Prospective Testing and Redesign of a Temporal Biomarker Based Risk Model for Patients With Septic Shock: Implications for Septic Shock Biology

• We prospectively tested the performance of the temporal version of the pediatric sepsis biomarker risk model (tPERSEVERE).
• tPERSEVERE performed poorly in the test cohort, prompting a redesign.
• The redesigned tPERSEVERE model performed well upon testing.
• The redesigned tPERSEVERE provides information regarding septic shock endotypes.Septic shock is characterized by individual heterogeneity and it is not known who is at greatest risk of poor outcome and would thus benefit from more aggressive treatment. We designed a biomarker-based model to estimate the risk of poor outcome in children with septic shock. The model measures biomarker concentrations over the early period of disease evolution, and estimates how the biomarker changes reflect changing risk for poor outcome. The model has potential to serve as a monitor to evaluate the effectiveness of therapy in children with septic shock and may provide information regarding the biological mechanisms of septic shock.

The temporal version of the pediatric sepsis biomarker risk model (tPERSEVERE) estimates the risk of a complicated course in children with septic shock based on biomarker changes from days 1 to 3 of septic shock. We validated tPERSEVERE performance in a prospective cohort, with an a priori plan to redesign tPERSEVERE if it did not perform well. Biomarkers were measured in the validation cohort (n = 168) and study subjects were classified according to tPERSEVERE. To redesign tPERSEVERE, the validation cohort and the original derivation cohort (n = 299) were combined and randomly allocated to training (n = 374) and test (n = 93) sets. tPERSEVERE was redesigned using the training set and CART methodology. tPERSEVERE performed poorly in the validation cohort, with an area under the curve (AUC) of 0.67 (95% CI: 0.58–0.75). Failure analysis revealed potential confounders related to clinical characteristics. The redesigned tPERSEVERE model had an AUC of 0.83 (0.79–0.87) and a sensitivity of 93% (68–97) for estimating the risk of a complicated course. Similar performance was seen in the test set. The classification tree segregated patients into two broad endotypes of septic shock characterized by either excessive inflammation or immune suppression.