Identification of pediatric septic shock subclasses based on genome-wide expression profiling.
Identification of pediatric septic shock subclasses based on genome-wide expression profiling.
复制标题
DOI：
10.1186/1741-7015-7-34
复制
发表时间：
2009-07-22
期刊：
影响因子：
9.3
通讯作者：
Shanley TP
中科院分区：
文献类型：
--
作者：
Wong HR;Cvijanovich N;Lin R;Allen GL;Thomas NJ;Willson DF;Freishtat RJ;Anas N;Meyer K;Checchia PA;Monaco M;Odom K;Shanley TP
感染性休克是一种异质性综合征，可能存在几个生物学亚类。感染性休克亚类的发现和鉴定可以为设计更特异的靶向治疗提供基础。在这里，我们测试了假设，儿科感染性休克亚类可以通过全基因组表达谱发现。使用来自98名感染性休克儿童的全血来源的RNA进行全基因组表达谱分析，然后采用一系列针对亚类发现和表征的生物信息学方法。三个假定的子类（子类A，B和C）最初确定的基础上的经验，发现为导向的表达过滤器和无监督的层次聚类。三个假定亚类的统计学比较（方差分析，Bonferonni校正，P < 0.05）鉴定了6，934个差异调节基因。这6,934个基因的K均值聚类产生了10个协调调节的基因簇，对应于多种信号传导和代谢途径，所有这些基因簇在三个亚类中均受到差异调节。留一交叉验证程序鉴定了100个具有最强预测值的基因，用于亚类鉴定。这100个基因中的44个对应于与适应性免疫系统和糖皮质激素受体信号传导相关的信号传导途径，其中大部分在A亚类患者中被抑制。亚类A患者的特征还在于与锌相关生物学相对应的基因的抑制。表型分析显示，A亚类患者比B和C亚类患者更年轻，疾病严重程度更高，死亡率更高。全基因组表达谱可以鉴定具有临床相关表型的儿科感染性休克亚类。
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. 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. 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. Genome-wide expression profiling can identify pediatric septic shock subclasses having clinically relevant phenotypes.
登录
查看更多内容
影响因子：
56.9
作者：
Golub, TR;Slonim, DK;Lander, ES
通讯作者：
Lander, ES
影响因子：
--
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
通讯作者：
Karl, IE
影响因子：
4.2
作者：
Ibs, KH;Rink, L
通讯作者：
Rink, L
影响因子：
46.9
作者：
Noble, William S.
通讯作者：
Noble, William S.
影响因子：
8.8
作者：
Marshall, JC;Vincent, JL;Reinhart, K
通讯作者：
Reinhart, K