427. Targeted Investigation of Outbreaks of Mycobacterium tuberculosis Infection using Whole Genome Sequences
Session: Poster Abstract Session: Novel Devices and Technologies
Thursday, October 18, 2012
Room: SDCC Poster Hall F-H
  • ID week San Diego Poster 2012.pdf (1.2 MB)
  • Background:

    Investigations into Mycobacterium tuberculosis (MTB) outbreaks are currently aided by 24-locus Mycobacterial Interspersed Repetitive Unit – Variable Number Tandem Repeat (MIRU-VNTR) typing in the UK and internationally. However, when there are no identifiable epidemiological links between patients, it is difficult to delineate outbreaks by this schema alone. It is unclear whether whole-genome sequencing (WGS) could enhance contact tracing efforts further.


    We used an Illumina platform to obtain whole-genome sequences from 396 MTB samples (260 patients) from the Midlands region of the UK, mapping the sequence reads to the H37Rv reference genome. To explore the relationships between MTB genomes from isolates highly likely to be related by transmission, we estimated the range of within-host diversity in 72 individuals and between-host diversity across 25 household outbreaks. We related the results to 11 MIRU-VNTR-based community clusters (168 patients) with variable epidemiological links to identify plausible transmission events.


    The genetic diversity within individuals and between household contacts spanned ≤5 single nucleotide polymorphisms (SNPs) in 94/97 (97%) sample pairs. Applying an arbitrary working threshold of ≤5 SNPs to 11 MIRU-VNTR-based community-clusters, 69/70 (99%) of epidemiologically related pairs versus 73/87 (84%) of pairs which had not been epidemiologically linked by contact tracing diverged by ≤5 SNPs (p=0.002).

    Among 196 isolates that had been typed at 24 MIRU-VNTR loci, 7 of 32 epidemiologically related pairs differed at 1 MIRU-VNTR locus and ≤5 SNPs. Two of 7 epidemiologically unlinked pairs differing at 1 or 2 MIRU-VNTR loci diverged by ≤5 SNPs.

    Further analysis of individual clusters demonstrated that the micro-evolutionary divergence of lineages within an outbreak could suggest direction of spread between patients and identify possible “super-spreaders” (figure). 


    WGS provides greater resolution and sensitivity than MIRU-VNTR typing for outbreak definition, ruling out relationships between some MIRU-VNTR matched cases, linking some MIRU-VNTR mismatched cases, and resolving the genetic structure of outbreak clusters.  

    Timothy Walker1, Camila Ip2, Jason Evans3, Georgia Kapatai4, Ruth Harrell4, Martin Dedicoat5, Philip Monk6, Peter Hawkey3, Julian Parkhill7, A. Sarah Walker, PhD1, Rory Bowden, PhD8, Derrick Crook, MB, BCh9, E. Grace Smith3 and Tim Peto, MB BS, DPhil2,10, (1)Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, (2)NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom, (3)Microbiology, Health Protection Agency, West Midlands Public Health Laboratory, Birmingham, United Kingdom, (4)West Midlands Health Protection Agency, Birmingham, United Kingdom, (5)Heart of England NHS Foundation Trust, Birmingham, United Kingdom, (6)Public Health, Health Protection Agency, East Midlands South, Leicester, United Kingdom, (7)Wellcome Trust Sanger Institute, Cambridge, United Kingdom, (8)Statistics, Oxford University, Oxford, United Kingdom, (9)NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom, (10)University of Oxford, Nuffield Department of Medicine, Oxford, United Kingdom


    T. Walker, None

    C. Ip, None

    J. Evans, None

    G. Kapatai, None

    R. Harrell, None

    M. Dedicoat, None

    P. Monk, None

    P. Hawkey, None

    J. Parkhill, None

    A. S. Walker, None

    R. Bowden, None

    D. Crook, None

    E. G. Smith, None

    T. Peto, None

    Findings in the abstracts are embargoed until 12:01 a.m. PST, Oct. 17th with the exception of research findings presented at the IDWeek press conferences.