Auditing evaluation artifacts and data leakage in large language model systems for rare disease diagnosis

Jian Yang, Peilin Liu, Xiaohan Li, Songda Li, Yu Cao +2

Augmented large language model (LLM) systems have reported high benchmark accuracies in rare disease diagnosis, yet their real-world clinical utility remains unproven. A recent meta-analysis flagged augmented LLM diagnostic evaluations as having a high risk of bias due to suspected data leakage; however, the precise impact of these vulnerabilities on model inference has yet to be fully quantified. In this study, we present a comprehensive empirical audit to quantify evaluation artifacts across prevailing AI paradigms, using a repository of over 60,000 cases from diverse public and independent clinical cohorts. By reconstructing a state-of-the-art agentic framework, we demonstrate that candidate-space contamination artificially inflates performance: enforcing strict cross-dataset isolation resulted in a marked performance decline, with the cross-dataset mean Recall@1 decreasing from 54.3% (under conventional one-vs-rest evaluation) to 40.3% (Hedges' g = 0.94). Similar spatial overfitting in supervised classifiers caused diagnostic accuracy to drop from an internal mean of 42.9% to 16.7% across external cohorts (Cohen's d = 2.01). Furthermore, we quantify how LLMs infer diagnoses…