title: Validation of a gene expression-based subclassification strategy for pediatric septic shock.
abstract: OBJECTIVE
  Septic shock heterogeneity has important implications for clinical trial implementation and patient management. We previously addressed this heterogeneity by identifying three putative subclasses of children with septic shock based exclusively on a 100-gene expression signature. Here we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort.
  
  
  METHODS
  Prospective observational study involving microarray-based bioinformatics.
  
  
  METHODS
  Multiple pediatric intensive care units in the United States.
  
  
  METHODS
  Separate derivation (n = 98) and validation (n = 82) cohorts of children with septic shock.
  
  
  METHODS
  None other than standard care.
  
  
  RESULTS
  Gene expression mosaics of the 100 class-defining genes were generated for 82 individual patients in the validation cohort. Using computer-based image analysis, patients were classified into one of three subclasses ("A," "B," or "C") based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. After subclassification, the clinical database was mined for phenotyping. Subclass A patients had higher illness severity relative to subclasses B and C as measured by maximal organ failure, fewer intensive care unit-free days, and a higher Pediatric Risk of Mortality score. Patients in subclass A were characterized by repression of genes corresponding to adaptive immunity and glucocorticoid receptor signaling. Separate subclass assignments were conducted by 21 individual clinicians using visual inspection. The consensus classification of the clinicians had modest agreement with the computer algorithm.
  
  
  CONCLUSIONS
  We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses have relevant clinical differences.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA. hector.wong@cchmc.org
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.forename: Natalie Z
authors.initials: NZ
authors.lastname: Cvijanovich
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Allen
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Thomas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
authors.forename: Nick
authors.initials: N
authors.lastname: Anas
authors.forename: Keith
authors.initials: K
authors.lastname: Meyer
authors.forename: Paul A
authors.initials: PA
authors.lastname: Checchia
authors.forename: Richard
authors.initials: R
authors.lastname: Lin
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bigham
authors.forename: Derek S
authors.initials: DS
authors.lastname: Wheeler
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Doughty
authors.forename: Ken
authors.initials: K
authors.lastname: Tegtmeyer
authors.forename: Sue E
authors.initials: SE
authors.lastname: Poynter
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kaplan
authors.forename: Ranjit S
authors.initials: RS
authors.lastname: Chima
authors.forename: Erika
authors.initials: E
authors.lastname: Stalets
authors.forename: Rajit K
authors.initials: RK
authors.lastname: Basu
authors.forename: Brian M
authors.initials: BM
authors.lastname: Varisco
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Barr
mesh_terms: D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D015278:Intensive Care Units, Pediatric; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D040081:Protein Array Analysis; D012307:Risk Factors; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000145:classification* / Q000175:diagnosis / Q000235:genetics*