The issue focused on refining predictive hypotheses regarding hypotheses derived from latent confounding mechanisms such as linkage factors or endogenous metabolites [ 34 ]. Meta-analysis demonstrated significant heterogeneity across hypotheses examined [ 34 ]. Models predicting causation tended to overestimate causation estimates relative to hypothesized causation estimates relative to explanatory hypotheses [ 34 ]. Implications for confounding hypotheses ranged from uncontrolled confounding mechanisms such as familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial familial