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



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.



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).



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.



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.
1 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, Ohio.|2 Department of Pediatrics and.
Hector R
0000-0001-7989-1173
HR
Wong
3 UCSF Benioff Children's Hospital Oakland, Oakland, California.
Natalie Z
NZ
Cvijanovich
4 Children's Hospital of Orange County, Orange, California.
Nick
N
Anas
5 Children's Mercy Hospital, Kansas City, Missouri.
Geoffrey L
GL
Allen
6 Penn State Children's Hospital, Hershey, Pennsylvania.
Neal J
NJ
Thomas
7 Akron Children's Hospital, Akron, Ohio.
Michael T
MT
Bigham
8 The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Scott L
SL
Weiss
8 The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Julie C
JC
Fitzgerald
9 Texas Children's Hospital and Baylor College of Medicine, Houston, Texas.
Paul A
PA
Checchia
10 Miami Children's Hospital, Miami, Florida.
Keith
K
Meyer
11 C. S. Mott Children's Hospital at the University of Michigan, Ann Arbor, Michigan.
Michael
M
Quasney
12 Nationwide Children's Hospital, Columbus, Ohio.
Mark
M
Hall
13 Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
Rainer
R
Gedeit
14 Children's National Health System, Washington, District of Columbia.
Robert J
RJ
Freishtat
15 Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.
Jeffrey
J
Nowak
16 Riley Hospital for Children, Indianapolis, Indiana.
Shekhar S
SS
Raj
17 Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, New Jersey; and.
Shira
S
Gertz
18 Children's Healthcare of Atlanta at Egleston, Atlanta, Georgia.
Jocelyn R
JR
Grunwell
19 Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Christopher J
CJ
Lindsell
D015415:Biomarkers / Q000097:blood; D054405:Chemokine CCL3 / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D053804:Granzymes / Q000097:blood*; D018840:HSP70 Heat-Shock Proteins / Q000097:blood*; D006801:Humans; D007223:Infant; D016209:Interleukin-8 / Q000097:blood*; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000097:blood*; D012333:RNA, Messenger / Q000097:blood*; D012372:ROC Curve; D015203:Reproducibility of Results; D018570:Risk Assessment; D012772:Shock, Septic / Q000097:blood*
D015415:Biomarkers; C515429:CCL3 protein, human; D054405:Chemokine CCL3; D018840:HSP70 Heat-Shock Proteins; C525621:HSPA1B protein, human; D016209:Interleukin-8; D012333:RNA, Messenger; C509213:GZMB protein, human; D053804:Granzymes; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8
biomarkers; mortality; sepsis; stratification