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Improved Risk Stratification in Pediatric Septic Shock Using Both Protein and mRNA Biomarkers. PERSEVERE-XP
Hector R Wong1,2, Natalie Z Cvijanovich3, Nick Anas4
11 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, Ohio.
Insights
A new model, PERSEVERE-XP, improves pediatric sepsis mortality risk prediction by incorporating additional genes. This enhanced model, linked to TP53, offers better stratification for children with septic shock.
Area of Science:
- Pediatric critical care medicine
- Biomarker discovery
- Genetics and genomics in sepsis
Background:
- The Pediatric Sepsis Biomarker Risk Model (PERSEVERE) was previously developed to assess mortality risk in pediatric septic shock.
- PERSEVERE utilized serum proteins linked to 80 mortality risk genes, leaving 68 genes unexamined.
- Septic shock pathophysiology involves complex genetic and molecular pathways influencing mortality.
Purpose of the Study:
- To evaluate if incorporating 68 previously unconsidered genes can enhance the predictive performance of the PERSEVERE model.
- To gain biological insights into the pathophysiology of pediatric septic shock through gene network analysis.
- To develop an improved risk stratification tool for 28-day mortality in pediatric septic shock.
Main Methods:
- Variable reduction identified biologically linked genes from the 68 unconsidered genes, revealing an 18-gene network associated with TP53.
- A novel risk stratification model, PERSEVERE-XP, was derived using classification and regression tree methodology, combining PERSEVERE probability with new gene data.
- The PERSEVERE-XP model was validated in independent derivation (n=307) and test (n=77) cohorts.
Main Results:
- PERSEVERE-XP demonstrated superior performance compared to PERSEVERE in predicting 28-day mortality.
- In the derivation cohort, PERSEVERE-XP achieved an AUC of 0.90 (95% CI, 0.85-0.95).
- In the test cohort, PERSEVERE-XP showed an AUC of 0.96 (95% CI, 0.91-1.0), confirming its robust predictive capability.
Conclusions:
- PERSEVERE-XP integrates protein and mRNA biomarkers for improved mortality risk stratification in pediatric septic shock, suggesting clinical utility.
- The model's performance enhancement highlights the significant role of TP53-related pathways in cellular division, repair, and metabolism in septic shock.
- PERSEVERE-XP represents a significant advancement over PERSEVERE, offering a more comprehensive approach to risk assessment in critically ill children.
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.