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Tumor is heterogeneous - a tumor sample usually consists of a set of subclones with distinct transcriptional profiles and potentially different degrees of aggressiveness and responses to drugs. Understanding tumor heterogeneity is therefore critical to precise cancer prognosis and treatment. In this paper, we introduce BayCount, a Bayesian decomposition method to infer tumor heterogeneity with highly over-dispersed RNA sequencing count data. Using negative binomial factor analysis, BayCount takes into account both the between-sample and gene-specific random effects on raw counts of sequencing reads mapped to each gene. For posterior inference, we develop an efficient compound Poisson based blocked Gibbs sampler. Through extensive simulation studies and analysis of The Cancer Genome Atlas lung cancer and kidney cancer RNA sequencing count data, we show that BayCount is able to accurately estimate the number of subclones, the proportions of these subclones in each tumor sample, and the gene expression profiles in each subclone. Our method represents the first effort in characterizing tumor heterogeneity using RNA sequencing count data that simultaneously removes the need of normalizing the counts, achieves statistical robustness, and obtains biologically and clinically meaningful insights.

BayCount: A Bayesian decomposition method for inferring tumor heterogeneity using RNA-Seq counts