Fig. 9.
Age plays a causal role in mortality which is largely mediated by the comorbidities accumulated with increasing age and general physiologic decline (A). These pathways dominate the unadjusted association and increasing age is associated with increased mortality. Adjustment for Charlson Comorbidity Index (CCI) score and metabolic equivalents (METs; a marker of functional capacity), which are mediators (or close descendants of the mediators) of the causal effects of age on mortality (shown in B) mostly blocks the causal association (grey arrows). This leaves the adjusted association (B) dominated by a noncausal pathway (red) caused by an unmeasured confounder (Ugene)—an aggressive genotype of cancer which presents at a younger age and increases mortality. The adjusted model therefore suggests increased mortality with younger age; a complete reversal of the unadjusted association. TNM, tumor-node-metastasis; Umorb, unmeasured morbidities.