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Theses - MRC Epidemiology Unit

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  • ItemEmbargo
    The role of the social environment in adolescent adiposity and physical activity
    Foubister, Campbell; Foubister, Campbell [0000-0002-2625-8478]
    Obesity and physical inactivity during adolescence are associated with an increased risk of mental and physical health outcomes including heart disease, and depression. There are widely accepted benefits of intervening to address excess adiposity and insufficient physical activity. It is important to address the settings that are most pertinent in shaping these. Given adolescents’ social reorienting towards friends and away from parents, the social environment, and in particular, the school, and digital social environment are key focusses of this thesis. This thesis is organised into two linked parts. In the first part of this thesis, I focus on the school social environment. I used data from GoActive, a large-scale physical activity intervention of adolescents living in the East of England (n=1,765). I explored associations between the school policy, social and physical environment and change in adolescent accelerometer-assessed physical activity. I tested many potential predictors of change as a hypotheses-generating exercise (Chapter 3). I found that friendship support for physical activity was predictive of change in physical activity, and that sex and socioeconomic status modified these relationships. In the second part of this thesis, I explored the association between social media use and adiposity using data from the Millennium Cohort Study, a large population-based cohort of young people in the UK. I first investigated these associations cross-sectionally, showing that social media use and measured BMI z-score at age 14 years was associated in girls at the ≥5 hours/day level (vs. 0 to <1 hours/day, no associations for boys) (n=10,798). This association was partially explained by sleep duration, depressive symptoms, body weight satisfaction, and wellbeing (Chapter 5). I then explored the prospective association between social media use at age 14 years and change in BMI z-score from age 14 to 17 years in boys and girls (n=8,024). I showed that greater social media use was associated with a lower change in BMI z-score at the 3 to <5 hours/day range (vs. 0 to <1) for boys, and at the 1 to <3 hours/day range for girls (Chapter 6). Overall, the results from my thesis suggests two key findings. First, friendship support for physical activity may be particularly important for increasing physical activity during adolescence. Second, although a negative association was found between social media use and change in BMI z-score at the population level, this finding must be interpreted cautiously given that associations were small, and are not consistent with the few studies completed to date which used self-reported BMI. However, associations differed by sex and there may be specific sub-populations at greater risk (e.g. extreme users, adolescents living with mental health challenges). The overall findings of this thesis highlight a need for further research to understand the potential influence of friendship support for physical activity, and to better understand and harness adolescents’ high engagement with social media use for combatting adolescent obesity.
  • ItemEmbargo
    Young people’s active travel in Asia
    Maulida, Rizka; Maulida, Rizka [0000-0001-6964-8831]
    **Background** The benefits of physical activity have been extensively documented and recognised. In addition to that, numerous studies have demonstrated a clear link between active travel and increased physical activity levels in young people. Active travel also has the potential to reduce air pollution by reducing motorised transport use. The promotion of active travel to school to enhance young people's physical activity and reduce air pollution can be harnessed globally, yet limited evidence exists specifically for Asia. **Aim** This thesis aims to assess the current state of active travel in young people in Asia, study its associations with physical activity and environmental factors, and explore how it is discussed in urban- related policies. **Study 1** I first investigated the association between school travel modes and physical activity levels among young people in Asia. I used an accelerometer-assessed physical activity data from 1,052 6 to 7-year-old school children from Guangzhou, China, to show that individuals who engage in active travel to school accumulate more minutes of moderate to vigorous physical activity overall. The difference ranged from 8% to 16% in average daily minutes of MVPA. **Study 2** In the subsequent analysis, I utilised data from 152,368 adolescents aged 13 to 17 years old from 31 Asian countries included in the Global School-based Student Health Survey to investigate the prevalence of active travel to school among adolescents in Asia. The findings showed that 55% of the adolescents in Asia regularly walk or cycle to school, with large variations observed across countries (e.g., 18% in