RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response
RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response
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DOI：
10.1038/s41598-020-65043-8
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发表时间：
2020-05-25
影响因子：
4.6
通讯作者：
Scriba, Thomas J.
中科院分区：
文献类型：
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作者：
Penn-Nicholson, Adam;Mbandi, Stanley Kimbung;Scriba, Thomas J.
迫切需要改进结核病诊断和监测治疗反应的工具。我们开发了一种强大而简单的基于PCR的宿主血液转录组签名RISK6，用于多种应用：识别有发病风险的个体，作为亚临床或临床结核病的筛查试验，以及监测结核病治疗。在7个独立队列中，使用定量实时（qRT）PCR通过盲法预测验证了RISK6效用。预后性能显着超过了以前的签名在同一队列中发现的。通过受试者工作特征曲线下面积评估，在HIV未感染者和HIV感染者中诊断亚临床和临床疾病的性能超过85%。作为结核病的筛查测试，90%特异性的灵敏度达到或接近世界卫生组织目标产品简介中为非痰基测试设定的基准。RISK6评分与肺免疫病理学活性相关，通过正电子发射断层扫描测量，并跟踪治疗反应，证明了作为治疗反应生物标志物的实用性，同时在治疗开始前预测治疗失败。通过手指针刺采集的毛细血管血样本的检测性能不劣于PAXgene管中采集的静脉血。这些结果支持将RISK6纳入快速、基于毛细血管血的床旁PCR装置中，以在田间研究中进行前瞻性评估。
Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.