Improved risk stratification in pediatric septic shock using both protein and mRNA Biomarkers: Persevere-XP

Hector R. Wong, Natalie Z. Cvijanovich, Nick Anas, Geoffrey L. Allen, Neal J. Thomas, Michael T. Bigham, Scott L. Weiss, Julie C. Fitzgerald, Paul A. Checchia, Keith Meyer, Michael Quasney, Mark Hall, Rainer Gedeit, Robert J. Freishtat, Jeffrey Nowak, Shekhar S. Raj, Shira Gertz, Jocelyn R. Grunwell, Christopher J. Lindsell

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)494-501
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume196
Issue number4
DOIs
StatePublished - Aug 15 2017

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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