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Title: Precision medicine in inflammatory bowel disease
Author: Walker, G.
Awarding Body: University of Exeter
Current Institution: University of Exeter
Date of Award: 2019
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Background: Individual patient variability may explain why despite a growing number of therapeutic options in the treatment of inflammatory bowel disease (IBD) many patients still suffer from disabling disease. Precision medicine aims to address this dilemma by improving the timing and delivery of healthcare for each patient by targeting treatment according to the application of biomarkers. I therefore sought biomarkers that could help deliver two key aspects of precision IBD medicine: accelerating time to diagnosis from the first onset of symptoms and predicting the risk of adverse drug reactions. Methods: I used prospective observational cohort studies firstly to explore the diagnostic accuracy of faecal calprotectin in distinguishing IBD from functional gut disorder in the primary care setting, and secondly, the factors associated with a delayed IBD diagnosis. Agnostic genome- and exome-wide association methodologies were used to investigate the association between genetic variants and thiopurine-induced myelosuppression in patients of European ancestry. Results: Faecal calprotectin is a clinically useful biomarker that helps General Practitioners (GPs) distinguish IBD from functional gut disorder in young adults and children. Use of calprotectin was not associated with time to IBD diagnosis, although its uptake in primary care was poor. The greatest component of the total time to diagnosis was the time it took patients to first present to their GP. In the adverse drug reaction study, I discovered a novel association between a variant in NUDT15 and thiopurine-induced myelosuppression. Conclusions and Impact: The actionable findings reported in this thesis have led to changes in clinical practice locally and nationally. Our primary care study of calprotectin has demonstrated how a faecal biomarker can help prioritise outpatient referrals and deliver cost-savings, leading to the adoption of our clinical pathway across several UK sites. The identification of NUDT15 variants as determinants of thiopurine-induced myelosuppression in European individuals has led to the rapid development of an NHS clinical service from the Exeter molecular genetics laboratory and in due course adoption of the test to the National Genomic Test Directory.
Supervisor: Morgan, N. ; Ahmad, T. ; Richardson, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Inflammatory bowel disease ; Crohns disease ; ulcerative colitis ; precision medicine ; stratified medicine ; pharmacogenetics