrict patient-level data sharing. Meta-analysis methods avoid this restriction but lose power, especially under per-site imbalance. Federated learning allows sites to share only summary statistics. Among the three dominant differential expression (DE) frameworks, Flimma federates limma-voom and FedPyDESeq2 federates DESeq2. edgeR, still preferred for small-sample and high-variability designs, lacks a federated counterpart. Its iteratively reweighted least squares (IRLS) and Cox-Reid dispersion estimation make federation harder than limma-voom's single-pass fit. Results: We present FedEdgeR, a federated edgeR implementation protected by secure multi-party computation (SMPC), covering IRLS GLM fitting, three-level dispersion estimation, and the likelihood-ratio test. We evaluate it on four representative RNA-seq datasets: two tumor/normal cohorts, a multi-cohort anti-PD-1 immunotherapy study, and a 6-sample paired stress-test. FedEdgeR matches pooled edgeR under various metrics, such as Pearson r ≥ 0.99999 on −log10 p-values, 100% complete top-100 DE gene overlap, and F1 = 1.000 at the nominal FDR level 0.05. It consistently outperforms Fisher, Stouffer, random-effects, and RankProd meta-analysis on every tested dataset.