Bulk-based hypothesis weighing to increase power in single-cell differential expression analysis

Due to the costs of single-cell sequencing, sample sizes are often relatively limited, sometimes leading to poorly reproducible results. In many contexts, however, larger bulk RNAseq data is available for the same conditions or experimental paradigm, which can be used as additional evidence of a generalizable differential expression pattern. Here, we show how such data can be used, via bulk-based hypothesis weighing (bbhw), to increase the power and robustness of single-cell differential state analysis. We find that all methods improve performance, with the best results obtained by applying a grouped Benjamini-Hochberg procedure on bins based on proportion-adjusted significance (PAS). These methods are implemented in the muscat package, and should be applicable to a broader range of scenarios.