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The 2021 WHO Catalogue of Mycobacterium Tuberculosis Complex Mutations Associated with Drug Resistance: A New Global Standard for Molecular Diagnostics

29 Pages Posted: 21 Sep 2021

See all articles by Timothy M. Walker

Timothy M. Walker

University of Oxford - Nuffield Department of Medicine

Paolo Miotto

Università Vita-Salute San Raffaele - IRCCS San Raffaele Scientific Institute

Claudio U. Köser

University of Cambridge - Department of Genetics

Philip William Fowler

University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital; University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, National Institute of Health Research Oxford Biomedical Research Centre

Jeff Knaggs

University of Oxford - Nuffield Department of Medicine

Zamin Iqbal

European Bioinformatics Institute (EMBL-EBI)

Martin Hunt

University of Oxford - Nuffield Department of Medicine

Leonid Chindelevitch

Imperial College London

Maha Farhat

Harvard University - Harvard Medical School

daniela Cirillo

Università Vita-Salute San Raffaele - IRCCS San Raffaele Scientific Institute

Iñaki Comas

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) - Institute of Biomedicine of Valencia

James E. Posey

Centers for Disease Control and Prevention (CDC), National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Division of Tuberculosis Elimination

Shaheed Vally Omar

National Health Laboratory Services (NHLS) - National Institute for Communicable Diseases

Timothy E. A. Peto

University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital

Anita Suresh

Foundation for Innovative New Diagnostics (FIND)

Swapna Uplekar

Foundation for Innovative New Diagnostics (FIND)

Sacha Laurent

Foundation for Innovative New Diagnostics (FIND)

Rebecca Colman

Foundation for Innovative New Diagnostics (FIND)

Carl-Michael Nathanson

World Health Organization - Global Tuberculosis Programme

Matteo Zignol

World Health Organization - Global Tuberculosis Programme

Ann Sarah Walker

University of Oxford - Nuffield Department of Medicine

The CRyPTIC Consortium

Independent

The Seq&Treat Consortium

Independent

Derrick W. Crook

University of Oxford - Nuffield Department of Medicine; University of Oxford - John Radcliffe Hospital

Nazir Ismail

World Health Organization - Global Tuberculosis Programme

Timothy C. Rodwell

University of California, San Diego (UCSD)

More...

Abstract

Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosis . There is currently no WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.

Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 M. tuberculosis isolates with paired whole-genome sequencing and phenotypic drug susceptibility data were amassed from 41 countries. Mutations were graded according to their odds ratio and associated false discovery rate corrected p-value, and their positive predictive value for phenotypic resistance. A series of expert rules were applied for final confidence grading of each mutation.

Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations’ pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.

Interpretation: This first WHO endorsed catalogue of molecular targets for M. tuberculosis drug susceptibility testing provides a global standard for resistance interpretation. It will be expanded as data emerge on phenotypically resistant isolates, including for new and repurposed drugs.

Funding: UNITAID, Wellcome, MRC, BMGF.

Declaration of Interest: C.U.K. is a consultant Becton Dickinson, the Foundation for Innovative New Diagnostics and the TB Alliance. C.U.K. is collaborating with PZA Innovation and Thermo Fisher Scientific. C.U.K. worked as a consultant for QuantuMDx, the Stop TB Partnership, the World Health Organization (WHO) Global TB Programme and the WHO Regional Office for Europe. C.U.K. gave a paid educational talk for Oxford Immunotec. Hain Lifescience covered C.U.K.’s and accommodation to present at a meeting. C.U.K. is an unpaid advisor to BioVersys and GenoScreen. E.R. is employed by Public Health England and holds an honorary contract with Imperial College London. I.F.L. is Director of the Scottish Mycobacteria Reference Laboratory. S.N. receives funding from German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG)tion EXC 2167. P.S. is a consultant at Genoscreen. T.R. is funded by NIH and DoD and receives salary support from the non-profit organization FIND. T.R. is a cofounder, board member and shareholder of Verus Diagnostics Inc, a company that was founded with the intent of developing diagnostic assays. Verus Diagnostics was not involved in any way with data collection, analysis or publication of the results. T.R. has not received any financial support from Verus Diagnostics. UCSD Conflict of Interest office has reviewed and approved T.R.’s role in Verus Diagnostics Inc. T.R. is a co-inventor of a provisional patent for a TB diagnostic assay (provisional patent #: 63/048.989). T.R. is a co-inventor on a patent associated with the processing of TB sequencing data (European Patent Application No. 14840432.0 & USSN 14/912,918). T.R. has agreed to “donate all present and future interest in and rights to royalties from this patent” to UCSD to ensure that he does not receive any financial benefits from this patent. S.S. is working and holding ESOPs at HaystackAnalytics Pvt. Ltd. (Product: Using whole genome sequencing for drug susceptibility testing for Mycobacterium tuberculosis). G.F.G. is listed as an inventor on patent applications for RBDdimer- based CoV vaccines. No other authors declare a conflict of
interest.

