The Effect of Model Directionality on Cell-Type-Specific Differential DNA Methylation Analysis

Calling differential methylation at a cell-type level from tissue-level bulk data is a fundamental challenge in genomics that has recently received more attention. These studies most often aim at identifying statistical associations rather than causal effects. However, existing methods typically make an implicit assumption about the direction of effects, and thus far, little to no attention has been given to the fact that this directionality assumption may not hold and can consequently affect statistical power and control for false positives. We demonstrate that misspecification of the model directionality can lead to a drastic decrease in performance and increase in risk of spurious findings in cell-type-specific differential methylation analysis, and we discuss the need to carefully consider model directionality before choosing a statistical method for analysis.