scMetaIntegrator: a meta-analysis approach to paired single-cell differential expression analysis.

Traditional differential gene expression methods are limited for analysis of single cell RNA-sequencing (scRNA-seq) studies that use paired repeated measures and matched cohort designs. Many existing approaches consider cells as independent samples, leading to high false positive rates while ignoring inherent sampling structures. Although pseudobulk methods address this, they ignore intra-sample expression variability and have higher false negatives rates. We propose a novel meta-analysis approach that accounts for biological replicates and cell variability in paired scRNA-seq data. Using both real and synthetic datasets, we show that our method, single-cell MetaIntegrator (https://github.com/Khatri-Lab/scMetaIntegrator), provides robust effect size estimates and reproducible p-values.