A Bayesian model of acquisition and clearance of bacterial colonization incorporating within-host variation

Abstract

Bacterial populations that colonize a host can play important roles in host health, including serving as a reservoir that transmits to other hosts and from which invasive strains emerge, thus emphasizing the importance of understanding rates of acquisition and clearance of colonizing populations. Studies of colonization dynamics have been based on assessment of whether serial samples represent a single population or distinct colonization events. With the use of whole genome sequencing to determine genetic distance between isolates, a common solution to estimate acquisition and clearance rates has been to assume a fixed genetic distance threshold below which isolates are considered to represent the same strain. However, this approach is often inadequate to account for the diversity of the underlying within-host evolving population, the time intervals between consecutive measurements, and the uncertainty in the estimated acquisition and clearance rates. Here, we present a fully Bayesian model that provides probabilities of whether two strains should be considered the same, allowing us to determine bacterial clearance and acquisition from genomes sampled over time. Our method explicitly models the within-host variation using population genetic simulation, and the inference is done using a combination of Approximate Bayesian Computation (ABC) and Markov Chain Monte Carlo (MCMC). We validate the method with multiple carefully conducted simulations and demonstrate its use in practice by analyzing a collection of methicillin resistant Staphylococcus aureus (MRSA) isolates from a large recently completed longitudinal clinical study. An R-code implementation of the method is freely available at: https://github.com/mjarvenpaa/bacterial-colonization-model.git.\n\nAuthor summaryAs colonizing bacterial populations are the source for much transmission and a reservoir for infection, they are a major focus of interest clinically and epidemiologically. Understanding the dynamics of colonization depends on being able to confidently identify acquisition and clearance events given intermittent sampling of hosts. To do so, we need a model of within-host bacterial population evolution from acquisition through the time of sampling that enables estimation of whether two samples are derived from the same population. Past efforts have frequently relied on empirical genetic distance thresholds that forgo an underlying model or employ a simple molecular clock model. Here, we present an inferential method that accounts for the timing of sample collection and population diversification, to provide a probabilistic estimate for whether two isolates represent the same colonizing strain. This method has implications for understanding the dynamics of acquisition and clearance of colonizing bacteria, and the impact on these rates by factors such as sensitivity of the sampling method, pathogen genotype, competition with other carriage bacteria, host immune response, and antibiotic exposure.