Analysis of survival data with non-proportional hazards: A comparison of propensity score weighted methods

Abstract

One of the most common ways researchers compare survival outcomes across treatments when confounding is present is using Cox regression. This model is limited by its underlying assumption of proportional hazards; in some cases, substantial violations may occur. Here we present and compare approaches which attempt to address this issue, including Cox models with time-varying hazard ratios; parametric accelerated failure time models; Kaplan-Meier curves; and pseudo-observations. To adjust for differences between treatment groups, we use Inverse Probability of Treatment Weighting based on the propensity score. We examine clinically meaningful outcome measures that can be computed and directly compared across each method, namely, survival probability at time T, median survival, and restricted mean survival. We conduct simulation studies under a range of scenarios, and determine the biases, coverages, and standard errors of the Average Treatment Effects for each method. We then apply these approaches to two published observational studies of survival after cancer treatment. The first examines chemotherapy in sarcoma, where survival is very similar initially, but after two years the chemotherapy group shows a benefit. The other study is a comparison of surgical techniques for kidney cancer, where survival differences are attenuated over time.