Improving the Clinical Application of Genetic Testing for Patients with Inherited Heart Disease

The difficulties associated with the clinical application of next generation sequencing (NGS) approaches can be substantial. However, the technology holds great potential to improve outcomes and risk management for inherited heart disease patients and their families. This PhD thesis focuses on three critical challenges associated with the clinical application of NGS technologies; (i) Understanding correlations between genetics and the clinical phenotype; (ii) the impact of uncertainty created by NGS-based genetic testing on the patient; and (iii) developing evidence-based approaches for improving current and future methods for returning complex genetic results. Two studies focused on understanding correlations between genetics and the clinical phenotype. Firstly, the study reported in Chapter two, which aimed to analyse genetic and phenotypic findings from a consecutive cohort of hypertrophic cardiomyopathy (HCM) families who had undergone comprehensive cardiac panel testing. We showed that increasing the number of genes included on HCM panels beyond the eight established sarcomere genes does not increase the diagnostic yield. However, identification of variants of uncertain significance increased dramatically from 13% to 36%. This result has important clinical implications. Increasing the number of genes screened does not necessarily improve the chance of identifying a family’s cause of disease but is likely to increase identification of uncertain results that can increase the complexity of discussions around inheritance and risk. We also showed that identification of multiple rare variants was associated with earlier disease onset, greater likelihood of family history of sudden cardiac death (SCD) and overall worse event-free survival (5/18 events versus 29/170 events, log-rank test p=0.008). Clinical heterogeneity is a hallmark feature of HCM and here we show one factor that can contribute to worse outcomes. The study reported in Chapter three aimed to describe the diverse genetic and phenotypic features of an international cohort of patients with a truncating variant in the desmoplakin (DSP) gene traditionally considered to cause arrhythmogenic right ventricular cardiomyopathy (ARVC). This is the first complete report of the diverse phenotype spectrum of DSP cardiomyopathy, suggesting that truncating variants in DSPshould be considered its own entity. We show that the phenotype associated with truncations in DSP is severe, with a high rate of SCD and characterised by left ventricular dysfunction and structural left ventricular involvement when compared with ‘classic’ ARVC. In addition, we show the functional domain in which DSP truncating variants reside has clinical significance. Key results from Chapter two and three emphasise the importance of correlating genetic variants with phenotype information. Data from this work is a step towards precision medicine whereby patients’ risk will be assessed and managed based on their genotype. In Chapter four we designed a qualitative study to explore attitudes, preferences, recall and psychosocial consequences of uncertain genetic results returned to HCM probands. The major themes we identified were knowledge and recall of complex genetic information, individual experiences with HCM genetic testing and communication and the value of information. In addition, those with uninformative results had a unique set of issues. We found that HCM probands undergoing genetic testing require additional support and information beyond the current practice model employed in the multidisciplinary specialist clinic setting. Importantly, many of the probands interviewed who received an uninformative or uncertain genetic result showed poor recall and understanding of genetic information. The final aim was to determine if a genetic counsellor led intervention using a communication aid for the delivery of HCM genetic test results improves the ability and confidence of the proband to communicate genetic results to at-risk relatives. This work is presented in Chapter five. We developed a study protocol for a randomised controlled trial with the primary outcome being the ability and confidence of the proband to communicate genetic results to at-risk relatives. We focused on transforming findings from the previous chapters into improved clinical practice. The a priori primary outcome did not show statistically significant differences between the control and intervention group, though the majority of probands in the intervention group achieved fair communication scores and had higher genetic knowledge scores than those in the control group. Importantly, we found that 29% of at-risk relatives were not informed of a genetic result in their family. We highlight the significant gap in our current approach to supporting family communication about genetics. The studies presented highlight that whilst genetic testing has significant potential for benefit in inherited heart disease families in terms of diagnosis, management and family screening there are issues to address in order to improve the clinical utility and application of a comprehensive approach to testing. Overall, the work contributes to understanding the genetic architecture of inherited heart diseases, the clinical impact of NGS results for patients, as well as highlighting that more work is needed to improve the clinical utility from an NGS approach to genetic testing

Measurement Effects in Decision-Making

When participants are shown a series of stimuli, their responses differ depending on whether they respond after each stimulus or only at the end of the series, in what we call a measurement effect. These effects have received paltry attention compared with more well-known order effects and pose a unique challenge to theories of decision-making. In a series of two preregistered experiments, we consistently find measurement effects such that responding to a stimulus reduces its impact on later stimuli. While previous research has found such effects in noncumulative tasks, where participants are instructed only to respond to the most recent stimulus, this may be the first demonstration of these effects when participants are asked to combine information across either two or four stimuli. We present modeling results showing that although several extant classical and quantum models fail to predict the direction of these effects, new versions can be created that can do so. Ways in which these effects can be described using either quantum or classical models are discussed, as well as potential connections with other well-known phenomena like the dilution effect

Preschool children's proto-episodic memory assessed by deferred imitation.

