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 8

Transcriptomic classification of active tuberculosis (TB) and other Fever cohort cases with 4 genes.

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Transcriptomic classification of active tuberculosis (TB) and other Feve...
(A) Relative expression of each of the genes indicated in peripheral blood of patients with active TB (AdjuVIT, n = 46) and other Fever (n = 70) cohorts. Box and whisker plots represent median, interquartile, and full range of data points, *P < 0.0001 (Mann-Whitney U test). (B) Receiver operating characteristic (ROC) analyses of support vector machine (SVM) discrimination of active TB (AdjuVIT) from other Fever patients using expression levels of the CD177 gene alone or all 4 of the genes indicated, by training half of the data used to derive rank order of SVM weightings and then testing on the second half of the data. ROC AUCs are shown in parentheses for each test. (C) Scatter plots of blood CD177 and blood neutrophil counts, and (D) blood haptoglobin (HP) transcripts and serum C-reactive protein (CRP) concentrations in AdjuVIT active TB and Fever cohorts. In C and D, dotted line represents regression line giving R2 value indicated.