Theses - MRC Epidemiology Unit

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The Role of Socioeconomic Position in Adolescent Physical Activity
Alliott, Olivia; Alliott, Olivia [0000-0002-1835-6852]
Background: There is strong evidence of health inequalities during and beyond adolescence and inequalities in the social determinants of health including physical activity. Unlike in children and adults, the impact of socioeconomic position (SEP) on physical activity behaviour during adolescence is unclear. Qualitative evidence aiming to understand this from the adolescent perspective is lacking, as are efforts to understand equitable approaches to physical activity promotion. Aim: Taking a mixed-methods approach, this thesis aims further our understanding of the role of SEP in adolescent physical activity and in the development of equitable physical activity promotion strategies. Project 1: First, I report on my systematic review of qualitative evidence to understand if adolescents' experiences of the barriers to and facilitators of physical activity differ by SEP. Synthesising 25 studies, the review shows that adolescents of a low-SEP experience more barriers to physical activity than those of middle- and high-SEP. These findings highlight adolescents of a low-SEP as a high-risk group, this is used to inform the approaches taken in the following project. Project 2: I then took a mixed-methods case study approach to evaluate whether socioeconomic inequalities arise during a school-based physical activity intervention. The findings of this project suggest school-based population level interventions have the potential to benefit students of a low-SEP, however differential engagement in the intervention and response to evaluation measures may have biased these conclusions. Throughout this project, I demonstrate a novel way of evaluating inequalities within young people’s physical activity interventions. Project 3: Given the promise of school-based physical activity interventions, I then planned to take a mixed-methods approach to evaluate the acceptability and feasibility of a targeted intervention applying Sport England’s satellite club model to the school setting. Unfortunately, this project could not be fully implemented due to the impact of the Covid-19 pandemic. The findings of an interim report, based on the initial stages of the intervention, highlight the potential for high-risk school-based approaches targeting young people in socioeconomically deprived contexts, providing direction for future research. Project 4: During the final project I took a qualitative approach to understand, from the perspective of adolescents living in socioeconomically deprived communities, whether the Covid-19 pandemic influenced their physical behaviour and their views on how we can help young people become more active moving forward. The findings further highlight socioeconomic inequalities in adolescent physical activity, which were exacerbated by the Covid-19 pandemic. Young people suggested implementing school-based physical activity interventions during the school day with a focus on fun and the structural environmental regeneration of socioeconomically deprived areas, to provide young people with safe and low-cost physical activity opportunities. Conclusions: This thesis highlights how young people living in the context of socioeconomic deprivation experience more barriers to physical activity when compared to other socioeconomic groups. Evidence for the potential of both population and high-risk school-based approaches in equitable physical activity promotion is presented, providing promising direction for the future of school-based intervention strategies. Adolescents’ experiences of the Covid-19 pandemic emphasise existent inequalities in physical activity and recommendations are made from the young person’s perspective for equitable physical activity promotion moving forward.
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Proteomic Signatures of Type 2 Diabetes and Related Metabolic Traits
Carrasco Zanini Sánchez, Julia; Carrasco Zanini Sánchez, Julia [0000-0002-3988-7505]
Advances in profiling technologies have enabled systematic assessment of a plethora of molecules from genome via proteome to a variety of metabolic phenotypes, providing unique opportunities to better understand disease mechanisms and identify molecular signatures that can help to predict, screen for and diagnose different diseases using agnostic discovery approaches. The proteome is at the centre of biological information transfer and therefore provides a unique source of actionable discoveries. The increasing global burden of Type 2 diabetes (T2D) calls for improved strategies to identify individuals at high-risk. However, the aetiology of this heterogenous disease remains incompletely understood, and some subgroups are poorly predicted or overlooked. The main aim of this thesis was to identify plasma proteomic signatures for improved risk prediction and aetiological understanding of T2D and related metabolic traits. I first conducted a systematic characterisation of the major phenotypic and genetic determinants of plasma protein levels, which showed a range of modifiable risk factors as causal determinants that improved interpretation of disease biomarkers and candidate mediators. To assess the integrated whole-body response to high glucose ingestion, I systematically characterised protein changes during an oral glucose tolerance test (OGTT). Around 11% of the measured proteome changed after the OGTT, pointing to groups of proteins with a differential response in insulin resistant compared to insulin sensitive individuals, and that were associated with long term cardiometabolic consequences. To go beyond understanding of molecular mechanisms associated or involved in glucose homeostasis and explore the predictive potential of the plasma proteome, I applied a machine learning framework to ~5,000 proteins measured at fasting. I identified a 3 protein signature that improved discrimination over clinical risk factors of isolated impaired glucose tolerance (iIGT), a group at high risk for T2D and comorbidities that is missed by current screening guidelines. Further systematic assessment showed that a sparse signature of features across the proteome, metabolome and genome improved risk prediction for incident T2D, of which the major driver was the T2D-polygenic score. However, individuals with HbA1c below the threshold for prediabetes but at high polygenic risk had a substantially lower cumulative T2D incidence than people with prediabetes. To investigate the predictive potential of plasma proteomics more broadly and disease-specificity of predictive biomarkers, I developed sparse protein models for the prediction of 24 diverse incident diseases across a range of clinical specialties. As few as five proteins improved the predictive performance of patient derived risk factors for seven diseases, revealing the potential of high-throughput proteomics for novel biomarker discovery and improved risk prediction across a range of diseases. This thesis demonstrates the potential of broad-capture plasma proteomics for identification of novel aetiological pathways and predictive biomarkers to improve or refine risk prediction and screening strategies, specifically for subgroups that are poorly captured by current clinical risk factors.
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Evaluating and understanding how interventions work to encourage shifts towards active travel
Xiao, Christina; Xiao, Christina [0000-0002-1183-0259]
Replacing motorised transport with active travel, such as walking or cycling for transport, has multiple environmental and health co-benefits. However, with the large variety of intervention forms that may be implemented to shift population levels of active travel, such as modifying the built environment or implementing policies that restrict the use of motorised vehicles, it is difficult to know which should be prioritised. It is thus important to understand which types of interventions are most effective at encouraging active travel uptake. This includes identifying whether there are mechanisms or underlying processes common to successful active travel interventions (i.e., intervention functions), or whether differences in intervention design or the specific components included (i.e., intervention form) can influence intervention effectiveness. Thus, this thesis aims to identify, evaluate, and understand the key characteristics of effective interventions to encourage shifts towards active travel. The first part of my research involves a systematic review comparing the effectiveness of carrot, stick, and a combination of the two, or carrot-and-stick transport interventions. Interventions with a stick strategy, such as those with functions involving taking away road space or leading to decreases in convenience, are less widely assessed in the literature compared to those with a carrot strategy, such as those aiming to increase access and safety for active travel. The findings also suggest that stick and carrot-and-stick interventions are more effective at either reducing driving or increasing active travel than carrot-only interventions. I also find that interventions seeking to influence driving behaviour using financial means or active travel by modifying access, safety, and space are more impactful than others. Having identified that there is a need to increase the evidence base on interventions that include a stick strategy, I evaluate three interventions with stick or carrot-and-stick strategies. The first is a study evaluating the London Ultra Low Emission Zone, an area-based vehicle charging scheme. I use data from the Children’s Health in London and Luton study, a parallel cohort study of primary school children. Children living further from school and exposed to the intervention had a higher likelihood to switch from inactive to active modes of travelling to school than those who were unexposed. The second evaluation study examines the introduction of low traffic neighbourhoods (LTNs) in Southwark, London. LTNs use physical barriers to restrict traffic from passing through residential streets while allowing pedestrians and cyclists to access the street. Moreover, other minor streetscape improvements to pedestrian infrastructure were made, and altogether, the interventions constitute carrot-and-stick strategies. Findings reveal that while traffic volumes and speeds decreased in some of the neighbourhoods, there were no corresponding increases in walking and cycling. The third evaluation study involves investigating an intervention with carrot and carrot-and-stick strategies. I use interrupted times series analyses of routinely collected cycle count data to assess how cycling levels changed following cycle lane expansions in Paris and Lyon in France. Although there were no discernible level or trend changes in cycling counts, cycling increased more in Paris compared to Lyon. Given that various cycling infrastructure designs were introduced in both cities, the final study explores how to advance our understanding of whether differences in cycling infrastructure design can influence intervention effectiveness. I develop a virtual street audit using Google Street View to characterise infrastructural changes made due to the French cycling lane interventions, from which I derive function scores. I find that cycling infrastructure forms that involves stick strategies, such as taking traffic lanes and parking space from drivers, have the highest associations with increases in cycling levels. Correspondingly, functions aiming to increase safety or space were found to be among the most impactful. This thesis adds to the literature by not only identifying common characteristics of effective active travel interventions, such as whether it includes a stick strategy, but also finding that these are relatively under-represented in the literature. My findings also suggest there may be a hierarchy of active travel needs that may be important to address when developing interventions, such as increasing safety and space for pedestrians and cyclists. To further increase intervention effectiveness, the intervention form, or the way interventions are designed and implemented, should align with their core functions and adapted based on individual contexts. Further research is needed taking consideration of intervention form, function, and contextual factors into account to strengthen and inform public health policy and practice.
