Blood transcriptomic diagnosis of pulmonary and extrapulmonary tuberculosis
Jennifer K Roe, Niclas Thomas, Eliza Gil, Katharine Best, Evdokia Tsaliki, Stephen Morris‑Jones, Sian Stafford, Nandi Simpson, Karolina D Witt, Benjamin Chain, Robert F Miller, Adrian Martineau, Mahdad Noursadeghi
Jennifer K Roe, Niclas Thomas, Eliza Gil, Katharine Best, Evdokia Tsaliki, Stephen Morris‑Jones, Sian Stafford, Nandi Simpson, Karolina D Witt, Benjamin Chain, Robert F Miller, Adrian Martineau, Mahdad Noursadeghi
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Clinical Research and Public Health Infectious disease

Blood transcriptomic diagnosis of pulmonary and extrapulmonary tuberculosis

Abstract

BACKGROUND. Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB.

METHODS. Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection.

RESULTS. We identified and validated elevated blood basic leucine zipper transcription factor 2 (BATF2) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1–negative individuals, and 0.85 in HIV-1–infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1.

CONCLUSIONS. Elevated blood BATF2 transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever.

FUNDING. MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR.

Authors

Jennifer K Roe, Niclas Thomas, Eliza Gil, Katharine Best, Evdokia Tsaliki, Stephen Morris‑Jones, Sian Stafford, Nandi Simpson, Karolina D Witt, Benjamin Chain, Robert F Miller, Adrian Martineau, Mahdad Noursadeghi

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Figure 3

Classification of active tuberculosis (TB) and healthy cases using blood BATF2 transcript expression levels.

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Classification of active tuberculosis (TB) and healthy cases using blood...
(A) Relative BATF2 gene expression in blood samples from separate HIV-negative and HIV-positive patient cohorts comparing active TB with either postrecovery patients (AdjuVIT), LTBI (Bloom and Kaforou), or healthy volunteers (Berry). Box and whisker plots represent median, interquartile, and full range of data points. Number of data points in each group is shown in parentheses below each plot. *P < 0.0001 (Mann-Whitney U test). (B) Receiver operating characteristic (ROC) analyses for discrimination of active TB in each of these cohorts using blood levels of BATF2 expression only. (C) ROC performance of SVM discrimination of active TB from LTBI in HIV-positive patients using genome‑wide blood transcriptional profiles after training on patients with active TB and after recovery. In B and C, ROC AUCs are shown in parentheses for each cohort.