Survival Analysis

We’ve finally reached the end of the road. This is the fifth and last post in a series building up to a Bayesian proportional hazards model for analyzing a stepped-wedge cluster-randomized trial. If you are just joining in, you may want to start at the beginning.

The model presented here integrates non-linear time trends and cluster-specific random effects—elements we’ve previously explored in isolation. There’s nothing fundamentally new in this post; it brings everything together. Given that the groundwork has already been laid, I’ll keep the commentary brief and focus on providing the code.

In recent posts, I introduced a Bayesian approach to proportional hazards modeling and then extended it to incorporate a penalized spline. (There was also a third post on handling ties when multiple individuals share the same event time.) This post describes another extension: a random effect to account for clustering in a cluster randomized trial. With this in place, I’ll be ready to tackle the final step—building a model for analyzing a stepped-wedge cluster-randomized trial that incorporates both splines and site-specific random effects.

Over my past few posts, I’ve been progressively building towards a Bayesian model for a stepped-wedge cluster randomized trial with a time-to-event outcome, where time will be modeled using a spline function. I started with a simple Cox proportional hazards model for a traditional RCT, ignoring time as a factor. In the next post, I introduced a nonlinear time effect. For the third post—one I initially thought was ready to publish—I extended the model to a cluster randomized trial without explicitly incorporating time. I was then working on the grand finale, the full model, when I ran into an issue: I couldn’t recover the effect-size parameter used to generate the data.

In my previous post, I outlined a Bayesian approach to proportional hazards modeling. This post serves as an addendum, providing code to incorporate a spline to model a time-varying hazard ratio non linearly. In a second addendum to come I will present a separate model with a site-specific random effect, essential for a cluster-randomized trial. These components lay the groundwork for analyzing a stepped-wedge cluster-randomized trial, where both splines and site-specific random effects will be integrated into a single model. I plan on describing this comprehensive model in a final post.

A recent conversation with a colleague about a large stepped-wedge design (SW-CRT) cluster randomized trial piqued my interest, because the primary outcome is time-to-event. This is not something I’ve seen before. A quick dive into the literature suggested that time-to-event outcomes are uncommon in SW-CRTs-and that the best analytic approach is not obvious. I was intrigued by how to analyze the data to estimate a hazard ratio while accounting for clustering and potential secular trends that might influence the time to the event.

A colleague reached out for help designing a cluster randomized trial to evaluate a clinical decision support tool for primary care physicians (PCPs), which aims to improve care for high-risk patients. The outcome will be a time-to-event measure, collected at the patient level. The unit of randomization will be the PCP, and one of the key design issues is settling on the number to randomize. Surprisingly, I’ve never been involved with a study that required a clustered survival analysis. So, this particular sample size calculation is new for me, which led to the development of simulations that I can share with you. (There are some analytic solutions to this problem, but there doesn’t seem to a consensus about the best approach to use.)

As I mentioned last time, I am working on an update of simstudy that will make generating survival/time-to-event data a bit more flexible. I previously presented the functionality related to competing risks, and this time I’ll describe generating survival data that has time-dependent hazard ratios. (As I mentioned last time, if you want to try this at home, you will need the development version of simstudy that you can install using devtools::install_github(“kgoldfeld/simstudy”).)

I am working on an update of simstudy that will make generating survival/time-to-event data a bit more flexible. There are two biggish enhancements. The first facilitates generation of competing events, and the second allows for the possibility of generating survival data that has time-dependent hazard ratios. This post focuses on the first enhancement, and a follow up will provide examples of the second. (If you want to try this at home, you will need the development version of simstudy, which you can install using devtools::install_github(“kgoldfeld/simstudy”).)

In the previous post I described how to determine the parameter values for generating a Weibull survival curve that reflects a desired distribution defined by two points along the curve. I went ahead and implemented these ideas in the development version of simstudy 0.4.0.9000, expanding the idea to allow for any number of points rather than just two. This post provides a brief overview of the approach, the code, and a simple example using the parameters to generate simulated data.

The package simstudy has some functions that facilitate generating survival data using an underlying Weibull distribution. Originally, I added this to the package because I thought it would be interesting to try to do, and I figured it would be useful for me someday (and hopefully some others, as well). Well, now I am working on a project that involves evaluating at least two survival-type processes that are occurring simultaneously. To get a handle on the analytic models we might use, I’ve started to try to simulate a simplified version of the data that we have.