Temporal robustness of biomarker-based classification algorithms for sepsis
Emma Rademaker, Rombout B. E. van Amstel, Said el Bouhaddani, Marc J. M. Bonten, Lennie Derde, Lonneke van Vught, Tom van der Poll, Lieuwe D. J. Bos, Harm‐Jan de Grooth, Olaf L. Cremer
Abstract
PURPOSE: Heterogeneity of the host response in sepsis hampers development of effective treatments. Several immunobiologically distinct subphenotypes (or endotypes) have been identified using data-driven analyses of single-timepoint biomarker data, but their temporal stability remains uncertain due to dynamic biology and statistical limitations. METHODS: We analyzed data from 345 sepsis patients across two ICU cohorts. 30 immune biomarkers were measured every 8 h for up to 7 days. Latent profile analysis was used to identify classes upon admission and re-classify patients at later timepoints. Temporal robustness was assessed by (1) inter-class transition rates, and (2) intra-class cohesion (regardless of label) using the Rand Index (RI). RESULTS: At ICU admission, three immune profiles were identified: profile A (149 patients, 43%) reflected adaptive immune activation (elevated IL-4, IL-5, RANTES, and GM-CSF); profile B (60 patients, 17%) a hyperinflammatory state (high IL-6, IL-8, IL-1Ra, and low protein C); and profile C (136 patients, 39%) broadly attenuated inflammation. By 48 h, the prevalences of A and B declined to 31% and 13%, while C increased to 56%. Inter-class transitions occurred most in patients assigned to A (41% of all 8-hourly transitions), compared to 39% and 22% for B and C. Intra-class cohesion across intervals was poor (median RI 65%, IQR 62-64%), indicating that patients classified together at admission did not remain consistently together. CONCLUSION: Sepsis patients were frequently reclassified across immune profiles over short intervals, with approximately one-third of subgroup peers changing at each timepoint. This instability challenges the clinical utility of biomarker-derived endotypes.