Open Access
Meat consumption and type 2 diabetes: investigating heterogeneity and potential causal mechanisms
Li, Chunxiao; Li, Chunxiao [0000-0002-5946-5457]
Type 2 diabetes (T2D) is a complex metabolic disease which affects more than 500 million people worldwide, imposing enormous burdens on affected individuals and their families, healthcare systems and societies. Healthy diets play a crucial role in preventing T2D and meat has been reported to be associated with an increased risk of T2D. However, it is unclear whether different types of meat are all associated with increased risk and whether associations are the same in all individuals and in all populations. Finally, there are uncertainties about the causal nature of the association and the mechanisms that may underlie it. In my PhD, I aimed to investigate these uncertainties in analyses of epidemiological studies. The initial elements of my work focused on refining measures of the exposure (meat intake) and the outcome (incident T2D) in the EPIC-Norfolk study, a population-based cohort study of over 25,000 participants. I worked on improving case ascertainment of T2D as the primary outcome in my analyses. I updated T2D case ascertainment in EPIC-Norfolk by linkage of multiple external data sources, including diabetic eye screening data and clinical biochemistry data. I identified over 2,000 additional incident diabetes cases. I then reported the association of self-reported intake of different types of meat with T2D in EPIC-Norfolk. Dietary biomarkers can provide complementary information about diet-disease associations. I used untargeted metabolomics profiling to derive metabolite scores to quantify the consumption of red meat, processed meat and poultry based on 781 circulating metabolites and 7-day diet diary data in 11,432 participants in EPIC-Norfolk. The best performing score was for red meat, comprising 139 metabolites and accounting for 17% of the explained variance of red meat consumption. Eleven top-ranking metabolites that were included in the red meat score were validated in a trial conducted by collaborators in Lyon, France. These metabolites were mainly classified into groups of lipids, amino acids, and xenobiotics, such as plasmalogens, trimethylamine N-oxide, and stearoylcarnitine. I then showed that this red meat metabolite score was strongly associated with T2D incidence in EPIC-Norfolk. I then investigated the potential causal roles of these eleven red meat-related metabolites in T2D incidence by conducting Mendelian randomisation (MR) analyses. I observed weak evidence of possible causal associations between meat-related metabolites and incident T2D, possibly due to limited power and weak genetic instruments. In an analysis in two large studies (EPIC-InterAct and UK Biobank), I evaluated whether the association between meat consumption and T2D incidence differed in sub-populations with varying genetic and clinical baseline risks. I found that meat intake was associated with incident T2D independently of genetic and clinical predisposition to T2D. This suggests that there are benefits of reducing meat intake on T2D burden in the entire population. Finally, I examined associations between types of meat intake (red meat, processed meat and poultry) and T2D risk based on a federated platform in the InterConnect, which enabled harmonised data analysis of 1.5 million individuals from 23 studies across the world. This meta-analysis of individual participant data provided unique evidence of meat-T2D associations in previously understudied populations, such as those in East Asia, and East Mediterranean. I included over 60,000 new-onset T2D cases with a median of 13 years of follow-up showing that consumption of red meat, processed meat and poultry were each individually associated with increased risk of T2D. In summary, my work provides strong evidence on the consistency of the association of meat consumption with T2D risk in sub-groups within European populations and also across heterogeneous populations worldwide. This has implications for public health approaches to T2D prevention.
Open Access
Improving our understanding of the use of online food delivery services to access food prepared out-of-home
Keeble, Matthew; Keeble, Matthew [0000-0002-1512-7421]
Food prepared out-of-home is typically energy-dense and nutrient-poor. More frequent consumption of this food is associated with poorer overall dietary patterns and obesity. Previous research has tended to focus on access to food prepared out-of-home in the physical food environment, which is often greatest in more deprived areas. However, this food can now also be accessed through online food delivery services. Although online food delivery services are globally established, there is limited public health knowledge about the prevalence of their use and factors influencing this, the sociodemographic characteristics of customers, and the extent to which the opportunity to use them is socioeconomically patterned. The aim of my thesis was to help better understand the use of online food delivery services to access food prepared out-of-home. First, I analysed survey data collected in 2018 to identify the prevalence of online food delivery service use and the sociodemographic characteristics of adult customers across Australia, Canada, Mexico, the United Kingdom, and the United States of America. From 19,378 respondents, around one in six had used an online food delivery service in the past week. Respondents who were male, younger, more highly educated, living with children and those who identified with an ethnic minority had greater odds of online food delivery service use. These patterns were similar in each country but the strength of associations varied. Notably, respondents with a high versus low level of education had greater odds of online food delivery service use in all countries except the United Kingdom. Second, I conducted telephone interviews with 22 adults living in England who were frequent online food delivery service customers. Participants reported that they could access a higher number of food outlets and a broader range of cuisines through online food delivery services compared with the physical food environment. Additionally, these services allowed participants to access exclusive price-promotions and use streamlined purchasing processes, which were seen as unique advantages. Participants reported that they believed the food available through online food delivery services was mostly unhealthy. Nevertheless, this food met their expectations about `takeaway food`. Despite reported drawbacks of online food delivery services, which included over-convenience and, paradoxically, access to unhealthy food, participants reported no intention to discontinue use because it was normal to purchase food prepared out-of-home in this manner. Informed by existing evidence and my qualitative research, I investigated associations between access to food prepared out-of-home through online food delivery services and online food delivery service use, and body weight. In my individual-level data-linkage study of 3067 adults living in Great Britain, the number of food outlets accessible online was positively associated with online food delivery service use in the past week. However, it was not associated with body weight. Despite the perspective of frequent customers, the number of cuisine types accessible online was not associated with online food delivery service use. Finally, I examined access to food prepared out-of-home through online food delivery services in England and variation according to area-level socioeconomic position. In a cross-sectional study, I found that the number of food outlets accessible online was highest in the most deprived areas of England in November 2019. I followed this with a repeat-cross sectional study that assessed changes in the number of food outlets accessible online over time, within the context of the Coronavirus Disease 2019 (COVID-19) pandemic. I found that it was only in the most deprived areas of England that the number of food outlets accessible online in March 2022 surpassed the number from November 2019. Taken together, these findings indicate that online access to food prepared out-of-home in England is socioeconomically patterned, and that inequalities therein widened over time. The findings from my thesis help better understand multiple aspects of online food delivery service use. The number of food outlets accessible online emerged as being particularly important. A higher number was positively associated with online food delivery service use, which suggests it can influence food purchasing practices. Indeed, this was supported by the views of frequent online food delivery service customers in my qualitative research. Additionally, the number of food outlets accessible online was highest in the most deprived areas of England in November 2019, and increasingly so over time compared with less deprived areas. Thus, the opportunity for online food delivery service use is unequal across the socioeconomic spectrum in England. Future research should seek to understand how food purchased through online food delivery services contributes to overall dietary patterns and health, and the need for public health intervention.
