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. A comprehensive basis for interpreting mutations to predict antibiotic resistance in tuberculosis http://ow.ly/hhwJ30g9jCY

中文翻译：

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一种解释结核分枝杆菌突变与表型耐药性之间关联的标准化方法

需要清楚地了解结核分枝杆菌抗生素耐药性的遗传基础，以加速开发基于基因序列的快速药敏试验方法。提取原始基因型-表型相关数据作为全面系统评价的一部分，以开发一种标准化分析方法，用于解释利福平、异烟肼、氧氟沙星/左氧氟沙星、莫西沙星、阿米卡星、卡那霉素、卷曲霉素、链霉素、乙硫异烟胺/丙硫异烟胺和吡嗪酰胺的耐药性相关突变. 计算了耐药和易感分离株的突变频率，以及将突变分类为高、中、最小或不确定的预测耐药性的新统计方法。我们确定了 286 个与耐药性相关的置信度分级突变。与表型方法相比，利福平的敏感性（95% CI）为 90.3%（89.6-90.9%），异烟肼为 78.2%（77.4-79.0%），特异性分别为 96.3%（95.7-96.8%）和 94.4 % (93.1–95.5%)，分别。对于二线药物，敏感性从卷曲霉素的 67.4%（64.1-70.6%）到莫西沙星的 88.2%（85.1-90.9%）不等，特异性从莫西沙星的 90.0%（87.1-92.5%）到 99.5%（99.0 –99.8%) 用于阿米卡星。本研究提供了一种标准化和全面的方法来解释突变作为结核分枝杆菌耐药表型的预测因子。这些数据对分子诊断和下一代测序的临床解释以及耐药结核病患者的有效个体化治疗具有重要意义。