Ethical Approval: Approval for CRyPTIC study was obtained by Taiwan Centers for Disease Control IRB No. 106209, University of KwaZulu Natal Biomedical Research Ethics Committee (UKZN BREC) (reference BE022/13) and University of Liverpool Central University Research Ethics Committees (reference 2286), Institutional Research Ethics Committee (IREC) of The Foundation for Medical Research, Mumbai (Ref nos. FMR/IEC/TB/01a/2015 and FMR/IEC/TB/01b/2015), Institutional Review Board of P.D. Hinduja Hospital and Medical Research Centre, Mumbai (Ref no. 915-15-CR [MRC]), scientific committee of the Adolfo Lutz Institute (CTC-IAL 47-J / 2017) and in the Ethics Committee (CAAE: 81452517.1.0000.0059) and Ethics Committee review by Universidad Peruana Cayetano Heredia (Lima, Peru) and LSHTM (London, UK).

Keywords: Mycobacterium tuberculosis, drug resistance, whole genome sequencing, catalogue, World Health Organization

Suggested Citation

Walker, Timothy M. and Miotto, Paolo and Köser, Claudio U. and Fowler, Philip William and Knaggs, Jeff and Iqbal, Zamin and Hunt, Martin and Chindelevitch, Leonid and Farhat, Maha and Cirillo, daniela and Comas, Iñaki and Posey, James E. and Omar, Shaheed Vally and Peto, Timothy E. A. and Suresh, Anita and Uplekar, Swapna and Laurent, Sacha and Colman, Rebecca and Nathanson, Carl-Michael and Zignol, Matteo and Walker, Ann Sarah and Consortium, The CRyPTIC and Consortium, The Seq&Treat and Crook, Derrick W. and Ismail, Nazir and Rodwell, Timothy C., The 2021 WHO Catalogue of Mycobacterium Tuberculosis Complex Mutations Associated with Drug Resistance: A New Global Standard for Molecular Diagnostics. Available at SSRN: https://ssrn.com/abstract=3923444 or http://dx.doi.org/10.2139/ssrn.3923444

Timothy M. Walker (Contact Author)

University of Oxford - Nuffield Department of Medicine ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Paolo Miotto

Università Vita-Salute San Raffaele - IRCCS San Raffaele Scientific Institute ( email )

Via Olgettina Milano, 60
Milan, 20132
Italy

Claudio U. Köser

University of Cambridge - Department of Genetics ( email )

Cambridge
United Kingdom

Philip William Fowler

University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital ( email )

Oxford, Oxfordshire, England
United Kingdom

University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, National Institute of Health Research Oxford Biomedical Research Centre ( email )

Oxford
United Kingdom

Jeff Knaggs

University of Oxford - Nuffield Department of Medicine ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Zamin Iqbal

European Bioinformatics Institute (EMBL-EBI) ( email )

Wellcome Genome Campus, Hinxton
Cambridge
United Kingdom

Martin Hunt

University of Oxford - Nuffield Department of Medicine ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Leonid Chindelevitch

Imperial College London

South Kensington Campus
Exhibition Road
London, SW7 2AZ
United Kingdom

Maha Farhat

Harvard University - Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Daniela Cirillo

Università Vita-Salute San Raffaele - IRCCS San Raffaele Scientific Institute ( email )

Via Olgettina Milano, 60
Milan, 20132
Italy

Iñaki Comas

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) - Institute of Biomedicine of Valencia ( email )

Valencia
Spain

James E. Posey

Centers for Disease Control and Prevention (CDC), National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Division of Tuberculosis Elimination ( email )

Atlanta, GA
United States

Shaheed Vally Omar

National Health Laboratory Services (NHLS) - National Institute for Communicable Diseases ( email )

Johannesburg
South Africa

Timothy E. A. Peto

University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital ( email )

Oxford, Oxfordshire, England
United Kingdom

Anita Suresh

Foundation for Innovative New Diagnostics (FIND) ( email )

Geneva
Switzerland

Swapna Uplekar

Foundation for Innovative New Diagnostics (FIND) ( email )

Geneva
Switzerland

Sacha Laurent

Foundation for Innovative New Diagnostics (FIND) ( email )

Geneva
Switzerland

Rebecca Colman

Foundation for Innovative New Diagnostics (FIND) ( email )

Geneva
Switzerland

Carl-Michael Nathanson

World Health Organization - Global Tuberculosis Programme ( email )

Geneva
Switzerland

Matteo Zignol

World Health Organization - Global Tuberculosis Programme ( email )

Geneva
Switzerland

Ann Sarah Walker

University of Oxford - Nuffield Department of Medicine ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Derrick W. Crook

University of Oxford - Nuffield Department of Medicine

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

University of Oxford - John Radcliffe Hospital ( email )

Oxford, Oxfordshire, England
United Kingdom

Nazir Ismail

World Health Organization - Global Tuberculosis Programme ( email )

Geneva
Switzerland

Timothy C. Rodwell

University of California, San Diego (UCSD)

9500 Gilman Drive
La Jolla, CA 92093
United States

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