G-estimation of structural nested mean models for interval-censored data using pseudo-observations

Two large-scale randomized clinical trials compared fenofibrate and placebo in diabetic patients with pre-existing retinopathy (FIELD study) or risk factors (ACCORD trial) on an intention-to-treat basis and reported a significant reduction in the progression of diabetic retinopathy in the fenofibrate arms. However, their analyses involved complications due to intercurrent events, that is, treatment-switching and interval-censoring. This article addresses these problems involved in estimation of causal effects of long-term use of fibrates in a cohort study that followed patients with type 2 diabetes for 8 years. We propose structural nested mean models (SNMMs) of time-varying treatment effects and pseudo-observation estimators for interval-censored data. The first estimator for SNMMs uses a nonparametric maximum likelihood estimator (MLE) as a pseudo-observation, while the second estimator is based on MLE under a parametric piecewise exponential distribution. Through numerical studies with real and simulated datasets, the pseudo-observations estimators of causal effects using the nonparametric Wellner-Zhan estimator perform well even under dependent interval-censoring. Its application to the diabetes study revealed that the use of fibrates in the first 4 years reduced the risk of diabetic retinopathy but did not support its efficacy beyond 4 years.