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Recent years saw a growing interest in predicting antibiotic resistance from whole-genome sequencing data, with promising results obtained for  Staphylococcus aureus  and  Mycobacterium tuberculosis . In this work, we gathered 6,574 sequencing read datasets of  M. tuberculosis  public genomes with associated antibiotic resistance profiles for both first and second-line antibiotics. We performed a systematic evaluation of  TBProfiler  and  Mykrobe , two widely recognized softwares allowing to predict resistance in  M. tuberculosis . The size of the dataset allowed us to obtain confident estimations of their overall predictive performance, to assess precisely the individual predictive power of the markers they rely on, and to study in addition how these softwares behave across the major  M. tuberculosis  lineages. While this study confirmed the overall good performance of these tools, it revealed that an important fraction of the catalog of mutations they embed is of limited predictive power. It also revealed that these tools offer different sensitivity/specificity trade-offs, which is mainly due to the different sets of mutation they embed but also to their underlying genotyping pipelines. More importantly, it showed that their level of predictive performance varies greatly across lineages for some antibiotics, therefore suggesting that the predictions made by these softwares should be deemed more or less confident depending on the lineage inferred and the predictive performance of the marker(s) actually detected. Finally, we evaluated the relevance of machine learning approaches operating from the set of markers detected by these softwares and show that they present an attractive alternative strategy, allowing to reach better performance for several drugs while significantly reducing the number of candidate mutations to consider.

A large scale evaluation of TBProfiler and Mykrobe for antibiotic resistance prediction in Mycobacterium tuberculosis