cellGeometry: ultra-fast single-cell deconvolution of bulk RNA-Seq using a geometric solution

Abstract Single-cell analysis has rapidly expanded to produce cell atlases encompassing all human tissues. However, computational methods to deconvolute bulk samples using single-cell reference data have failed to keep pace with the increasing data size. Here we present cellGeometry, which uses non-negative geometric deconvolution (NGD), an intuitive vector projection method featuring non-negative matrix regularisation. Using matrix operations, cellGeometry scales to massive datasets and is ultrafast. Benchmarked using simulations from single-cell/nucleus RNA-Seq datasets with >3 million cells, cellGeometry is more accurate than existing methods and more robust against noise simulating different sequencing chemistries. It identifies outlying residual genes which may unveil pathogenic changes in gene expression and the presence of cell types absent from the reference. cellGeometry’s flexible architecture allows merging of single-cell reference signatures to expand the range of cell types being deconvoluted. Validated against real bulk RNA blood and tissue samples, cellGeometry produces more accurate and realistic results.