TY - JOUR
T1 - A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis
AU - Miotto, Paolo
AU - Tessema, Belay
AU - Tagliani, Elisa
AU - Chindelevitch, Leonid
AU - Starks, Angela M.
AU - Emerson, Claudia
AU - Hanna, Debra
AU - Kim, Peter S.
AU - Liwski, Richard
AU - Zignol, Matteo
AU - Gilpin, Christopher
AU - Niemann, Stefan
AU - Denkinger, Claudia M.
AU - Fleming, Joy
AU - Warren, Robin M.
AU - Crook, Derrick
AU - Posey, James
AU - Gagneux, Sebastien
AU - Hoffner, Sven
AU - Rodrigues, Camilla
AU - Comas, Iñaki
AU - Engelthaler, David M.
AU - Murray, Megan
AU - Alland, David
AU - Rigouts, Leen
AU - Lange, Christoph
AU - Dheda, Keertan
AU - Hasan, Rumina
AU - Ranganathan, Uma Devi K.
AU - McNerney, Ruth
AU - Ezewudo, Matthew
AU - Cirillo, Daniela M.
AU - Schito, Marco
AU - Köser, Claudio U.
AU - Rodwell, Timothy C.
N1 - Publisher Copyright:
© ERS 2017.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - A clear understanding of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence. Raw genotype-phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance. We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6-90.9%), while for isoniazid it was 78.2% (77.4-79.0%) and their specificities were 96.3% (95.7-96.8%) and 94.4% (93.1-95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1-70.6%) for capreomycin to 88.2% (85.1-90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1-92.5%) for moxifloxacin to 99.5% (99.0-99.8%) for amikacin. This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis.
AB - A clear understanding of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence. Raw genotype-phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance. We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6-90.9%), while for isoniazid it was 78.2% (77.4-79.0%) and their specificities were 96.3% (95.7-96.8%) and 94.4% (93.1-95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1-70.6%) for capreomycin to 88.2% (85.1-90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1-92.5%) for moxifloxacin to 99.5% (99.0-99.8%) for amikacin. This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis.
UR - http://www.scopus.com/inward/record.url?scp=85043462793&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85043462793&partnerID=8YFLogxK
U2 - 10.1183/13993003.01354-2017
DO - 10.1183/13993003.01354-2017
M3 - Article
C2 - 29284687
AN - SCOPUS:85043462793
SN - 0903-1936
VL - 50
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 6
M1 - 1701354
ER -