TY - JOUR
T1 - Improved risk stratification in pediatric septic shock using both protein and mRNA Biomarkers
T2 - Persevere-XP
AU - Wong, Hector R.
AU - Cvijanovich, Natalie Z.
AU - Anas, Nick
AU - Allen, Geoffrey L.
AU - Thomas, Neal J.
AU - Bigham, Michael T.
AU - Weiss, Scott L.
AU - Fitzgerald, Julie C.
AU - Checchia, Paul A.
AU - Meyer, Keith
AU - Quasney, Michael
AU - Hall, Mark
AU - Gedeit, Rainer
AU - Freishtat, Robert J.
AU - Nowak, Jeffrey
AU - Raj, Shekhar S.
AU - Gertz, Shira
AU - Grunwell, Jocelyn R.
AU - Lindsell, Christopher J.
N1 - Funding Information:
Supported by National Institutes of Health grants R01 GM099773 and R01 GM108025 (H.R.W.).
Publisher Copyright:
Copyright © 2017 by the American Thoracic Society.
PY - 2017/8/15
Y1 - 2017/8/15
N2 - 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.
AB - 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.
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U2 - 10.1164/rccm.201701-0066OC
DO - 10.1164/rccm.201701-0066OC
M3 - Article
C2 - 28324661
AN - SCOPUS:85028608785
VL - 196
SP - 494
EP - 501
JO - American Review of Respiratory Disease
JF - American Review of Respiratory Disease
SN - 1073-449X
IS - 4
ER -