Calling differential DNA methylation at cell-type resolution: an objective status-quo

Due to cost and logistical reasons, Epigenome-Wide-Association Studies (EWAS) are normally performed in complex tissues, resulting in average DNA methylation profiles over potentially many different cell-types, which can obscure important cell-type specific associations with disease. Identifying the specific cell-types that are altered is a key hurdle for elucidating causal pathways to disease, and consequently statistical algorithms have recently emerged that aim to address this challenge. Comparisons between these algorithms are of great interest, yet here we find that the main comparative study so far was substantially biased and potentially misleading. By using this study as an example, we highlight some of the key issues that need to be considered to ensure that future assessments between methods are more objective.