title: Microevolutionary analysis of Clostridium difficile genomes to investigate transmission.
abstract: BACKGROUND
  The control of Clostridium difficile infection is a major international healthcare priority, hindered by a limited understanding of transmission epidemiology for these bacteria. However, transmission studies of bacterial pathogens are rapidly being transformed by the advent of next generation sequencing.
  
  
  RESULTS
  Here we sequence whole C. difficile genomes from 486 cases arising over four years in Oxfordshire. We show that we can estimate the times back to common ancestors of bacterial lineages with sufficient resolution to distinguish whether direct transmission is plausible or not. Time depths were inferred using a within-host evolutionary rate that we estimated at 1.4 mutations per genome per year based on serially isolated genomes. The subset of plausible transmissions was found to be highly associated with pairs of patients sharing time and space in hospital. Conversely, the large majority of pairs of genomes matched by conventional typing and isolated from patients within a month of each other were too distantly related to be direct transmissions.
  
  
  CONCLUSIONS
  Our results confirm that nosocomial transmission between symptomatic C. difficile cases contributes far less to current rates of infection than has been widely assumed, which clarifies the importance of future research into other transmission routes, such as from asymptomatic carriers. With the costs of DNA sequencing rapidly falling and its use becoming more and more widespread, genomics will revolutionize our understanding of the transmission of bacterial pathogens.
authors.forename: Xavier
authors.initials: X
authors.lastname: Didelot
authors.forename: David W
authors.initials: DW
authors.lastname: Eyre
authors.forename: Madeleine
authors.initials: M
authors.lastname: Cule
authors.forename: Camilla L C
authors.initials: CL
authors.lastname: Ip
authors.forename: M Azim
authors.initials: MA
authors.lastname: Ansari
authors.forename: David
authors.initials: D
authors.lastname: Griffiths
authors.forename: Alison
authors.initials: A
authors.lastname: Vaughan
authors.forename: Lily
authors.initials: L
authors.lastname: O'Connor
authors.forename: Tanya
authors.initials: T
authors.lastname: Golubchik
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Batty
authors.forename: Paolo
authors.initials: P
authors.lastname: Piazza
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Rory
authors.initials: R
authors.lastname: Bowden
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Donnelly
authors.forename: Kate E
authors.initials: KE
authors.lastname: Dingle
authors.forename: Mark
authors.initials: M
authors.lastname: Wilcox
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.forename: Derrick W
authors.initials: DW
authors.lastname: Crook
authors.forename: Tim E A
authors.initials: TE
authors.lastname: Peto
authors.forename: Rosalind M
authors.initials: RM
authors.lastname: Harding
mesh_terms: D016360:Clostridioides difficile / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D003015:Clostridium Infections / Q000453:epidemiology / Q000382:microbiology / Q000635:transmission*; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D023281:Genomics; D006801:Humans; D011995:Recombination, Genetic