In silico cancer immunotherapy trials uncover the consequences of therapy-specific response patterns for clinical trial design and outcome.

Late-stage cancer immunotherapy trials often lead to unusual survival curve shapes, like delayed curve separation or a plateauing curve in the treatment arm. It is critical for trial success to anticipate such effects in advance and adjust the design accordingly. Here, we use in silico cancer immunotherapy trials - simulated trials based on three different mathematical models - to assemble virtual patient cohorts undergoing late-stage immunotherapy, chemotherapy, or combination therapies. We find that all three simulation models predict the distinctive survival curve shapes commonly associated with immunotherapies. Considering four aspects of clinical trial design - sample size, endpoint, randomization rate, and interim analyses - we demonstrate how, by simulating various possible scenarios, the robustness of trial design choices can be scrutinized, and possible pitfalls can be identified in advance. We provide readily usable, web-based implementations of our three trial simulation models to facilitate their use by biomedical researchers, doctors, and trialists.

Testing Graphical Causal Models Using the R Package "dagitty".

Causal diagrams such as directed acyclic graphs (DAGs) are used in several scientific fields to help design and analyze studies that aim to infer causal effects from observational data; for example, DAGs can help identify suitable strategies to reduce confounding bias. However, DAGs can be difficult to design, and the validity of any DAG-derived strategy hinges on the validity of the postulated DAG itself. Researchers should therefore check whether the assumptions encoded in the DAG are consistent with the data before proceeding with the analysis. Here, we explain how the R package 'dagitty', based on the web tool dagitty.net, can be used to test the statistical implications of the assumptions encoded in a given DAG. We hope that this will help researchers discover model specification errors, avoid erroneous conclusions, and build better models. © 2021 The Authors. Basic Protocol 1: Constructing and importing DAG models from the dagitty web interface Support Protocol 1: Installing R, RStudio, and the dagitty package Basic Protocol 2: Testing DAGs against categorical data Basic Protocol 3: Testing DAGs against continuous data Support Protocol 2: Testing DAGs against continuous data with non-linearities Basic Protocol 4: Testing DAGs against a combination of categorical and continuous data.