Section of Paediatrics and Wellcome Trust Centre for Clinical Tropical Medicine, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom ; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.
PLoS Med. 2013 Oct;10(10):e1001538. doi: 10.1371/journal.pmed.1001538. Epub 2013 Oct 22.
A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test.
Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87-100]; specificity 90%, 95% CI [80-97]) and TB from OD (sensitivity 93%, 95% CI [83-100]; specificity 88%, 95% CI [74-97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85-100]; specificity 94%, 95% CI [84-100]) and OD patients (sensitivity 100%, 95% CI [100-100]; specificity 96%, 95% CI [93-100]). Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group.
In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions. Please see later in the article for the Editors' Summary.
在非洲，控制结核病的主要障碍是难以诊断活动性结核病（TB），尤其是在 HIV 感染的情况下。我们假设一种独特的宿主血液 RNA 转录特征将能够区分 TB 与 HIV 感染和未感染患者中的其他疾病（OD），并且这可能是一种简单诊断测试的基础。
在南非和马拉维建立了成人病例对照队列，包括 584 名患者，这些患者要么患有 TB（通过培养从疑似 TB 患者的痰液或组织样本中分离出结核分枝杆菌[M.TB]来确认），要么患有 OD（即 TB 被认为是鉴别诊断的一部分，但后来被排除），要么患有潜伏性 TB 感染（LTBI）的健康个体。将个体随机分配到训练（80%）和测试（20%）队列中。评估了血液转录谱，并在训练队列中确定了区分 TB 与 LTBI 和 OD 的显著差异表达转录本的最小集合。27 个转录本特征可区分 TB 与 LTBI，44 个转录本特征可区分 TB 与 OD。为了评估我们的特征，我们使用了一种新的计算方法来计算每个患者的疾病风险评分（DRS）。首先在测试队列中评估基于该评分的分类，然后在一个独立的公开可用数据集（GSE19491）中进行验证。在我们的测试队列中，DRS 可区分 TB 与 LTBI（灵敏度 95%，95%CI[87-100]；特异性 90%，95%CI[80-97]）和 TB 与 OD（灵敏度 93%，95%CI[83-100]；特异性 88%，95%CI[74-97]）。在独立验证队列中，TB 患者可与 LTBI 个体（灵敏度 95%，95%CI[85-100]；特异性 94%，95%CI[84-100]）和 OD 患者（灵敏度 100%，95%CI[100-100]；特异性 96%，95%CI[93-100]）区分开来。我们研究的局限性包括仅使用培养确认的 TB 患者，以及尽管使用了广泛的临床调查来为每个患者分配诊断组，但在一小部分 OD 患者中仍可能存在 TB 误诊的可能性。
在我们的研究中，血液转录特征可区分 HIV 感染和未感染非洲成年人中的 TB 与其他常见疾病。我们基于这些特征的 DRS 可作为一种适合在 HIV 流行国家使用的 TB 检测方法进行开发。需要进一步评估这些特征和 DRS 在具有与 TB 一致的症状的患者前瞻性人群中的表现，以确定其在操作条件下的临床价值。请在文章后面查看编辑摘要。
