title: Prospective Testing and Redesign of a Temporal Biomarker Based Risk Model for Patients With Septic Shock: Implications for Septic Shock Biology.
abstract: 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.
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors: Hector R
authors: HR
authors: Wong
authors: UCSF Benioff Children's Hospital Oakland, Oakland, CA, United States.
authors: Natalie Z
authors: NZ
authors: Cvijanovich
authors: Children's Hospital of Orange County, Orange, CA, United States.
authors: Nick
authors: N
authors: Anas
authors: Children's Mercy Hospital, Kansas City, MO, United States.
authors: Geoffrey L
authors: GL
authors: Allen
authors: Penn State Hershey Children's Hospital, Hershey, PA, United States.
authors: Neal J
authors: NJ
authors: Thomas
authors: Akron Children's Hospital, Akron, OH, United States.
authors: Michael T
authors: MT
authors: Bigham
authors: The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors: Scott L
authors: SL
authors: Weiss
authors: The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
authors: Julie
authors: J
authors: Fitzgerald
authors: Texas Children's Hospital and Baylor College of Medicine, Houston, TX, United States.
authors: Paul A
authors: PA
authors: Checchia
authors: Miami Children's Hospital, Miami, FL, United States.
authors: Keith
authors: K
authors: Meyer
authors: CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI, United States.
authors: Michael
authors: M
authors: Quasney
authors: Nationwide Children's Hospital, Columbus, OH, United States.
authors: Mark
authors: M
authors: Hall
authors: Children's Hospital of Wisconsin, Milwaukee, WI, United States.
authors: Rainer
authors: R
authors: Gedeit
authors: Children's National Medical Center, Washington, DC, United States.
authors: Robert J
authors: RJ
authors: Freishtat
authors: Children's Hospital and Clinics of Minnesota, Minneapolis, MN, United States.
authors: Jeffrey
authors: J
authors: Nowak
authors: Riley Hospital for Children, Indianapolis, IN, United States.
authors: Shekhar S
authors: SS
authors: Raj
authors: Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, NJ, United States.
authors: Shira
authors: S
authors: Gertz
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, United States.
authors: Kelli
authors: K
authors: Howard
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, United States.
authors: Kelli
authors: K
authors: Harmon
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, United States.
authors: Patrick
authors: P
authors: Lahni
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, United States.
authors: Erin
authors: E
authors: Frank
authors: Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors: Kimberly W
authors: KW
authors: Hart
authors: Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors: Christopher J
authors: CJ
authors: Lindsell
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008962:Models, Theoretical; D063868:Patient Outcome Assessment; D011379:Prognosis; D011446:Prospective Studies; D015203:Reproducibility of Results; D012306:Risk; D012680:Sensitivity and Specificity; D012772:Shock, Septic / Q000175:diagnosis* / Q000453:epidemiology / Q000209:etiology / Q000378:metabolism*
chemical_list: D015415:Biomarkers
keywords: Biomarkers; Endotype; Immune Suppression; Inflammation; Modeling; Outcome; Prediction; Sepsis