Bayesian Estimation of Mixture Models with Prespecified Elements to Compare Drug Resistance in Treatment-Naïve and Experienced Tuberculosis Cases

We propose a Bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among Mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected from treatment-experienced patients reflect both transmitted and acquired resistance, the latter of which may or may not be associated with lower transmissibility. The comparison of the resistance pathways constructed from these two groups of drug-resistant strains provides insight into which pathways preferentially lead to the development of multiple drug resistant strains that are transmissible. We apply the proposed statistical methods to data from worldwide surveillance of drug-resistant tuberculosis collected by the World Health Organization over 13 years. Author Summary: Drug-resistant tuberculosis (TB) initially arises as a result of the sporadic appearance and subsequent selection of drug-resistant M. tuberculosis mutants. Such strains may or may not be associated with fitness costs affecting their ability to transmit and cause disease. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission. Those collected from treatment-experienced patients reflect strains that may or may not be associated with lower transmissibility. Determining which strains are sufficiently fit to be transmitted and cause disease can aid in developing effective strategies to combat the spread of resistance. Branching trees are graphical models used to infer the sequence of several binary events (i.e. a pathway) that have occurred in an unknown order. We propose a novel method using branching trees with prespecified components to compare evolutionary pathways among different populations. We apply our model to understand if there are unique drug-resistant pathways found only amongst treatment experienced patients that might reflect acquired resistant disease associated with fitness costs that limits its ability to transmit. Our methods can be generalized to any biological process for which the assumption of an ascending markov process applies.