Embargo
Application of biomarker-based assessment of dietary patterns to nutritional epidemiology: observational and interventional investigations with a focus on the Mediterranean diet and type 2 diabetes
Sobiecki, Jakub Grzegorz; Sobiecki, Jakub [0000-0003-2641-2313]
Existing evidence on healthy dietary patterns suggests that they are modestly inversely associated with incidence of common non-communicable diseases, and in particular cardiometabolic diseases. Trials are rarely feasible to assess causality of these relationships which motivates leveraging observational data with improved methodological approaches. In this PhD thesis, I attempted to address the common limitation in nutritional epidemiology of subjective assessment of adherence to dietary patterns. Chapter 2: I conducted a systematic review of the effects of Mediterranean diet interventions on nutritional biomarkers. I identified 29 trials reporting on 25 biomarkers eligible for meta-analysis (5-18 studies available per biomarker). Circulating carotenoids, vitamin C and fatty acids emerged as candidate biomarkers of compliance. Effect sizes were mostly small which likely reflected the multifaceted nature of whole diet interventions and insufficient validity of single analytes as biomarkers of adherence to the Mediterranean dietary pattern. Chapter 3: I used the EPIC-InterAct case-cohort study which measured nutritional biomarkers at scale (~13,000 subcohort participants and ~9,000 incident type 2 diabetes cases) to evaluate the utility of combining them into biomarker scores predictive of adherence to dietary patterns, and to test their associations with incidence of type 2 diabetes. The available biomarkers included circulating carotenoids, vitamins C and 25(OH)D, fatty acid profiles, iron status biomarkers and cations. The dietary patterns of interest were the Mediterranean diet, alternative Healthy Eating Index-2010 and the Dietary Approaches to Stop Hypertension. The analyses showed modest correlations of the biomarker scores with their respective dietary patterns (r ~0.3) and statistically significant inverse associations with disease risk (hazard ratios ~0.8 per standard deviations of the scores). Chapter 4: I established a collaboration with one of the randomised trials identified in Chapter 2, the MedLey trial, to address the limitations of internal derivation and validation of the biomarker scores. It compared the effects of a partial-feeding Mediterranean diet intervention with continuation of habitual diet in Australia on circulating carotenoids and fatty acids, 29 of which overlapped with those available in EPIC-InterAct. Using end-of-trial biomarker concentrations as predictors of the randomised assignment (n = 128), I developed a biomarker score which discriminated well between the trial arms (C-statistic = 0.88). It was robustly inversely associated with incidence of type 2 diabetes in EPIC-InterAct (hazard ratio 0.71 per standard deviation; 95% confidence and prediction intervals: 0.65-0.77 and 0.55-0.91). Chapter 5: I additionally used the combined InterAct-MedLey data to test generalisability of biomarker scores of the Mediterranean diet. I derived a series of biomarker scores predictive of self-reported adherence to the Mediterranean diet in EPIC-InterAct countries, the MedLey trial baseline sample, and non-InterAct participants of the EPIC-Norfolk cohort (~5,000 with relevant biomarkers). Controlling for multiple testing, values of 8/13 biomarker scores were higher in the Mediterranean diet intervention than the control group of the MedLey trial, and 10/13 scores were inversely associated with incidence of type 2 diabetes in EPIC-InterAct. Chapter 6: In the EPIC-Norfolk study, I investigated the impact of expanding a base set of predictors from circulating carotenoids and fatty acids with additional groups of nutritional biomarkers (urinary sodium, potassium and sugars, urinary and serum phytoestrogens, circulating vitamin C, iron status biomarkers, cations and stable isotopes) or using metabolomics on (i.) the correlations between self-reported Mediterranean diet and its biomarker scores and (ii.) the associations between the biomarker scores and incident cardiovascular disease, cancer, type 2 diabetes and mortality (n range ~500-11,000). The base set biomarker score had a moderate cross-validated correlation with self-report (r = 0.40) and the performance was similar or decreased with inclusion of additional nutritional biomarkers (r range: 0.30-0.41) and modestly improved with metabolomics (r = 0.46). Biomarker scores were inversely associated with disease and mortality outcomes, and use of different sets of biomarkers modified the strength of association for few diet-disease associations. Inverse associations were notably stronger for type 2 diabetes (hazard ratio ~0.80 per standard deviation of biomarker scores) than for other outcomes (range ~0.90-0.95). Chapter 7: I conducted an outcome-wide analysis of 27 incident noncommunicable diseases in the EPIC-Norfolk study using as exposures the biomarker scores derived throughout the thesis (n range ~7,000-11,000) and dietary self-report of the Mediterranean diet (n ~22,000). Controlling for multiple testing, inverse associations were robustly detected across ≥2 of 4 methods of exposure assessment for type 2 diabetes, chronic obstructive pulmonary disease, and heart failure. At the nominal α = 0.05, corresponding relationships were identified for ischaemic heart disease, renal disease, oesophageal and stomach cancers, and cataracts. This PhD identified combinations of nutritional biomarkers as plausible biomarkers of the Mediterranean diet for application in epidemiological investigations. These findings contribute towards development of methods of objective assessment of diet and strengthen the evidence on the inverse relationship between the Mediterranean diet and cardiometabolic disease.
Open Access
Epidemiological studies of the aetiological associations between nutritional biomarkers and cardiometabolic risk factors in Cameroon
Mba Maadjhou, Berjauline Camille
Suboptimal diets are among the leading factors fuelling the global rise in the prevalence of type 2 diabetes and other metabolic disorders. Most epidemiological studies of the associations between diet and nutritional factors and metabolic outcomes have relied on self-report instruments. Nutritional biomarkers offer a complementary objective approach but have not been widely applied in African settings to test associations between diet and metabolic outcomes. This thesis aimed to examine the relationship between diet and nutritional factors assessed using a wide range of objectively measured nutritional biomarkers and metabolic outcomes in a population-based study in adults in rural and urban Cameroon (n= 651). I spent the first part of my PhD in the laboratory measuring circulating vitamin D, folate, holotranscobalamin, carotenoids and tocopherol using mass spectrometry techniques. Subsequently, I undertook analyses to describe the patterns and identify factors affecting these nutritional biomarkers reflecting dietary intakes and plasma zinc, which was measured in an external laboratory. Most of the biomarkers showed distinct patterns by age, sex, level of education, physical activity levels and rural/urban area of residence. I then investigated the independent cross-sectional associations of these biomarkers with metabolic risk factors exploring the possibility of both linear and non-linear associations and adjusting for a wide range of potential confounders. Circulating folate and carotenoids, which are associated with intake of fruits and vegetables, showed an inverse association with the metabolic syndrome score and fasting glucose respectively. Holotranscobalamin, a biomarker that reflects intake of animal-sourced foods, was positively associated with the metabolic syndrome score. Circulating zinc, reflecting intake of protein-rich foods, was inversely associated with several markers of glucose homeostasis (fasting and 2-h glucose and homeostatic model assessment for insulin resistance). Higher 25-hydroxy-vitamin D, a marker of vitamin D status, was associated with lower fasting glucose. Finally, I investigated the potential effect modification by rural/urban area of residence, sex and body mass index on the association between the biomarker and metabolic outcomes. Overall this PhD showed 1) Rural and urban differences in the distribution of the nutritional biomarkers in Cameroon 2) Significant associations of the studied biomarkers reflecting dietary intakes with metabolic risk factors. Findings from my PhD advance the understanding of the role of diet and nutritional factors on metabolic health in adults in Cameroon. Diet is modifiable, making it a realistic target for public health intervention to improve metabolic health in this population.
