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Canadian Team Tackles Tuberculosis Outbreak with Sequencing, Social Network Analyses

By Andrea Anderson

NEW YORK (GenomeWeb News) – In a paper appearing online last night in the New England Journal of Medicine, Canadian researchers describe how they used whole-genome sequencing and social network analyses to trace transmission events and find socio-economic factors behind a British Columbia TB outbreak.

In contrast to genotyping data pointing to a clonal outbreak, the team's whole-genome analyses of dozens of Mycobacterium tuberculosis isolates uncovered two different lineages behind the outbreak, which affected 41 individuals in the Canadian province between May 2006 and late 2009.

"Through whole-genome sequencing we could see that there were two separate lineages spreading simultaneously within the population, both starting at the same point in time," senior author Patrick Tang, a researcher with the British Columbia Centre for Disease Control, told GenomeWeb Daily News.

"If we combine that with the social network analysis data, we have two pieces of very powerful information that can allow us to track the organism as it spreads throughout the population," he added.

In this case, incorporating social network data led the team to at least one factor that may have helped spark the outbreak: a rise in crack cocaine use that coincided with the early TB transmission events in the community.

"[W]e show that a socioenvironmental factor — most likely increased crack cocaine use — triggered the simultaneous expansion of two extant lineages of M. tuberculosis that was sustained by key members of a high-risk social network," Tang and his co-authors wrote.

In their initial analyses, the team found that M. tuberculosis isolates from the 41 individuals involved in the outbreak all shared the same genotype based on a standardized method known as mycobacterial interspersed repetitive unit-variable-number tandem-repeats, or MIRU-VNTR.

Even so, Tang explained, because it assesses just 24 sites across the bacterial genome, MIRU-VNTR offered a relatively low resolution look at outbreak bugs.

"Using the traditional genotyping, you're able to confirm that there's an outbreak, but that's where the story ends," Tang said. "You can't easily tease out who transmitted to whom."

To get a more refined view, he and his colleagues then turned to whole-genome sequencing, using the Illumina GAII to sequence 32 outbreak isolates and four historical isolates with the same MIRU-VNTR genotype from past sporadic TB cases in the community.

Because the microorganism undergoes microevolution as it passes from one person to the next, whole-genome sequence data provides an opportunity to track how the bug moves between affected individuals in an outbreak, Tang explained.

Compared with the M. tuberculosis CDC1551 reference strain, the researchers found 204 SNPs in the newly sequenced isolates. In contrast to genotyping and restriction fragment length polymorphism data, the patterns of these SNPs revealed two parallel M. tuberculosis lineages in the outbreak.

Meanwhile, by adding information gleaned from a social network questionnaire exploring everything from social interactions and travel history to drug and alcohol use, the researchers found evidence that the start of the outbreak corresponded with a jump in crack cocaine use.

Of the 41 individuals affected by the outbreak, they noted, 61 percent reported using crack cocaine in the past. In addition, police records in the community pointed to a peak in crack use around the time that the first TB cases occurred during the outbreak.

"We figure that crack cocaine would have been one of the triggers of this outbreak and also facilitated spread of this outbreak," Tang noted.

The social network and whole-genome data also helped the team track down a "super-spreader" individual who appears to have infected several others during the outbreak.

Along with clues about disease transmission patterns, Tang explained, the insights gained through this type of study would likely be useful for helping inform public health officials who want to pinpoint at-risk populations and prevent further disease transmission.

Given the level of resolution available with whole-genome approaches, he speculates that whole-genome sequencing will likely become routine for those dealing with outbreaks of TB and other infectious diseases.

"I think in the next five years or so, probably it will become routine," he said. "As we standardize our methods for sequence analysis and the cost of sequencing and the speed of sequencing improve."

For their part, Tang and his colleagues plan to use a similar strategy to study the spread of methicillin resistant Staphylococcus aureus in British Columbia. They are also turning their attention to another, ongoing TB outbreak in the province and eventually plan to analyze multiple M. tuberculosis isolates from the same individuals over time to learn more about how these bugs change in response to treatment.

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