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

Developing a clinically feasible personalized medicine approach to pediatric septic shock.

Author information

1
1 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, Ohio.

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

PMID:
25489881
PMCID:
PMC4351580
DOI:
10.1164/rccm.201410-1864OC
[Indexed for MEDLINE]
Free PMC Article

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