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Deep amplicon sequencing for culture-free prediction of susceptibility or resistance to 13 anti-tuberculous drugs

Agathe Jouet, Cyril Gaudin, Nelly Badalato, Caroline Allix-Béguec, Stéphanie Duthoy, Alice Ferré, Maren Diels, Yannick Laurent, Sandy Contreras, Silke Feuerriegel, Stefan Niemann, Emmanuel André, Michel K. Kaswa, Elisa Tagliani, Andrea Cabibbe, Vanessa Mathys, Daniela Cirillo, Bouke C. de Jong, Leen Rigouts, Philip Supply
European Respiratory Journal 2020; DOI: 10.1183/13993003.02338-2020
Agathe Jouet
1GenoScreen, Lille, France
12These authors contributed equally to this work
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Cyril Gaudin
1GenoScreen, Lille, France
12These authors contributed equally to this work
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Nelly Badalato
1GenoScreen, Lille, France
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  • ORCID record for Nelly Badalato
Caroline Allix-Béguec
1GenoScreen, Lille, France
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Stéphanie Duthoy
1GenoScreen, Lille, France
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Alice Ferré
1GenoScreen, Lille, France
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Maren Diels
2BCCM/ITM, Mycobacterial culture collection, Institute of Tropical Medicine, Antwerp, Belgium
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Yannick Laurent
1GenoScreen, Lille, France
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Sandy Contreras
1GenoScreen, Lille, France
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Silke Feuerriegel
3Molecular and Experimental Mycobacteriology, Research Centre Borstel, Borstel, Germany
4German Centre for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel, Borstel, Germany
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Stefan Niemann
3Molecular and Experimental Mycobacteriology, Research Centre Borstel, Borstel, Germany
4German Centre for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel, Borstel, Germany
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Emmanuel André
5Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
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Michel K. Kaswa
6National Tuberculosis Program, Kinshasa, DR Congo
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Elisa Tagliani
7Emerging Bacterial Pathogens, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • ORCID record for Elisa Tagliani
Andrea Cabibbe
7Emerging Bacterial Pathogens, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Vanessa Mathys
8Unit Bacterial Diseases Service, Infectious diseases in Humans, Sciensano, Brussels, Belgium
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Daniela Cirillo
7Emerging Bacterial Pathogens, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Bouke C. de Jong
9Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
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Leen Rigouts
9Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
10Department of Biomedical Sciences, Antwerp University, Antwerp, Belgium
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Philip Supply
11Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 -CIIL - Center for Infection and Immunity of Lille, Lille, France
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  • For correspondence: philip.supply@ibl.cnrs.fr
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Abstract

Conventional molecular tests for detecting Mycobacterium tuberculosis complex (MTBC) drug resistance on clinical samples cover a limited set of mutations. Whole genome sequencing (WGS) typically requires culture. Here, we evaluated the Deeplex Myc-TB targeted deep sequencing assay for prediction of resistance to 13 anti-tuberculous drugs/drug classes, directly applicable on sputum. With MTBC DNA tests, the limit of detection was 100–1000 genome copies for fixed resistance mutations. Deeplex Myc-TB captured in silico 97.1–99.3% of resistance phenotypes correctly predicted by WGS from 3651 MTBC genomes. On 429 isolates, the assay predicted 92.2% of 2369 first- and second-line phenotypes, with a sensitivity of 95.3% and specificity of 97.4%. Fifty-six of 69 (81.2%) residual discrepancies with phenotypic results involved pyrazinamide, ethambutol, and ethionamide, and low-level rifampicin- or isoniazid-resistance mutations, all notoriously prone to phenotypic testing variability. Only 2 of 91 (2.2%) resistance phenotypes undetected by Deeplex Myc-TB had known resistance-associated mutations by WGS analysis outside Deeplex Myc-TB targets. Phenotype predictions from Deeplex Myc-TB analysis directly on 109 sputa from a Djibouti survey matched those of MTBSeq/PhyResSE/Mykrobe, fed with WGS data from subsequent cultures, with a sensitivity of 93.5/98.5/93.1% and specificity of 98.5/97.2/95.3%. Most residual discordances involved gene deletions/indels and 3–12% heteroresistant calls undetected by WGS analysis, or natural pyrazinamide resistance of globally rare “M. canettii” strains then unreported by Deeplex Myc-TB. On 1494 arduous sputa from a Democratic Republic of the Congo survey, 14 902 of 19 422 (76.7%) possible susceptible or resistance phenotypes could be predicted culture-free. Deeplex Myc-TB may enable fast, tailored tuberculosis treatment.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Jouet is an employee of Genoscreen.

Conflict of interest: Dr. Gaudin is an employee of Genoscreen.

Conflict of interest: Dr. Badalato is an employee of Genoscreen.

Conflict of interest: Dr. Allix-Béguec is an employee of Genoscreen.

Conflict of interest: Dr. Duthoy is an employee of Genoscreen.

Conflict of interest: Dr. Ferré is an employee of Genoscreen.

Conflict of interest: Diels has nothing to disclose.

Conflict of interest: Dr. Laurent is an employee of Genoscreen.

Conflict of interest: Dr. Contreras is an employee of Genoscreen.

Conflict of interest: Dr. Feuerriegel has nothing to disclose.

Conflict of interest: Dr. Niemann reports grants from German Center for Infection Research, grants from Excellenz Cluster Precision Medicine in Chronic Inflammation EXC 2167, grants from Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG), grants from ECDC public tender: OJ/2017/OCS/7766

Conflict of interest: Dr. André has nothing to disclose.

Conflict of interest: Dr. Kaswa has nothing to disclose.

Conflict of interest: Dr. Tagliani has nothing to disclose.

Conflict of interest: Dr. Cabibbe has nothing to disclose.

Conflict of interest: Dr. Mathys has nothing to disclose.

Conflict of interest: Dr. cirillo has nothing to disclose.

Conflict of interest: Dr. de Jong has nothing to disclose.

Conflict of interest: Dr. Rigouts has nothing to disclose.

Conflict of interest: Dr. Supply reports personal fees from Genoscreen, grants from European Union PathoNGen-Trace project (FP7- 278864), during the conduct of the study.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received June 15, 2020.
  • Accepted September 3, 2020.
  • Copyright ©ERS 2020
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Deep amplicon sequencing for culture-free prediction of susceptibility or resistance to 13 anti-tuberculous drugs
Agathe Jouet, Cyril Gaudin, Nelly Badalato, Caroline Allix-Béguec, Stéphanie Duthoy, Alice Ferré, Maren Diels, Yannick Laurent, Sandy Contreras, Silke Feuerriegel, Stefan Niemann, Emmanuel André, Michel K. Kaswa, Elisa Tagliani, Andrea Cabibbe, Vanessa Mathys, Daniela Cirillo, Bouke C. de Jong, Leen Rigouts, Philip Supply
European Respiratory Journal Jan 2020, 2002338; DOI: 10.1183/13993003.02338-2020

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Deep amplicon sequencing for culture-free prediction of susceptibility or resistance to 13 anti-tuberculous drugs
Agathe Jouet, Cyril Gaudin, Nelly Badalato, Caroline Allix-Béguec, Stéphanie Duthoy, Alice Ferré, Maren Diels, Yannick Laurent, Sandy Contreras, Silke Feuerriegel, Stefan Niemann, Emmanuel André, Michel K. Kaswa, Elisa Tagliani, Andrea Cabibbe, Vanessa Mathys, Daniela Cirillo, Bouke C. de Jong, Leen Rigouts, Philip Supply
European Respiratory Journal Jan 2020, 2002338; DOI: 10.1183/13993003.02338-2020
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