Clinical Comparator Dependence of Inflammatory and Hematologic Biomarker Discrimination for Sepsis: A Matched Retrospective Study Using MIMIC-IV Emergency Department Data

Background: The diagnostic performance of sepsis biomarkers may vary according to the clinical comparator population. We evaluated 11 routinely available inflammatory and hematologic biomarkers in two matched diagnostic settings. Methods: We conducted a retrospective observational study using linked MIMIC-IV, MIMIC-IV-ED, and MIMIC-IV-Note data. Adult emergency department episodes were classified as sepsis, suspected infection without sepsis, or controls without suspected infection. Comparison-specific profile matching retained the same 525 sepsis episodes in both analyses, together with 214 controls without suspected infection and 315 episodes with suspected infection without sepsis. Biomarker discrimination was assessed using area under the receiver operating characteristic curve (AUROC) with DeLong inference. Results: Against controls without suspected infection, C-reactive protein (CRP) had the highest AUROC (0.786; 95% CI, 0.748–0.823), followed by absolute lymphocyte count (0.654; 0.613–0.696) and the neutrophil-to-lymphocyte ratio (NLR; 0.636; 0.594–0.677). Against suspected infection without sepsis, absolute lymphocyte count had the highest AUROC (0.677; 0.641–0.714), followed by NLR (0.626; 0.588–0.664), whereas CRP discrimination decreased to 0.555 (0.514–0.595). The cross-setting difference for CRP was 0.231 (95% CI, 0.183–0.278; Holm-adjusted p <0.001). Sensitivity analyses produced similar qualitative findings. Conclusions: Biomarker discrimination for sepsis varied according to the clinical comparator population, with the magnitude of cross-setting change differing across biomarkers. CRP showed the largest change, whereas absolute lymphocyte count retained modest discrimination in both settings. These findings emphasize the importance of interpreting biomarker performance within clinically relevant diagnostic contrasts.