Whole genome sequencing for improved understanding of Mycobacterium tuberculosis transmission in a remote circumpolar region

Abstract

Few studies have used genomic epidemiology to understand tuberculosis (TB) transmission in rural and remote settings – regions often unique in history, geography and demographics. To improve our understanding of TB transmission dynamics in Yukon Territory (YT), a circumpolar Canadian territory, we conducted a retrospective analysis in which we combined epidemiological data collected through routine contact investigations with clinical and laboratory results. Mycobacterium tuberculosis isolates from all culture-confirmed TB cases in YT (2005–2014) were genotyped using 24-locus Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats (MIRU-VNTR) and compared to each other and to those from the neighbouring province of British Columbia (BC). Whole genome sequencing (WGS) of genotypically clustered isolates revealed three sustained transmission networks within YT, two of which also involved BC isolates. While each network had distinct characteristics, all had at least one individual acting as the probable source of three or more culture-positive cases. Overall, WGS revealed that TB transmission dynamics in YT are distinct from patterns of spread in other, more remote Northern Canadian regions, and that the combination of WGS and epidemiological data can provide actionable information to local public health teams.

Pathogen Genomics in Public Health

“…In California, WGS allowed public health workers to refute more than half of suspected outbreaks initially identified by conventional genotyping, saving time and resources (personal communication, Tambi Shaw, California Department of Public Health). Early experience in U.K., 5 Canadian, 31,32 and Dutch 33 tuberculosis programs has also confirmed that WGS supports more effective investigations by more accurately defining outbreaks 5,31,33 , providing insights into transmission dynamics, 34 and sometimes suggesting the presence of previously unidentified cases or possible "super-spreaders" that should be prioritized for isolation and treatment. 5,31 WGS may also indicate whether recurrent cases are due to reactivation or reinfection, information useful in evaluating program effectiveness.…”

Comparison of routine field epidemiology and whole genome sequencing to identify tuberculosis transmission in a remote setting

“…The fourth discordant case had a MIRU-VNTR pattern common to both YT and BC, and while WGS placed this isolate with a genomically distinct YT sub-cluster within this group (see Fig. 3: WClust-1 in our previous work [18]), the field team classified the individual with this isolate as having acquired TB within BC based on epidemiological information.

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“…When we compared source case assignments during the in-person consensus meeting, the discussion revealed that the team using field-based data struggled with the complex social network of this cluster – many connections between individuals, while the team using WGS data were challenged by the minimal genomic diversity between YT isolates (0–4 SNVs). The presence of a minority variant in one WClust-1 case [18] divided the cluster into two genomically linked sub-clusters, facilitating source identification at the consensus meeting. While there was no strong agreement between the two team's source case assignments, the field-based methods did accurately link individuals to the correct WClust-1 genomic sub-cluster for 11 of 13 persons (85%) with only one individual linked to the incorrect genomic sub-cluster, and a second individual thought to have acquired their infection in BC due to an absence of clear epidemiological connections.…”

“…Here, we compare WGS to 24-locus Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats (MIRU-VNTR) coupled to robust traditional field epidemiology to inform TB transmission, outbreaks and reactivation of LTBI. We recently reported [18] the results of these reconstructions. In this study, we present the comparison of our two different approaches as well as qualitative user feedback on the utility of genotyping and genomics in a remote setting with a comprehensive TB CI programme.…”

“…The Yukon Territory (YT), located in Canada's Northwest, has a higher TB incidence (12.1 per 100 000) than the Canadian average (4.9 per 100 000), but lower than other Northern Canadian settings [16, 17]. The majority of YT residents diagnosed with TB are Canadian-born (93.8%) and live in remote regions (84.4%) [18]. All YT TB cases are managed by a small team of public health professionals, many of whom have deep and long-standing ties to the territory; this strong tradition of engagement between TB nurses, community nurses and YT's communities means the local communicable disease unit has uniquely detailed insights into the social networks underlying YT's TB clusters.…”