Estimating individual treatment effects on COPD exacerbations by causal machine learning on randomised controlled trials

Rationale Estimating the causal effect of an intervention at individual level, also called individual treatment effect (ITE), may help in identifying response prior to the intervention. Objectives We aimed to develop machine learning (ML) models which estimate ITE of an intervention using data from randomised controlled trials and illustrate this approach with prediction of ITE on annual chronic obstructive pulmonary disease (COPD) exacerbation rates. Methods We used data from 8151 patients with COPD of the Study to Understand Mortality and MorbidITy in COPD (SUMMIT) trial ( NCT01313676 ) to address the ITE of fluticasone furoate/vilanterol (FF/VI) versus control (placebo) on exacerbation rate and developed a novel metric, Q-score, for assessing the power of causal inference models. We then validated the methodology on 5990 subjects from the InforMing the PAthway of COPD Treatment (IMPACT) trial ( NCT02164513 ) to estimate the ITE of FF/umeclidinium/VI (FF/UMEC/VI) versus UMEC/VI on exacerbation rate. We used Causal Forest as causal inference model. Results In SUMMIT, Causal Forest was optimised on the training set (n=5705) and tested on 2446 subjects (Q-score 0.61). In IMPACT, Causal Forest was optimised on 4193 subjects in the training set and tested on 1797 individuals (Q-score 0.21). In both trials, the quantiles of patients with the strongest ITE consistently demonstrated the largest reductions in observed exacerbations rates (0.54 and 0.53, p<0.001). Poor lung function and blood eosinophils, respectively, were the strongest predictors of ITE. Conclusions This study shows that ML models for causal inference can be used to identify individual response to different COPD treatments and highlight treatment traits. Such models could become clinically useful tools for individual treatment decisions in COPD.