From Study Design to Executable Code: Automating Target Trial Emulation with Large Language Models

Introduction: Implementing target trial emulation (TTE) study methods as end-to-end executable analytic code is technically demanding, and producing standardized, reproducible scripts consistently across research teams remains a persistent challenge. We aimed to develop a framework that translates free-text study descriptions into standardized analytic specifications and executable Strategus R scripts for the Observational Health Data Sciences and Informatics (OHDSI) ecosystem. Methods: We developed THESEUS (Text-guided Health-study Estimation and Specification Engine Using Strategus), which operates through two sequential steps. Large language models (LLMs) first map descriptions of the study into a constrained JavaScript Object Notation (JSON) schema (standardization step), after which the structured specifications are converted into R scripts with a self-auditing loop for error correction (code generation step). We evaluated eight proprietary LLMs using texts extracted from the methods section of 15 OHDSI-based TTE studies, and externally validated the framework on texts from 5 non-OHDSI studies, across three input settings: primary analysis text only, full analyses text, and full methods sections. Standardization was evaluated at the study-level (whether all parameters in a study were correctly extracted) and at the field-level (sensitivity and false positive rate per individual parameter) with field-level evaluation applied to the full analyses text and full methods sections input settings. Code generation was assessed by executability of the produced R scripts before and after self-auditing. Results: In the standardization step, study-level accuracy across models ranged from 0.91 to 0.98 for primary analysis, 0.67 to 0.87 for full analyses, and 0.67 to 0.85 for full methods sections in OHDSI studies, whereas the corresponding ranges were 0.73 to 0.93, 0.60 to 0.87, and 0.27 to 0.47 in non-OHDSI studies. At the field-level, sensitivity across models under the full analyses text input setting ranged from 0.73 to 0.90 with 0.27 to 0.67 false positives per study in OHDSI studies, and from 0.71 to 0.90 with 0.20 to 1.00 false positives per study in non-OHDSI studies, depending on input setting. For code generation, first-run executability ranged from 0.80 to 1.00 for OHDSI studies and improved to 0.93 to 1.00 after self-auditing. In non-OHDSI studies, first-run executability ranged from 0.60 to 1.00, improving to 1.00 after self-auditing. Discussion: THESEUS demonstrates that pairing a standardized data model with a structured analysis framework enables reliable LLM-powered automation of the coding step in observational research. THESEUS supports the reliable translation of natural-language study descriptions into executable, shareable code in standardized observational research settings. This approach has the potential to lower the technical barriers to participation in observational research for a broader range of investigators.