title: Linking healthcare associated norovirus outbreaks: a molecular epidemiologic method for investigating transmission.
abstract: BACKGROUND
  Noroviruses are highly infectious pathogens that cause gastroenteritis in the community and in semi-closed institutions such as hospitals. During outbreaks, multiple units within a hospital are often affected, and a major question for control programs is: are the affected units part of the same outbreak or are they unrelated transmission events? In practice, investigators often assume a transmission link based on epidemiological observations, rather than a systematic approach to tracing transmission.Here, we present a combined molecular and statistical method for assessing:1) whether observed clusters provide evidence of local transmission and2) the probability that anecdotally|linked outbreaks truly shared a transmission event.
  
  
  METHODS
  76 healthcare associated outbreaks were observed in an active and prospective surveillance scheme of 15 hospitals in the county of Avon, England from April 2002 to March 2003. Viral RNA from 64 out of 76 specimens from distinct outbreaks was amplified by reverse transcription-PCR and was sequenced in the polymerase (ORF 1) and capsid (ORF 2) regions. The genetic diversity, at the nucleotide level, was analysed in relation to the epidemiological patterns.
  
  
  RESULTS
  Two out of four genetic and epidemiological clusters of outbreaks were unlikely to have occurred by chance alone, thus suggesting local transmission. There was anecdotal epidemiological evidence of a transmission link among 5 outbreaks pairs. By combining this epidemiological observation with viral sequence data, the evidence of a link remained convincing in 3 of these pairs. These results are sensitive to prior beliefs of the strength of epidemiological evidence especially when the outbreak strains are common in the background population.
  
  
  CONCLUSIONS
  The evidence suggests that transmission between hospitals units does occur. Using the proposed criteria, certain hypothesized transmission links between outbreaks were supported while others were refuted. The combined molecular/epidemiologic approach presented here could be applied to other viral populations and potentially to other pathogens for a more thorough view of transmission.
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, London, UK. b.lopman@imperial.ac.uk
authors.forename: Ben A
authors.initials: BA
authors.lastname: Lopman
authors.forename: Chris
authors.initials: C
authors.lastname: Gallimore
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Gray
authors.forename: Ian B
authors.initials: IB
authors.lastname: Vipond
authors.forename: Nick
authors.initials: N
authors.lastname: Andrews
authors.forename: Joyshri
authors.initials: J
authors.lastname: Sarangi
authors.forename: Mark H
authors.initials: MH
authors.lastname: Reacher
authors.forename: David W
authors.initials: DW
authors.lastname: Brown
mesh_terms: D017250:Caliciviridae Infections / Q000453:epidemiology / Q000635:transmission* / Q000821:virology*; D003428:Cross Infection / Q000453:epidemiology / Q000635:transmission* / Q000821:virology*; D004196:Disease Outbreaks; D018562:Disease Transmission, Infectious; D004739:England / Q000453:epidemiology; D005759:Gastroenteritis / Q000453:epidemiology* / Q000821:virology; D006801:Humans; D017720:Molecular Epidemiology / Q000379:methods; D029322:Norovirus / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction