The Effect of Substance Use on Brain Ageing: A New Causal Inference Framework for Incomplete and Massive Phenomic Data

Although substance use is known to be associated with cognitive decline during ageing, its direct influence on the central nervous system remains unclear. In this study, we aim to investigate the potential influence of substance use on accelerated brain ageing by estimating the mean potential brain age gap (BAG) index, the difference between brain age and actual age, under different alcohol and tobacco intake in a large UK Biobank (UKB) cohort with extensive phenomic data reflecting a comprehensive life-style profile. We face two major challenges: (1) a large number of phenomic variables as potential confounders and (2) a small proportion of participants with complete phenomic data. To address these challenges, we first develop a new ensemble learning framework to establish robust estimation of mean potential outcome in the presence of many confounders. We then construct a data integration step to borrow information from larger than 90 percentages UKB participants with incomplete phenomic data to improve efficiency. Extensive numerical studies demonstrate the superiority of our method over competing methods, in terms of smaller estimation bias and variability. Our analysis results reveal significant effects for both frequent alcohol drinking and tobacco smoking by accelerating brain ageing in 0.24 and 0.32 years, respectively.