FIGURE 1.

Overview of analysis procedures. (a) Within the non-overlapping training set, (i) the optimal predictive model for estimating predicted brain age was obtained using machine learning model; (ii) the predictive model was corrected to reduce the estimation bias and further used to estimate the adjusted predictive brain age; and (iii) the outcome variable [i.e. adjusted brain age gap (BAG)] was calculated by subtracting the chronological age by the adjusted predictive brain age. (b) In the testing set, the adjusted BAG was estimated based on the corrected predictive model in (a), and the causal effect of smoking behavior (e.g., smoking status) on adjusted BAG was evaluated through Mendelian randomization analysis. Smoking status was a binary trait consisting of nonsmokers and smokers