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

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

doi:10.1016/j.ebiom.2018.07.019

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Mycobacterial 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. Methods: We 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. Findings: 1999 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. 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. MIRU-VNTR performance varies markedly by lineage. Funding: Public Health England, Health Innovation Challenge Fund, NIHR Health Protection Research Unit Oxford, NIHR Oxford Biomedical Research Centre.

Original language	English
Pages (from-to)	122-130
Number of pages	9
Journal	EBioMedicine
Volume	34
DOIs	https://doi.org/10.1016/j.ebiom.2018.07.019
Publication status	Published - Aug 2018

Bibliographical note

Funding Information:
This study is supported by the Health Innovation Challenge Fund (a parallel funding partnership between the Wellcome Trust [WT098615/Z/12/Z] and the Department of Health [grant HICF-T5?358]) and NIHR Oxford Biomedical Research Centre. Professor Derrick Crook is affiliated to the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England. Professor Crook is based at University of Oxford. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Publisher Copyright:
© 2018 The Authors

Keywords

MIRU-VNTR
Molecular epidemiology
Mycobacterium tuberculosis
Outbreak investigation
Research in context
Single nucleotide variation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ebiom.2018.07.019

Cite this

Wyllie, D., Davidson, J., Grace Smith, E., Rathod, P., Crook, D. W., Peto, T. E. A., Robinson, E., Walker, T., & Campbell, C. (2018). A Quantitative Evaluation of MIRU-VNTR Typing Against Whole-Genome Sequencing for Identifying Mycobacterium tuberculosis Transmission: A Prospective Observational Cohort Study. EBioMedicine, 34, 122-130. https://doi.org/10.1016/j.ebiom.2018.07.019

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

abstract = "Background: Mycobacterial 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. Methods: We 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. Findings: 1999 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. 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. MIRU-VNTR performance varies markedly by lineage. Funding: Public Health England, Health Innovation Challenge Fund, NIHR Health Protection Research Unit Oxford, NIHR Oxford Biomedical Research Centre.",

keywords = "MIRU-VNTR, Molecular epidemiology, Mycobacterium tuberculosis, Outbreak investigation, Research in context, Single nucleotide variation",

author = "David Wyllie and Jennifer Davidson and {Grace Smith}, E. and Priti Rathod and Crook, {Derrick W.} and Peto, {Tim E.A.} and Esther Robinson and Tim Walker and Colin Campbell",

note = "Funding Information: This study is supported by the Health Innovation Challenge Fund (a parallel funding partnership between the Wellcome Trust [WT098615/Z/12/Z] and the Department of Health [grant HICF-T5?358]) and NIHR Oxford Biomedical Research Centre. Professor Derrick Crook is affiliated to the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England. Professor Crook is based at University of Oxford. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = aug,

doi = "10.1016/j.ebiom.2018.07.019",

language = "English",

volume = "34",

pages = "122--130",

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Wyllie, D, Davidson, J, Grace Smith, E, Rathod, P, Crook, DW, Peto, TEA, Robinson, E, Walker, T & Campbell, C 2018, 'A Quantitative Evaluation of MIRU-VNTR Typing Against Whole-Genome Sequencing for Identifying Mycobacterium tuberculosis Transmission: A Prospective Observational Cohort Study', EBioMedicine, vol. 34, pp. 122-130. https://doi.org/10.1016/j.ebiom.2018.07.019

TY - JOUR

T1 - A Quantitative Evaluation of MIRU-VNTR Typing Against Whole-Genome Sequencing for Identifying Mycobacterium tuberculosis Transmission

T2 - A Prospective Observational Cohort Study

AU - Wyllie, David

AU - Davidson, Jennifer

AU - Grace Smith, E.

AU - Rathod, Priti

AU - Crook, Derrick W.

AU - Peto, Tim E.A.

AU - Robinson, Esther

AU - Walker, Tim

AU - Campbell, Colin

N1 - Funding Information: This study is supported by the Health Innovation Challenge Fund (a parallel funding partnership between the Wellcome Trust [WT098615/Z/12/Z] and the Department of Health [grant HICF-T5?358]) and NIHR Oxford Biomedical Research Centre. Professor Derrick Crook is affiliated to the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England. Professor Crook is based at University of Oxford. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Publisher Copyright: © 2018 The Authors

PY - 2018/8

Y1 - 2018/8

N2 - Background: Mycobacterial 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. Methods: We 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. Findings: 1999 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. 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. MIRU-VNTR performance varies markedly by lineage. Funding: Public Health England, Health Innovation Challenge Fund, NIHR Health Protection Research Unit Oxford, NIHR Oxford Biomedical Research Centre.

AB - Background: Mycobacterial 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. Methods: We 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. Findings: 1999 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. 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. MIRU-VNTR performance varies markedly by lineage. Funding: Public Health England, Health Innovation Challenge Fund, NIHR Health Protection Research Unit Oxford, NIHR Oxford Biomedical Research Centre.

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KW - Mycobacterium tuberculosis

KW - Outbreak investigation

KW - Research in context

KW - Single nucleotide variation

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JO - EBioMedicine

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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