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Introduction: The variable number of tandem repeats (VNTR) typing method is used to study tuberculosis (TB) transmission. Clustering of Mycobacterium tuberculosis isolates with identical VNTR patterns is assumed to reflect recent transmission. Hence, clusters are thought to be homogeneous regarding antibiotic resistance. In practice, however, also heterogeneous clusters are identified. This study investigates the prevalence and characteristics of heterogeneous VNTR clusters and assesses whether isolates in these clusters remain clustered when subjected to whole genome sequencing (WGS).Methods: In the period 2004-2016, 9,072 isolates were included. Demographic and epidemiological linkage data were obtained from the Netherlands Tuberculosis Register. VNTR clusters were defined as homogeneous when isolates shared identical resistance profiles, or as heterogeneous if both susceptible and (varying) resistant isolates were found. Multivariate logistic regression analysis was performed to identify factors associated with heterogeneous clustering. Isolates from 2016 were subjected to WGS and a genetic distance of 12 single nucleotide polymorphisms (SNPs) was used as cut-off for WGS clustering.Results: In total, 4,661/9,072 (51%) isolates were clustered in 985 different VNTR clusters, of which 217 (22%) were heterogeneous. Patient characteristics associated with heterogeneous clustering were non-Dutch ethnicity (OR 1.46 [1.22-1.75]), asylum seeker (OR 1.51 [1.24-1.85]), extra pulmonary TB (OR 1.26 [1.09-1.46]), previous TB diagnosis (OR 1.38 [1.04-1.82]), and non-contact of a TB patient (OR 1.35 [1.08-1.69]). With WGS, 34% of heterogeneous and 78% of homogeneous isolates from 2016 remained clustered.Conclusion: Heterogeneous VNTR clusters are common, but seem to be explained by a substantial degree of false clustering by VNTR when compared to WGS. |
