Transforming Tuberculosis control

TB's genetic 'family tree' holds the key to tackling outbreaks quickly and effectively

Detailed investigation for one substance abuse cluster. Time of onset of symptoms, diagnosis and treatment. [doi:10.1016/S1473-3099(12)70277-3]

NEW genetic sequencing techniques can map the 'family tree' of a Tuberculosis (TB) outbreak allowing the spread of disease to be tackled quickly and effectively.
Researchers, led by the Oxford Biomedical Research Centre, the Health Protection Agency in Birmingham and the Wellcome Trust Sanger Institute in Cambridge, have pioneered the whole genome sequencing (WGS) method through a study of 254 TB cases in the Midlands.
The method, published in the Lancet Infectious Diseases, compares the genetic information from the TB germs of each patient to determine with a high degree of accuracy whether cases are isolated, or if there is an outbreak of the potentially fatal disease.
By genetically mapping the spread of infection it can also show who has given the disease to whom and help identify potential 'super spreaders' before any information has been collected from patients.
Armed with this data, public health bodies can assess how much transmission is taking place and thereby target efforts quickly, efficiently and effectively to where it is needed most.
Lead investigator Professor Tim Peto, at the Oxford Biomedical Research Centre, said: "This will result in a major rebalancing of the public health approach to the spread of TB.

"It will make them far more focused on where the problems are and make them more efficient and effective."

Co-investigators Drs. Grace Smith and Philip Monk, senior members of the HPA TB control programme, described the research as a 'revolution in TB control', adding "at present you have to put a lot of work into contact tracing to find links between cases. This is extremely difficult particularly when people often lead such chaotic lives.

" We hope that this will contribute to the introduction of WGS into routine analysis of TB transmission. "

Dr Julian Parkhill

"By identifying so-called super spreaders we can target our work effectively. In terms of the public health management of TB, that is a major paradigm shift."

TB cases in the UK remain relatively low. However, the number of cases has risen slightly over the past decade, with 8,963 cases reported in 2011 (source: Health Protection Agency). Many cases are isolated, but there have been numerous outbreaks across the country over recent years.
Current practice sees public health bodies depend on people with TB volunteering information about their movements, family and friends, to identify further cases and piece together the potential spread of the disease. Until now this approach has been aided by limited genetic typing techniques that are only able to rule out transmission between cases, and not reliably confirm transmission.
The process of identifying outbreaks has therefore been time consuming, relying on the information people are able to give and occasionally throwing up 'false connections', leading to wasted effort by health bodies.
By sequencing the whole genome the new technique allows linking of cases and the mapping of outbreaks, and has the ability to predict the existence of undiagnosed cases.
Dr Julian Parkhill, investigator from the wellcome Trust Sanger Institute, said: "We are very pleased to have been able to work with the teams in Oxford and and Birmingham on this important study. We hope that this will contribute to the introduction of WGS into routine analysis of TB transmission, which we believe will become increasingly valuable for clinical practice in the future."
WGS is used to measure the genetic distance between TB strains to accurately link cases before any additional patient data has been collected. By analysing the evolving pattern of mutations it is possible to work out the direction of transmission and identify potential 'super-spreaders'.
Prof Peto said: "This work gives a level of certainty you could never have before about who belongs to a transmission chain.

"The information is in the germ, and it speaks for itself."

Notes to Editors

Publication details

Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study
Dr Timothy M Walker MRCP, Camilla LC Ip PhD, Ruth H Harrell PhD, Jason T Evans PhD, Georgia Kapatai PhD, Martin J Dedicoat MRCP, David W Eyre MRCP, Daniel J Wilson DPhil, Prof Peter M Hawkey FRCPath, Prof Derrick W Crook FRCPath, Prof Julian Parkhill PhD, David Harris DPhil, A Sarah Walker PhD, Rory Bowden PhD, Philip Monk FFPHM, E Grace Smith FRCPath c †, Prof Tim EA Peto FRCP
The Lancet Infectious Diseases 2012
DOI: 10.1016/S1473-3099(12)70277-3

Funding

Medical Research Council, Wellcome Trust, National Institute for Health Research, and the Health Protection Agency.

Participating Centres

Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
Department of Statistics, University of Oxford, Oxford, UK
West Midlands Public Health Laboratory, Health Protection Agency, Heart of England NHS Foundation Trust, Birmingham, UK
Heartlands Hospital and Birmingham Chest Clinic, Heart of England NHS Foundation Trust, Birmingham, UK
Oxford National Institute of Health Research Biomedical Research Centre, John Radcliffe Hospital, Headington, Oxford, UK
School of Immunity and Infection, University of Birmingham, Birmingham, UK
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge

The NIHR Oxford Biomedical Research Centre

The NIHR Oxford Biomedical Research Centre is a partnership between the research expertise of the Oxford University Hospitals NHS Trust and the University of Oxford. Its main aim is to enable clinical research for patient benefit and foster innovation to improve healthcare. It is funded by the National Institute for Health Research (NIHR). The NIHR provides the NHS with the support and infrastructure it needs to conduct first-class research funded by the Government and its partners alongside high-quality patient care, education and training. Its aim is to support outstanding individuals (both leaders and collaborators), working in world class facilities (both NHS and university), and conducting leading edge research focused on the needs of patients.

Website

www.oxfordbrc.org

Oxford University's Medical Sciences Division

Oxford University's Medical Sciences Division is recognized internationally for its outstanding research and teaching, attracting the brightest minds from all over the world. It is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students, and brings in around two-thirds of Oxford University's external research income. Listed by itself, that would make it the fifth largest university in the UK in terms of research grants and contracts. Oxford is home to the UK's top-ranked medical school, and partnerships with the local NHS Trusts enable patients to benefit from the close links between medical research and healthcare delivery.

UK CRC Modernising Medical Microbiology Consortium

UK CRC Modernising Medical Microbiology Consortium is a UK wide consortium funded by the Wellcome Trust and MRC, between the University of Oxford, Health Protection Agency (HPA) and the Wellcome Trust Sanger Institute; to establish how revolutionary new technologies can be optimally integrated into microbiology research and service strategic vision

Website

http://www.modmedmicro.ac.uk

The Health Protection Agency

The Health Protection Agency is an independent UK organisation that was set up by the government in 2003 to protect the public from threats to their health from infectious diseases and environmental hazards. In April 2013, subject to the usual approvals procedures for establishing new bodies, the Health Protection Agency will become part of a new organisation called Public Health England, an executive agency of the Department of Health.

Website

www.hpa.org.uk

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

Website

http://www.sanger.ac.uk/

The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.