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Title: The role of whole-genome sequencing technology in the control and treatment of Mycobacterium tuberculosis infection
Author: Walker, Timothy M.
ISNI:       0000 0004 6062 3576
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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In 2013 an estimated 9 million patients were diagnosed with tuberculosis across the globe, leading to 1.5 million deaths. In the UK, just under 8,000 cases were notified. Where resources allow, tuberculosis control is based on the identification of outbreaks, and the timely diagnosis and appropriate treatment of infected patients. However, current methods for identifying tuberculosis outbreaks are limited in their specificity, whilst the definitive diagnostic tests remain culture-dependent and can hence take weeks before producing a result. Whole-genome sequencing (WGS) technology is now affordable, rapid and accurate, and in this thesis I explore its potential both for detecting transmission and for identifying the genetic variation underlying drug resistance. Understanding the degree of M. tuberculosis genetic diversity within and between epidemiologically related individuals is a prerequisite to using WGS to identify Mycobacterium tuberculosis transmission. In chapter 3 I outline how this diversity is rarely greater than 5 nucleotide variants and also describe how the pattern of genetic diversity within an outbreak relates to the epidemiologically recognised transmission patterns. In chapter 4 I apply the findings from chapter 3 to all tuberculosis cases in Oxfordshire over a 6-year period to show that although most patients with tuberculosis were born in a high-incidence country, the odds of transmission among UK-born patients are in fact greater. These findings have contributed to the decision by Public Health England to invest in the routine whole-genome sequencing of M. tuberculosis from 2015. In chapter 5 I explore whether the potential utility of future sequence data can be increased by also predicting phenotypic drug susceptibility. I therefore devise an algorithm to characterise relevant genetic variation associated with phenotypic drug resistance or susceptibility. I conclude that WGS has a significant contribution to make towards improving patient outcomes and decreasing onward transmission of disease.
Supervisor: Peto, Tim Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available