associated with specific substances, for example [105, 109]. Other studies have not adjusted for other substance co-morbidities [110], which may enhance detection of generalizable genetic variant associations. To our knowledge, there has been no formal testing to outline the best scenarios for future addiction studies to balance statistical power with the use of unassessed vs. assessed controls. Ultimately, study design decisions will depend on the primary research question and expected misclassification rate. For strategizing adjustment for co-morbid addictions, simulation testing of genetically correlated outcomes and covariates suggests that the impact of covariate adjustment depends on the direction and magnitude of correlation with the outcome [120].