This is the author accepted manuscript. The final version is available from Taylor & Francis via http://dx.doi.org/10.1080/09658211.2014.963625In two experiments, both employing deferred imitation, we studied the developmental origins of episodic memory in two- to three-year-old children by adopting a "minimalist" view of episodic memory based on its What-When-Where ("WWW": spatiotemporal plus semantic) content. We argued that the temporal element within spatiotemporal should be the order/simultaneity of the event elements, but that it is not clear whether the spatial content should be egocentric or allocentric. We also argued that episodic recollection should be configural (tending towards all-or-nothing recall of the WWW elements). Our first deferred imitation experiment, using a two-dimensional (2D) display, produced superior-to-chance performance after 2.5 years but no evidence of configural memory. Moreover, performance did not differ from that on a What-What-What control task. Our second deferred imitation study required the children to reproduce actions on an object in a room, thereby affording layout-based spatial cues. In this case, not only was there superior-to-chance performance after 2.5 years but memory was also configural at both ages. We discuss the importance of allocentric spatial cues in episodic recall in early proto-episodic memory and reflect on the possible role of hippocampal development in this process

Sparing or sharing? Differing approaches to managing agricultural and environmental spaces in England and Ontario

The ability to balance agricultural production and environmental conservation in the face of increasing demand for food, fuel and fibre poses a major challenge for governments around the world. This challenge is explored in two areas of comparison: Ontario, Canada and England, UK in order to understand how each has balanced agriculture and environment in its land use policies. England and Ontario share similarities that suggest lessons and instruments may be transferrable to achieve similar land use objectives. Through the use of a thematic analysis of policy documentation, from each case study area, themes are identified demonstrating differences in approaches, and underlying policy preferences, associated with balancing agriculture and the environment. Specifically, results suggest that policymakers in Ontario hold a preference for land-sparing and leanings towards the productivist paradigm, whereas the land-sharing approach coupled with evidence of post-productivism is more common in England. The structural similarities of these cases provides insights into less tangible aspects of either context, such as policymaker preferences, where different approaches have emerged from a similar foundation. Moreover, as England transitions out of the EU, it may draw on the experiences of other jurisdictions in the design of a new suite of agri-environmental policies, with Ontario's approach providing one alternative. Overall, this paper contributes to our understanding of the manifestation of land-sparing/sharing and productivism/post-productivism in real world policy contexts and the relationship between both sets of concepts

Cultural and Dietary Factors Influencing Traditional Latino Meal Patterns: Findings from Focus Group Discussion

Background: Despite a high prevalence of nutrition-related health disparities experienced by Latinos in the United States, there is limited recent information that can be used by health professionals to develop effective nutrition interventions for this diverse population. Purpose: The purpose of this study was to obtain qualitative information regarding usual dietary patterns of Latinos from Pomona, California, and utilize this data in the development of a tailored nutrition intervention. Methods: Latina women ages 30- 70, from a low socio-economic community sample, participated in one of three focus groups, and discussed eating patterns, recipes, and dietary concerns. Participants self-identified as the primary household food purchaser and preparer. Demographics and acculturation were assessed using validated surveys. Results: All participants (n=17) were considered less acculturated to the United States. Participants reported that traditional recipes and family preferences have the greatest influence on foods prepared, however they tend to be less healthy items. Motivators for eating healthy included maintaining family health and preventing weight gain. Barriers included conflicting meal schedules among family members and individual food preferences. Conclusion: To reduce health disparities for Latinos, cultural and dietary factors of communities, along with perceived motivators and barriers to making healthy choices, should be considered when developing tailored nutrition interventions

