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Defining a genetic relatedness cut-off to exclude recent MRSA transmission: a genomic epidemiology analysis

Published version
Peer-reviewed

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Authors

Coll, Francesc 
Raven, Kathy 
Blane, Elizabeth 

Abstract

Background Whole-genome sequencing (WGS) of bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a transformative tool for the detection of outbreaks. WGS can be applied in genomic epidemiology investigations to confirm or refute bacterial outbreaks, supporting targeted and efficient infection control interventions. Recent patient-to-patient transmission can be ruled out, for infection control purposes, if the genetic relatedness between their bacterial isolates (as measured by the number of single nucleotide polymorphisms (SNPs)), is greater than a defined threshold. Here, we aim to define a SNP cut-off above which recent transmission can be ruled out. Methods Our findings were informed by three approaches applied to two patient cohorts, whose MRSA isolates were sequenced. First, we applied a linear mixed model to estimate the S. aureus substitution rate and within-host diversity in a cohort of 459 people with multiple isolates sequenced per individual. Second, we applied a simulated transmission model to this genomic dataset. Third, we used a second cohort of 778 patients to determine the genetic distance to capture 95% of epidemiologically linked cases. Findings The linear mixed model estimated a substitution rate of 5 whole-genome (wgSNPs), or 3 core-genome SNPs (cgSNPs), per genome per year and quantified the within-host diversity to be 19 wgSNPs (95 percentile), or 10 cgSNPs, giving a combined SNP cut-off of 24 wgSNPs (13 cgSNPs) to detect transmission within six months. The transmission model suggested a 17 wgSNPs (12 cgSNPs) cut-off to detect 95% of transmission events within the same timeframe. In the second cohort, we determined that a 22 wgSNPs (11 cgSNPs) captured 95% of epidemiologically linked cases within six months. Interpretation Based on multiple lines of evidence, we propose a conservative a 25 whole-genome or 15 core-genome SNP cut-off above which recent transmission can be ruled out.

Description

Keywords

Genomics, Humans, Methicillin, Methicillin-Resistant Staphylococcus aureus, Retrospective Studies, Staphylococcal Infections, Staphylococcus aureus

Journal Title

Lancet Microbe

Conference Name

Journal ISSN

2666-5247
2666-5247

Volume Title

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (098600/Z/12/Z)
National Institute for Health and Care Research (HICF-T5-342)