Embargo
Using human genomics to decipher biological mechanisms underlying reproductive ageing and fertility in women
Stankovic, Stasa
Women are born with a non-renewable ovarian reserve, which is depleted throughout reproductive life. When this reserve is exhausted, they experience menopause and cease ovulating. Importantly, menopause timing is highly variable and can impact health outcomes in later life. One in 100 women experience menopause before the age of 40. As natural fertility begins to decline 10 years prior to menopause, the age of menopause impacts reproductive options for many women, leading to increased demand for fertility treatments, which have low success rate. This is especially important as more women delay childbearing. Endocrine and imaging tests used in the clinical setting only record changes in ovarian function that have already taken place, thus disabling early prediction and timely identification of women with reduced reproductive lifespan. Human genetic studies have attempted to overcome this problem by identifying genetic markers associated with menopause timing and thus providing substantial insight into the biological mechanisms governing ovarian ageing. However, previous approaches have been largely restricted to assessing common genetic variation, leaving many aspects of the trait biology unexplored. This dissertation describes five distinct projects that advance our understanding of the genetic determinants of female reproductive ageing by employing state-of-art genomic and proteomic technologies with robust functional models. Chapter 3 uses whole exome sequence data to identify rare protein-coding variants associated with menopause timing in ~120K women in the UK Biobank (UKBB), and implicates five novel ANM genes with effect sizes up to ~5 times larger than previously discovered for common variants. Notably, heterozygous loss of ZNF518A shortens reproductive lifespan by delaying puberty timing in girls and reducing ANM by nearly 6 years in carriers, an effect larger than any variation currently tested in clinical genetics for premature ovarian ageing. Furthermore, I provide evidence that ZNF518A is a master transcriptional regulator of ovarian development and establishment of the ovarian reserve in foetal life, thus highlighting novel mechanisms involved in ANM aetiology. I also identify a new cancer predisposition gene, SAMHD1, which has a comparable effect size in women and men to well-established genes such as CHEK2, further reinforcing the link between cancer and reproductive ageing. Finally, I show that mothers with genetic susceptibility to earlier ovarian ageing have a higher rate of de novo mutations in their offspring. This provides direct evidence that female germline mutation rate is heritable and highlights a mechanism for maternal effects on offspring health. Chapter 4 extends the exome sequence analysis to an extreme form of early menopause, i.e. POI, which is often considered a monogenic disorder, with pathogenic mutations reported in ~100 genes. However, such reports are based 5 on small numbers of individuals without independent replication, or/and no functional validation. I systematically evaluate the penetrance of these reported genes in ~120K UKBB women, 2,231 of whom reported ANM before age 40. In this largest study of POI to date, I find limited evidence to support any previously reported autosomal dominant gene. For nearly all these genes I could rule out even modest penetrance, with 97.8% of all identified protein truncating variants found in reproductively healthy women with ANM over 40. In addition, I demonstrate novel haploinsufficiency effects in studied POI genes, including TWNK and SOHLH2. Collectively my results suggest that most POI cases are likely oligogenic or polygenic in nature, which has major implications for future clinical genetic testing and counselling. Chapter 5 presents the first proteogenomic study for the ANM targeting 4,775 distinct proteins measured from plasma samples of 10,713 European ancestry individuals in the Fenland study. Although this analysis did not identify robust protein candidates associated with ANM, it demonstrates the potential of such approaches to discover new biomarkers. Chapter 6 presents the largest genomic meta-analysis for age at menarche on ~566,000 women of European ancestry and 696 genomic loci that contribute to regulation of menarche timing. I use this data to explore biological mechanisms and overlap between genetic architectures of reproductive health outcomes. I provide the first evidence on the enrichment of DDR mechanisms for menarche timing, indicating the involvement of DDR in regulation of both extremes of reproductive lifespan, i.e. menarche and menopause. In addition, I report first gene candidates that I speculate may act via oocyte-specific mechanisms to modify reproductive longevity. I also highlight DDR and other novel mechanisms, including ribosome biogenesis, which impact multiple reproductive health outcomes, such as polycystic ovarian syndrome (PCOS), twinning and number of children (NEB). Finally, I demonstrate the first population genomic evidence on the role of DDR related mechanisms in various anthropometric, metabolic and reproductive health outcomes, indicating that DDR could act as a marker of health outcomes beyond cancer. Combining human genomic evidence with cutting edge CRISPR technology and the In vitro gametogenesis system, in Chapter 7 I investigate the role of PARP-1 in proliferation of primordial germ cells during the establishment of the ovarian reserve. I demonstrate suggestive evidence on the role of PARP-1 in decreasing ANM in women and, paradoxically, that deletion of PARP-1 increases the efficiency of primordial germ cell production in vitro. I speculate that, despite the initial increase in primordial germ cells in the PARP-1 knockout, the quality of these cells could be compromised, thus ultimately limiting the functional ovarian pool. Collectively, these findings provide significant insights into the biological processes of reproductive ageing in women and have the potential to guide future experimental work aimed towards identification of new therapies for enhancing reproductive function and preserving fertility in women, as well as designing intervention strategies to prevent or diminish menopause-related health outcomes.
Embargo
Detection, causes and consequences of sex chromosome mosaicism
Zhao, Yajie; Zhao, Yajie [0000-0002-2747-0219]
Sex chromosome mosaicism, including male mosaic loss of chromosome Y (LOY) and female mosaic loss of chromosome X (LOX), is the most common form of clonal haematopoiesis (CH) that can be defined as the age-related clonal expansion of blood cells with somatic mutations. With the decreased cost of sequencing, the development of new bioinformatics methods and the emergence of large cohorts with both genotype and phenotype data, there has been much progress in the detection, causes and consequences of sex chromosome mosaicism especially LOY. On the contrary, the studies of LOX are still very limited. The most recent genome-wide association study (GWAS) to investigate the genetic determinants of LOY in 205,011 males identified 156 independent signals and highlighted a key role for genes involved in cell-cycle regulation and DNA damage response. Population studies typically determine LOY using genotype intensities derived from genotype array data, the accuracy of which varies by the number of Y chromosome probes on the array and are technically noisy. Inaccurate estimation of LOY reduces the power to identify genetic and phenotypic associations with LOY. To overcome these constraints, I developed a robust estimator of LOY , which was derived from several orthogonal approaches using both whole exome sequence and genotype array data. The same method was also implemented for LOX. In chapter 2, in genetic data derived from 205,604 UK Biobank males and 243,765 females, the new method improved the accuracy of LOY/LOX estimation as measured by the strength of association between LOY/LOX and age, smoking status, and polygenic risk of LOY/LOX derived from previous GWAS. In chapter 3, I then used this revised and validated LOY instrument to conduct a new GWAS of LOY status in the UK Biobank. Beyond the previously identified 156 signals, I identified 22 novel LOY-associated loci. I leveraged the shared genetic architecture between LOY and other related traits to improve the power to identify variants associated with the risk of myeloproliferative neoplasm (MPN). Based on available MPN GWAS summary statistics, I identified 13 novel loci reaching genome-wide significance, including locus near PARP1, which encodes an established target of cancer therapy. The method used to detect somatic LOY/LOX can also be used to identify congenital sex chromosome abnormalities. In chapter 4, the detection method and characterisation of male sex chromosome abnormalities were reported, as a similar study on female sex chromosome abnormalities in UK Biobank had already been published. The whole exome sequence also provided the chance to explore the effect of rare non-synonymous variants, which are rarely captured by GWAS arrays. In chapter 5, the first exome-wide association study (ExWAS) for LOY was conducted on over 80,000 men from UK Biobank. As well as CHEK2, which had been identified on a previous GWAS on LOY, a novel gene, GIGYF1, was identified, in which loss-of-function variants increased the risk of LOY and Type 2 diabetes (T2D) by 6-fold. This finding illuminated the potential link between LOY and metabolism. In chapter 6, the first ExWAS of LOX and an extended ExWAS of LOY were performed on over 450,000 samples from UK Biobank. For LOY, the power increase was observed for the two identified genes, CHEK2 and GIGYF1. In addition, loss of function variants in three clonal haematopoiesis of indeterminate potential (CHIP) genes, DNMT3A, TET2 and ASXL1, were negatively associated with LOY. For LOX, rare damaging variants in FBXO10 were identified to increase the risk of LOX. In summary, this thesis shows that the accuracy of estimating LOY/LOX was improved by combining multiple approaches using both GWAS array and whole exome sequence data. Using both GWAS and ExWAS approaches, the thesis further improved the understanding of the genetic causes of sex chromosome mosaicism. This innovative approach improved the power to detect novel mechanisms that regulate clonal mosaicism in blood and can be used to enhance the identification of novel genes associated with the risk of related cancers.