the United Arab Emirates to 84% in Myanmar). Overall, older and male adolescents, and adolescents with underweight and normal BMI category are more likely to actively travel to school. **Study 3** To investigate what could be driving the between countries variation, in my third study, I examined the association between the prevalence of active travel to school and country-level social and physical environmental correlates in Asia. This study showed that Asian countries with a greater number of people living in urban areas, lower levels of overall adult physical activity and higher levels of night-time light have a lower prevalence of adolescent active travel to school. Country-level physical and social environmental correlates explained some of the regional variance in active travel to school. **Study 4** In the last study, I conducted a document analysis to explore the ways in which young people’s active travel is considered in National Urban Policy (NUP) documents in selected Asian countries and to identify opportunities for supporting the improvement of young people’s active travel in Asia. I applied thematic coding on NUP documents from 15 Asian countries available on the UN-Habitat’s Urban Policy Platform website. The findings showed that countries’ national urban policies in Asia overlooked the opportunity to promote physical activity in young people through active travel and that the link between active travel within the transport context and health is nearly non-existent in these NUP documents. **Conclusions** This thesis provides an understanding of young people’s active travel in Asia and its associations with physical activity, environmental correlates and urban policy. Engaging in active travel to school contributes to more physical activity overall. However, only half of the adolescents in Asia are engaging in active travel to school, with differences between countries driven partially by environmental correlates. National urban policies in Asia overlooked the opportunity to promote physical activity in young people through active travel.
  • ItemEmbargo
    Examining inequalities in behavioural weight management interventions
    Birch, Jack Michael; Birch, Jack [0000-0001-6292-1647]
    Interventions designed to support individuals to change their health behaviours, such as behavioural weight management interventions, typically require a high amount of personal agency (such as time, money, and education) to be effective. As a result, these interventions may benefit advantaged groups with greater resources more than those who are less advantaged, and consequently may be inequitable and exacerbate health inequalities. However, there is currently limited empirical evidence about whether behavioural weight management interventions contribute to inequalities in overweight and obesity. This thesis has examined whether there are inequalities in the attendance and effectiveness of behavioural weight management interventions using data from of randomised controlled trials. Across four projects, I considered inequalities in these interventions in a range of individual-level characteristics captured by the PROGRESS-Plus framework (Place of residence, Race/ethnicity, Occupation, Gender/sex, Education, Socioeconomic status, Social capital, Plus other factors where discrimination may occur such as age and sexual orientation) and across a range of different outcomes (uptake, adherence, weight loss, weight loss maintenance, eating behaviour, physical activity, wellbeing, and mental health). My first project was a systematic review of inequalities in the uptake of, adherence to, and effectiveness of behavioural weight management interventions (thesis Chapter 2). I narratively synthesised data from 103 trials and summarised findings in harvest plots. Fifty-six trials considered inequalities in relation to at least one of intervention or trial uptake (n=15), intervention adherence (n=15), trial attrition (n=32), or weight outcome (n=34). Most trials found no inequalities gradient for trial uptake, intervention adherence and trial attrition. If a gradient was observed, it favoured those considered ‘more advantaged’. A limitation of this systematic review is that the individual analyses in each trial are unlikely to be sufficiently powered to detect inequalities in intervention effectiveness should they exist, and that the data and analyses reported were not similar enough to be meta-analysed. A way to mitigate these limitations is to access individual-level data from trials so that data can be harmonised and appropriate analyses conducted across all trials. Consequently, my second project was a two-stage individual participant data meta-analysis (IPD-MA) of UK-based trials of behavioural weight management interventions (thesis Chapters 3-5). I obtained and harmonised data from 12 out of 14 eligible trials and reanalysed each trial to consider if there were inequalities in 1) the effectiveness of interventions at 12-month follow-up, and 2) attendance of these interventions. I then meta-analysed the relevant coefficients. The difference in weight loss between the intervention and control groups was 