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A prospective blood RNA signature for tuberculosis disease risk

Background Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; bloo... Full description

Journal Title: Lancet (London England), 2016-03-01, Vol.387 (10035), p.2312-2322
Main Author: Zak, Daniel E.
Other Authors: Penn-Nicholson, Adam , Scriba, Thomas J. , Thompson, Ethan , Suliman, Sara , Amon, Lynn M. , Mahomed, Hassan , Erasmus, Mzwandile , Whatney, Wendy , Hussey, Gregory D. , Abrahams, Deborah , Kafaar, Fazlin , Hawkridge, Tony , Verver, Suzanne , Hughes, E. Jane , Ota, Martin , Sutherland, Jayne , Howe, Rawleigh , Dockrell, Hazel M. , Boom, W. Henry , Thiel, Bonnie , Ottenhoff, Tom H. M. , Mayanja-Kizza, Harriet , Crampin, Amelia C. , Downing, Katrina , Hatherill, Mark , Valvo, Joe , Shankar, Smitha , Parida, Shreemanta K. , Kaufmann, Stefan H. E. , Walzl, Gerhard , Aderem, Alan , Hanekom, Willem A.
Format: Electronic Article Electronic Article
Language: English
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Article
Quelle: Alma/SFX Local Collection
ID: ISSN: 0140-6736
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5392204
title: A prospective blood RNA signature for tuberculosis disease risk
format: Article
creator:
  • Zak, Daniel E.
  • Penn-Nicholson, Adam
  • Scriba, Thomas J.
  • Thompson, Ethan
  • Suliman, Sara
  • Amon, Lynn M.
  • Mahomed, Hassan
  • Erasmus, Mzwandile
  • Whatney, Wendy
  • Hussey, Gregory D.
  • Abrahams, Deborah
  • Kafaar, Fazlin
  • Hawkridge, Tony
  • Verver, Suzanne
  • Hughes, E. Jane
  • Ota, Martin
  • Sutherland, Jayne
  • Howe, Rawleigh
  • Dockrell, Hazel M.
  • Boom, W. Henry
  • Thiel, Bonnie
  • Ottenhoff, Tom H. M.
  • Mayanja-Kizza, Harriet
  • Crampin, Amelia C.
  • Downing, Katrina
  • Hatherill, Mark
  • Valvo, Joe
  • Shankar, Smitha
  • Parida, Shreemanta K.
  • Kaufmann, Stefan H. E.
  • Walzl, Gerhard
  • Aderem, Alan
  • Hanekom, Willem A.
subjects:
  • Article
ispartof: Lancet (London, England), 2016-03-01, Vol.387 (10035), p.2312-2322
description: Background Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; blood was collected every 6 months. A prospective signature of risk was derived from whole blood RNA-Sequencing data by comparing participants who ultimately developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. The latter participants were household contacts of adults with active pulmonary tuberculosis disease. Findings Of 6,363 adolescents screened, 46 progressors and 107 matched controls were identified. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% confidence interval, 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA-Seq and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
url: Link