Open Access
What influences government policymaking? The case of childhood obesity in England
Theis, Dolly Rose Zarina
Abstract What influences government policymaking? The case of childhood obesity in England | Dolly Rose Zarina Theis In England today, four out of the top five risk factors of healthy life years lost to death, disability and disease are related to diet and physical activity. The government has proposed hundreds of policies since the early 1990s related to these behaviours. Such policy has largely been presented as ‘obesity policy’, or at least presented as solutions to tackle increased obesity prevalence and related inequalities. In 1993, 58% of men, 49% of women and 25% of children aged 2 to 15 in England were living with obesity or excess weight, which increased to 68%, 60% and 30% respectively by 2019. The aim of this thesis was to investigate why, after 30 years of government obesity policy, has obesity prevalence and related inequalities not been successfully reduced, and in particular to understand how and why government obesity policy comes about. Study 1 was a mixed-methods analysis of all government obesity strategies and policies in England published between 1992 and 2020 using a theory-based analytical framework, content analysis and applied thematic analysis. The interpretation drew on both thematic analysis and quantitative findings. I found that the government has published 14 strategies either wholly or partially dedicated to tackling obesity in England in the last 30 years and that these have contained 689 individual policies. Policies have largely been proposed in a way that does not readily lead to implementation; the majority rely on individuals to change their own behaviour rather than making that easier by shaping external influences; and the government has relied more on voluntary rather than regulatory measures. The findings indicate that the government’s failure to tackle obesity so far may not only be due to the nature and types of policies proposed, but also the way government has proposed them. Drawing on Study 1, I adopted a pragmatic approach to conduct an in-depth case study to understand how one of the 14 obesity strategies – Childhood Obesity: A plan for action (2016) (COP) – came about. Study 2 applied theory-testing process-tracing to examine how COP came about, including what (e.g., evidence and events) and who was most influential, and study 3 also applied theory-testing process- tracing to examine the particular role of policy entrepreneurs by analysing the influence of celebrity chef and campaigner Jamie Oliver. I developed a novel theoretical conceptual framework combining the core concepts from three policy process theories – Multiple Streams Framework, Advocacy Coalition Framework and Punctuated Equilibrium Theory - to test in Study 2, and for Study 3, I tested Aviram et al.’s (2020) policy entrepreneur framework. 2 I found that policy process and policy entrepreneur theory helped to explain the key influences in the policy process, but not necessarily the causal order or relative importance at particular times. In Study 2, I found that the government policy process leading up to COP published in 2016 involved all key conditions for policy change, as identified in previous studies, but it was the substantial expert-seeking activities, political will-building between key political actors, actions of policy entrepreneurs, key institutional factors (political cycles and changes in government), and policy windows that enabled it to result in policy change. Many of these influences were more influential after the government’s decision agenda had been set and policy formation had begun. The case showed how much of the most important policy processes were largely hidden from public view and even from members of government. For example, the Soft Drinks Industry Levy (SDIL) was almost an entirely hidden policy process until it was announced in the March 2016 Budget and demonstrated the potential effectiveness of political considerations in increasing policy experimentation and innovation, as it led to the tailored sugar tax design. The case also demonstrated how exogenous events can obstruct policy and political continuity. In Study 3, I found that the most influential strategies involved a combination at first to build momentum around a particular policy problem and solution, followed by gaining access to decision- makers and strategically using symbols and storytelling to frame issues and solutions persuasively. He demonstrated how effective being “relentless but practical” can be, i.e., not relenting in efforts to achieve policy change, but recognising that political decision-making is difficult, so welcoming even imperfect policy change or progress. The findings in this thesis shed novel light on government obesity policy and the related policy process in England, emphasising that process is just as important as the policy ideas themselves. The substantial scale and scope and methodological nature of the research conducted in this thesis provides a broad and deep understanding of government obesity policymaking in England, with several key implications for policy, practice and research. The thesis sheds light on the substantial gap in empirical research that uses and applies theory on the government obesity policy process, particularly in the context of England. The studies help fill that gap whilst offering guidance on possible future research, including critically assessing the quality of the most influential evidence used in the policy process or comparative research that analyses the government obesity policy process under different governments or between different countries. The thesis also provides useful learnings for policy and practice, including how to propose policies in a way that more readily leads to implementation, how to create conditions that increase the chance of policy change, and what strategies and traits to use to influence the policy process more effectively.
Open Access
The role of mental health in adult behavioural weight management interventions
Jones, Rebecca; Jones, Beckie [0000-0003-2197-1175]
Established evidence reports that there is a bidirectional relationship between obesity and mental health, with obesity as both a cause and consequence of poor mental health. Treatments for obesity and poor mental health should account for this relationship, but often this is not the case. Behavioural weight management interventions are the most common form of obesity treatment across the United Kingdom. Whilst there is good evidence that these interventions can benefit physical health, the evidence for the effect on mental health is limited and unclear. By understanding how these interventions may impact mental health, potential adverse effects can be identified, and future intervention development informed to provide more effective support. The overall aim of this thesis was to investigate the role of participant mental health in adult behavioural weight management interventions. The specific objectives were (i) to determine the short- and long-term impact of behavioural weight management interventions on the mental health of adults with overweight and obesity; (ii) to identify how participant mental health is associated with attendance and engagement with a behavioural weight management intervention and trial; (iii) to identify participant characteristics associated with changes in mental health in adults with obesity during and after a behavioural weight management intervention; and (iv) to explore participant experiences of a behavioural weight management intervention to better understand how well the intervention supports participant mental health, and how the intervention could be adapted to provide more effective support. In Chapter Two, I conducted a systematic review and meta-analysis to assess the impact of behavioural weight management interventions on mental health in adults with overweight and obesity, compared to minimal intervention, ‘standard care’, or inactive control groups. I found evidence to suggest that, on average, interventions may benefit some aspects of mental health at intervention-end and 12 months from baseline. Notably, I found no evidence to suggest that interventions negatively impacted mental health (relative to comparator groups). In Chapter Three, I present the study details and participant characteristics from the Weight loss Referrals for Adults in Primary care (WRAP) trial, which acted as a data source for Chapters Four, Five, and Six. In Chapter Four, I conducted quantitative analyses to investigate whether participant mental health at baseline was associated with attendance and engagement with a behavioural weight management intervention and completion of follow-up assessments in the associated randomised controlled trial. I found evidence to suggest that intervention participants are less likely to attend intervention sessions, engage with intervention resources, and attend study follow-up visits if they report higher levels of depression or anxiety or lower scores for quality of life or satisfaction with life at baseline. In Chapter Five, I conducted quantitative analyses to assess the long-term impact of behavioural weight management interventions on symptoms of depression and anxiety. I found no evidence of a difference between intervention and control groups for changes in depression and anxiety symptoms at 5 years from baseline. On average, participants across all randomised groups did not experience meaningful changes (defined by minimal important difference) in depression and anxiety from baseline to 5 years. In Chapter Six, I conducted quantitative analyses to identify participant characteristics associated with changes in mental health during and after a behavioural weight management intervention. I found that those reporting higher baseline anxiety were likely to experience decreases in anxiety symptoms and increases in depression symptoms up to 5 years from baseline, whereas those reporting higher baseline depression were likely to experience decreases in depression symptoms and increases in anxiety symptoms up to 5 years from baseline. In Chapter Seven, I explored participants’ mental health experiences during a remote behavioural weight management intervention to support adults with overweight or obesity during the COVID-19 pandemic (SWiM-C). I conducted semi-structured interviews with twenty participants and used reflexive thematic analysis to identify patterns of meaning across the dataset relevant to mental health. Findings suggest that participants experienced multiple factors related to and external to the intervention that negatively impacted their mental health, yet aspects of the SWiM-C intervention appeared to support some participants to adaptively manage the decline in their mental health. As a whole, this thesis offers three main contributions to the field. Firstly, thesis findings suggest that, on average, behavioural weight management interventions appear to have net positive or neutral impacts on mental health. However, a proportion of participants do experience a decline in their mental health, and these appear to be participants beginning the intervention with poorer mental health. Next, my findings suggest that there may be a bidirectional relationship between intervention attendance/engagement and participant mental health. Specifically, findings suggest that i) poorer mental health at baseline is associated with lower rates of intervention attendance and engagement, and that ii) managing competing demands can lead to reduced intervention engagement which subsequentially worsens mental health. Finally, thesis findings suggest that results from trials of behavioural weight management interventions may be biased to those who are most mentally healthy at the beginning of the trial. The findings of this thesis contribute new insight into the role of mental health in adult behavioural weight management interventions. Thesis findings highlight a need for greater research into the role of mental health in behavioural weight management interventions; for example, greater research on i) the impact of interventions on mental health, ii) the mechanisms by which this impact may occur, iii) and approaches to better support participant mental health during weight management efforts would be of value.
Controlled Access
The descriptive and aetiological epidemiology of physical activity: composition, volume, and intensity.
