A powerful framework for differential co-expression analysis of general risk factors.

Differential co-expression analysis (DCA) aims to identify genes in a pathway whose shared expression depends on a risk factor. While DCA provides insights into the biological activity of diseases, existing methods are limited to categorical risk factors and/or suffer from bias due to batch and variance-specific effects. We propose a new framework, Kernel-based Differential Co-expression Analysis (KDCA), that harnesses correlation patterns between genes in a pathway to detect differential co-expression arising from general (i.e., continuous, discrete, or categorical) risk factors. Using various simulated pathway architectures, we find that KDCA accounts for common sources of bias to control the type I error rate while substantially increasing the power compared to the standard eigengene approach. We then applied KDCA to The Cancer Genome Atlas thyroid data set and found several differentially co-expressed pathways by age of diagnosis and BRAF mutation status that were undetected by the eigengene method. Collectively, our results demonstrate that KDCA is a powerful testing framework that expands DCA applications in expression studies.