Causal reductions in cardiovascular disease (CVD) with the Mediterranean diet (MedDiet) are supported by randomized trials, but the ability of nonrandomized studies to provide causal inferences in nutritional epidemiology is questioned. The "Seguimiento Universidad de Navarra" (SUN) project, conducted during 1999-2019 with 18,419 participants, was used to try to refute non-causal explanations for the inverse association found between adherence to the MedDiet and reduced CVD risk. A framework of different analytical strategies is proposed: alternative definitions of the exposure, exploration of residual confounding, resampling methods, depiction of absolute risks across the follow-up period, trial emulation, and negative controls. Additionally, we calculated the rate advancement period (RAP). We found that one standard deviation increase in the most frequently used MedDiet score was associated with a 29% relative reduction in CVD risk (95% Confidence Interval [CI] 14-41%), which is almost identical to that found in 2 randomized trials. The RAP of CVD would be postponed by an average of 7.9 years (95% CI: 1.6 to 14.2 years) by switching from low (MDS = 0 to2) to high (MDS = 7 to 9) adherence to the MedDiet in the fully adjusted model. Sensitivity analyses, graphical representations of absolute risks, trial emulation, and negative controls also supported causality. In conclusion, a framework of analytical approaches supported the causal effect of the MedDiet on CVD prevention using observational data. Similar methodology could be applied for causal inferences regarding other hypotheses.
Keywords: Mediterranean diet; causal inference; observational studies; risk assessment; statistical modeling of disease risk.