Lindsay, Timothy; Lindsay, Timothy [0000-0003-2857-1764]
Physical activity is known to play a role in the prevention of obesity and related cardiometabolic conditions. However, in order to develop targeted public health interventions, it is first necessary to understand how levels of physical activity vary in different populations, along with the determinants of physical activity and its association with intermediate disease traits. This thesis presents the results of descriptive studies of physical activity in three population cohorts: the UK-based National Diet and Nutrition Survey, the Cambridgeshire-based Fenland Study, and the Russian-based Know Your Heart Study, along with an ecological analysis of 35 population estimates of physical activity energy expenditure from populations as diverse as Arctic Inuit to the Maasai of Kenya. In summary, the analysis shows that physical varies by age, sex, BMI and location. The thesis additionally presents the results of two aetiological studies, one examining the associations between energy intake and macronutrient composition as the exposure, and physical activity energy expenditure as the outcome, and the other examining the joint associations of physical activity volume and intensity as the exposure with body-fatness as the outcome. Those analyses show that volume, be it intake or expenditure, is more strongly associated with the outcome than the underlying macronutrient composition or intensity. Overall, the body of work presented in this thesis represents a meaningful addition to the physical activity literature and adds specific additional information about the determinants of, and associations with, physical activity.
Open Access
Aetiological role of early lifestyle exposures in puberty timing
Cheng, Tuck Seng; Cheng, Tuck Seng [0000-0003-4442-7332]
Amidst the global secular trends towards earlier timing of pubertal development, there are abundant evidence from various populations that early puberty timing is associated with higher risks for a wide range of subsequent adverse physical and mental health outcomes. Despite the increasing recognition that rapid growth and obesity during prepubertal childhood may promote earlier puberty, it is unclear whether lifestyle behaviours are determinants of puberty timing. This thesis aimed to explore whether diet and physical activity in childhood are associated with puberty timing, using a combination of robust analytical approaches. First, to understand the disease relevance of puberty timing independent of adiposity, published findings on the associations between puberty timing and risks for type 2 diabetes and/or impaired glucose tolerance (T2D/IGT) were systematically reviewed and pooled by inverse-variance-weighted random-effects models. Based on 28 studies in Western and Asian settings, earlier timing of puberty in females, indicated by age at menarche, was consistently associated with higher T2D/IGT risk in women (n=1,228,306). Similarly, in the only one identified study in males (n=197,714 British men), relatively younger (versus ‘about average’) voice breaking was associated with higher risk of T2D. These associations were only partially mediated by adiposity, thus warranting examination of the determinants of puberty timing that act through or are independent of changes in adiposity. I then investigated the associations of total energy and macronutrient intakes with timings of several puberty traits in boys (n=3811) and girls (n=3919) in the Avon Longitudinal Study of Parents and Children in the United Kingdom (UK). Integrating comprehensive data on dietary intakes and puberty development from early childhood until young adulthood, higher prepubertal childhood intakes of total energy in both sexes, and protein (including animal and plant-based proteins) in girls were associated with earlier timings of puberty onset and progression and peak height velocity, independent of adiposity during puberty. Further, in the same cohort, I examined the associations of dietary and plasma phospholipid fatty acids with puberty timing in boys (n=3654) and girls (n=3872). Based on repeatedly assessed dietary intakes and objective measures of fatty acids during prepuberty, higher dietary intake of polyunsaturated fatty acids, and higher plasma concentrations of dihomo-γ-linolenic acid (20:3n6) and palmitoleic acid (16:1n7) were associated with earlier puberty timing in girls, but not in boys. In Mendelian Randomization (MR) analyses, higher genetically predicted circulating dihomo-γ-linolenic acid but not palmitoleic acid was associated with earlier menarche in girls. Finally, I tested the associations between accelerometer-measured physical activity prior to puberty and subsequent puberty timing in boys (n=2531) and girls (n=3079) in the UK Millennium Cohort Study. Lower total daily movement, regardless of physical activity intensity, was consistently associated with higher risk for earlier puberty timing in both sexes, independent of body mass index. Using a MR model approach, higher genetically predicted sedentary activities were associated with earlier puberty timing. This thesis uses a variety of data types and analytical triangulation approaches to demonstrate specific lifestyle behaviours, namely dietary intakes and physical activity, during prepubertal childhood, as potential determinants of the timing of pubertal development in both boys and girls. These findings may inform future interventions to avoid early puberty timing as part of a life course approach to prevention of non-communicable diseases.
Open Access
Investigation of Genetic and Behavioural Determinants of Type 2 diabetes and Glycaemic Traits
Cai, Lina; Cai, Lina [0000-0003-2598-8388]
Type 2 diabetes (T2D) is a complex chronic disease which is associated with micro- and macro-vascular complications and premature mortality. This multifactorial disease originates from a complex interplay between genetic, behavioural and environmental risk factors, the underlying mechanisms of which are unclear. The goal of this thesis was to investigate the contributions of genetic, metabolic and behavioural risk factors in the aetiology of T2D by studying large-scale population studies, in order to provide insights for the development of T2D prevention and intervention strategies. I first conducted a genome-wide association study on T2D in a large prospective cohort study for T2D, the EPIC-InterAct study. This work provides a valuable resource for the research community to conduct in-depth genetic investigations on T2D. The strongest T2D-associated genetic variant was at the established TCF7L2 locus. I then used the profiling of behavioural factors in the EPIC-InterAct study to show that there was no interaction between TCF7L2 genetic variants and an index of the number of health behaviour goals achieved, a measure that was strongly associated with diabetes risk. In a meta-analysis of three randomised controlled trials designed to investigate the effect of lifestyle intervention on the risk of developing T2D, I showed that there was no overall interaction between TCF7L2 and allocation to the intervention rather than the control arm. However, there was an interaction in one trial, which focused more on physical activity and dietary change than on weight change. In an analysis of a detailed quantitative metabolic trait study, I demonstrated a specific interaction between TCF7L2 and physical activity energy expenditure (PAEE). These data suggest that genetic targeting could have additive effects with health behaviour interventions and may be more valuable for personalised prevention if linked to very specific behaviours. To build on this observation and explore the potential mechanisms through which physical activity may affect the risk of T2D in different genetic subgroups, I undertook a systematic investigation of interaction effects between PAEE and genetic risk scores for glycaemic traits in the Fenland study. I did not find any significant interaction. Alternatively, using an agnostic approach, I searched for potential interactions with PAEE across the genome. Preliminary analyses detected three variants showing genome-wide significant interaction effects, although the mechanisms were unclear. As obesity is a strong risk factor for T2D and a previous study had reported that BMI modifies the effect of LAMA1 gene on T2D risk, I undertook an in-depth analysis of this potential interaction in the large-scale UKBB and EPIC-InterAct studies. I showed and confirmed that LAMA1 has a stronger effect on T2D among lean individuals compared with obese individuals in independent studies. Observational studies suggest that low cardiovascular fitness (CRF) is an independent T2D risk factor. However, it is unclear whether the association is causal or is due to confounding. I performed the largest genetic discovery of cardiorespiratory fitness in the UKBB study and developed a genetic risk score for CRF. In Mendelian randomisation analyses, I showed that the associations of this score with T2D and hyperinsulinaemia were compatible with underlying causal relationships. High-throughput metabolomics based on large-scale population studies offers a great opportunity for providing direct biological insights and identifying physiological alterations linking risk factors to T2D. I characterised the metabolic profiles of physical activity and cardiorespiratory fitness and identified shared and distinct signatures highlighting the roles of branched-chain amino acid metabolism and fatty acid oxidation. Overall, my PhD work contributes towards 1) a wider understanding of interpersonal differences for diabetes risk in response to behavioural factors based on variable genetic make-up and its implication in population-level diabetes prevention and intervention strategies 2) the discovery of the genetic basis of cardiorespiratory fitness and the provision of strong evidence supporting its causal role for T2D; 3) the characterisation of metabolic profiles of physical activity and cardiorespiratory fitness and the generation of hypotheses for potential biological pathways and physiological mechanisms underlying their influences on diabetes development.
