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Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing
Open accessAbstract
BACKGROUND: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. METHODS: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).
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“Studies in other areas of medicine have also found lower NPVs of even highly sensitive and specific tests in situations where the pretest probability of a disease is high23,26,27.”
From Diagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability (2024) · cites this paper as [26]
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Metadata
- Authors
- The CRyPTIC Consortium and the 100, 0. G. P.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-10-11
- Volume
- 379
- Issue
- 15
- Pages
- 1403-1415
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6121966
- OpenAlex
- W2902271181
- Cited by
- 500
- References
- 22
- Citations by year
- 2026: 25 · 2025: 41 · 2024: 58 · 2023: 61 · 2022: 78 · 2021: 65 · 2020: 89 · 2019: 72 · 2018: 9
- FWCI
- 44.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- New England Journal of Medicine (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by)
- PubMed Central (acceptedVersion, cc-by)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- HAL (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Florence Research (University of Florence) (submittedVersion)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Seventh Framework Programme (278864)
- European Research Council (638553-TB-ACCELERATE)
- Wellcome Trust and the Royal Society Sir Henry Dale Fellowships (101237/Z/13/Z, 102541/A/13/Z)
- National University of Singapore Yong Loo Lin School of Medicine Aspiration Fund (NUHSRO/2014/069/AF-New Idea/04)
- Ministerio de Economía y Competitividad (SAF2016-77346-R)
- National Science and Technology Key Program of China (2014ZX10003002)
- National Basic Research program of China (2014CB744403)
- Health Services and Delivery Research Programme
- Bill and Melinda Gates Foundation (OPP1133541)
- Wellcome Trust (200205/Z/15/Z)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Infectious Diseases › Infectious Diseases and Tuberculosis
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Keywords
- Mycobacterium tuberculosis complex, first-line antituberculosis drugs, isoniazid resistance, rifampicin resistance, ethambutol resistance, pyrazinamide resistance, drug resistance mutations, whole genome sequencing, genotype-phenotype correlation, negative predictive value
- MeSH terms
- Whole Genome Sequencing, Antitubercular Agents, Ethambutol, Genotype, Humans, Isoniazid, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis, Phenotype, Pyrazinamide, Rifampin, Tuberculosis, Genome, Bacterial, Drug Resistance, Bacterial
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