Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a prospective, multicentre cohort study
Authors: Long T Hoang, Pooja Jain, Timesh D Pillay, Mica Tolosa-Wright, Umar Niazi, Yemisi Takwoingi, Alice Halliday, Luis C Berrocal-Almanza, Jonathan J Deeks, Peter Beverley, Onn Min Kon, Ajit Lalvani
Journal: The Lancet Infectious Diseases (2021)

BackgroundBlood 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.MethodsThe 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.FindingsBetween 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.InterpretationIn 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.FundingNational Institute for Health Research.