Application of whole genome sequencing to epidemiologic investigation of infectious disease

Next generation molecular epidemiology: Lecture 15: Application of whole genome sequencing to  epidemiologic investigation of infectious disease National Institute of Infectious Disease January 19, 2017 Scope of investigations covered by next generation molecular epidemiology Identifying …  risk factors that could not be identified by conventional or       early-generation molecular biology laboratory methods new or hidden transmission pathways direction or chain of transmission of an infectious agent endogenous reactivation vs exogenous reinfection ecological niches from which clonal pathogenic strains are selected and disseminate pathogen microbial population structures associated with a syndrome host commensal microbial population structures that determine noncommunicable disease outcomes WGS vs other genotyping methods to conduct epidemiologic investigations: Examples  WGS vs PFGE in healthcare-associated infections  WGS vs MIRU-VNTR to characterize TB transmission  WGS vs MLST to investigate MRSA hospital outbreak WGS vs PFGE in healthcare-associated outbreaks (Salipante, et al J Clin Micro 2015)  Number of outbreaks of  Acinetobacter baumanii (15)  Vancomycin-resistant Enterococcus faecium (19)  Methicillin-resistant Staphylococcus aureus (17) Criteria for interpreting PFGE patterns (Tenover et al, J Clin Microbiol 1995;33:2233) Category Number of mutations Typical number of band differences Indistinguishable 0 Closely related 2-3 Possibly related 4-6 Different >3 >7 WGS vs PFGE (Salipante et al, 2015) Organism VRE MRSA A baumanii Total Indistinguishable by PFGE (n=90) Different by PFGE (n= 81) WGS Clonal Non-Clonal WGS Clonal Non-Clonal 55 64 0 0 15 26 18 35 28 81 WGS vs PFGE (Salipante et al, 2015) Organism VRE MRSA A baumanii Total Closely related by PFGE (n=148) Possibly related by PFGE (n=93) WGS Clonal Non-Clonal WGS Clonal Non-Clonal 0 12 12 81 23 32 136 0 4 58 23 89 WGS vs other genotyping methods to conduct epidemiologic investigations: Examples  WGS vs PFGE in healthcare-associated infections  WGS vs MIRU-VNTR to characterize TB transmission  WGS vs MLST to investigate MRSA hospital outbreak Identifying hidden transmission pathways and social networks that facilitate transmission  Tuberculosis community cluster in British Columbia, Canada (Gardy et al New Engl J Med, 2011) www.worldatlas.com Example 4: TB outbreak in British Columbia, Canada, 2006-08 (Gardy et al, NEJM, 2011)  Between May 2006-Dec 2008, 41 new cases of TB identified, all with an identical MIRU-VNTR genotype pattern  Whole genome sequencing done on 36 TB outbreak in British Columbia, Canada, 2006-08 (Gardy et al, NEJM, 2011) Two major lineages of M tuberculosis identified; transmission sustained by a social network involving cocaine use WGS vs other genotyping methods to conduct epidemiologic investigations: Examples  WGS vs PFGE in healthcare-associated infections  WGS vs MIRU-VNTR to characterize TB transmission  WGS vs MLST to investigate MRSA hospital outbreak MRSA outbreak in a hospital (Harris, SR et al, Lancet ID, 2013)  Problem:  Putative MRSA outbreak in a special care baby unit (SCBU) in Cambridge, UK over 6-months in 2011  Conventional epidemiologic analysis performed at SCBU  12 infants colonized and suspected to be linked but not confirmed  MLST showed it to belong to new ST (2371, contains PVL); related to ST22 MRSA outbreak in a hospital…cont  WGS of all SCBU and community isolates of MRSA with identical drug-susceptibility profile done  26 related cases found in SCBU, postnatal ward, and community Harris SR et al, Lancet ID, 2013 Harris SR et al, Lancet ID, 2013 Harris SR et al, Lancet ID, 2013 MRSA outbreak in a hospital summary  Suspected MRSA outbreak confirmed by WGS analysis  WGS analysis helped to fill the gaps in transmission chain  Transmission occurred between mothers in postnatal ward  Community transmission documented (involved family members)  Healthcare worker implicated in transmission route— contributed to persistence of the outbreak, even after deep clean of SCBU  Number of SNPs increased over time of the outbreak MRSA outbreak in a hospital—caveats of WGS analysis  WGS analysis done within year of beginning of outbreak  Retrospective data  Can this be done prospectively?  Infection control team has to suspect or identify a putative outbreak  WGS analysis dependent on isolation of an organism  Screening done at SCBU once a week References • Salipante SJ et al. Application of Whole‐Genome Sequencing for  Bacterial Strain Typing in Molecular Epidemiology. J Clin Microbiol.  2015; 53:1072–1079 • Gardy JL et al. Whole‐Genome Sequencing and Social‐Network Analysis  of a Tuberculosis Outbreak. New Engl J Med. 2011;364:730‐9 • Harris, SR et al. Whole‐genome sequencing for analysis of an outbreak  of meticillin‐resistant Staphylococcus aureus: a descriptive study.  Lancet ID, 2013;13:130‐136  ... Salipante SJ et al.? ?Application? ?of? ?Whole? ? ?Genome? ?Sequencing? ?for  Bacterial Strain Typing in Molecular Epidemiology. J Clin Microbiol.  2015; 53:1072–1079 • Gardy JL et al.? ?Whole? ? ?Genome? ?Sequencing? ?and Social‐Network Analysis ... transmission route— contributed to persistence of the outbreak, even after deep clean of SCBU  Number of SNPs increased over time of the outbreak MRSA outbreak in a hospital—caveats of WGS analysis  WGS... JL et al.? ?Whole? ? ?Genome? ?Sequencing? ?and Social‐Network Analysis  of? ?a Tuberculosis Outbreak. New Engl J Med. 2011;364:730‐9 • Harris, SR et al.? ?Whole? ? ?genome? ?sequencing? ?for analysis? ?of? ?an outbreak  of? ?meticillin‐resistant Staphylococcus aureus: a descriptive study.