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Mol Biol Evol. 2019 Mar 1;36(3):587-603. doi: 10.1093/molbev/msy242.

Beyond the SNP Threshold: Identifying Outbreak Clusters Using Inferred Transmissions.

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Department of Mathematics, Imperial College London, London, UK.
British Columbia Centre for Disease Control, Communicable Disease Prevention and Control Services, Vancouver, Canada.
School of Population and Public Health, University of British Columbia, Vancouver, Canada.
Department of Epidemiology, Columbia University Mailman School of Public Health, New York, USA.
Phthisiopneumology Institute, Chisinau, Republic of Moldova.
Yale University School of Public Health, New Haven.
Department of Mathematics, Simon Fraser University, Vancouver, Canada.


Whole-genome sequencing (WGS) is increasingly used to aid the understanding of pathogen transmission. A first step in analyzing WGS data is usually to define "transmission clusters," sets of cases that are potentially linked by direct transmission. This is often done by including two cases in the same cluster if they are separated by fewer single-nucleotide polymorphisms (SNPs) than a specified threshold. However, there is little agreement as to what an appropriate threshold should be. We propose a probabilistic alternative, suggesting that the key inferential target for transmission clusters is the number of transmissions separating cases. We characterize this by combining the number of SNP differences and the length of time over which those differences have accumulated, using information about case timing, molecular clock, and transmission processes. Our framework has the advantage of allowing for variable mutation rates across the genome and can incorporate other epidemiological data. We use two tuberculosis studies to illustrate the impact of our approach: with British Columbia data by using spatial divisions; with Republic of Moldova data by incorporating antibiotic resistance. Simulation results indicate that our transmission-based method is better in identifying direct transmissions than a SNP threshold, with dissimilarity between clusterings of on average 0.27 bits compared with 0.37 bits for the SNP-threshold method and 0.84 bits for randomly permuted data. These results show that it is likely to outperform the SNP-threshold method where clock rates are variable and sample collection times are spread out. We implement the method in the R package transcluster.


SNP; public health; transmission clusters; whole-genome sequencing

[Available on 2020-03-01]
[Indexed for MEDLINE]

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