Machine Learning Model Analysis and Data Visualization with Small Molecules Tested in a Mouse Model of Mycobacterium tuberculosis Infection (2014–2015)

Abstract

The renewed urgency to develop new treatments for Mycobacterium tuberculosis (<i>Mtb</i>) infection has resulted in large-scale phenotypic screening and thousands of new active compounds <i>in vitro</i>. The next challenge is to identify candidates to pursue in a mouse <i>in vivo</i> efficacy model as a step to predicting clinical efficacy. We previously analyzed over 70 years of this mouse <i>in vivo</i> efficacy data, which we used to generate and validate machine learning models. Curation of 60 additional small molecules with <i>in vivo</i> data published in 2014 and 2015 was undertaken to further test these models. This represents a much larger test set than for the previous models. Several computational approaches have now been applied to analyze these molecules and compare their molecular properties beyond those attempted previously. Our previous machine learning models have been updated, and a novel aspect has been added in the form of mouse liver microsomal half-life (MLM <i>t</i>_1/2) and <i>in vitro</i>-based <i>Mtb</i> models incorporating cytotoxicity data that were used to predict <i>in vivo</i> activity for comparison. Our best <i>Mtb</i> <i>in vivo</i> models possess fivefold ROC values > 0.7, sensitivity > 80%, and concordance > 60%, while the best specificity value is >40%. Use of an MLM <i>t</i>_1/2 Bayesian model affords comparable results for scoring the 60 compounds tested. Combining MLM stability and <i>in vitro</i> <i>Mtb</i> models in a novel consensus workflow in the best cases has a positive predicted value (hit rate) > 77%. Our results indicate that Bayesian models constructed with literature <i>in vivo</i> <i>Mtb</i> data generated by different laboratories in various mouse models can have predictive value and may be used alongside MLM <i>t</i>_1/2 and <i>in vitro</i>-based <i>Mtb</i> models to assist in selecting antitubercular compounds with desirable <i>in vivo</i> efficacy. We demonstrate for the first time that consensus models of any kind can be used to predict <i>in vivo</i> activity for <i>Mtb</i>. In addition, we describe a new clustering method for data visualization and apply this to the <i>in vivo</i> training and test data, ultimately making the method accessible in a mobile app