Spectral detection of condition-specific biological pathways in single-cell gene expression data

Single cell RNA sequencing is an ubiquitous method for studying changes in cellular states within and across conditions. Differential expression (DE) analysis may miss subtle differences, especially where transcriptional variability is not unique to a specific condition, but shared across multiple conditions or phenotypes. Here, we present CDR-g (Concatenate-Decompose-Rotate genomics), a fast and scalable strategy based on spectral factorisation of gene coexpression matrices. CDR-g detects subtle changes in gene coexpression across a continuum of biological states in multi-condition single cell data. CDR-g collates these changes and builds a detailed profile of differential cell states. Applying CDR-g, we show that it identifies biological pathways not detected using conventional DE analysis and delineates novel, condition-specific subpopulations in single-cell datasets.