BACKGROUND : Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drugsusceptibility
testing is slow and expensive, and commercial genotypic assays screen only common resistancedetermining
mutations. We used whole-genome sequencing to characterise common and rare mutations predicting
drug resistance, or consistency with susceptibility, for all fi rst-line and second-line drugs for tuberculosis.
METHODS : Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis
genomes. For 23 candidate genes identifi ed from the drug-resistance scientifi c literature, we algorithmically
characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised.
We then assessed the ability of these characterisations to predict phenotypic drug-susceptibility testing for an
independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those
characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance.
FINDINGS : We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these
mutations, we could predict 89·2% of the validation-set phenotypes with a mean 92·3% sensitivity (95% CI
90·7–93·7) and 98·4% specifi city (98·1–98·7). 10·8% of validation-set phenotypes could not be predicted because
uncharacterised mutations were present. With an in-silico comparison, characterised resistance determinants had
higher sensitivity than the mutations from three line-probe assays (85·1% vs 81·6%). No additional resistance
determinants were identifi ed among mutations under selection pressure in non-candidate genes.
INTERPRETATION : A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used
clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically
predicted. This approach could be integrated into routine diagnostic workfl ows, phasing out phenotypic drugsusceptibility
testing while reporting drug resistance early.