Meta-Analysis Identification of Highly Robust and Differential Immune-Metabolic Signatures of Systemic Host Response to Acute and Latent Tuberculosis in Children and Adults.
Meta-Analysis Identification of Highly Robust and Differential Immune-Metabolic Signatures of Systemic Host Response to Acute and Latent Tuberculosis in Children and Adults.
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DOI：
10.3389/fgene.2018.00457
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发表时间：
2018
影响因子：
3.7
通讯作者：
Ghazal P
中科院分区：
文献类型：
--
作者：
Bah SY;Forster T;Dickinson P;Kampmann B;Ghazal P
背景资料：全血表达谱分析是描绘感染的鉴别诊断特征的主要手段，但易受高变异性的影响，这降低了功效并使临床有用性复杂化。迄今为止，用于临床使用的确证性高置信度表达谱特征仍然不确定。在这里，我们试图评估差异表达特征的可重复性和确认性，包括分子和细胞途径，在多个国际临床观察研究中调查儿童和成人全血转录组对结核病（TB）的反应。方法和结果：使用全血对人类结核病的基因表达库进行系统检索和质量控制评估，得到11个数据集，共1073例患者，来自非洲、欧洲和南美洲。采用非参数估计的错误预测百分比进行高置信度差异表达分析的荟萃分析。应用去卷积分析来推断免疫细胞比例的变化，并使用途径数据库资源进行富集测试。荟萃分析确定了高置信度的差异表达基因，包括372个成人活动性TB与潜伏性TB（LTBI），332个成人活动性TB与对照（CON），5个LTBI与CON，415个儿童活动性TB与LTBI。值得注意的是，这些确证性标志物在用于诊断TB的已发表特征中具有低代表性。高置信度基因集的途径生物学分析揭示了显性代谢和先天免疫途径特征，而抑制的特征富含适应性信号传导途径和减少的T和B细胞比例。儿童TB显示出独特的强炎性小体拮抗剂特征（IL1RN和ILR2），而成人TB患者显示出显著优势的I型和II型IFN标记。该研究的主要局限性包括缺乏有关潜在混杂因素的数据。结论：荟萃分析确定了高置信度的确证性免疫代谢和细胞表达的研究签名，无论人口资源设置，艾滋病毒状态和流行病病原体。值得注意的是，先前鉴定的TB诊断特征标记物显示与确证性荟萃分析的一致性有限。总体而言，我们的结果支持使用验证性表达标签来指导结核病的优化诊断、预后和治疗监测模式。
Background: Whole blood expression profiling is a mainstay for delineating differential diagnostic signatures of infection yet is subject to high variability that reduces power and complicates clinical usefulness. To date, confirmatory high confidence expression profiling signatures for clinical use remain uncertain. Here we have sought to evaluate the reproducibility and confirmatory nature of differential expression signatures, comprising molecular and cellular pathways, across multiple international clinical observational studies investigating children and adult whole blood transcriptome responses to tuberculosis (TB). Methods and findings: A systematic search and quality control assessment of gene expression repositories for human TB using whole blood resulted in 11 datasets with a total of 1073 patients from Africa, Europe, and South America. A non-parametric estimation of percentage of false prediction was used for meta-analysis of high confidence differential expression analysis. Deconvolution analysis was applied to infer changes in immune cell proportions and enrichment tests applied using pathway database resources. Meta-analysis identified high confidence differentially expressed genes, comprising 372 in adult active-TB versus latent-TB (LTBI), 332 in adult active-TB versus controls (CON), five in LTBI versus CON, and 415 in childhood active-TB versus LTBI. Notably, these confirmatory markers have low representation in published signatures for diagnosing TB. Pathway biology analysis of high confidence gene sets revealed dominant metabolic and innate-immune pathway signatures while suppressed signatures were enriched with adaptive signaling pathways and reduced proportions of T and B cells. Childhood TB showed uniquely strong inflammasome antagonist signature (IL1RN and ILR2), while adult TB patients exhibit a significant preponderance type I and type II IFN markers. Key limitations of the study include the paucity of data on potential confounders. Conclusion: Meta-analysis identified high confidence confirmatory immune-metabolic and cellular expression signatures across studies regardless of the population resource setting, HIV status and circulating endemic pathogens. Notably, previously identified diagnostic signature markers for TB show limited concordance with the confirmatory meta-analysis. Overall, our results support the use of the confirmatory expression signatures for guiding optimized diagnostic, prognostic, and therapeutic monitoring modalities in TB.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
3.1
作者：
Kee, Seung-Jung;Kwon, Yong-Soo;Ryang, Dong-Wook
通讯作者：
Ryang, Dong-Wook
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.4
作者：
McNab, Finlay W.;Berry, Matthew P. R.;Graham, Christine M.;Bloch, Susannah A. A.;Oni, Tolu;Wilkinson, Katalin A.;Wilkinson, Robert J.;Kon, Onn M.;Banchereau, Jacques;Chaussabel, Damien;O'Garra, Anne
通讯作者：
O'Garra, Anne
影响因子：
168.9
作者：
Fine, PEM;Ponnighaus, JM;Peto, R
通讯作者：
Peto, R