Whole-Genome Sequencing Predicting Phenotypic Antitubercular Drug Resistance: Meta-analysis

Background For simultaneous prediction of phenotypic drug susceptibility test (pDST) for multiple antituberculosis drugs, the whole genome sequencing (WGS) data can be analyzed using either a catalog-based approach, wherein 1 causative mutation suggests resistance, (eg, World Health Organization catalog) or noncatalog-based approach using complicated algorithm (eg, TB-profiler, machine learning). The aim was to estimate the predictive ability of WGS-based tests with pDST as the reference, and to compare the 2 approaches.Methods Following a systematic literature search, the diagnostic test accuracies for 14 drugs were pooled using a random-effect bivariate model.Results Of 779 articles, 44 with 16 821 specimens for meta-analysis and 13 not for meta-analysis were included. The areas under summary receiver operating characteristic curve suggested test accuracy was excellent (0.97-1.00) for 2 drugs (isoniazid 0.975, rifampicin 0.975), very good (0.93-0.97) for 8 drugs (pyrazinamide 0.946, streptomycin 0.952, amikacin 0.968, kanamycin 0.963, capreomycin 0.965, para-aminosalicylic acid 0.959, levofloxacin 0.960, ofloxacin 0.958), and good (0.75-0.93) for 4 drugs (ethambutol 0.926, moxifloxacin 0.896, ethionamide 0.878, prothionamide 0.908). The noncatalog-based and catalog-based approaches had similar ability for all drugs.Conclusions WGS accurately identifies isoniazid and rifampicin resistance. For most drugs, positive WGS results reliably predict pDST positive. The 2 approaches had similar ability.Clinical Trials Registration UMIN-ID UMIN000049276. Whole-genome sequencing (WGS) accurately identifies isoniazid and rifampicin resistance. For most drugs, positive WGS results are reliable to predict phenotypic drug sensitivity. Noncatalog-based approach does not improve the predictive value for phenotypic antituberculosis drugs resistance compared to catalog-based approach.