A causal model for subgroup effects in randomized screening trials
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The primary analysis of randomized cancer screening trials for cancer typically adheres to the intention-to-screen (ITT) principle, measuring cancer-specific mortality reductions between screening and control arms. These mortality reductions result from a combination of the screening regimen, screening technology and the effect of the early, screening-induced, treatment. This motivates addressing these different aspects separately. Here we are interested in the causal effect of early versus delayed treatments on cancer mortality among the screening-detectable subgroup, which under certain assumptions is estimable from conventional randomized screening trial using instrumental variable type methods. To define the causal effect of interest, we formulate a simplified causal multi-state model for screening trials, based on a hypothetical intervention trial where screening detected individuals would be randomized into early versus delayed treatments. The cancer-specific mortality reductions after screening detection are quantified by a cause-specific hazard ratio. For this, we propose two estimators, based on an estimating equation and a likelihood expression. The methods extend existing instrumental variable methods for time-to-event and competing risks outcomes to time-dependent intermediate variables. Using the causal model as a data generating mechanism, we investigate the performance of the new estimators, and compare them to two previously proposed ones. In addition, we illustrate the proposed method in the context of CT screening for lung cancer using the US National Lung Screening Trial (NLST) data.
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