Long diagnostic wait times hinder international efforts to address antibiotic resistance in M. tuberculosis. Pathogen whole genome sequencing, coupled with statistical and machine learning models, offers a promising solution. However, generalizability and clinical adoption have been limited by a lack of interpretability, especially in deep learning methods. Here, we present two deep convolutional neural networks that predict antibiotic resistance phenotypes of M. tuberculosis isolates: a multi-drug CNN (MD-CNN), that predicts resistance to 13 antibiotics based on 18 genomic loci, with AUCs 82.6-99.5% and higher sensitivity than state-of-the-art methods; and a set of 13 single-drug CNNs (SD-CNN) with AUCs 80.1-97.1% and higher specificity than the previous state-of-the-art. Using saliency methods to evaluate the contribution of input sequence features to the SD-CNN predictions, we identify 18 sites in the genome not previously associated with resistance. The CNN models permit functional variant discovery, biologically meaningful interpretation, and clinical applicability.
© 2022. The Author(s).