RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response
Adam Penn‐Nicholson, Stanley Kimbung Mbandi, Ethan Thompson, Simon C. Mendelsohn, Sara Suliman, Novel N. Chegou, Stephanus T. Malherbe, Fatoumatta Darboe, Mzwandile Erasmus, Willem A. Hanekom, Nicole Bilek, Michelle Fisher, Stefan H. E. Kaufmann, Jill Winter, Melissa Murphy, Robin Wood, Carl Morrow, Ildiko Van Rhijn, Branch Moody, Megan Murray, Bruno B. Andrade, Timothy R. Sterling, Jayne S. Sutherland, Kogieleum Naidoo, Nesri Padayatchi, Gerhard Walzl, Mark Hatherill, Daniel E. Zak, Thomas J. Scriba, The Adolescent Cohort Study team, Fazlin Kafaar, Leslie Workman, Humphrey Mulenga, E. Jane Hughes, Onke Xasa, Ashley Veldsman, Yolundi Cloete, Deborah Abrahams, Sizulu Moyo, Sebastian Gelderbloem, Michèle Tameris, Hennie Geldenhuys, Rodney Ehrlich, Suzanne Verver, Larry Geiter, Gillian F. Black, Gian van der Spuy, Kim Stanley, Magdalena Kriel, Nelita du Plessis, Nonhlanhla Nene, Teri Roberts, Léanie Kleynhans, Andrea Gutschmidt, Bronwyn Smith, André G. Loxton, Gerhardus Tromp, David L. Tabb, Tom H. M. Ottenhoff, Michèl R. Klein, Mariëlle C. Haks, Kees L. M. C. Franken, Annemieke Geluk, Krista E. van Meijgaarden, Simone A. Joosten, W. Henry Boom, Bonnie Thiel, Harriet Mayanja-Kizza, Moses Joloba, Sarah Zalwango, Mary Nsereko, Brenda Okwera, Hussein Kisingo, Shreemanta K. Parida, Robert Golinski, Jeroen Maertzdorf, January Weiner, Marc Jacobson, Hazel M. Dockrell, Steven G. Smith, Patricia Gorak‐Stolinska, Yun‐Gyoung Hur, Maeve K. Lalor, Ji‐Sook Lee, Amelia C. Crampin, Neil French, Bagrey Ngwira, Anne Ben‐Smith, Kate E. Watkins, Lyn Ambrose, Felanji Simukonda, Hazzie Mvula, Femia Chilongo, Jacky Saul, Keith Branson, Hassan Mahomed, E. Jane Hughes, Onke Xasa, Ashley Veldsman, Katrina Downing
Abstract
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.