RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response
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. ,   The Adolescent Cohort Study team, Kafaar Fazlin , Workman Leslie , Mulenga Humphrey , Hughes E. Jane , Xasa Onke , Veldsman Ashley , Cloete Yolundi , Abrahams Deborah , Moyo Sizulu , Gelderbloem Sebastian , Tameris Michele , Geldenhuys Hennie , Ehrlich Rodney , Verver Suzanne , Geiter Larry ,   The GC6-74 Consortium, Black Gillian F. , van der Spuy Gian , Stanley Kim , Kriel Magdalena , Du Plessis Nelita , Nene Nonhlanhla , Roberts Teri , Kleynhans Leanie , Gutschmidt Andrea , Smith Bronwyn , Loxton Andre G. , Tromp Gerhardus , Tabb David , Ottenhoff Tom H. M. , Klein Michel R. , Haks Marielle C. , Franken Kees L. M. C. , Geluk Annemieke , van Meijgaarden Krista E. , Joosten Simone A , Boom W. Henry , Thiel Bonnie , Mayanja-Kizza Harriet , Joloba Moses , Zalwango Sarah , Nsereko Mary , Okwera Brenda , Kisingo Hussein , Parida Shreemanta K. , Golinski Robert , Maertzdorf Jeroen , Weiner January , Jacobson Marc , Dockrell Hazel , Smith Steven , Gorak-Stolinska Patricia , Hur Yun-Gyoung , Lalor Maeve , Lee Ji-Sook , Crampin Amelia C. , French Neil , Ngwira Bagrey , Ben-Smith Anne , Watkins Kate , Ambrose Lyn , Simukonda Felanji , Mvula Hazzie , Chilongo Femia , Saul Jacky , Branson Keith , Mahomed Hassan , Hughes E. Jane , Xasa Onke , Veldsman Ashley , Downing Katrina , Mulenga Humphrey , Abel Brian , Bowmaker Mark , Kagina Benjamin , Chung William Kwong , Sadoff Jerry , Sizemore Donata , Ramachandran S , Barker Lew , Brennan Michael , Weichold Frank , Muller Stefanie , Geiter Larry , Kassa Desta , Abebe Almaz , Mesele Tsehayenesh , Tegbaru Belete , van Baarle Debbie , Miedema Frank , Howe Rawleigh , Mihret Adane , Aseffa Abraham , Bekele Yonas , Iwnetu Rachel , Tafesse Mesfin , Yamuah Lawrence , Ota Martin , Hill Philip , Adegbola Richard , Corrah Tumani , Antonio Martin , Togun Toyin , Adetifa Ifedayo , Donkor Simon , Andersen Peter , Rosenkrands Ida , Doherty Mark , Weldingh Karin , Schoolnik Gary , Dolganov Gregory , Van Tran ,   The SATVI Clinical and Laboratory Team, Arendsen Denis , Africa Hadn , Baartman Veronica , Filander Elizabeth , Gwintsa Cynthia , Mabwe Simbarashe , Makhethe Lebohang , Moses Miriam , Onrust Raida , van Rooyen Michele , Steyn Marcia , Valley Habibullah ,   The ScreenTB Consortium, Ahlers Petri , van der Spuy Gian , van Rensburg Ilana , Mutavhatsindi Hygon , Manngo Portia , Stanley Kim , Hiemstra Andriette , McAnda Shirley , Mendy Joseph , Gindeh Awa , Mbayo Georgetta , Trawally Ebrima , Owolabi Olumuyiwa , Mayanja-Kizza Harriet , Nsereko Mary , Namuganga Anna-Rita , Kizito Saudah Nambiru , Mihret Adane , Ayalew Sosina , Howe Rawleigh , Tarekegne Azab , Tessema Bamlak , Nepolo Emmanuel , Sheehama Joseph , Gunther Gunar , Diergaardt Azaria , Pazvakavambwa Uapa , Dockrell Hazel , Ottenhoff Tom , Fat Elisa Tjon Kon , Herdigein Shannon , Corstjens Paul , Geluk Annemieke ,   The AE-TBC Consortium, Kriel Magdalena , van der Spuy Gian , Loxton Andre G. , Stanley Kim , Kriel Belinda , Kotzé Leigh A , Awoniyi Dolapo O. , Maasdorp Elizna , Owolabi Olumuyiwa , Sillah Abdou , Mendy Joseph , Gindeh Awa , Donkor Simon , Togun Toyin , Ota Martin , Mayanja-Kizza Harriet , Namuganga Ann Ritah , Muzanye Grace , Nsereko Mary , Peters Pierre , van der Vyver Marieta , Amutenya Faustina N. , Nelongo Josefina N. , Monye Lidia , Sheehama Jacob A. , Iipinge Scholastica , Crampin Amelia C. , Simukonda Felanji , Amberbir Alemayehu , Chilongo Femia , Houben Rein , Kassa Desta , Gebrezgeabher Atsbeha , Mesfin Getnet , Belay Yohannes , Gebremichael Gebremedhin , Alemayehu Yodit , Howe Rawleigh , Mihret Adane , Bekele Yonas , Tessema Bamlak , Yamuah Lawrence , Ottenhoff Tom H. M. , Geluk Annemieke , Franken Kees L. M. C. , Corstjens Paul L. A. M. , Fat Elisa M. Tjon Kon , de Dood Claudia J. , van der Ploeg-van Schip Jolien J. , Rosenkrands Ida , Aagaard Claus , Esterhuyse Maria M. , Cliff Jacqueline M. , Dockrell Hazel M. ,   The RePORT Brazil Team, Cubillos-Angulo Juan M. , Fukutani Kiyoshi F. , Paixão Laise , Khouri Ricardo , Melo Sayonara , Andrade Alice , Rebouças-Silva Jéssica , Malta Hayna , Queiroz Artur T. L. , Rolla Valeria C. , Cavalcante Solange , Durovni Betina , Cordeiro-Santos Marcelo , Kritski Afranio , Lapa e Silva José R. , Figueiredo Marina C. ,   Peruvian Household Contacts Cohort Team, Tamara Kattya Lopez , Tamara Kattya Lopez , León Segundo R. , Garcia Leonid Lecca ,   The CAPRISA IMPRESS team, Govender Dhineshree , Hassan-Moosa Razia , Naidoo Anushka , Adams Rochelle , Samsunder Natasha , Lewis Lara 
Published: May 2020

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.