title: Developing a clinically feasible personalized medicine approach to pediatric septic shock.
abstract: BACKGROUND
  Using microarray data, we previously identified gene expression-based subclasses of septic shock with important phenotypic differences. The subclass-defining genes correspond to adaptive immunity and glucocorticoid receptor signaling. Identifying the subclasses in real time has theranostic implications, given the potential for immune-enhancing therapies and controversies surrounding adjunctive corticosteroids for septic shock.
  
  
  OBJECTIVE
  To develop and validate a real-time subclassification method for septic shock.
  
  
  METHODS
  Gene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (NanoString nCounter) and visualized using gene expression mosaics. Study subjects (n = 168) were allocated to the subclasses using computer-assisted image analysis and microarray-based reference mosaics. A gene expression score was calculated to reduce the gene expression patterns to a single metric. The method was tested prospectively in a separate cohort (n = 132).
  
  
  RESULTS
  The NanoString-based data reproduced two septic shock subclasses. As previously, one subclass had decreased expression of the subclass-defining genes. The gene expression score identified this subclass with an area under the curve of 0.98 (95% confidence interval [CI95] = 0.96-0.99). Prospective testing of the subclassification method corroborated these findings. Allocation to this subclass was independently associated with mortality (odds ratio = 2.7; CI95 = 1.2-6.0; P = 0.016), and adjunctive corticosteroids prescribed at physician discretion were independently associated with mortality in this subclass (odds ratio = 4.1; CI95 = 1.4-12.0; P = 0.011).
  
  
  CONCLUSIONS
  We developed and tested a gene expression-based classification method for pediatric septic shock that meets the time constraints of the critical care environment, and can potentially inform therapeutic decisions.
authors.affiliation: 1 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, Ohio.
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.forename: Natalie Z
authors.initials: NZ
authors.lastname: Cvijanovich
authors.forename: Nick
authors.initials: N
authors.lastname: Anas
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Allen
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Thomas
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bigham
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weiss
authors.forename: Julie
authors.initials: J
authors.lastname: Fitzgerald
authors.forename: Paul A
authors.initials: PA
authors.lastname: Checchia
authors.forename: Keith
authors.initials: K
authors.lastname: Meyer
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
authors.forename: Michael
authors.initials: M
authors.lastname: Quasney
authors.forename: Mark
authors.initials: M
authors.lastname: Hall
authors.forename: Rainer
authors.initials: R
authors.lastname: Gedeit
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nowak
authors.forename: Raj S
authors.initials: RS
authors.lastname: Shekhar
authors.forename: Shira
authors.initials: S
authors.lastname: Gertz
authors.forename: Emily
authors.initials: E
authors.lastname: Dawson
authors.forename: Kelli
authors.initials: K
authors.lastname: Howard
authors.forename: Kelli
authors.initials: K
authors.lastname: Harmon
authors.forename: Eileen
authors.initials: E
authors.lastname: Beckman
authors.forename: Erin
authors.initials: E
authors.lastname: Frank
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lindsell
mesh_terms: D002648:Child; D002675:Child, Preschool; D005240:Feasibility Studies; D005260:Female; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D015278:Intensive Care Units, Pediatric; D008297:Male; D008432:Mathematical Computing; D016017:Odds Ratio; D010641:Phenotype; D057285:Precision Medicine; D011446:Prospective Studies; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D015398:Signal Transduction / Q000235:genetics
chemical_list: D005938:Glucocorticoids
keywords: adaptive immunity; gene expression; glucocorticoids; sepsis; subclassification