BackgroundExisting module-based differential co-expression methods identify differences in gene-gene relationships across phenotype or exposure structures by testing for consistent changes in transcription abundance. Current methods only allow for assessment of co-expression variation across a singular, binary or categorical exposure or phenotype, limiting the information that can be obtained from these analyses.MethodsHere, we propose a novel approach for detection of differential co-expression that simultaneously accommodates multiple phenotypes or exposures with binary, ordinal, or continuous data types.ResultsWe report an application to two cohorts of asthmatic patients with varying levels of asthma control to identify associations between gene co-expression and asthma control test scores. Results suggest that both expression levels and covariances of ADORA3, ALOX15, and IDO1 are associated with asthma control.ConclusionACDC is a flexible extension to existing methodology that can detect differential co-expression across varying external variables.