How serious is bias in effect estimation in randomised trials with survival data given risk heterogeneity and informative censoring?

It is often assumed that randomisation will prevent bias in estimation of treatment effects from clinical trials, but this is not true of the semiparametric Proportional Hazards model for survival data when there is underlying risk heterogeneity. Here, a new formula is proposed for estimation of this bias, improving on a previous formula through ease of use and clarity regarding the role of the mid‐study cumulative hazard rate, shown to be an important factor for the bias magnitude. Informative censoring (IC) is recognised as a source of bias. Here, work on selection effects among survivors due to risk heterogeneity is extended to include IC. A new formula shows that bias in causal effect estimation under IC has two sources: one consequent on heterogeneity and one from the additional impact of IC. The formula provides new insights not previously shown: there may less bias under IC than when there is no IC and even, in principle, zero bias. When tested against simulated data, the new formulae are shown to be very accurate for prediction of bias in Proportional Hazards and accelerated failure time analyses which ignore heterogeneity. These data are also used to investigate the performance of accelerated failure time models which explicitly model risk heterogeneity (‘frailty models’) and G estimation. These methods remove bias when there is simple censoring but not with informative censoring when they may lead to overestimation of treatment effects. The new formulae may be used to help researchers judge the possible extent of bias in past studies. Copyright © 2017 John Wiley & Sons, Ltd.     

Estimating net survival: the importance of allowing for informative censoring

Net survival, the one that would be observed if cancer were the only cause of death, is the most appropriate indicator to compare cancer mortality between areas or countries. Several parametric and non-parametric methods have been developed to estimate net survival, particularly when the cause of death is unknown. These methods are based either on the relative survival ratio or on the additive excess hazard model, the latter using the general population mortality hazard to estimate the excess mortality hazard (the hazard related to net survival). The present work used simulations to compare estimator abilities to estimate net survival in different settings such as the presence/absence of an age effect on the excess mortality hazard or on the potential time of follow-up, knowing that this covariate has an effect on the general population mortality hazard too. It showed that when age affected the excess mortality hazard, most estimators, including specific survival, were biased. Only two estimators were appropriate to estimate net survival. The first is based on a multivariable excess hazard model that includes age as covariate. The second is non-parametric and is based on the inverse probability weighting. These estimators take differently into account the informative censoring induced by the expected mortality process. The former offers great flexibility whereas the latter requires neither the assumption of a specific distribution nor a model-building strategy. Because of its simplicity and availability in commonly used software, the nonparametric estimator should be considered by cancer registries for population-based studies.