A likelihood-based hypothesis testing approach is implemented for assessing causal mediation. For example, it could be used to test for mediation of a known causal association between a DNA variant, the 'instrumental variable', and a clinical outcome or phenotype by gene expression or DNA methylation, the potential mediator. Another example would be testing mediation of the effect of a drug on a clinical outcome by the molecular target. The hypothesis test generates a p-value or permutation-based FDR value with confidence intervals to quantify uncertainty in the causal inference. The outcome can be represented by either a continuous or binary variable, the potential mediator is continuous, and the instrumental variable can be continuous or binary and is not limited to a single variable but may be a design matrix representing multiple variables.
