Original Investigation 

Infectious Diseases

Multicenter Validation of Clinical Sepsis Phenotypes

Chang Ho Yoon, Daniel Sjöholm, Kristin E. Wickstrøm, et al

JAMA Netw Open 2026;9;(6):e2616134. doi:10.1001/jamanetworkopen.2026.16134

Key Points

Question  Are the 4 clinical phenotypes of sepsis derived from Sepsis Endotyping in Emergency Care (SENECA) data generalizable across independent, international patient cohorts?

Findings  In this multisite retrospective cohort study of 48 246 patient encounters, there was poor consistency between the SENECA-derived phenotypes and the phenotypes derived at 3 independent clinical sites.

Meaning  This study found that the 4 clinical phenotypes of sepsis derived from SENECA data lack generalizability across independent cohorts, suggesting that they may not be suitable for universal clinical application in their current form.

Abstract

Importance  Four clinical phenotypes of sepsis based on data from electronic health records have been proposed. Although promising, the generalizability of these phenotypes remains uncertain, and multisite validation is needed.

Objective  To validate, using the same methods and inclusion criteria, the 4 clinical phenotypes derived from Sepsis Endotyping in Emergency Care (SENECA) data.

Design, Setting, and Participants  This multisite retrospective cohort study uses data on adult patients admitted to the emergency departments in Stockholm, Sweden (January 1, 2011, to September 1, 2023); Oxford, England (February 4, 2014, to June 20, 2021); and Oslo, Norway (January 4, 2019, to October 9, 2023) university hospitals. Included encounters are those with body fluid cultures taken, documented antibiotic administration, and Sequential Organ Failure Assessment scores of 2 or more, all within 6 hours of admission. Data analysis was conducted from November 2, 2023, to September 1, 2025.

Main Outcomes and Measures  Consensus clustering with k-means was used to derive 4 clinical phenotypes at each site, comparing them with the SENECA-derived phenotypes, as well as with one another.

Results  There were 30 865 patient encounters in Stockholm (mean [SD] age, 68 [16] years; 18 165 men [59%]), 15 575 in Oxford (mean [SD] age, 71 [18] years; 9067 men [58%]), and 1806 in Oslo (mean [SD] age, 71 [17] years; 1068 men [59%]). There was little consistency between the SENECA clinical phenotypes and each site’s own phenotypes, with a Cohen κ of 0.32 for Stockholm, 0.37 for Oslo, and 0.40 for Oxford; the Adjusted Rand Indices were 0.21 for Stockholm, 0.27 for Oslo, and 0.26 for Oxford. There was also little consistency between the phenotypes derived in Stockholm, Oxford, and Oslo.

Conclusions and Relevance  This study suggests that the 4 clinical phenotypes of the SENECA data are not generalizable across 3 independent cohorts. This calls for further exploration of possible underlying sepsis subgroups using alternative approaches that mitigate the inherent stochasticity in many unsupervised and semisupervised clustering methods.