Prognosis of cancer survivors: estimation based on differential equations.

We present a method for estimating several prognosis parameters for cancer survivors. The method utilizes the fact that these parameters solve differential equations driven by cumulative hazards. By expressing the parameters as solutions to differential equations, we develop generic estimators that are easy to implement with standard statistical software. We explicitly describe the estimators for prognosis parameters that are often employed in practice, but also for parameters that, to our knowledge, have not been used to evaluate prognosis. We then apply these parameters to assess the prognosis of five common cancers in Norway.

Causal inference with recurrent and competing events.

Many research questions concern treatment effects on outcomes that can recur several times in the same individual. For example, medical researchers are interested in treatment effects on hospitalizations in heart failure patients and sports injuries in athletes. Competing events, such as death, complicate causal inference in studies of recurrent events because once a competing event occurs, an individual cannot have more recurrent events. Several statistical estimands have been studied in recurrent event settings, with and without competing events. However, the causal interpretations of these estimands, and the conditions that are required to identify these estimands from observed data, have yet to be formalized. Here we use a formal framework for causal inference to formulate several causal estimands in recurrent event settings, with and without competing events. When competing events exist, we clarify when commonly used classical statistical estimands can be interpreted as causal quantities from the causal mediation literature, such as (controlled) direct effects and total effects. Furthermore, we show that recent results on interventionist mediation estimands allow us to define new causal estimands with recurrent and competing events that may be of particular clinical relevance in many subject matter settings. We use causal directed acyclic graphs and single world intervention graphs to illustrate how to reason about identification conditions for the various causal estimands based on subject matter knowledge. Furthermore, using results on counting processes, we show that our causal estimands and their identification conditions, which are articulated in discrete time, converge to classical continuous time counterparts in the limit of fine discretizations of time. We propose estimators and establish their consistency for the various identifying functionals. Finally, we use the proposed estimators to compute the effect of blood pressure lowering treatment on the recurrence of acute kidney injury using data from the Systolic Blood Pressure Intervention Trial.

On null hypotheses in survival analysis.

The conventional nonparametric tests in survival analysis, such as the log-rank test, assess the null hypothesis that the hazards are equal at all times. However, hazards are hard to interpret causally, and other null hypotheses are more relevant in many scenarios with survival outcomes. To allow for a wider range of null hypotheses, we present a generic approach to define test statistics. This approach utilizes the fact that a wide range of common parameters in survival analysis can be expressed as solutions of differential equations. Thereby, we can test hypotheses based on survival parameters that solve differential equations driven by cumulative hazards, and it is easy to implement the tests on a computer. We present simulations, suggesting that our tests perform well for several hypotheses in a range of scenarios. As an illustration, we apply our tests to evaluate the effect of adjuvant chemotherapies in patients with colon cancer, using data from a randomized controlled trial.

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

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.