PT - JOURNAL ARTICLE AU - Jonathan Mitchel AU - M. Grace Gordon AU - Richard K. Perez AU - Evan Biederstedt AU - Raymund Bueno AU - Chun Jimmie Ye AU - Peter V. Kharchenko TI - Tensor decomposition reveals coordinated multicellular patterns of transcriptional variation that distinguish and stratify disease individuals AID - 10.1101/2022.02.16.480703 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.02.16.480703 4099 - http://biorxiv.org/content/early/2022/02/18/2022.02.16.480703.short 4100 - http://biorxiv.org/content/early/2022/02/18/2022.02.16.480703.full AB - Tissue- and organism-level biological processes often involve coordinated action of multiple distinct cell types. Current computational methods for the analysis of single-cell RNA-sequencing (scRNA-seq) data, however, are not designed to capture co-variation of cell states across samples, in part due to the low number of biological samples in most scRNA-seq datasets. Recent advances in sample multiplexing have enabled population-scale scRNA-seq measurements of tens to hundreds of samples. To take advantage of such datasets, here we introduce a computational approach called single-cell Interpretable Tensor Decomposition (scITD). This method extracts “multicellular gene expression patterns” that vary across different biological samples. These patterns capture how changes in one cell type are connected to changes in other cell types. The multicellular patterns can be further associated with known covariates (e.g., disease, treatment, or technical batch effects) and used to stratify heterogeneous samples. We first validated the performance of scITD using in vitro experimental data and simulations. We then applied scITD to scRNA-seq data on peripheral blood mononuclear cells (PBMCs) from 115 patients with systemic lupus erythematosus and 56 healthy controls. We recapitulated a well-established pan-cell-type signature of interferon-signaling that was associated with the presence of anti-dsDNA autoantibodies and a disease activity index. We further identified a novel multicellular pattern that appears to potentiate renal involvement for patients with anti-dsDNA autoantibodies. This pattern was characterized by an expansion of activated memory B cells along with helper T cell activation and is predicted to be mediated by an increase in ICOSLG-ICOS interaction between monocytes and helper T cells. Finally, we applied scITD to two PBMC datasets from patients with COVID-19 and identified reproducible multicellular patterns that stratify patients by disease severity. Overall, scITD is a flexible method for exploring co-variation of cell states in multi-sample single-cell datasets, which can yield new insights into complex non-cell-autonomous dependencies that define and stratify disease.Competing Interest StatementP.V.K. serves on the Scientific Advisory Board to Celsius Therapeutics Inc. and Biomage Inc. P.V.K. consults National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation. C.J.Y. is a SAB member for and hold equity in Related Sciences and ImmunAI, a consultant for and hold equity in Maze Therapeutics and a consultant for Trex Bio. C.J.Y. has received research support from Chan Zuckerberg Initiative, Chan Zuckerberg Biohub and Genentech.