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Title: A clinical and ethical evaluation of secondary findings in the era of clinical whole-genome sequencing
Author: Mackley, Michael
ISNI:       0000 0004 6494 4238
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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With transformative initiatives like the UK's 100,000 Genomes Project underway, vast amounts of data from genome sequencing are being generated. Genomic results are being actively returned to participants, although policies around their management remain inconsistent and a subject of debate. Secondary findings (SF) have been of particular concern - variants associated with health conditions other than the indication for sequencing, which may or may not be medically actionable. I have conducted a mixed methods study to explore the current transitional period and the issue of secondary findings, and inform future management. Following a narrative review of the literature around SF in genome sequencing and a focused systematic review of primary studies on stakeholder views towards the subject (Part I), gaps in the current literature were identified. These were, chiefly: (1) the need for diverse stakeholder views based on experience making actual decisions around SF; and, (2) empirical data - phenotypic, psychological, behavioural - on actual returned SF. Thus, taking advantage of the local programme of translational genome sequencing, I conducted qualitative studies involving genomic healthcare professionals and genome sequencing participants, to explore their views towards genomic medicine and SF (Part II). Following this, I detail a case study illustrating the process and challenges of returning an SF, as well as outline a study designed to collect empirical data on actual returned SF and present preliminary data to this end (Part III). I illustrate that secondary findings will be a part of tomorrow's genomic medicine: cautious optional screening of actionable SF (including treatable conditions and carrier status information) appears favourable. However, if SF are to be a part of the genomic medicine paradigm, several barriers must be considered: insufficient connectivity between specialties, variant interpretation, clinical interpretation and management, and overpromise and expectations (including recontact in light of new information). In order to overcome these challenges, individuals in unselected populations must be prospectively phenotyped to derive more accurate estimates of population-level penetrance and better understand the full phenotypic spectrum, and we must explore the downstream impact of disclosure. As genome sequencing is mainstreamed, clear evidence-based guidelines for SF in genome sequencing will be essential if harms are to be minimised and benefits are to be maximised, both for participants and the healthcare system at large. At this point, albeit cautiously, we must 'learn by doing'.
Supervisor: Parker, Michael J. ; Watkins, Hugh ; Ormondroyd, Elizabeth Sponsor: Rhodes Trust ; University of Oxford
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Genomics ; Secondary Findings ; Qualitative research ; Genome sequencing ; Clinical genetics ; Ethical ; legal and social implications ; Stakeholder views