Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK.
Guy's and St Thomas' National Health Service Foundation Trust and King's College London National Institute for Health Research Biomedical Research Centre Translational Bioinformatics Platform, Guy's Hospital, London, UK.
Lancet Infect Dis. 2021 Mar;21(3):366-375. doi: 10.1016/S1473-3099(20)30928-2. Epub 2021 Jan 25.
Blood transcriptomic signatures for diagnosis of tuberculosis have shown promise in case-control studies, but none have been prospectively designed or validated in adults presenting with the full clinical spectrum of suspected tuberculosis, including extrapulmonary tuberculosis and common differential diagnoses that clinically resemble tuberculosis. We aimed to evaluate the diagnostic accuracy of transcriptomic signatures in patients presenting with clinically suspected tuberculosis in routine practice.
The Validation of New Technologies for Diagnostic Evaluation of Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years) suspected of having tuberculosis in the routine clinical inpatient and outpatient setting were recruited at ten National Health Service hospitals in England for IDEA and were included in VANTDET if they provided consent for genomic analysis. Patients had whole blood taken for microarray analysis to measure abundance of transcripts and were followed up for 6-12 months to determine final diagnoses on the basis of predefined diagnostic criteria. The diagnostic accuracy of six signatures derived from the cohort and three previously published transcriptomic signatures with potentially high diagnostic performance were assessed by calculating area under the receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities.
Between Nov 25, 2011, and Dec 31, 2013, 1162 participants were enrolled. 628 participants (aged ≥16 years) were included in the analysis, of whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with highest performance for identifying all active tuberculosis gave an AUC-ROC of 0·87 (95% CI 0·81-0·92), sensitivity of 77% (66-87), and specificity of 84% (74-91). The best-performing published signature gave an AUC-ROC of 0·83 (0·80-0·86), sensitivity of 78% (73-83), and specificity of 76% (70-80). For detecting highly probable tuberculosis, the best novel signature yielded results of 0·86 (0·71-0·95), 77% (56-94%), and 77% (57-95%). None of the relevant cohort-derived or previously published signatures achieved the WHO-defined targets of paired sensitivity and specificity for a non-sputum-based diagnostic test.
In a clinically representative cohort in routine practice in a low-incidence setting, transcriptomic signatures did not have adequate accuracy for diagnosis of tuberculosis, including in patients with highly probable tuberculosis where the unmet need is greatest. These findings suggest that transcriptomic signatures have little clinical utility for diagnostic assessment of suspected tuberculosis.
National Institute for Health Research.
血液转录组特征在结核病诊断的病例对照研究中显示出了一定的前景，但还没有前瞻性设计或验证其在临床上表现出完整的疑似结核病临床谱的成年人中的效果，包括肺外结核病和临床上类似于结核病的常见鉴别诊断。我们旨在评估转录组特征在常规临床实践中疑似结核病患者中的诊断准确性。
新技术在诊断结核病评估中的验证（VANTDET）研究嵌套在英格兰二级保健机构的一项前瞻性、多中心队列研究（IDEA 11/H0722/8）中。在英格兰的十家国家卫生服务医院中，根据常规临床住院和门诊环境中对结核病的怀疑，招募了年龄≥16 岁的患者（IDEA），并在他们同意进行基因组分析的情况下将其纳入 VANTDET 研究。对患者进行全血采集，用于微阵列分析，以测量转录物的丰度，并进行 6-12 个月的随访，根据预先定义的诊断标准确定最终诊断。通过计算接收者操作特征曲线（ROC）下的面积（AUC-ROC）、敏感性和特异性来评估来自队列的六个特征和三个具有潜在高诊断性能的先前发表的转录组特征的诊断准确性。
在 2011 年 11 月 25 日至 2013 年 12 月 31 日期间，共纳入了 1162 名参与者。共有 628 名（年龄≥16 岁）参与者纳入分析，其中 212 名（34%）有培养确诊的结核病，89 名（14%）有高度可能的结核病，327 名（52%）排除了结核病。对于识别所有活动性结核病的表现最佳的新型特征，AUC-ROC 为 0.87（95%CI 0.81-0.92），敏感性为 77%（66-87），特异性为 84%（74-91）。表现最佳的已发表特征的 AUC-ROC 为 0.83（0.80-0.86），敏感性为 78%（73-83），特异性为 76%（70-80）。对于检测高度可能的结核病，最佳的新型特征的结果为 0.86（0.71-0.95）、77%（56-94%）和 77%（57-95%）。没有任何相关的队列衍生或先前发表的特征达到了世界卫生组织对非痰液为基础的诊断检测的敏感性和特异性配对的定义目标。
在低发病率环境下的常规临床代表性队列中，转录组特征的诊断结核病的准确性不够，包括在高度可能患有结核病的患者中，这是最迫切需要的。这些发现表明，转录组特征在诊断疑似结核病方面的临床应用价值有限。
英国国家卫生研究院。
