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BMC Medicine

, 7:34

First Online: 22 July 2009Received: 08 July 2009Accepted: 22 July 2009DOI: 10.1186-1741-7015-7-34

Cite this article as: Wong, H.R., Cvijanovich, N., Lin, R. et al. BMC Med 2009 7: 34. doi:10.1186-1741-7015-7-34


BackgroundSeptic shock is a heterogeneous syndrome within which probably exist several biological subclasses. Discovery and identification of septic shock subclasses could provide the foundation for the design of more specifically targeted therapies. Herein we tested the hypothesis that pediatric septic shock subclasses can be discovered through genome-wide expression profiling.

MethodsGenome-wide expression profiling was conducted using whole blood-derived RNA from 98 children with septic shock, followed by a series of bioinformatic approaches targeted at subclass discovery and characterization.

ResultsThree putative subclasses subclasses A, B, and C were initially identified based on an empiric, discovery-oriented expression filter and unsupervised hierarchical clustering. Statistical comparison of the three putative subclasses analysis of variance, Bonferonni correction, P < 0.05 identified 6,934 differentially regulated genes. K-means clustering of these 6,934 genes generated 10 coordinately regulated gene clusters corresponding to multiple signaling and metabolic pathways, all of which were differentially regulated across the three subclasses. Leave one out cross-validation procedures indentified 100 genes having the strongest predictive values for subclass identification. Forty-four of these 100 genes corresponded to signaling pathways relevant to the adaptive immune system and glucocorticoid receptor signaling, the majority of which were repressed in subclass A patients. Subclass A patients were also characterized by repression of genes corresponding to zinc-related biology. Phenotypic analyses revealed that subclass A patients were younger, had a higher illness severity, and a higher mortality rate than patients in subclasses B and C.

ConclusionGenome-wide expression profiling can identify pediatric septic shock subclasses having clinically relevant phenotypes.

AbbreviationsANOVAanalysis of variance

DAVIDdatabase for annotation, visualization, and integrated discovery

ERKepidermal growth factor

GEOgene expression omnibus

IPAingenuity pathways analysis

IQRintra-quartile range

JAKJanus kinase

MAPKmitogen-activated protein kinase

MIAMEminimum information about a microarray experiment

NF-κBnuclear factor kappa-light-chain-enhancer of activated B cells

PPARαperoxisome proliferator-activated receptor

PRISMpediatric risk of mortality

RMArobust multiple-array average

RXRαretinoid × receptor

STATsignal transducers and activator of transcription.

Electronic supplementary materialThe online version of this article doi:10.1186-1741-7015-7-34 contains supplementary material, which is available to authorized users.

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Autor: Hector R Wong - Natalie Cvijanovich - Richard Lin - Geoffrey L Allen - Neal J Thomas - Douglas F Willson - Robert J Fr


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