Improved Risk Stratification in Pediatric Septic Shock Using Both Protein and mRNA Biomarkers. PERSEVERE-XP.

Document Type

Article

Publication Date

8-15-2017

Identifier

DOI: 10.1164/rccm.201701-0066OC; PMCID: PMC5564676

Abstract

RATIONALE: We previously derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate baseline mortality risk in children with septic shock. The PERSEVERE biomarkers are serum proteins selected from among the proteins directly related to 80 mortality risk assessment genes. The initial approach to selecting the PERSEVERE biomarkers left 68 genes unconsidered.

OBJECTIVES: To determine if the 68 previously unconsidered genes can improve upon the performance of PERSEVERE and to provide biological information regarding the pathophysiology of septic shock.

METHODS: We reduced the number of variables by determining the biological linkage of the 68 previously unconsidered genes. The genes identified through variable reduction were combined with the PERSEVERE-based mortality probability to derive a risk stratification model for 28-day mortality using classification and regression tree methodology (n = 307). The derived tree, PERSEVERE-XP, was then tested in a separate cohort (n = 77).

MEASUREMENTS AND MAIN RESULTS: Variable reduction revealed a network consisting of 18 mortality risk assessment genes related to tumor protein 53 (TP53). In the derivation cohort, PERSEVERE-XP had an area under the receiver operating characteristic curve (AUC) of 0.90 (95% confidence interval, 0.85-0.95) for differentiating between survivors and nonsurvivors. In the test cohort, the AUC was 0.96 (95% confidence interval, 0.91-1.0). The AUC of PERSEVERE-XP was superior to that of PERSEVERE.

CONCLUSIONS: PERSEVERE-XP combines protein and mRNA biomarkers to provide mortality risk stratification with possible clinical utility. PERSEVERE-XP significantly improves on PERSEVERE and suggests a role for TP53-related cellular division, repair, and metabolism in the pathophysiology of septic shock.

Journal Title

American journal of respiratory and critical care medicine

Volume

196

Issue

4

First Page

494

Last Page

501

MeSH Keywords

Biomarkers; Chemokine CCL3; Child; Child, Preschool; Cohort Studies; Female; Granzymes; HSP70 Heat-Shock Proteins; Humans; Infant; Interleukin-8; Male; Matrix Metalloproteinase 8; RNA, Messenger; ROC Curve; Reproducibility of Results; Risk Assessment; Shock, Septic

Keywords

biomarkers; mortality; sepsis; stratification

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