A Quantitative Evaluation of MIRU-VNTR Typing Against Whole-Genome Sequencing for Identifying Mycobacterium tuberculosis Transmission: A Prospective Observational Cohort Study.

David H Wyllie,Tim E.A Peto,Esther Robinson,E Grace Smith,Jennifer A Davidson,Derrick W Crook,Colin Campbell,Tim Walker,Priti Rathod

doi:10.1016/j.ebiom.2018.07.019

Abstract

BackgroundMycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) typing is widely used in high-income countries to determine Mycobacterium tuberculosis relatedness. Whole-genome sequencing (WGS) is known to deliver greater specificity, but no quantitative prospective comparison has yet been undertaken.MethodsWe studied isolates from the English Midlands, sampled consecutively between 1 January 2012 and 31 December 2015. In addition to routinely performed MIRU-VNTR typing, DNA was extracted from liquid cultures and sequenced using Illumina technology. Demographic and epidemiological data for the relevant patients were extracted from the Enhanced Tuberculosis Surveillance system run by Public Health England. Closely related samples, defined using a threshold of five single nucleotide variants (SNVs), were compared to samples with identical MIRU-VNTR profiles, to samples from individuals with shared epidemiological risk factors, and to those with both characteristics.Findings1999 patients were identified for whom at least one M. tuberculosis isolate had been MIRU-VNTR typed and sequenced. Comparing epidemiological risk factors with close genetic relatedness, only co-residence had a positive predictive value of over 5%. Excluding co-resident individuals, 18.6% of patients with identical MIRU-VNTR profiles were within 5 SNVs. Where patients also shared social risk factors and ethnic group, this rose to 48%. Only 8% of MIRU-VNTR linked pairs in lineage 1 were within 5 SNV, compared to 31% in lineage 4.InterpretationIn the setting studied, this molecular epidemiological study shows MIRU-VNTR typing and epidemiological risk factors are poorly predictive of close genomic relatedness, assessed by SNV. MIRU-VNTR performance varies markedly by lineage.FundingPublic Health England, Health Innovation Challenge Fund, NIHR Health Protection Research Unit Oxford, NIHR Oxford Biomedical Research Centre.

Highlights

In 2016 there were 5664 notified cases of tuberculosis in the England, with an incidence of 10.2 per 100,000 population [1]
We excluded 551 isolates because MIRU-VNTR typing had already been performed on a previous isolate within that calendar year, as
To quantify how the relationship between MIRU-VNTR and single nucleotide variants (SNVs) differed by lineage, we modelled SNV distances between paired isolates, assuming a linear relationship with MIRU-VNTR profile distances over the range of 0–3 MIRU-VNTR locus differences

Summary

Introduction

In 2016 there were 5664 notified cases of tuberculosis in the England, with an incidence of 10.2 per 100,000 population [1]. Despite a steady fall in incidence since its peak early this decade, this remains the highest rate in western Europe, outside of the Iberian peninsula [2] This decline has occurred across almost all population groups with only a third due to decreases in the numbers of migrants from high TB burden countries. In England, as in many high-income countries, tuberculosis transmission has been identified with the help of Mycobacterial Interspersed Repetitive UnitVariable Number Tandem Repeat (MIRU-VNTR) typing, which clusters cultured isolates on the basis of their molecular fingerprints [6, 7]. Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) typing is widely used in high-income countries to determine Mycobacterium tuberculosis relatedness. Interpretation: In the setting studied, this molecular epidemiological study shows MIRU-VNTR typing and epidemiological risk factors are poorly predictive of close genomic relatedness, assessed by SNV.

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Results

Conclusion