🤖 AI Summary
This study addresses the challenge that data-driven protocol selection in target trial emulation often invalidates statistical inference. To resolve this, the authors propose a two-stage strategy based on sample splitting: the first subsample is used to explore and finalize the target trial protocol, while the second, independent subsample is employed to implement the selected protocol and conduct causal inference. Inspired by the exploratory-to-confirmatory paradigm in clinical trials, this approach decouples protocol specification from inference, thereby preserving the flexibility of scientific exploration while rigorously maintaining nominal coverage guarantees for statistical inference. By integrating sample splitting, target trial emulation, and causal inference, the work provides both theoretical assurance and a practical framework for valid statistical inference in observational studies.
📝 Abstract
Target trial emulation has improved comparative effectiveness research by making the causal question, assumptions, and analysis plan explicit. However, target trial protocols are usually developed iteratively. After examining the data, investigators revise the protocol to reflect which target trials the observational data can realistically support. While this iterative procedure is part of normal scientific practice, it raises concerns about selective choices and invalid statistical inference. A simple procedure can address these concerns. This procedure is based on sample splitting. In the initial split, investigators explore the data to define a target trial protocol. When these choices are made, the target trial protocol is implemented on the second split. Although the investigators made data-informed choices to select the target trial protocol, the inference has the usual coverage guarantees. The procedure is created to mirror how trialists move from pilot studies to a phase 3 trial. First, they use data from pilots and early-phase trials to learn and decide on a final protocol. Then they implement this protocol and analyze a new set of data in a phase 3 trial.