Abstract
Pathogen genome sequencing can reveal details of transmission histories and is a powerful tool in the fight against infectious disease. In particular, within-host pathogen genomic variants identified through heterozygous nucleotide base calls are a potential source of information to identify linked cases and infer direction and time of transmission. However, using such data effectively to model disease transmission presents a number of challenges, including differentiating genuine variants from those observed due to sequencing error, as well as the specification of a realistic model for within-host pathogen population dynamics. Here we propose a new Bayesian approach to transmission inference, BadTrIP (BAyesian epiDemiological TRansmission Inference from Polymorphisms), that explicitly models evolution of pathogen populations in an outbreak, transmission (including transmission bottlenecks), and sequencing error. BadTrIP enables the inference of host-to-host transmission from pathogen sequencing data and epidemiological data. By assuming that genomic variants are unlinked, our method does not require the computationally intensive and unreliable reconstruction of individual haplotypes. Using simulations we show that BadTrIP is robust in most scenarios and can accurately infer transmission events by efficiently combining information from genetic and epidemiological sources; thanks to its realistic model of pathogen evolution and the inclusion of epidemiological data, BadTrIP is also more accurate than existing approaches. BadTrIP is distributed as an open source package (https://bitbucket.org/nicofmay/badtrip) for the phylogenetic software BEAST2. We apply our method to reconstruct transmission history at the early stages of the 2014 Ebola outbreak, showcasing the power of within-host genomic variants to reconstruct transmission events.
Highlights
Understanding transmission is important for devising effective policies and measures that limit the spread of infectious diseases
Our approach makes use of pathogen genetic information, notably genetic variants at low frequency within host that are usually discarded, and combines it with epidemiological information of host exposure to infection. This leads to accurate reconstruction of transmission even in cases where abundant within-host pathogen genetic variation and weak transmission
We show with simulations and with an analysis of the beginning of the 2014 Ebola outbreak that our approach is applicable in many scenarios, improves our understanding of transmission dynamics, and will contribute to finding and limiting sources and routes of transmission, and preventing the spread of infectious disease
Summary
Understanding transmission is important for devising effective policies and measures that limit the spread of infectious diseases. Accurately inferring transmission between hosts is becoming more feasible. This requires robust statistical approaches that make use of the full extent of genetic and epidemiological data available. We present a new approach that makes use of within-host genetic variation and epidemiological data to infer transmission. A number of approaches have been developed that reconstruct transmission from genetic data. While the phylogenetic signal can be very informative of transmission, it can be misleading [10, 11], due to within-host variation that can generate discrepancies between the phylogenetic and epidemiological relatedness of hosts, and can bias estimates of infection times [12, 13]
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