Mendelian Randomization Analysis of the Causal Effect of Cigarette Smoking on Hospital Costs

Introduction: Knowledge of the impact of smoking on health care costs is important for establishing the external effects of smoking and for evaluating policies intended to modify this behavior. Conventional analysis of this association is difficult because of omitted variable bias, reverse causality, and measurement error. 

Aims and Methods: We approached these challenges using a Mendelian Randomization study design; genetic variants associated with smoking behaviors were used in instrumental variables models with inpatient hospital costs (calculated from electronic health records) as the outcome. We undertook genome-wide association studies to identify genetic variants associated with smoking initiation and a composite smoking index (reflecting cumulative health impacts of smoking) on up to 300 045 individuals (mean age: 57 years at baseline, range 39-72 years) in the UK Biobank. We followed individuals up for a mean of 6 years. 

Results: Genetic liability to initiate smoking (ever vs. never smoking) was estimated to increase mean per-patient annual inpatient hospital costs by £477 (95% confidence interval (CI): £187 to £766). A one-unit change in genetic liability to the composite smoking index (range: 0-4.0) increased inpatient hospital costs by £204 (95% CI: £105 to £303) per unit increase in this index. There was some evidence that the composite smoking index causal models violated the instrumental variable assumptions, and all Mendelian Randomization models were estimated with considerable uncertainty. Models conditioning on risk tolerance were not robust to weak instrument bias. 

Conclusions: Our findings have implications for the potential cost-effectiveness of smoking interventions. Implications: We report the first Mendelian Randomization analysis of the causal effect of smoking on health care costs. Using two smoking phenotypes, we identified substantial impacts of smoking on inpatient hospital costs, although the causal models were associated with considerable uncertainty. These results could be used alongside other evidence on the impact of smoking to evaluate the cost-effectiveness of antismoking interventions and to understand the scale of externalities associated with this behavior.