Semiparametric Joint Modeling to Estimate the Treatment Effect on a Longitudinal Surrogate with Application to Chronic Kidney Disease Trials (2412.14124v1)

Abstract: In clinical trials where long follow-up is required to measure the primary outcome of interest, there is substantial interest in using an accepted surrogate outcome that can be measured earlier in time or with less cost to estimate a treatment effect. For example, in clinical trials of chronic kidney disease (CKD), the effect of a treatment is often demonstrated on a surrogate outcome, the longitudinal trajectory of glomerular filtration rate (GFR). However, estimating the effect of a treatment on the GFR trajectory is complicated by the fact that GFR measurement can be terminated by the occurrence of a terminal event, such as death or kidney failure. Thus, to estimate this effect, one must consider both the longitudinal outcome of GFR, and the terminal event process. Available estimation methods either impose restrictive parametric assumptions with corresponding maximum likelihood estimation that is computationintensive or other assumptions not appropriate for the GFR setting. In this paper, we build a semiparametric framework to jointly model the longitudinal outcome and the terminal event, where the model for the longitudinal outcome is semiparametric, and the relationship between the longitudinal outcome and the terminal event is nonparametric. The proposed semiparametric joint model is flexible and can be extended to include nonlinear trajectory of the longitudinal outcome easily. An estimating equation based method is proposed to estimate the treatment effect on the slope of the longitudinal outcome (e.g., GFR slope). Theoretical properties of the proposed estimators are derived. Finite sample performance of the proposed method is evaluated through simulation studies. We illustrate the proposed method using data from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trail to examine the effect of Losartan on GFR slope.