In silico evaluation of WHO-endorsed molecular methods to detect drug resistant tuberculosis

Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of dru...

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Published in:Scientific reports Vol. 12; no. 1; pp. 17741 - 13
Main Authors: Brankin, Alice, Seifert, Marva, Georghiou, Sophia B., Walker, Timothy M., Uplekar, Swapna, Suresh, Anita, Colman, Rebecca E.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 22.10.2022
Nature Publishing Group
Nature Portfolio
Subjects:
692/699
692/699/255
692/699/255/1856
Amikacin
Antibiotics
Antitubercular Agents - pharmacology
Antitubercular Agents - therapeutic use
Capreomycin
Diagnostic tests
Drug resistance
Genotype
Humanities and Social Sciences
Humans
Isoniazid
Kanamycin
Levofloxacin
Microbial Sensitivity Tests
Moxifloxacin
multidisciplinary
Mutation
Mycobacterium tuberculosis - genetics
Pyrazinamide
Rifampin
Science
Science (multidisciplinary)
Tuberculosis
Tuberculosis, Multidrug-Resistant - diagnosis
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Multidrug-Resistant - genetics
World Health Organization
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Abstract Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe-based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist.
AbstractList Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe-based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist.
Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe-based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist.Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe-based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist.
Abstract Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe-based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist.
ArticleNumber 17741
Author Suresh, Anita
Colman, Rebecca E.
Seifert, Marva
Walker, Timothy M.
Uplekar, Swapna
Brankin, Alice
Georghiou, Sophia B.
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  givenname: Timothy M.
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  givenname: Swapna
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Snippet Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been...
Abstract Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been...
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SubjectTerms 692/699
692/699/255
692/699/255/1856
Amikacin
Antibiotics
Antitubercular Agents - pharmacology
Antitubercular Agents - therapeutic use
Capreomycin
Diagnostic tests
Drug resistance
Genotype
Humanities and Social Sciences
Humans
Isoniazid
Kanamycin
Levofloxacin
Microbial Sensitivity Tests
Moxifloxacin
multidisciplinary
Mutation
Mycobacterium tuberculosis - genetics
Pyrazinamide
Rifampin
Science
Science (multidisciplinary)
Tuberculosis
Tuberculosis, Multidrug-Resistant - diagnosis
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Multidrug-Resistant - genetics
World Health Organization
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