Statistical methods
diabetes
HYPERTENSION, DIABETES, TYPE 2 DIABETES, DYSLIPIDEMIA
The association between upgraded adherence to the MedDiet (using yearly cumulative averages) and type 2 diabetes was analyzed with multivariable time-varying Cox models. In these time-varying Cox models, the values of the variable that changed over time was the yearly cumulative average up to the current visit of each patient. For that aim, we time split the dataset into multiple rows per participant based on each visit (please see a very small synthetic example to mimic the data in the Supplementary material). Robust variance estimators were used to account for potential intra-cluster correlations among members of the same household or the same clinic in a small subset of participants. The main exposure were cumulative averages of MEDAS score, calculated as the mean of all time points up to that follow-up visit, including the baseline assessment and up to 7-year follow-up (i.e., 8 time points). Participants with missing values for MEDAS at any time point were assigned the mean of the score between the previous and posterior visit. Hazard Ratios (HRs) were calculated for the three categories of cumulative averages of the MEDAS ( 8 to < 10, 10 to < 12, and ≥ 12 scores) using as reference category the group with lowest adherence (MEDAS < 8). An additional HR was calculated for each 2-point increment in the MEDAS score (roughly equivalent to its standard deviation), considered as a quantitative variable. To quantify a linear trend, we conducted a Wald test for linear trend by assigning the median intake within each of the four categories and modeling this as a continuous variable. Multivariate model 1 was adjusted for age, sex, smoking status (never/current/former), dyslipidemia, hypertension, total energy intake level (kcal/d), physical activity (quintiles), and education (primary/secondary/university). Multivariable model 2 was additionally adjusted for propensity scores derived from estimated probabilities of allocation in the trial [Subgroup analyses by sex, age (< 70 or ≥ 70 years), trial arm, BMI (< 30 or ≥ 30 kg/mIncidence of diabetes was plotted by joint classification according to average MEDAS scores from years 1 to 7 (< 10 or ≥ 10) and randomized arm (merging both MedDiet groups together, and, only in an ancillary analysis by comparing only MedDiet + EVOO versus control). For these plots, we used standardization with inverse probability weighting (IPW) to control for confounding. Weighting factors were the previously mentioned potential confounders.We also run (only as a reference) a conventional Cox model using In a subset of 889 participants, information on a validated plasma metabolomic signature of MEDAS, comprised of 67 metabolites, was available. This signature has been well validated in PREDIMED and other cohorts with a reported r = 0.31–0.37 in PREDIMED [Two tailed P values < 0.05 were considered significant and 95% confidence intervals were always computed.