Automated causal inference in application to randomized controlled clinical trials

Randomized controlled trials (RCTs) are considered the gold standard for testing causal hypotheses in the clinical domain; however, the investigation of prognostic variables of patient outcome in a hypothesized cause-effect route is not feasible using standard statistical methods. Here we propose a new automated causal inference method (AutoCI) built on the invariant causal prediction (ICP) framework for the causal reinterpretation of clinical trial data. Compared with existing methods, we show that the proposed AutoCI allows one to clearly determine the causal variables of two real-world RCTs of patients with endometrial cancer with mature outcome and extensive clinicopathological and molecular data. This is achieved via suppressing the causal probability of non-causal variables by a wide margin. In ablation studies, we further demonstrate that the assignment of causal probabilities by AutoCI remains consistent in the presence of confounders. In conclusion, these results confirm the robustness and feasibility of AutoCI for future applications in real-world clinical analysis. The invariant causal prediction (ICP) framework tries to determine the causal variables given an outcome variable, but considerable effort is needed to adapt existing ICP methods to the clinical domain. The authors propose an automated causal inference method that could potentially address the challenges of applying the ICP framework to complex clinical datasets.