Recently, a study claimed that a reference-free cell-type deconvolution method, called ReFACTor, leads to improved power and improved estimates of cell-type composition compared to competing reference-free and reference-based methods in the context of Epigenome-Wide Association Studies (EWAS). However, we identified many critical flaws (both conceptual and statistical in nature), which seriously question the validity of the claims. We outlined constructive criticism in a recent correspondence

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... tter. The purpose of this letter is two-fold. First, to present additional analyses, which demonstrate that our original criticism is statistically sound. Second, to highlight additional serious concerns, which have not yet been addressed. In summary, we find that ReFACTor has not been demonstrated to outperform state-of-the-art reference-free methods such as SVA or RefFreeEWAS, nor state-of-the-art reference-based methods. Thus, the claim that ReFACTor represents an advance over the state-of-the-art is not supported by an objective and rigorous statistical analysis of the data.