Data-driven detection of subtype-specific and differentially expressed genes

Tissue or cell subtype-specific and differentially-expressed genes (SDEGs) are defined as being differentially expressed in a particular tissue or cell subtype among multiple subtypes. Detecting SDEGs plays a critical rolse in molecularly characterizing and identifying tissue or cell subtypes, and facilitating supervised deconvolution of complex tissues. Unfortunately, classic differential analysis assumes a convenient null hypothesis and associated test statistic that is subtype-non-specific and thus, resulting in a high false positive rate and/or lower detection power with respect to particular subtypes. Here we introduce One-Versus-Everyone Fold Change (OVE-FC) test for detecting SDEGs. To assess the statistical significance of such test, we also propose the scaled test statistic OVE-sFC together with a mixture null distribution model and a tailored permutation scheme. Validated with realistic synthetic data sets on both type 1 error and detection power, OVE-FC/sFC test applied to two benchmark gene expression data sets detects many known and de novo SDEGs. Subsequent supervised deconvolution results, obtained using the SDEGs detected by OVE-FC/sFC test, showed superior performance in deconvolution accuracy when compared with popular peer methods.