Penalized estimation of complex, non-linear exposure-lag-response associations

Abstract

We propose a novel approach for the flexible modeling of complex exposure-lag-response associations in time-to-event data, where multiple past exposures within a defined time window are cumulatively associated with the hazard. Our method allows for the estimation of a wide variety of effects, including potentially smooth and smoothly time-varying effects as well as cumulative effects with leads and lags, taking advantage of the inference methods that have recently been developed for generalized additive mixed models. We apply our method to data from a large observational study of intensive care patients in order to analyze the association of both the timing and the amount of artificial nutrition with the short term survival of critically ill patients. We evaluate the properties of the proposed method by performing extensive simulation studies and provide a systematic comparison with related approaches.

Keywords: Cumulative effects; Exposure-lag-response association; Penalized additive models; Reproducible research; Survival analysis; Time-dependent covariates.