Brexit and UK Environmental Policy and Politics

In 2016 the United Kingdom (UK) voted in a referendum to leave the European Union (EU). Whilst the environment did not feature significantly in the referendum campaign it has emerged as a major focus for the UK Government as it prepares for Brexit. Since the UK joined the EU in 1973, its approach to environmental policy-making has been profoundly shaped by processes of Europeanisation. Consequently, disentangling the UK from the environmental acquis communautaire will be a huge undertaking. Whilst the Government has committed to the pursuit of a ‘Green Brexit’ there are on-going concerns that Brexit will lead to weaker environmental ambition and governance. It may also produce policy divergence across the UK as the environmental sector is devolved and has become a site of constitutional conflict over the powers of the devolved nations of Scotland, Wales and Northern Ireland. A once stable policy area characterised by a broad cross-party and cross-national consensus therefore is, post-Brexit, increasingly likely to become a focus for constitutional and party political conflict and competition

Otolith chemoscape analysis in whiting links fishing grounds to nursery areas

Understanding life stage connectivity is essential to define appropriate spatial scales for fisheries management and develop effective strategies to reduce undersized bycatch. Despite many studies of population structure and connectivity in marine fish, most management units do not reflect biological populations and protection is rarely given to juvenile sources of the fished stock. Direct, quantitative estimates which link specific fishing grounds to the nursery areas which produced the caught fish are essential to meet these objectives. Here we develop a continuous-surface otolith microchemistry approach to geolocate whiting (Merlangius merlangus) and infer life stage connectivity across the west coast of the UK. We show substantial connectivity across existing stock boundaries and identify the importance of the Firth of Clyde nursery area. This approach offers fisheries managers the ability to account for the benefits of improved fishing yields derived from spatial protection while minimising revenue loss

Improved traceability in seafood supply chains is achievable by minimising vulnerable nodes in processing and distribution networks

Seafood is a globally traded commodity, often involving complex supply chains which have varying degrees of traceability. A robust traceability system for seafood supply chains enables the collection and communication of key information about catch and fisheries origins vital for assurance of the legality and sustainability of seafood products. End-to-end traceability is increasingly demanded by retailers, consumers, NGOs and regulatory bodies to ensure food safety, deter IUU fishing and verify sustainable and ethical credentials. Here, we map three UK seafood supply chains and evaluate traceability performance in: Dover sole landed in the south west of England, North-East Atlantic (NEA) mackerel landed at Peterhead, Scotland, and brown crab and European lobster, landed at Bridlington, England. Through a comparative analysis of traceability performance, this study suggests improvements to the technologies, processes, and systems for traceability in the seafood sector. The application of monitoring technologies and regulatory changes across the sector have increased traceability and potentially reduced instances of IUU fishing. While shorter supply chains are more likely to achieve end-to-end traceability, vulnerable nodes in processing and distribution networks may result in a loss of seafood traceability. While traceability systems may provide sustainability information on seafood, a high level of traceability performance does not necessarily equate to a sustainable source fishery. Encouragingly, while UK seafood supply chains are meeting minimum regulatory requirements for traceability, in the present study, many stakeholders have indicated ambitions towards traceability best practice in order to provide confidence and trust in the UK fishing industry

What does Brexit mean for the UK’s Climate Change Act?

This article examines the potential implications of the United Kingdom’s exit from the European Union (so-called ‘Brexit’) for the success and survival of the country’s flagship climate policy, the Climate Change Act 2008. The impact of a ‘soft’ and a ‘hard’ Brexit for the main features of the Climate Change Act are assessed, building on documentary evidence and elite interviews with key policy-makers and policy-shapers. The article argues that the long-term viability of the Climate Change Act was being threatened even before the EU referendum, and that Brexit will do little to improve this situation. Even though the existence of the Climate Change Act is not under immediate threat, a range of issues presented by Brexit risk undermining its successful implementation

The Use of Complementary and Alternative Medicine by Adults and Children in the South

A community of students, at different ranks, and two faculty members engaged in the development of a research project aimed at studying the consumption of complementary and/or alternative medicine (CAM) in the South. A well-established store in the community was identified for the study because of its focus on natural products and well-being. The students and faculty developed a CAM survey and the store owners provided feedback and gave approval to conduct the study on their patrons. The survey explored CAM use among adults and children in comparison to CAM uses in other regions of the country. Challenges and lessons learned from the engaged project are discussed, along with the findings that included family remedies and folklore recipes used in the South for varying ailments and symptoms