Whole-Genome Sequencing as Tool for Investigating International Tuberculosis Outbreaks: A Systematic Review

Abstract

Background: Whole-genome sequencing (WGS) can support the investigation of tuberculosis (TB) outbreaks. The technique has been applied to estimate the timing and directionality of transmission and to exclude cases from an investigation. This review assesses how WGS was applied in international outbreak investigations and discusses the advantages and challenges of the application of WGS. Methods: Databases were searched for reports on international TB outbreak investigations. Information was extracted on: Why was WGS applied?; How was WGS applied?; Organizational issues; WGS methodology; What was learned/what were the implications of the WGS investigation?; and challenges and lessons learned. Results: Three studies reporting on international outbreak investigations were identified. Retrospective WGS sequencing was performed in all studies and prospective typing in two to study TB transmission. In one study, WGS data were produced centrally (i.e., in one laboratory) and analysis was done centrally. In two studies, WGS data production was done in a decentralized manner, and analysis was centralized in one laboratory. Three groups of professionals were involved in the international outbreak investigation: public health authorities, laboratory experts, and clinicians. The reported WGS methodology applied differed between the studies in some aspects, e.g., sequencing platform; quality measures, percentage of the reference genome covered, and the mean genomic coverage; analysis, use of a reference genome or de novo assembly; and software used for alignment and analysis. In all three studies, in-house scripts were used for variance calling, and the single nucleotide polymorphism (SNP) approach was used for analysis. All outbreak investigation reports stated that WGS refuted suspected transmission events and provided supporting evidence for epidemiological data. Several challenges were reported of which most were not related to WGS. The only challenge related to WGS was the timeframe of getting WGS data if WGS is not routinely performed. Conclusions: WGS was considered a useful addition in international TB outbreak investigations. Further standardization of the WGS methodology and good structures for international collaboration and coordination are needed to take full advantage of this new technology. Whether the use of WGS results in earlier detection of cases and thus limits transmission still needs to be determined.

Improving tuberculosis surveillance by detecting international transmission using publicly available whole genome sequencing data

“…We identified several molecular clusters including isolates from multiple countries, suggesting larger events of international transmission of TB. We expected to find international TB transmission events, also considering previous studies reporting cross-border molecular clusters [ 5 , 7 ]. Looking at the collected metadata, we identified several clusters with multiple isolates from the same patient or multiple autopsy samples collected from the same patient [ 34 , 35 ].…”

“…In comparison, WGS analysis offers a much higher discriminatory power and allows inferring (or excluding) TB transmission at a higher resolution [ 4 ]. In a recent systematic review, van der Werf et al identified three studies that used WGS to investigate the international transmission of TB [ 7 ].…”

Whole-genome sequencing for rapid, reliable and routine investigation of Mycobacterium tuberculosis transmission in local communities

“…A growing number of publications demonstrated the utility of M. tuberculosis WGS in critical situations, such as international outbreaks [12]. For instance, a recent study demonstrated the presence of a circulating cluster of multidrug-resistant TB (MDR-TB) strains in European countries involving patients from countries of the African Horn and Sudan [13].…”

Improving tuberculosis surveillance by detecting international transmission using publicly available whole-genome sequencing data

“…We identified several molecular clusters including isolates from multiple countries, suggesting larger events of international transmission of TB. We expected to find international TB-transmission events, also considering previous studies reporting cross-border molecular clusters [5, 7]. Looking at the collected metadata, we identified several clusters with multiple isolates from the same patient or multiple autopsy samples collected from the same patient [29, 30].…”

“…In comparison, WGS analysis offers a much higher discriminatory power and allows for inferring (or excluding) TB transmission at a higher resolution [4]. In a recent systematic review, van der Werf and co-authors identified three studies that used WGS to investigate the international transmission of TB [7].…”