Open Access
Changes to marketing in response to sugary beverage taxation: the Soft Drinks Industry Levy in the United Kingdom
Forde, Hannah; Forde, Hannah [0000-0001-7447-7264]
Background: Overall sugar intake in the United Kingdom (UK) continues to exceed recommended levels. As high sugar consumption contributes to multiple non-communicable diseases, the World Health Organization recommends the implementation of sugary beverage taxes (SBT). To this end, the UK government introduced a levy on soft drinks manufacturers in 2018, known as the Soft Drinks Industry Levy (SDIL). SBTs are likely to lead to a variety of reactions among stakeholders across the food sector that may, in turn, impact on beverage, and sugar, consumption. Reactions of soft drinks companies may be particularly important in this regard. It has been hypothesised that soft drinks companies may respond to an SBT with marketing to protect their profits. Many definitions of marketing exist, sharing an understanding that marketing is a multi-component process that encompasses many activities, often coordinated by strategy. There is substantial literature acknowledging that marketing is an important determinant of dietary behaviours and inequalities. Though existing research on SBTs has explored their impacts on some features of marketing (such as changes to price or formulation), many other features have been overlooked (such as promotion). Furthermore, existing evidence has often failed to situate itself within a wider understanding of marketing as reflecting strategic coordination of activities. This risks overlooking the mechanisms through which changes in marketing in response to an SBT may enhances or undermine the SBTs impact on public health. Aims: This dissertation aimed to understand what ‘marketing’ encompasses in the context of SBTs, explore whether marketing changes are likely to influence the outcomes of SBTs, and assess marketing changes that followed the SDIL. Method 1: First, a scoping review of reviews using principles of critical interpretive synthesis was used to find conceptual confusion in the study of food and drink marketing in the public health literature to date. From these results, I concluded that future studies of marketing, including those specific to SBTs, should be grounded in the understanding that a broad range of separate marketing activities take effect in integration. Method 2: Second, I fitted multinomial logistic regression models to the 2017 cross-section of the International Food Policy Study, to explore the association between exposure to one form of marketing – sugary beverage promotion – and sugary beverage consumption. In doing so, I found exposure to promotion was associated with the consumption of sugary beverages. . The results tentatively suggest that changes to this form of sugary beverage marketing following an SBT could influence subsequent consumption behaviours, and thus the outcomes of the SBT. Method 3: Third, thematic analysis of 18 interviews with representatives from academia, civil society and industry, explored how marketing might change following the SDIL. Analyses unearthed the breadth and variety of anticipated changes that marketing might encompass, the decision-making contributing to a companies’ selection of these changes, and factors within and external to a company that might lead to heterogeneous responses across the soft drinks industry. Method 4: Finally, I used interrupted time series analyses to explore changes in leading soft drinks companies’ expenditure on advertising following the announcement and implementation of the SDIL. Analyses used advertising expenditure data supplied by Nielsen, a market research company, that measures expenditure through various media types (though excluding some novel forms of digital media). Though there was no evidence of changes in expenditure, it is possible that promotion changed in other ways, for example through greater use of digital media platforms. Conclusions: Evidence presented in this dissertation adds to existing literature by presenting a more comprehensive study of marketing in the context of SBTs. Together, this evidence illustrates that ‘marketing’ could be an important lens through which the complexity and breadth of soft drinks company responses to an SBT might be understood. Doing so has the potential to inform the design of policy strategies around SBTs that pre-empt adverse responses by soft drinks companies, such as complementary polices that restrict any increases in advertising, and thus may have better health outcomes. Moreover, embedding a greater appreciation of marketing in the design of public health policies might help them elicit commercial responses that amplify favourable health outcomes without harming profit, achieving both public health and commercial goals.
Open Access
Investigating the Role of Inflammatory Biomarkers and Incretins in the Aetiology of Type 2 Diabetes and Coronary Heart Disease using Human Genetics
Bowker, Nicholas; Bowker, Nicholas [0000-0002-8794-894X]
Background: The relevance of inflammatory and incretin-related signalling pathways in the aetiology of cardiometabolic diseases is of considerable pharmacological interest but remains uncertain. Evidence from animal models and epidemiological studies point to a role for chronic inflammation for the pathophysiology of type 2 diabetes (T2D), with interleukin-6 (IL-6) proposed as a key player. Incretins such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are hormones that stimulate a decrease in blood glucose. Their receptors are existing T2D drug targets, yet the efficacy and safety of GIP mono- and dual agonists e.g. tirzepatide are still unknown. Genetic approaches can help to address limitations of earlier studies and systematically assess the roles of IL-6 and GIP mediated signalling for cardiometabolic diseases. Aims: To investigate the potential causal roles of IL-6 and GIP receptor signalling for the risk of cardiometabolic diseases, specifically T2D and coronary heart disease (CHD), through analysis of large-scale genetic data from patient and population-based studies. Methods: 1) Systematic literature searches were conducted for each topic and the existing evidence summarised in the introduction. 2) A partial loss-of-function missense variant (Asp358Ala) in the IL-6 receptor gene (IL6R) was used to estimate the effect of IL-6R inhibition on T2D risk in 260,614 cases and 1,350,640 controls. 3) An observational meta-analysis of new unpublished and published studies (5,421 T2D cases, 31,562 non-cases) was conducted to compare observational and genetically predicted effects of IL6 levels on T2D. 4) The specificity of the IL6R variant was tested by including genetic and observational associations from a range of other inflammatory markers. 5) Large-scale genomic data from 23 cardiometabolic diseases as well as anthropometric, lipid, glycaemic and ~6,000 ‘omic (metabolomic and proteomic) traits were brought together to systematically assess associations of a known missense variant in GIPR, E354, and infer specificity and potential beneficial or harmful effects of GIPR mono agonism. Bayesian multi-trait colocalisation was used to distinguish trait clusters driven by shared causal variants to identify independent causal variants driving specific trait associations. Findings: IL-6 levels (both measured and genetically predicted) were associated with T2D risk, with a small but significant effect (odds ratio (OR) 95% confidence interval (CI) for the Asp358Ala partial loss of function variant 0.98 (0.97, 0.99); p=2x10-7). Genetic mediation analyses estimated that IL-6 levels mediated up to 5% of the association between BMI and T2D. Colocalisation results at the GIPR locus identify E354 as the driver of a shared signal for GIP (higher), T2D and related traits (lower risk), and adiposity (higher) with high posterior probability (>0.97), and demonstrate that this is distinct from cardiovascular and lipid associations nearby in APOE (rs7412; PP >0.99). Interpretation: Large-scale genetic and prospective observational data provide evidence that IL-6 mediated inflammation is implicated in T2D aetiology but suggest that the impact of this pathway on disease risk in the general population is likely to be small. At the GIPR locus, distinct genetic signals were shown to drive associations of glycaemic and adiposity traits versus CHD and lipid traits. This study provides evidence that inclusion of GIPR agonists in dual agonists could potentiate the protective effect of GLP1 agonists on diabetes without undue cardiovascular risk, while the effects of GIP on weight gain are counteracted by GLP-1.
Open Access
Digital phenotyping through multimodal, unobtrusive sensing
(2021-02-23) Perez Pozuelo, Ignacio; Perez Pozuelo, Ignacio [0000-0003-1150-2754]
The growing adoption of multimodal wearable and mobile devices, such as smartphones and wrist-worn watches has generated an increase in the collection of physiological and behavioural data at scale. This digital phenotyping data enables researchers to make inferences regarding users’ physical and mental health at scale, for the first time. However, translating this data into actionable insights requires computational approaches that turn unlabelled, multimodal time-series sensor data into validated measures that can be interpreted at scale. This thesis describes the derivation of novel computational methods that leverage digital phenotyping data from wearable devices in large-scale populations to infer physical behaviours. These methods combine insights from signal processing, data mining and machine learning alongside domain knowledge in physical activity and sleep epidemiology. First, the inference of sleeping windows in free-living conditions through a heart rate sensing approach is explored. This algorithm is particularly valuable in the absence of ground truth or sleep diaries given its simplicity, adaptability and capacity for personalization. I then explore multistage sleep classification through combined movement and cardiac wearable sensing and machine learning. Further, I demonstrate that postural changes detected through wrist accelerometers can inform habitual behaviours and are valuable complements to traditional, intensity-based physical activity metrics. I then leverage the concomitant responses of heart rate to physical activity that can be captured through multimodal wearable sensors through a self-supervised training task. The resulting embeddings from this task are shown to be useful for the downstream classification of demographic factors, BMI, energy expenditure and cardiorespiratory fitness. Finally, I describe a deep learning model for the adaptive inference of cardiorespiratory fitness (VO2max) using wearable data in free living conditions. I demonstrate the robustness of the model in a large UK population and show the models’ adaptability by evaluating its performance in a subset of the population with repeated measures ~6 years after the original recordings. Together, this work increases the potential of multimodal wearable and mobile sensors for physical activity and behavioural inferences in population studies. In particular, this thesis showcases the potential of using wearable devices to make valuable physical activity, sleep and fitness inferences in large cohort studies. Given the nature of the data collected and the fact that most of this data is currently generated by commercial providers and not research institutes, laying the foundations for responsible data governance and ethical use of these technologies will be critical to building trust and enabling the development of the field of digital phenotyping.
