A systematic evaluation of cell-type-specific differential methylation analysis in bulk tissue.

We conducted a systematic assessment of computational models-CellDMC, TCA, HIRE, TOAST, and CeDAR-for detecting cell-type-specific differential methylation CpGs in bulk methylation data profiled using the Illumina DNA Methylation BeadArrays. This assessment was performed through simulations and case studies involving two epigenome-wide association studies (EWAS) on rheumatoid arthritis and major depressive disorder. Our evaluation provided insights into the strengths and limitations of each model. The results revealed that the models varied in performance across different metrics, sample sizes, and computational efficiency. Additionally, we proposed integrating the results from these models using the minimum p-value ($minpv$) and average p-value ($avepv$) approaches. Our findings demonstrated that these aggregation methods significantly improved performance in identifying cell-type-specific differential methylation CpGs.