Developing a Clinically Feasible Personalized Medicine Approach to Pediatric Septic Shock

Am J Respir Crit Care Med. 2015 Feb 1;191(3):309-15. doi: 10.1164/rccm.201410-1864OC.

Abstract

Rationale: 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.

Objectives: 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).

Measurements and main 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.

Keywords: adaptive immunity; gene expression; glucocorticoids; sepsis; subclassification.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Validation Study

MeSH terms

  • Child
  • Child, Preschool
  • Feasibility Studies
  • Female
  • Gene Expression Regulation
  • Glucocorticoids / therapeutic use
  • Humans
  • Infant
  • Intensive Care Units, Pediatric
  • Male
  • Mathematical Computing
  • Odds Ratio
  • Phenotype
  • Precision Medicine*
  • Prospective Studies
  • Reproducibility of Results
  • Severity of Illness Index
  • Shock, Septic / diagnosis*
  • Shock, Septic / genetics*
  • Shock, Septic / mortality
  • Shock, Septic / therapy
  • Signal Transduction / genetics

Substances

  • Glucocorticoids