AI-driven discovery of minimal sepsis biomarkers for disease detection and progression: precision medicine across diverse populations

Background: Sepsis biomarker research over the past 30 years has been plagued by the use of wrong animal models and inappropriate patient selections, leading to the failure of translating findings into precision medicine. Thousands of sepsis-related gene biomarkers have been published, but this excess hinders medical advancement because (1) an overwhelming number of genes make targeted drug development and precision medicine unfeasible; (2) many biomarkers lack cross-cohort validation, rendering them clinically unhelpful. Our goal is to identify a highly informative, single-digit set of sepsis biomarkers to advance precision medicine. Methods: We conducted large-scale research on heterogeneous populations, including patients with sepsis, severe sepsis, and septic shocks, and collected plasma samples from 32 sepsis patients and 18 healthy controls at Renmin Hospital of Wuhan University, China. RNA was isolated using the HYCEZMBIO Serum/Plasma RNA Kit, and RT-qPCR was performed on the Roche Light Cycler 480 platform. An AI-based max-logistic competing classifier was applied across 11 cohorts with thousands of samples, using both self-designed and public datasets to identify the most critical sepsis biomarkers. Results: Our analysis highlights CKAP4, FCAR, and RNF4 as key genetic drivers in sepsis-related variations. In whole blood, NONO is crucial for immune response, while in plasma, PLEKHO1 and BMP6 reveal further genetic heterogeneities. Pediatric patients also exhibit significant contributions from RNASE2 and OGFOD3. These genes form the most effective miniature set of biomarkers. Conclusion: Achieving 99.42% accuracy across cohorts, this miniature set outperforms larger published gene sets. These findings provide critical insights for personalized risk assessment, targeted drug development, and tailored treatments for both adult and pediatric sepsis patients.