RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinic...

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Bibliographic Details
Published in:	Scientific reports 2020-05, Vol.10 (1), p.8629, Article 8629
Main Authors:	Penn-Nicholson, Adam, Mbandi, Stanley Kimbung, Thompson, Ethan, Mendelsohn, Simon C, Suliman, Sara, Chegou, Novel N, Malherbe, Stephanus T, Darboe, Fatoumatta, Erasmus, Mzwandile, Hanekom, Willem A, Bilek, Nicole, Fisher, Michelle, Kaufmann, Stefan H E, Winter, Jill, Murphy, Melissa, Wood, Robin, Morrow, Carl, Van Rhijn, Ildiko, Moody, Branch, Murray, Megan, Andrade, Bruno B, Sterling, Timothy R, Sutherland, Jayne, Naidoo, Kogieleum, Padayatchi, Nesri, Walzl, Gerhard, Hatherill, Mark, Zak, Daniel, Scriba, Thomas J
Format:	Article
Language:	eng
Subjects:	Adolescent Area Under Curve Biomarkers - metabolism Capillary tubes Cohort Studies Female HIV HIV Infections - complications HIV Infections - pathology Human immunodeficiency virus Humans Lung - diagnostic imaging Lung - innervation Lung - pathology Male Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - isolation & purification Point-of-Care Systems Positron emission tomography Prognosis Real-Time Polymerase Chain Reaction - methods RNA, Bacterial - metabolism ROC Curve Sensitivity analysis Sensitivity and Specificity Sputum Tuberculosis Tuberculosis - complications Tuberculosis - diagnosis Tuberculosis - microbiology
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Summary:	Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.
ISSN:	2045-2322 2045-2322