0.98kg larger for male compared to female participants, despite lower overall weight loss in men. The difference between intervention and control weight change was 2kg larger for participants of a White ethnicity compared to those from other ethnic groups, showing that these interventions may contribute to inequalities in obesity by ethnicity. I also found some evidence that behavioural weight management interventions had less effect in those who lived in areas of higher deprivation, although this was not consistent across the deprivation gradient. The intervention effect did not differ by occupation, education, socioeconomic status (annual household income), social capital (marital status), and age. There was no association between attendance and ethnicity, occupation, gender/sex, education, socioeconomic status (IMD and annual household income), social capital (marital status), and age. The first two studies in this thesis focused on inequalities in effectiveness of behavioural weight management interventions at the 12-month follow up time point. Generally, there is a paucity of follow up data beyond this time point in UK-based randomised controlled trials. However, in the WRAP (Weight loss Referrals for Adults in Primary Care) trial there was an opportunity to consider if there are inequalities in the weight trajectories of participants up to five-year follow up. In the third study of this thesis, I conducted cohort analyses using data from the WRAP trial to consider if there are inequalities in weight change from one- to five-years post intervention baseline (thesis Chapter 6). This is important as weight regain often occurs post intervention. I did not find evidence of inequalities by ethnicity, occupation, gender, education, nor socioeconomic status, though older age was associated with lesser weight regain or greater weight loss between one- and five-years post-intervention. The final project in this thesis used data from a trial of a web-based intervention to support weight management during Covid-19 (SWiM-C, thesis Chapter 7). I codesigned the baseline demographics questionnaire for this trial; as a result, data across a broad range of PROGRESS-Plus criteria were collected, such as access to green space, food insecurity, and perceived social support. I considered if there were differential effects of the SWiM-C across a range of outcomes including weight, eating behaviour, physical activity, wellbeing, and mental health. I found that the intervention had a differential effect by marital status; it had a greater effect on weight, eating behaviour, and mental health in those who were living as single versus those who were married, in a civil partnership or cohabiting. I also found evidence that the SWiM-C intervention had a greater effect on weight in those who were unable to work due to sickness or disability versus those who were working full-time or were self-employed. I did not find evidence of a differential intervention effect by the other PROGRESS-Plus characteristics on weight, nor did I find consistent evidence of differential intervention effectiveness on the remaining outcomes. Overall, this thesis makes several important contributions to the field. First, I identified characteristics in which there are inequalities in the effectiveness of behavioural weight management interventions. I found that these interventions have a greater effect in men (versus women) and that this effect was produced by men gaining weight overall in the control group; weight loss in the intervention group was similar between men and women. I also found that these interventions were more effective in participants from White, versus minority, ethnic groups, meaning they likely exacerbate existing health inequalities by ethnicity. Second, there were several of the PROGRESS-Plus characteristics I did not find evidence of inequalities in behavioural weight management interventions by, such as occupation, education, and socioeconomic status (particularly annual household income). Similarly, I did not find evidence of inequalities in attendance to behavioural weight management interventions. Third, I assessed the representativeness of trial participants and reporting of inequality related data in trials of behavioural weight management interventions. I found that, beyond gender or sex and age, the PROGRESS-Plus characteristics were inconsistently reported and that trials of behavioural weight management interventions were not representative of the population living with overweight and obesity. The fourth contribution of my thesis to the field is that it adds data to the field where there was a previous paucity of data; this is particularly the case in Chapters 6 and 7 which were the first analyses of inequalities in weight regain following weight loss intervention (Chapter 6) and in outcomes other than weight (Chapter 7). Future research should further explore the inequalities by ethnicity to ensure the effects of behavioural weight management interventions do not widen existing health inequalities, and how to better engage men into generic behavioural weight management interventions given their effectiveness.
