My research projects

Covariate-adaptive randomization (CAR) is widely implemented in clinical trials to balance prognostic covariates across treatment arms. Continuous covariates are often discretized into strata in practice, yet its consequences are not clearly understood. This paper provides a comprehensive overview on the impact of discretization, on both the CAR design process and the inferential results thereafter. We establish the asymptotic properties of both imbalance measures and treatment effect estimators under discretized and non-discretized settings. Practical recommendations are given on when and how discretization should be employed. We show that discretization in design is generally recommended, as it enhances robustness against model misspecification. However, if the true model is known, the most efficient strategy is to balance covariates according to that model in the design. The theoretical results are corroborated by extensive simulation studies and an empirical application to a diabetes trial dataset. Together, the results clarify the gains and losses of discretization in CAR and pave the way for learning impact of discretization to other designs and beyond.

Individual patient data (IPD) are essential for statistical analysis in clinical research, yet access is often limited due to privacy concerns, high data-sharing costs, and proprietary restrictions. Conventional approaches to synthetic data generation, such as generative adversarial networks (GANs), require a large piece of IPD as training set. We propose a training-free, three-step method to create synthetic IPD for survival data, requiring no IPD for training. In summary, it digitizes the reported Kaplan–Meier (KM) plots and generates covariates that match the reconstructed data. Compared with existing IPD reconstruction methods, our approach is the first to exploit Scalable Vector Graphics (SVG) for high-accuracy digitization, and the first to provide covariate information. We demonstrate the method's potential through two detailed case studies and complementary simulation studies.

Pocock and Simon's minimization method is a popular approach for covariate-adaptive randomization in clinical trials. Valid statistical inference with data collected under the minimization method requires the knowledge of the limiting covariance matrix of within-stratum imbalances, whose existence is only recently established. In this work, we propose a bootstrap-based estimator for this limit and establish its consistency, in particular, by Le Cam's third lemma. As an application, we consider in simulation studies adjustments to existing robust tests for treatment effects with survival data by the proposed estimator. It shows that the adjusted tests achieve a size close to the nominal level, and unlike other designs, the robust tests without adjustment may have an asymptotic size inflation issue under the minimization method.

Systematic literature review of clinical trials drives regulatory decision-making, but conventional screening and extraction are time-consuming, labor-intensive, and vulnerable to study selection bias. We propose two fit-to-purpose multi-agentic systems (MAS) for systematic literature review, with human-in-the-loop. The screening MAS uses multiple LLM agents with heterogeneous personas and multi-round cross-review, and uniformly improves accuracy over a single-LLM baseline. The extraction MAS combines standardization, an iterative correction loop, and retrieval-based context control to ensure accuracy and scalability. Both MAS are specifically designed to support Human-In-The-Loop which is essential for clinical decisions. The novelty of the proposed approach lies in the system architecture rather than in any single foundation tools: the system can naturally benefit from future improvements in the underlying tools, for instance, stronger LLM agents, retrieval engines, image recognition methods, etc. As a real-world application, a published network meta-analysis is reproduced by the MAS. The result recovers all trials from the original study and identifies additional eligible trials missed by manual review, leading to updated clinical conclusions.

Minimal residual disease (MRD) has been endorsed by the FDA Oncology Drugs Advisory Committee as an endpoint for accelerated approval in multiple myeloma based on individual patient data collected from randomized trials. However, emerging data from recent trials were not included. A novel artificial intelligence (AI)–assisted framework is proposed, which automates information identification and extraction, providing up-to-date analyses that confirm moderate trial-level and strong individual patient–level associations between MRD rates at suspected complete response (MRD-CR) and survival endpoints in multiple myeloma. Specifically, this study utilized an AI-assisted framework that identifies relevant studies and filters critical information to analyze published data via 2 independent objectives. First, we examined the trial-level association using the coefficients of determination (R²) and its 95% confidence intervals (CI) based on published statistics of treatment effects on MRD and various endpoints. Next, we generated synthetic individual patient data with covariates through AI-curated tools to estimate the individual-level association. The AI tool searched for eligible randomized clinical trials (RCT). A total of 20 two-arm comparisons from 19 RCTs were analyzed. Trial-level analysis showed an R² of 0.71 (95% CI, 0.52–0.89) pooling disease subpopulations. Furthermore, AI techniques were applied to create synthetic individual data, combining information extracted from Kaplan–Meier curves and subgroup analyses from published literatures. Using generated synthetic data, we estimated the individual-level correlation between MRD-CR rates and progression-free survival outcomes with a bivariate copula model and calculated a global odds ratio of 7.28 (95% CI, 5.60–8.95).