Causal inference in continuous time: an example on prostate cancer therapy

In marginal structural models (MSMs), time is traditionally treated as a discrete parameter. In survival analysis on the other hand, we study processes that develop in continuous time. Therefore, Røysland (2011. A martingale approach to continuous-time marginal structural models. Bernoulli 17, 895–915) developed the continuous-time MSMs, along with continuous-time weights. The continuous-time weights are conceptually similar to the inverse probability weights that are used in discrete time MSMs. Here, we demonstrate that continuous-time MSMs may be used in practice. First, we briefly describe the causal model assumptions using counting process notation, and we suggest how causal effect estimates can be derived by calculating continuous-time weights. Then, we describe how additive hazard models can be used to find such effect estimates. Finally, we apply this strategy to compare medium to long-term differences between the two prostate cancer treatments radical prostatectomy and radiation therapy, using data from the Norwegian Cancer Registry. In contrast to the results of a naive analysis, we find that the marginal cumulative incidence of treatment failure is similar between the strategies, accounting for the competing risk of other death.

A causal framework for classical statistical estimands in failure-time settings with competing events

Mats Julius Stensrud

In failure-time settings, a competing event is any event that makes it impossible for the event of interest to occur. For example, cardiovascular disease death is a competing event for prostate cancer death because an individual cannot die of prostate cancer once he has died of cardiovascular disease. Various statistical estimands have been defined as possible targets of inference in the classical competing risks literature. Many reviews have described these statistical estimands and their estimating procedures with recommendations about their use. However, this previous work has not used a formal framework for characterizing causal effects and their identifying conditions, which makes it difficult to interpret effect estimates and assess recommendations regarding analytic choices. Here we use a counterfactual framework to explicitly define each of these classical estimands. We clarify that, depending on whether competing events are defined as censoring events, contrasts of risks can define a total effect of the treatment on the event of interest or a direct effect of the treatment on the event of interest not mediated by the competing event. In contrast, regardless of whether competing events are defined as censoring events, counterfactual hazard contrasts cannot generally be interpreted as causal effects. We illustrate how identifying assumptions for all of these counterfactual estimands can be represented in causal diagrams, in which competing events are depicted as time-varying covariates. We present an application of these ideas to data from a randomized trial designed to estimate the effect of estrogen therapy on prostate cancer mortality.

2020

The additive hazard estimator is consistent for continuous-time marginal structural models

Pal Christie Ryalen, Mats Julius Stensrud

Marginal structural models (MSMs) allow for causal analysis of longitudinal data. The standard MSM is based on discrete time models, but the continuous-time MSM is a conceptually appealing alternative for survival analysis. In applied analyses, it is often assumed that the theoretical treatment weights are known, but these weights are usually unknown and must be estimated from the data. Here we provide a sufficient condition for continuous-time MSM to be consistent even when the weights are estimated, and we show how additive hazard models can be used to estimate such weights. Our results suggest that continuous-time weights perform better than IPTW when the underlying process is continuous. Furthermore, we may wish to transform effect estimates of hazards to other scales that are easier to interpret causally. We show that a general transformation strategy can be used on weighted cumulative hazard estimates to obtain a range of other parameters in survival analysis, and explain how this strategy can be applied on data using our R packages ahw and transform.hazards.

2019

Transforming cumulative hazard estimates

Pal Christie Ryalen, Mats Julius Stensrud

Time-to-event outcomes are often evaluated on the hazard scale, but interpreting hazards may be difficult. Recently in the causal inference literature concerns have been raised that hazards actually have a built-in selection bias that prevents simple causal interpretations. This is a problem even in randomized controlled trials, where hazard ratios have become a standard measure of treatment effects. Modelling on the hazard scale is nevertheless convenient, for example to adjust for covariates; using hazards for intermediate calculations may therefore be desirable. In this paper we present a generic method for transforming hazard estimates consistently to other scales at which these built-in selection biases are avoided. The method is based on differential equations and generalizes a well-known relation between the Nelson–Aalen and Kaplan–Meier estimators. Using the martingale central limit theorem, we show that covariances can be estimated consistently for a large class of estimators, thus allowing for rapid calculation of confidence intervals. Hence, given cumulative hazard estimates based on, for example, Aalen’s additive hazard model, we can obtain many other parameters without much more effort. We give several examples and the associated estimators. Coverage and convergence speed are explored via simulations, and the results suggest that reliable estimates can be obtained in real-life scenarios.

2018