  • ItemOpen Access
    Modelling the health impacts of urban transport in Africa
    Tatah, Lambed; Tatah, Lambed [0000-0002-8967-6917]
    Africa is rapidly urbanising and motorising, complicating its existing urban transport impacts such as high road traffic injuries, air pollution, and decreasing physical activity derived from walking and cycling. This situation highlights a need to develop healthy and sustainable urban transport systems on the continent. Modelling studies can help unpack the effects of urban transport plans and policies, thus facilitating evidence generation for policymaking. However, the use of modelling approaches in Africa is limited. This thesis aimed to increase understanding of the health impacts of changes in African urban transport systems through modelling. I started by exploring travel and physical activity behaviours and their data sources in selected African cities to elicit the context and address some challenges related to model data inputs from surveys. Secondly, I explored health integration in urban transport policies to gauge the transport sector’s commitment to supporting health goals and the range of meaningful modelling scenarios for engaging stakeholders in the African context. Thirdly, I reviewed modelling studies on transport health impacts to synthesise modelling approaches and guide model selection and adaptation. Finally, I modelled urban transport health impacts in five African cities for four scenarios: cycling, bus, car and motorcycle. Each scenario represented a 5% increase in the chosen transport mode. Surveys using travel and time-use diaries were valuable sources of travel behaviour data. Travel behaviour case studies from four cities, Nairobi and Kisumu (Kenya), Yaoundé (Cameroon), and Accra (Ghana), showed a wide variation of immobility and daily travel duration across cities, with walking as the primary mode and privately owned small-capacity public transport as the second. Motorcycles were also an essential component of public transportation in some cities. The physical activity case study from Accra showed high levels of background physical activity with a substantial contribution from transport. However, there was a significant disagreement between the Global Physical Activity Questionnaire and travel diary physical activity measurements, signalling precaution when using these crucial data sources for modelling. The policy analysis from Cameroon showed the integration of physical activity and non-communicable diseases in the policies of some sectors but not the transport sector, suggesting that modellers need simple illustrative scenarios to pitch transport health benefits to the naive transport sector. The systematic review identified several models in different contexts and various scenarios. Studies on the application of models in low-and middle-income countries were scarce, but overall review findings could guide transport health impact modelling in African cities. The modelling study in five African cities showed reduced adverse outcomes from shifts towards cycling and bus for public transport, mainly from gains in physical activity and reduction in air pollution, as road traffic fatalities were significant for the cycling scenario in some cities. Comparatively, car and motorcycle scenarios showed increased adverse outcomes from air pollution and physical inactivity, with additional road injuries for the motorcycle scenario across cities. The thesis sheds light on using relatively complex tools to elicit the health impacts of changes in urban transport in contexts with limited data, making a case for transport policies that favour active travel even in settings where active travel is already prevalent. It provides cross-city results, which help cities compare the effects of similar policies in different contexts, supporting collaboration amongst cities and increasing opportunities to learn from one another. Additionally, the thesis highlights our limited understanding of travel behaviour from available surveys and caveats in model adaptation as priority areas for future research.
  • ItemEmbargo
    Genetic Determinants of Body Weight and Physical Maturation Across the Life Course
    Kaisinger, Lena; Kaisinger, Lena [0000-0002-0849-3191]
    Evidence points to early life as a critical period of heightened susceptibility to factors that alter the risk of later-life non-communicable diseases. Two early life risk factors increasingly recognised as important for adult health are early puberty timing and childhood obesity. Both factors are influenced by the environment, as demonstrated by their rapid increase in prevalence over time, but their susceptibility is also largely genetically determined. This thesis aimed to investigate the genetic determinants of these early life factors to improve understanding of their underlying biology and links to later life health using a combination of analytical approaches. First, this thesis identified six genes in which rare heterozygous loss-of-function variants impact puberty timing (KDM4C, MC3R, MKRN3, PDE10A, TACR3, ZNF483) by performing an exome-wide association study on recalled age at menarche (N~220,000) and age at voice breaking (N~180,000) in the UK Biobank. To better understand which biological factors influence puberty timing, I used a Mendelian randomisation approach to infer the causal effects of sex hormones and markers of glucose metabolism on puberty timing in girls and boys. Higher testosterone bioactivity, insulin-like growth factor 1 bioaction and insulin resistance appeared to promote earlier puberty timing in both sexes. Next, the relationship between childhood adiposity and puberty timing was investigated. Using longitudinal childhood body weight data from the Norwegian Mother, Father and Child cohort study and a clustering approach, I found that 55% of the common genetic signals for age at menarche primarily affect puberty with no effect on early-life weight, whereas 45% are also related to changes in early-life weight before puberty onset. Both early weight-related and weight-unrelated mechanisms drive the link between early puberty timing and later-life outcomes. Given the close relationship between childhood adiposity and female puberty timing, I applied