Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.
Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.
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DOI：
10.1056/nejmoa1800474
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发表时间：
2018-10-11
期刊：
影响因子：
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通讯作者：
Zhu B
中科院分区：
文献类型：
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作者：
CRyPTIC Consortium and the 100,000 Genomes Project;Allix-Béguec C;Arandjelovic I;Bi L;Beckert P;Bonnet M;Bradley P;Cabibbe AM;Cancino-Muñoz I;Caulfield MJ;Chaiprasert A;Cirillo DM;Clifton DA;Comas I;Crook DW;De Filippo MR;de Neeling H;Diel R;Drobniewski FA;Faksri K;Farhat MR;Fleming J;Fowler P;Fowler TA;Gao Q;Gardy J;Gascoyne-Binzi D;Gibertoni-Cruz AL;Gil-Brusola A;Golubchik T;Gonzalo X;Grandjean L;He G;Guthrie JL;Hoosdally S;Hunt M;Iqbal Z;Ismail N;Johnston J;Khanzada FM;Khor CC;Kohl TA;Kong C;Lipworth S;Liu Q;Maphalala G;Martinez E;Mathys V;Merker M;Miotto P;Mistry N;Moore DAJ;Murray M;Niemann S;Omar SV;Ong RT;Peto TEA;Posey JE;Prammananan T;Pym A;Rodrigues C;Rodrigues M;Rodwell T;Rossolini GM;Sánchez Padilla E;Schito M;Shen X;Shendure J;Sintchenko V;Sloutsky A;Smith EG;Snyder M;Soetaert K;Starks AM;Supply P;Suriyapol P;Tahseen S;Tang P;Teo YY;Thuong TNT;Thwaites G;Tortoli E;van Soolingen D;Walker AS;Walker TM;Wilcox M;Wilson DJ;Wyllie D;Yang Y;Zhang H;Zhao Y;Zhu B
世界卫生组织建议对结核分枝杆菌复合群进行普遍的药物敏感性测试，以指导治疗决策并改善结果。我们评估了DNA测序是否可以准确预测一线抗结核药物的抗生素敏感性。 从六大洲16个国家的分离株中获得了异烟肼、利福平、乙胺丁醇和吡嗪酰胺的全基因组序列和相关表型。对于每个分离株，在9个基因中鉴定出与耐药性和药物敏感性相关的突变，并预测个体表型，除非还存在未知关联的突变。为了确定全基因组测序如何指导一线药物治疗，预测了完整的易感性谱。如果预测对异烟肼和其他药物敏感，或在影响这些其他药物的基因中含有未知关联的突变，则预测这些药物为泛敏感。我们模拟了阴性预测值如何随着耐药率的变化而变化。分析了10，209个分离株。预测的表型比例最大的是利福平（9，660/10，130;（95.4%）），最低的是乙胺丁醇（8，794/9，794;（89.8%））。预测异烟肼、利福平、乙胺丁醇和吡嗪酰胺耐药的敏感性分别为97.1%、97.5%、94.6%和91.3%，敏感性分别为99.0%、98.8%、93.6%和96.8%。对于5，865/7，516（78.0%）株具有完整表型谱的分离株，正确预测了5，250（89.5%）种药物谱。其中，3，952/4，037（97.9%）的泛易感性预测是正确的。当耐药率低于47.0%时，97.5%的模拟药物谱的阴性预测值超过95%。 一线药物的表型检测可以逐步减少，而代之以DNA测序，以指导抗结核药物治疗。
The World Health Organization recommends universal drug susceptibility testing for Mycobacterium tuberculosis complex to guide treatment decisions and improve outcomes. We assessed whether DNA sequencing can accurately predict antibiotic susceptibility profiles for first-line anti-tuberculosis drugs. Whole-genome sequences and associated phenotypes to isoniazid, rifampicin, ethambutol and pyrazinamide were obtained 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 were predicted to be pan-susceptible if predicted susceptible to isoniazid and to other drugs, or contained mutations of unknown association in genes affecting these other drugs. We simulated how negative predictive value changed with drug-resistance prevalence. 10,209 isolates were analysed. The greatest proportion of phenotypes were predicted for rifampicin (9,660/10,130; (95.4%)) and the lowest for ethambutol (8,794/9,794; (89.8%)). Isoniazid, rifampicin, ethambutol and pyrazinamide resistance was correctly predicted with 97.1%, 97.5% 94.6% and 91.3% sensitivity, and susceptibility with 99.0%, 98.8%, 93.6% and 96.8% specificity, respectively. 5,250 (89.5%) drug profiles were correctly predicted for 5,865/7,516 (78.0%) isolates with complete phenotypic profiles. Among these, 3,952/4,037 (97.9%) predictions of pan-susceptibility were correct. The negative predictive value for 97.5% of simulated drug profiles exceeded 95% where the prevalence of drug-resistance was below 47.0%. Phenotypic testing for first-line drugs can be phased down in favour of DNA sequencing to guide anti- tuberculosis drug therapy.