Proposal summaries
B4142 - Decision-Making Dashboard for Designing Diabesity Prevention Programmes for Children and Young People - 13/09/2022
Obesity and Type 2 diabetes (T2D) (together, called 'diabesity') has an extensive economic burden, a negative impact on healthy life expectancy and is linked to lower quality of life particularly in children and young people (CYP). Diabesity is also strongly linked to health inequity: CYP who are from ethnic minorities, with lower socio-economic position, have much higher risk of diabesity and the poor health associated with it. We have recently shown, using data from primary care records, sharp rises in pre-diabetes and T2D in CYP; incidence rates of T2D in CYP have increased almost threefold from 2005 to 2019. There is an urgent need to invest in diabesity prevention and the development and implementation of specific plans to improve the care of CYP with diabesity. Obesity is the main risk factor for T2D which we are able to modify. Risk of T2D rises with increasing BMI, and only 1.5% of children with T2D have a healthy weight. Interventions to manage weight and physical activity have the potential to reduce T2D risk. Whilst we have identified a number of risk factors for diabesity, we do not know enough about how these multiple factors interact together and across time. This is known as a complex system, with multiple factors interacting and developing together across time. Complex systems make it difficult to identify prevention or intervention strategies that will work for everyone, because of the wide variation of possibilities in the system. This means that, for complex health problems like diabesity, we need to better understand and map the complex system before we can determine what prevention or intervention services would work for who, and when, and at what cost. This would also us to 'tailor' prevention programmes to specific groups to make them as effective as possible as well as estimating their economic costs and benefits.
In this project we will map the complex system of diabesity in CYP, integrating the existing literature with data collected in primary care and birth cohort studies (ALSPAC, Born in Bradford and the Millennium cohort), as well as expert stakeholder input. We will then use a simulation technique called agent-based modeling, which is used to study complex systems and allows us to use artificial intelligence to model what would happen if we introduce a prevention programme with specific features at specific time points to specific groups of people. We will also include health economic data in the model so that economic costs and benefits of programs can be modelled.
The final output of the project will be an open access decision making 'dashboard': a state-of-the-art multi-agent systems simulation tool for Type 2 diabetes prevention in children and young people with which policy makers, commissioners, service providers and clinicians can simulate tailored prevention programmes and strategies for their target population. We will produce training and support materials to maximise usability and uptake. The 'Diabesity Dashboard' will support commissioning of real-life programs tailored for specific groups that are most likely to work and be cost effective.
B4139 - Childhood predictors of later-emerging ADHD among women - 13/09/2022
Until recently, attention deficit hyperactivity disorder (ADHD) was thought of as a childhood disorder that mostly affected boys; thus the majority of ADHD research neglects ADHD among girls, and to an even greater extent, ADHD among adult women. While in childhood, ADHD has a strong male preponderance (10:1 to 2:1 male:female ratio), by adulthood this imbalance has disappeared and women make up 50% of the adult ADHD population. One explanation for this change could be that girls with ADHD are missed in childhood and only join the ADHD population in adulthood when they are asked to report their own symptoms, rather than relying on parent or teacher report. This is supported by research that finds teachers are less likely to identify ADHD symptoms among girls, and that girls are more likely to present with symptoms of inattention than hyperactivity/impulsivity, which may cause them to ‘fly under the radar’ of parents and teachers. Alternatively, some girls may not the exhibit the full disorder in childhood, but their symptoms may be exacerbated by the challenges of adolescence and young adulthood, such that they begin to meet full ADHD criteria in adulthood. To better understand what characterizes these cases of missed/subthreshold ADHD among girls, this proposal seeks to identify childhood risk factors among girls across socioenvironmental, behavioural and cognitive domains that predict later-emerging adult ADHD.
B4138 - Financial difficulties and the cost of living crisis - 13/09/2022
With the current cost of living crisis, it is important to include relevant questions on financial difficulties in the next questionnaires going out to both G0 and G1 in order to understand the impact this will have on their lives.
B4137 - How and why does ADHD lead to depression in young people - 12/09/2022
Depression is the leading mental health cause of disability in the world and has become more common in young people in the last few years. Young people with attention deficit/hyperactivity disorder (ADHD) are around five-times more likely to experience depression than those without ADHD. Depression in those with ADHD is especially serious – for example with a higher risk of suicide compared to either condition alone. However, standard interventions for depression do not seem to be as effective for young people with ADHD. To be able to advise future depression interventions, we need to understand the link between ADHD and depression. This project will examine (i) how the link between ADHD and depression develops across childhood, adolescence and young adulthood, (ii) cognitive and clinical factors that link ADHD and depression, and (iii) interpersonal relationship problems that link ADHD and depression.