a multi-variate modelling approach, Genomic Structural Equation Modelling, to various childhood adiposity-related phenotypes, including age at menarche, to boost power for the discovery of childhood adiposity loci. This approach identified 526 loci robustly associated with childhood adiposity, several displaying differing effects on adiposity across the life course. The implicated genes pointed to known biological pathways in the central nervous system but also to the pancreas and insulin signalling. Lastly, building on the observation of age-specific adiposity loci, I performed an exome-wide association study on both comparative body size age 10 (N~414,000) and adult body mass index (N~420,000) in the UK Biobank, identifying female-specific adult obesity genes (DIDO1, PTPRG, SLC12A5) as well as genes with childhood-specific effects (MADD, OBSCN). Several of these genes suggest roles of neuron death, apoptosis and deoxyribonucleic acid damage response mechanisms in obesity susceptibility across the life course. In summary, this thesis provides novel insights into the genetic architecture of puberty timing and adiposity across the life course, highlighting biological mechanisms underlying these traits and the trajectories linking them to later life health. These findings provide directions for future research and inform putative interventions targeting early puberty timing and childhood obesity as part of a life course approach to preventing non-communicable diseases.
  • ItemEmbargo
    School-based health promotion: understanding the educational context to facilitate change
    Ryan, Mairead; Ryan, Mairead [0000-0001-8165-4978]
    The World Health Organisation recommends children and adolescents aged 5-18 years engage in an average of 60 minutes of at least moderate-intensity physical activity per day across the week. This helps them meet their multiple physical, mental and well-being needs. A substantial proportion (67-81%) of children and adolescents worldwide are not meeting these guidelines. Global intervention efforts, which largely focus on school settings, are reported to have failed and reasons for intervention outcomes remain poorly understood. To improve understanding of these outcomes, and the school context as a venue to facilitate change, I adopted an interdisciplinary approach, integrating theory and evidence from the fields of both Public Health and Educational research, to consider and address existing knowledge gaps in the field. In the first part of this thesis, I examined how interventions have been implemented to date. Teachers are typically tasked with delivering interventions, but the effectiveness of the training they receive is poorly understood. I investigated programmes provided in research and real-world contexts. Study 1 involved a systematic review and meta-analysis of staff training programmes within 51 trials of school-based physical activity interventions. I identified characteristics (e.g., use of theory) and behaviour change techniques (e.g., feedback, action planning) positively associated with intervention fidelity and student outcomes. Most training programmes included few of these features, and were not designed based on Educational research about teacher professional development. In study 2, I surveyed teachers (n=170) who participated in professional development programmes aimed at supporting the implementation of the UK government’s largest policy targeting physical activity promotion in primary schools in England. I assessed the design features of programmes undertaken, and measured the use of 14 mechanisms hypothesised to facilitate four proposed purposes of professional development: 1) to learn knowledge, 2) to master skills, 3) to motivate action towards a goal, and 4) to facilitate implementation of acquired knowledge into practice. Most participants attended programmes that addressed just one or two of these functions. Teachers that attended programmes addressing all four functions, comprising less than 25% of participants, reported experiencing greater impacts on their practice. In the second part of this thesis, I aimed to improve understanding of the school context as a venue to facilitate change, exploring understudied school-level environmental and policy correlates of student physical activity. In study 3, I analysed data from primary school-age students in Australia (n=684). I examined students’ use of school playground infrastructure and associations between infrastructure use, break time step cadence and cardio-respiratory fitness. Boys reported greater use of playground infrastructure than girls. Regular use of some items (e.g., playing fields) was associated with a higher break time step cadence and fitness test score. Gender differences were observed in the strength of some associations. For example, associations between playing field use and cardio-respiratory fitness were stronger in boys; associations between teacher-organised games and break time step cadence were stronger in girls. In the final study, I examined associations between school uniforms and student physical activity, using population-level data from 135 countries. Across all age groups, compliance with physical activity guidelines was lower in countries with uniform practices compared to those without. Among primary school-aged students, uniformed countries showed a greater gender gap in meeting activity guidelines, favouring boys, compared to non-uniformed countries. Associations between school uniforms and population gender inequalities in physical activity were also greater in high-income countries than in countries with other income classifications. This thesis contributes valuable insights into how interventions have been implemented to date and the school context as a setting to facilitate change. Studies 1 and 2 indicate that teachers tasked with implementing interventions are often provided with training that is unlikely to change their behaviour. Studies 3 and 4 identify novel school-level environmental and policy correlates of student physical activity. The interdisciplinary literature and studies presented in this thesis can contribute to the development of more effective and gender-equitable interventions to promote physical activity.
