Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis
复制标题
DOI：
10.1128/jcm.00467-17
复制
发表时间：
2017-10-01
影响因子：
9.4
通讯作者：
Ochsner, Urs A.
中科院分区：
文献类型：
--
作者：
De Groote, Mary A.;Sterling, David G.;Ochsner, Urs A.
用于活动性结核病诊断的新型非痰生物标志物检测是全球结核病控制的重中之重。我们对来自7个结核病流行国家的1470份血清样本进行了深入的蛋白质组学分析。所有样本均来自具有提示活动性肺结核症状和体征的患者，这些患者通过培养和临床随访系统地确认或排除了结核病。34%的样本中存在HIV合并感染，25%的样本痰涂片阴性。血清蛋白生物标志物通过l1正则化逻辑回归和Kolmogorov-Smirnov （KS）统计的稳定性选择进行鉴定。使用SYWC、kallistatin、complement C9、gelsolin、testican-2和醛缩酶C等6种宿主反应标记物（HR6模型）的朴素贝叶斯分类器在训练集（灵敏度-特异性曲线下面积[AUC]为0.94）和盲法验证集（AUC为0.92）中区分结核病和非结核病样本表现良好。对于先前描述的结核病标记物，如IP-10、LBP、FCG3B和TSP4，以及许多以前与结核病无关的新蛋白，差异表达也非常显著（P < 10(- 20)）。中位折叠变化最大的蛋白是SAA（血清淀粉样蛋白A）、NPS-PLA2（分泌磷脂酶A2）和CA6（碳酸酐酶6）。世卫组织已经发布了用于诊断活动性结核病的非痰液生物标志物检测的目标产品简介（TPPs），用于治疗启动（TPP# 1）和基于社区的分诊或转诊检测（TPP# 2）。HR6模型具有90%的敏感性和80%的特异性，低于TPP# 1，但达到了TPP# 2的性能标准。总之，我们确定并验证了活动性结核病的六标记特征，保证了在患者附近平台上的诊断开发。
New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up. HIV coinfection was present in 34% of samples, and 25% were sputum smear negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naive Bayes classifier using six host response markers (HR6 model), including SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C, performed well in a training set (area under the sensitivity-specificity curve [AUC] of 0.94) and in a blinded verification set (AUC of 0.92) to distinguish TB and non-TB samples. Differential expression was also highly significant (P < 10 (- 20)) for previously described TB markers, such as IP-10, LBP, FCG3B, and TSP4, and for many novel proteins not previously associated with TB. Proteins with the largest median fold changes were SAA (serum amyloid protein A), NPS-PLA2 (secreted phospholipase A2), and CA6 (carbonic anhydrase 6). Target product profiles (TPPs) for a non-sputum biomarker test to diagnose active TB for treatment initiation (TPP# 1) and for a community-based triage or referral test (TPP# 2) have been published by the WHO. With 90% sensitivity and 80% specificity, the HR6 model fell short of TPP# 1 but reached TPP# 2 performance criteria. In conclusion, we identified and validated a six-marker signature for active TB that warrants diagnostic development on a patient-near platform.