Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis.
Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis.
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全基因组诊断肺结核的表达：一种多螺旋分析。
DOI：
10.1016/s2213-2600(16)00048-5
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Khatri P
中科院分区：
文献类型：
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作者：
Sweeney TE;Braviak L;Tato CM;Khatri P
活动性肺结核难以诊断，治疗反应也难以有效监测。世界卫生组织共识声明呼吁采用新的非痰诊断方法。本研究的目的是对公开数据集中的样本进行综合多队列分析，以得出活动性结核病患者外周血中的诊断基因集。我们搜索了两个公共基因表达微阵列存储库并保留了检查全血中活动性肺结核感染临床队列的数据集。我们使用经过验证的多队列分析框架，比较了潜伏性结核病或其他疾病患者与活动性结核病患者的基因表达。三个数据集被用作发现数据集，并使用荟萃分析方法来评估这些队列中的基因效应。然后，我们验证了其余 11 个数据集中的三个基因集的诊断能力。分析中总共包含 14 个数据集，其中包含来自 10 个国家的成人和儿童患者的 2572 个样本。其中，三个数据集 (N=1023) 用于发现一组对活动性结核病高度诊断的三个基因（GBP5、DUSP3 和 KLF2）。我们在由来自十个国家的儿童和成人组成的八个独立数据集中验证了这三个基因组对区分活动性结核病和健康对照的诊断能力（ROC曲线下总面积 (AUC) 0·90 [95% CI 0·85–0·95]）、潜伏性结核病（0·88 [0·84–0·92]）和其他疾病（0·84 [0·80–0·95]）。三基因组的表达不受 HIV 感染状态、细菌耐药性或 BCG 疫苗接种的影响。此外，在另外四个队列中，我们发现活动性结核病患者在治疗期间结核病评分有所下降。总体而言，我们的综合多队列分析在全血中产生了一个三基因集，可以对活动性结核病进行强有力的诊断，并在多个独立队列中得到验证，并且在诊断和监测治疗反应方面具有潜在的临床应用。在用于临床环境之前，需要进行前瞻性实验室验证。国家过敏和传染病研究所、国家医学图书馆、斯坦福儿童健康研究所、大学外科医生协会以及比尔和梅琳达·盖茨基金会。
Active pulmonary tuberculosis is difficult to diagnose and treatment response is difficult to effectively monitor. A WHO consensus statement has called for new non-sputum diagnostics. The aim of this study was to use an integrated multicohort analysis of samples from publically available datasets to derive a diagnostic gene set in the peripheral blood of patients with active tuberculosis. We searched two public gene expression microarray repositories and retained datasets that examined clinical cohorts of active pulmonary tuberculosis infection in whole blood. We compared gene expression in patients with either latent tuberculosis or other diseases versus patients with active tuberculosis using our validated multicohort analysis framework. Three datasets were used as discovery datasets and meta-analytical methods were used to assess gene effects in these cohorts. We then validated the diagnostic capacity of the three gene set in the remaining 11 datasets. A total of 14 datasets containing 2572 samples from 10 countries from both adult and paediatric patients were included in the analysis. Of these, three datasets (N=1023) were used to discover a set of three genes (GBP5, DUSP3, and KLF2) that are highly diagnostic for active tuberculosis. We validated the diagnostic power of the three gene set to separate active tuberculosis from healthy controls (global area under the ROC curve (AUC) 0·90 [95% CI 0·85–0·95]), latent tuberculosis (0·88 [0·84–0·92]), and other diseases (0·84 [0·80–0·95]) in eight independent datasets composed of both children and adults from ten countries. Expression of the three-gene set was not confounded by HIV infection status, bacterial drug resistance, or BCG vaccination. Furthermore, in four additional cohorts, we showed that the tuberculosis score declined during treatment of patients with active tuberculosis. Overall, our integrated multicohort analysis yielded a three-gene set in whole blood that is robustly diagnostic for active tuberculosis, that was validated in multiple independent cohorts, and that has potential clinical application for diagnosis and monitoring treatment response. Prospective laboratory validation will be required before it can be used in a clinical setting. National Institute of Allergy and Infectious Diseases, National Library of Medicine, the Stanford Child Health Research Institute, the Society for University Surgeons, and the Bill and Melinda Gates Foundation.