Serajian, M.; Marini, S.; Alanko, J.; Noyes, N.; Prosperi, M.; Boucher, C.

We develop a robust machine learning classifier using both linear and nonlinear models (i.e., LASSO logistic regression (LR) and random forests (RF)) to predict the phenotypic resistance of \\emph{Mycobacterium tuberculosis} (MTB) for a broad range of antibiotic drugs. We use data from the CRyPTIC consortium to train our classifier, which consists of whole genome sequencing and antibiotic susceptibility testing (AST) phenotypic data for 13 different antibiotics. To train our model, we assemble the sequence data into genomic contigs, identify all unique 31-mers in the set of contigs, and build a feature matrix M, where M[i,j] is equal to the number of times the $i$-th 31-mer occurs in the j-th genome. Due to the size of this feature matrix (over 350 million unique 31-mers), we build and use a sparse matrix representation. Our method, which we refer to as MTB++, leverages compact data structures and iterative methods to allow for the screening of all the 31-mers in the development of both LASSO LR and RF. MTB++ is able to achieve high discrimination (F-1 greater than 80\\%) for the first-line antibiotics. Moreover, MTB++ had the highest F-1 score in all but three classes and was the most comprehensive since it had a F-1 score greater than 75\\% in all but four (rare) antibiotic drugs. We use our feature selection to contextualize the 31-mers that are used for the prediction of phenotypic resistance, leading to some insights about sequence similarity to genes in MEGARes. Lastly, we give an estimate of the amount of data that is needed in order to provide accurate predictions.