Distinguishing imported cases from locally acquired cases within a geographically limited genomic sample of an infectious disease (preprint)

ABSTRACT The ability to distinguish imported cases from locally acquired cases has important consequences for the selection of public health control strategies. Genomic data can be useful for this, for example using a phylogeographic analysis in which genomic data from multiple locations is compared to determine likely migration events between locations. However, these methods typically require good samples of genomes from all locations, which is rarely available. Here we propose an alternative approach that only uses genomic data from a location of interest. By comparing each new case with previous cases from the same location we are able to detect imported cases, as they have a different genealogical distribution than that of locally acquired cases. We show that, when variations in the size of the local population are accounted for, our method has good sensitivity and excellent specificity for the detection of imports. We applied our method to data simulated under the structured coalescent model and demonstrate relatively good performance even when the local population has the same size as the external population. Finally, we applied our method to several recent genomic datasets from both bacterial and viral pathogens, and show that it can, in a matter of seconds or minutes, deliver important insights on the number of imports to a geographically limited sample of a pathogen population.

Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks (preprint)

Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches to reconstruct outbreaks exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is stable among repeated serial samples from the same host, is transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.

Comparative evaluation of the transmissibility of SARS-CoV-2 variants of concern (preprint)

Since the start of the SARS-CoV-2 pandemic in late 2019, several variants of concern (VOC) have been reported, such as B.1.1.7, B.1.351, P.1, and B.1.617.2. The exact reproduction number Rt for these VOCs is important to determine appropriate control measures. Here, we estimated the transmissibility for VOCs and lineages of SAR-CoV-2 based on genomic data and Bayesian inference under an epidemiological model to infer the reproduction number (Rt). We analyzed data for multiple VOCs from the same time period and countries, in order to compare their transmissibility while controlling for geographical and temporal factors. The lineage B had a significantly higher transmissibility than lineage A, and contributed to the global pandemic to a large extent. In addition, all VOCs had increased transmissibility when compared with other lineages in each country, indicating they are harder to control and present a high risk to public health. All countries should formulate specific prevention and control policies for these VOCs when they are detected to curve their potential for large-scale spread.

Emerging phylogenetic structure of the SARS-CoV-2 pandemic (preprint)

Since spilling over into humans, SARS-CoV-2 has rapidly spread across the globe, accumulating significant genetic diversity. The structure of this genetic diversity, and whether it reveals epidemiological insights, are fundamental questions for understanding the evolutionary trajectory of this virus. Here we use a recently developed phylodynamic approach to uncover phylogenetic structures underlying the SARS-CoV-2 pandemic. We find support for three SARS-CoV-2 lineages co-circulating, each with significantly different demographic dynamics concordant with known epidemiological factors. For example, Lineage C emerged in Europe with a high growth rate in late February, just prior to the exponential increase in cases in several European countries. Mutations that characterize Lineage C in particular are non-synonymous and occur in functionally important gene regions responsible for viral replication and cell entry. Even though Lineages A and B had distinct demographic patterns, they were much more difficult to distinguish. Continuous application of phylogenetic approaches to track the evolutionary epidemiology of SARS-CoV-2 lineages will be increasingly important to validate the efficacy of control efforts and monitor significant evolutionary events in the future.