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.
Highlights
Introduction(f) Prognostic performance of RISK6 for incident TB in household contacts from South Africa, The Gambia or Ethiopia, measured by quantitative real-time (qRT)-PCR on RNA from whole blood RNA collected within 1 year of TB diagnosis from participants of the GC6-74 cohort
Centre, and Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa. 9Department of Global Health and Social Medicine, and Division of Global Health Equity, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 10Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil. 11Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA. 12Vaccines and Immunity, Medical Research Council Unit, Fajara, The Gambia. 13Centre for the AIDS Programme of Research in Africa, Durban, South Africa. 14South African Medical Research Council-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Durban, South Africa. 34These authors contributed : Adam www.nature.com/scientificreports diagnosis (d)
We sought to discover and validate a parsimonious and robust blood transcriptomic signature with applicability for predicting incident TB, as a triage test for identifying those who should be further investigated for TB disease, and for monitoring of TB treatment response
Summary
(f) Prognostic performance of RISK6 for incident TB in household contacts from South Africa, The Gambia or Ethiopia, measured by qRT-PCR on RNA from whole blood RNA collected within 1 year of TB diagnosis from participants of the GC6-74 cohort. Experimental regimens tested in recent clinical trials have been inadequate to cure treatment-refractory patients[3] These data support the accepted principle that TB exists in a pathophysiological spectrum that spans several stages of infection, subclinical and active disease, including distinct stages of treatment outcome. We assessed performance of RISK6 by blind prediction as a prognostic test for incident TB, as a TB diagnostic in HIV-uninfected and HIV-infected individuals, including individuals presenting with symptoms requiring investigation for TB at primary health care centres, and as a treatment response biomarker. We tested the robustness of RISK6 and report performance of RISK6 measured in capillary blood samples collected by finger-prick, facilitating the way for incorporation into point-of-care diagnostic devices
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