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titleA prospective blood RNA signature for tuberculosis disease risk
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creatorZak, Daniel E. ; Penn-Nicholson, Adam ; Scriba, Thomas J. ; Thompson, Ethan ; Suliman, Sara ; Amon, Lynn M. ; Mahomed, Hassan ; Erasmus, Mzwandile ; Whatney, Wendy ; Hussey, Gregory D. ; Abrahams, Deborah ; Kafaar, Fazlin ; Hawkridge, Tony ; Verver, Suzanne ; Hughes, E. Jane ; Ota, Martin ; Sutherland, Jayne ; Howe, Rawleigh ; Dockrell, Hazel M. ; Boom, W. Henry ; Thiel, Bonnie ; Ottenhoff, Tom H. M. ; Mayanja-Kizza, Harriet ; Crampin, Amelia C. ; Downing, Katrina ; Hatherill, Mark ; Valvo, Joe ; Shankar, Smitha ; Parida, Shreemanta K. ; Kaufmann, Stefan H. E. ; Walzl, Gerhard ; Aderem, Alan ; Hanekom, Willem A.
creatorcontribZak, Daniel E. ; Penn-Nicholson, Adam ; Scriba, Thomas J. ; Thompson, Ethan ; Suliman, Sara ; Amon, Lynn M. ; Mahomed, Hassan ; Erasmus, Mzwandile ; Whatney, Wendy ; Hussey, Gregory D. ; Abrahams, Deborah ; Kafaar, Fazlin ; Hawkridge, Tony ; Verver, Suzanne ; Hughes, E. Jane ; Ota, Martin ; Sutherland, Jayne ; Howe, Rawleigh ; Dockrell, Hazel M. ; Boom, W. Henry ; Thiel, Bonnie ; Ottenhoff, Tom H. M. ; Mayanja-Kizza, Harriet ; Crampin, Amelia C. ; Downing, Katrina ; Hatherill, Mark ; Valvo, Joe ; Shankar, Smitha ; Parida, Shreemanta K. ; Kaufmann, Stefan H. E. ; Walzl, Gerhard ; Aderem, Alan ; Hanekom, Willem A.
descriptionBackground Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; blood was collected every 6 months. A prospective signature of risk was derived from whole blood RNA-Sequencing data by comparing participants who ultimately developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. The latter participants were household contacts of adults with active pulmonary tuberculosis disease. Findings Of 6,363 adolescents screened, 46 progressors and 107 matched controls were identified. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% confidence interval, 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA-Seq and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation The whole blood tuberculosis risk signature prospectively identified persons at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. Funding Bill and Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union and the South African Medical Research Council (detail at end of text).
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descriptionBackground Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; blood was collected every 6 months. A prospective signature of risk was derived from whole blood RNA-Sequencing data by comparing participants who ultimately developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. The latter participants were household contacts of adults with active pulmonary tuberculosis disease. Findings Of 6,363 adolescents screened, 46 progressors and 107 matched controls were identified. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% confidence interval, 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA-Seq and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation The whole blood tuberculosis risk signature prospectively identified persons at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. Funding Bill and Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union and the South African Medical Research Council (detail at end of text).
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notes
0Daniel E. Zak, Adam Penn-Nicholson and Thomas J. Scriba contributed equally to this article.
1The GC6-74 cohort study team: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany:Stefan H.E. Kaufmann (GC6-74 Principal Investigator), Shreemanta K. Parida, Robert Golinski, Jeroen Maertzdorf, January Weiner 3rd, Marc JacobsonDST/NRF Centre of Excellence for Biomedical TB Research and MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg, South Africa:Gerhard Walzl, Gillian Black, Gian van der Spuy, Kim Stanley, Daleen Kriel, Nelita Du Plessis, Nonhlanhla Nene, Andre Loxton, Novel ChegouDepartment of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands:Tom H.M. Ottenhoff, Michel Klein, Marielle Haks, Kees Franken, Annemieke Geluk, Krista Meijgaarden, Simone JoostenTuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA:W. Henry Boom, Bonnie ThielDepartment of Medicine and Department of Microbiology, College of Health Sciences, Faculty of Medicine, Makerere University, Kampala, Uganda:Harriet Mayanja-Kizza, Moses Joloba, Sarah Zalwango, Mary Nsereko, Brenda Okwera, Hussein KisingoDepartment of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom:Hazel Dockrell, Steven Smith, Patricia Gorak-Stolinska, Yun-Gyoung Hur, Maeve Lalor, Ji-Sook LeeKaronga Prevention Study, Chilumba, Malawi:Amelia C Crampin, Neil French, Bagrey Ngwira, Anne Ben Smith, Kate Watkins, Lyn Ambrose, Felanji Simukonda, Hazzie Mvula, Femia Chilongo, Jacky Saul, Keith BransonSouth African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine & Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa:Sara Suliman, Thomas Scriba, Hassan Mahomed, Jane Hughes, Katrina Downing, Adam Penn-Nicholson, Humphrey Mulenga, Brian Abel, Mark Bowmaker, Benjamin Kagina, William Kwong Chung, Willem HanekomAeras, Rockville, MD, USA:Jerry Sadoff, Donata Sizemore, S Ramachandran, Lew Barker, Michael Brennan, Frank Weichold, Stefanie Muller, Larry GeiterEthiopian Health & Nutrition Research Institute, Addis Ababa, Ethiopia:Desta Kassa, Almaz Abebe, Tsehayenesh Mesele, Belete TegbaruUniversity Medical Centre, Utrecht, The Netherlands:Debbie van Baarle, Frank MiedemaArmauer Hansen Research Institute, Addis Ababa, Ethiopia:Rawleigh Howe, Adane Mihret, Abraham Aseffa, Yonas Bekele, Rachel Iwnetu, Mesfin Tafesse, Lawrence YamuahVaccines & Immunity Theme, Medical Research Council Unit, Fajara, The Gambia:Martin Ota, Jayne Sutherland, Philip Hill, Richard Adegbola, Tumani Corrah, Martin Antonio, Toyin Togun, Ifedayo Adetifa, Simon DonkorDepartment of Infectious Disease Immunology, Statens Serum Institute, Copenhagen, Denmark:Peter Andersen, Ida Rosenkrands, Mark Doherty, Karin WeldinghDepartment of Microbiology and Immunology, Stanford University, Stanford, California, USA:Gary Schoolnik, Gregory Dolganov, Tran Van
2The following authors are Full Professors: Gregory HusseyHazel DockrellHenry BoomTom OttenhoffHariett Mayanja-KizzaStefan H.E. KaufmannGerhard WalzlWillem Hanekom
3Ethan Thompson and Sara Suliman contributed equally to this article.
4The ACS cohort study team: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine & Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa:Fazlin Kafaar, Leslie Workman, Humphrey Mulenga, Thomas Scriba, Rodney Ehrlich, Deborah Abrahams, Sizulu Moyo, Sebastian Gelderbloem, Michele Tameris, Hennie Geldenhuys, Willem Hanekom, Gregory HusseySchool of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa:Rodney EhrlichKNCV Tuberculosis Foundation, The Hague, and Amsterdam Institute of Global Health and Development, Academic Medical Centre, Amsterdam, The Netherlands:Suzanne VerverAeras, Rockville, MD, USA:Larry Geiter
abstractBackground Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease may lead to interventions that impact the epidemic. Methods Healthy, M. tuberculosis infected South African adolescents were followed for 2 years; blood was collected every 6 months. A prospective signature of risk was derived from whole blood RNA-Sequencing data by comparing participants who ultimately developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex qRT-PCR, the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. The latter participants were household contacts of adults with active pulmonary tuberculosis disease. Findings Of 6,363 adolescents screened, 46 progressors and 107 matched controls were identified. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% confidence interval, 63·2–68·9) and a specificity of 80·6% (79·2–82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA-Seq and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6–64·3) and a specificity of 82·8% (76·7–86) in 12 months preceding tuberculosis. Interpretation The whole blood tuberculosis risk signature prospectively identified persons at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. Funding Bill and Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union and the South African Medical Research Council (detail at end of text).
pmid27017310
doi10.1016/S0140-6736(15)01316-1
oafree_for_read