Open Access
Common 'Inborn Errors' of Metabolism in the General Population
(2021-03-23) Au Yeung, Victoria; Au Yeung, Victoria [0000-0002-0823-3963]
Inborn errors of metabolism (IEMs) are a group of disorders characterised by the toxic accumulation or deficiency of circulating molecules (‘metabolites’) caused by rare genetic mutations. Previous studies have identified select examples where common variants at genes known to cause rare Mendelian diseases, including IEMs (e.g. LPL, DBH, PPM1K), are linked to phenotypic consequences in the general population that also occur in patients with the corresponding rare disease. Advances in genetic and metabolic profiling at an epidemiological scale now provide an opportunity to systematically identify such examples in the population and characterise their downstream effects on health. To assess the value of untargeted metabolomic profiling for the study of common complex diseases, I identified candidate mediators of the association between weight gain and future type 2 diabetes risk based on untargeted, large-scale metabolomic profiling of a large prospective cohort. Integration of metabolomics, genetic profiling and comprehensive longitudinal follow up for a range of diseases together with the application of Bayesian and genetic epidemiological methods enabled the identification of 20 candidate mediators. These reflected genetic susceptibility to adiposity and insulin resistance and explained most of the increased T2D risk associated with weight gain. To systematically characterise the phenotypic effects of variation at IEM-causing genes, I identified sentinel variants at these genes associated with plasma metabolites affected in the corresponding IEM across the genome. Of the 202 ‘IEM familiar’ variants (IFVs) detected, 187 at 89 loci were not previously reported as pathogenic for the corresponding IEM in ClinVar and 51 of these were associated with extreme metabolite levels (<2.5th or >97.5th percentile) or had non-additive effects on metabolite levels. Phenome-wide assessment identified 1,553 IFV-phenotype associations at 108 loci. Of the detected associations, 703 at 54 loci were of particular interest as the phenotype related to a symptom of the corresponding IEM. At 24 of these 54 loci, genetic colocalisation detected shared genetic signals for IEM-related metabolites and phenotypes. For example, in line with norepinephrine deficiency causing dizziness on standing in severe cases of rare orthostatic hypotension (OMIM #223360), I identified a genetic signal at the dopamine beta hydroxylase (DBH) locus associated with decreased levels of the downstream catecholamine vanillylmandelate in the general population (IFV EAF=0.074). This signal was shared with that for lower risk of hypertension (based on 462,933 participants in UK Biobank) and other blood pressure-related phenotypes with high posterior probability of colocalisation (PPcolocalisation=0.94, with >99% of the probability explained by the IFV). This work uses untargeted metabolomic profiling to identify underlying disease mechanisms and demonstrate the proof-of-principle that common variants can have similar health consequences to those caused by rare mutations at the same IEM gene.
Open Access
A mixed methods investigation of factors influencing decision-making for new active living infrastructure in different contexts
Le Gouais, Anna; Le Gouais, Anna [0000-0002-3800-2090]
Physical inactivity increases the risk of many non-communicable diseases. The built environment is an important determinant of physical activity and the ways in which places are designed and built may lock in, or out, opportunities for greater physical activity and improved health outcomes. Policies and guidelines support the creation of active living infrastructure (walking and cycling infrastructure and open spaces); however, local social, environmental and political context may influence what is built in practice. The aim of this mixed methods thesis is to investigate what influences the creation of new active living infrastructure across different contexts. It also explores the value of different methods to demonstrate impacts of new walking and cycling infrastructure. The first two studies are qualitative investigations exploring decision-making for active living infrastructure across three areas of England and in Jamaica. These involve semi-structured interviews with public health practitioners, urban and transport planners, environmental and civil society stakeholders and councillors. I then synthesise the findings from these studies to gain additional insights from across different country contexts. Building on the qualitative study findings, I investigate quantitatively the association of context with use, users and benefit-cost ratios of new walking and cycling infrastructure, using repeat cross-sectional data from 84 new walking and cycling schemes in the United Kingdom (Sustrans’ Connect2 programme). I also explore the association between use and physical activity using pragmatic monitoring data from Connect2 alongside more scientifically rigorous longitudinal cohort data from three of those schemes (the iConnect study). My final qualitative study follows on to investigate issues about perceptions of contextual relevance of case study examples. This involves semi-structured interviews with a sub-sample of participants from the first England qualitative study, using Connect2 walking and cycling route examples and results from my quantitative analysis as discussion prompts. I identified three themes in this thesis: how to bridge the gap between policy and practice for creating active living infrastructure; issues of inequality; and synthesising evaluations across contexts. I find that the benefits of active living infrastructure can be under-valued and suggest that formal and informal roles can facilitate sharing of believable stories, including case studies, to influence decision-makers. Whilst new walking and cycling infrastructure is associated with large relative increases in pedestrians and cyclists, and increases in physical activity, lack of monitoring and evaluation, reliance on market forces, and views on individual agency may be detrimental to tackling inequality. Greater collaboration between public health practitioners and non-health sectors could emphasise multi-sectoral outcomes of active living infrastructure, including wider economic impacts.
Open Access
Early Life Determinants of Metabolic and Reproductive Health
Hollis, Benjamin
Events in early life have consistently been associated with health outcomes in later life. The ‘developmental origins’ theory first hypothesised that adverse conditions in-utero can lead to physiological adaptations in the developing foetus which have long lasting influences on health. This concept has been extended to early childhood and adolescence, whereby exposures during critical periods of development can impact health throughout the life course of an individual. In particular, a secular trend for a decreasing age of puberty onset has been linked to the global increases in prevalence of cardio-metabolic diseases and cancer. It has been suggested that childhood obesity and lifetime sex hormone exposure may act as key mediating factors in this relationship. As the prevalence of obesity continues to rise globally and consequent comorbidities place an increasing burden on healthcare systems, understanding the mechanisms that link early life events to later life health have become of increasing importance. While environmental exposures are often cited as being highly influential on growth and development, the role of genetics has become gradually more apparent in recent years. This has been aided by the availability of increasingly large data resources. Genetic studies have shown that many developmental traits are highly heritable and share genetic determinants with metabolic and reproductive health outcomes. In this thesis I use data from large-scale, population-based resources to further elucidate the role of genetic and epigenetic factors in explaining observed associations between developmental traits and later life metabolic and reproductive health. I begin by examining the genetic aetiology of puberty timing in men, a key stage of sexual development which is understudied compared to women. I identify 29 novel genes involved in the control of puberty timing, implicating new biological pathways and demonstrate genetic correlations between earlier age of puberty and adverse health in adulthood. I then expand on the theme of genetic discovery by conducting genome-wide association studies (GWAS) for reproductive traits in the UK Biobank study. These outcomes have important societal and public health impacts but many have not previously been investigated from a genetic perspective. I identify over 800 variant-trait associations, highlighting genomic regions with highly pleiotropic influences on a diverse range of reproductive traits. This data is then leveraged to construct a framework for conducting phenome-wide association studies (PheWAS), which is used to explore the extent to which both BMI and sex hormone exposure act as mediating factors to explain the link between earlier puberty and heightened reproductive health risks. I go on to examine mechanisms linking early life markers of development to adult health. I investigate the association between weight at birth and body composition in adulthood, determining that foetal and maternal-specific genetic determinants of birth weight have differential influences on fat and lean mass distribution. Downstream analyses suggest that these operate through distinct biological pathways, adding to our understanding of the association between low birth weight and poor health. Finally, I conduct an epigenome-wide association study (EWAS) as a complementary approach to GWAS for both BMI and puberty timing to identify additional genomic loci associated with both traits. Using EWAS data I present evidence for a casual epigenetic effect on puberty timing, functioning through both BMI-mediated and independent pathways. The findings from this thesis contribute to the understanding of the genetic determinants of early life developmental processes and their relationship with later health, which have important implications for the improvement of individualised disease prevention and management.