Abstract
BackgroundPatients with Mycobacterium tuberculosis isolates sharing identical DNA fingerprint patterns can be epidemiologically linked. However, municipal health services in the Netherlands are able to confirm an epidemiological link in only around 23% of the patients with isolates clustered by the conventional variable number of tandem repeat (VNTR) genotyping. This research aims to investigate whether whole genome sequencing (WGS) is a more reliable predictor of epidemiological links between tuberculosis patients than VNTR genotyping.MethodsVNTR genotyping and WGS were performed in parallel on all Mycobacterium tuberculosis complex isolates received at the Netherlands National Institute for Public Health and the Environment in 2016. Isolates were clustered by VNTR when they shared identical 24-loci VNTR patterns; isolates were assigned to a WGS cluster when the pair-wise genetic distance was ≤ 12 single nucleotide polymorphisms (SNPs). Cluster investigation was performed by municipal health services on all isolates clustered by VNTR in 2016. The proportion of epidemiological links identified among patients clustered by either method was calculated.ResultsIn total, 535 isolates were genotyped, of which 25% (134/535) were clustered by VNTR and 14% (76/535) by WGS; the concordance between both typing methods was 86%. The proportion of epidemiological links among WGS clustered cases (57%) was twice as common than among VNTR clustered cases (31%).ConclusionWhen WGS was applied, the number of clustered isolates was halved, while all epidemiologically linked cases remained clustered. WGS is therefore a more reliable tool to predict epidemiological links between tuberculosis cases than VNTR genotyping and will allow more efficient transmission tracing, as epidemiological investigations based on false clustering can be avoided.
Highlights
The Netherlands is a low incidence country with 5.2 tuberculosis cases per 100,000 inhabitants
variable number of tandem repeat (VNTR) genotyping and whole genome sequencing (WGS) were performed in parallel on all Mycobacterium tuberculosis complex isolates received at the Netherlands National Institute for Public Health and the Environment in 2016
Isolates were clustered by VNTR when they shared identical 24-loci VNTR patterns; isolates were assigned to a WGS cluster when the pair-wise genetic distance was 12 single nucleotide polymorphisms (SNPs)
Summary
The Netherlands is a low incidence country with 5.2 tuberculosis cases per 100,000 inhabitants. In 2015, only 23% of cases clustered by VNTR genotyping could be epidemiologically linked by municipal health services [8] This low degree of confirmation is assumed to be partly due to false clustering as a result of the low rate of change of VNTR loci in the genome of M. tuberculosis, rather than insufficient epidemiological investigations. This might be especially true for isolates from patients originating from high-prevalence geographic areas such as the Horn of Africa, where transmission is less efficiently interrupted by tuberculosis control efforts and strains may be genetically highly conserved [9, 10]. This research aims to investigate whether whole genome sequencing (WGS) is a more reliable predictor of epidemiological links between tuberculosis patients than VNTR genotyping
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