  • ItemEmbargo
    Understanding physical activity in parents.
    Simpson, Rachel
    Physical activity has many benefits for both physical and mental health. Parents can also experience additional gains, for example an improved ability to cope with the daily challenges of being a parent and closer relationships with children through co-participation. Despite this, review-level evidence has shown that parents are less active than non-parents. The aim of my PhD was to investigate correlates of and experiences of physical activity amongst parents in order to identify groups which are more at risk of insufficient physical activity and ways of increasing physical activity levels amongst parents. My thesis consists of six chapters: an overall introduction, four chapters relating to my projects, and an overall discussion. Chapter 2 presents a systematic scoping review of research on parental physical activity to identify the breadth and scope of the current quantitative and qualitative evidence available on this topic. I included 214 articles relating to a wide range of relevant quantitative and qualitative studies. However, studies of paternal physical activity and device-assessment were still underrepresented. Most of the research also related to North America, and parents of infants, toddlers, preschoolers or primary school-aged children. Chapter 3 addresses the underrepresentation of device-assessed parental physical activity in the literature base whilst investigating the association between two factors specific to parents, number and ages of children, and maternal physical activity. These cross-sectional analyses showed that mothers in the Southampton Women’s Survey with multiple children and only children aged <5 years old did less accelerometer-assessed moderate or vigorous physical activity. I concluded that interventions and policies are needed to increase their opportunities for higher intensity physical activity. Chapter 4 investigates other potential correlates of self-reported and/or device-assessed parental physical activity. To address the underrepresentation of fathers identified in the scoping review, I also examined differences in correlates by parental gender where possible. I showed that one correlate had a negative and 15 a positive association with self-reported parental physical activity, and one had a negative and two a positive association with device-assessed parental physical activity. I concluded that policies and interventions are needed which focus on the incorporation of physical activity as part of daily life, which is also aligned with the ethic of care. There needs to be a focus on family-based promotion and creation of wider built, natural and social environments conducive to physical activity. Parents living with overweight or obesity may be a priority group to target in interventions. Psychosocial factors may play a role in increasing parental physical activity but more research is needed in this area. Further exploring the findings of Chapter 3, Chapter 5 is a primary qualitative investigation to examine mothers’ and fathers’ experiences of physical activity as their children move from infancy to primary school. I identified five themes, three of which I focussed on as they were most relevant to the research question: “whether and how physical activity changes depends on the domain”, “influence of the child” and “influence of self”. My PhD highlights the need for more paternal physical activity research and wider use of device-assessment of parental physical activity. In the final chapter, I discuss the use of theoretical frameworks in my thesis and the methodological considerations of my projects. I also present recommendations for policy, public health and future research.
  • ItemEmbargo
    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.
  • ItemEmbargo
    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.
  • ItemEmbargo
    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.
  • ItemOpen 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.
  • ItemOpen 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.
  • ItemEmbargo
    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.
  • ItemOpen 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.
  • ItemOpen Access
    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.
  • ItemOpen Access
    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.
  • ItemOpen 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.
  • ItemOpen 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.
  • ItemControlled 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.
  • ItemOpen 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.