Identification of pediatric septic shock subclasses based on genome-wide expression profiling.
BACKGROUND
Septic 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.


METHODS
Genome-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.


RESULTS
Three 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.


CONCLUSIONS
Genome-wide expression profiling can identify pediatric septic shock subclasses having clinically relevant phenotypes.
Wong
Hector R
HR
Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. hector.wong@cchmc.org
Cvijanovich
Natalie
N
Lin
Richard
R
Allen
Geoffrey L
GL
Thomas
Neal J
NJ
Willson
Douglas F
DF
Freishtat
Robert J
RJ
Anas
Nick
N
Meyer
Keith
K
Checchia
Paul A
PA
Monaco
Marie
M
Odom
Kelli
K
Shanley
Thomas P
TP
D001773:Blood Cells / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D003627:Data Interpretation, Statistical; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012772:Shock, Septic / Q000145:classification*
D012313:RNA