B4136 - The mechanisms underlying relative protection from diabetes in multiple islet autoantibody positive individuals who develop diab - 08/09/2022
Research questions to be addressed in this study
More than half of type 1 diabetes cases are diagnosed in adulthood and the majority of these occur in individuals with no family history, yet the natural history of adult-onset type 1 diabetes (T1D) has never been explored. The work described in this application will
• Determine the frequency of islet autoimmunity in UK adults by screening 40,000 members of the adult general population for risk of T1D.
• Invite to long-term monitoring “at risk” individuals (single and multiple autoantibody positive) from the general population. A comparator population of “at risk” adult first degree relatives from the Bart’s Oxford (BOX) study and UK TrialNet will be monitored in parallel. This will prepare the way for the T1D community to learn how to interpret risk in adults, both general population and first-degree relatives.
• Examine islet autoantibody characteristics, genetic susceptibility and pancreatic function to predict Slow Progressors
• In a blinded analysis, test whether the individuals identified have distinct immune profiles (antigen-specific CD8 T cells responses absent, increased Regulatory T cell frequency with decreased suppressive capacity and Increased expression of CD95 on B cells) compared with progressors and age-matched controls)
B4140 - Estimating the causal effect of body mass index on platelet function - 08/09/2022
Obesity is associated with an increased risk of arterial thrombosis, which results in heart attacks or stroke. Platelets are essential for haemostasis, however, in thrombosis platelets become hyper-activated. There is observational evidence that obesity is associated with platelet hyper-activation, but it is unknown whether the effect is causal. Within this project, I aim to use the largest cohort with platelet function and genetic data, the Framingham Heart Study (FHS), to interrogate this relationship. This will be coupled with the design and implementation of a recall study. Here, I aim to recall participants in the Avon Longitudinal Study of Parents And Children (ALSPAC) based on body mass index (BMI), including participants with variants of MC4R, a gene involved in energy homeostasis. A loss of function mutation has been shown to increase average fat mass by 15kg. As alleles are randomly assigned at conception, this variant should not be associated with confounding factors such as smoking habits. I will perform deep platelet phenotyping on participants (carriers and non-carriers of this variant), including electron microscopy and platelet proteomics to identify differences in platelet activation. These analyses will estimate whether BMI has a causal relationship with platelet function and may point towards mechanisms, which could refine antiplatelet treatment regimes in people with obesity.
B4132 - Creating a healthy control sample for investigating the metabolomic footprint of weight loss - 08/09/2022
Obesity is known to have effects on cellular metabolism, which is reflected in a person’s circulating metabolome. Metabolomics, defined as the measurement and study of circulating small molecules that are the substrates and products of cellular metabolism, is increasingly used by epidemiologists to provide a functional read-out of bulk cellular activity and a proxy to individual current health. This approach also provides insight into biological pathways linking exposures and disease.
Measuring the metabolome of people with measured body mass index (BMI) allows us to look for ways in which BMI affects the metabolome. Metabolites found to be associated with BMI can then be further investigated and linked to cellular pathways – knowledge which will help us to understand the pathology of obesity. We have already begun to look at how bariatric surgery (within the By-Band-Sleeve trial (BBS), https://bristoltrialscentre.blogs.bristol.ac.uk/details-of-studies/by-ba...) and non-surgical weight loss interventions (within the DiRECT trial, https://www.directclinicaltrial.org.uk/) affect the metabolome. We want to use samples collected during routine ALSPAC clinics to characterize the metabolome of a healthy cohort. By analysing ALSPAC samples at the same time as samples from BBS (i.e., within the same experiment) we will be able to analyse the data together (without concerns of batch structure) and compare the metabolome of healthy ALSPAC participants to patients before and after bariatric surgery. When brought together with other work from our group, this study will enable us to unpick the metabolomic effects that are associated with BMI and their relevance to disease.
B4135 - The role of maternal and childhood diet and nutrition in the development of childhood ADHD and impaired cognitive ability - 26/08/2022
Attention Deficit Hyperactivity Disorder (ADHD) is the commonest neurodevelopmental disorder of childhood, but its causes are largely unknown. Symptoms include inattention and forgetfulness, as well as hyperactivity and impulsiveness. More generally, sub-optimal cognitive development (difficulty processing thoughts, remembering, and problem solving) in childhood is associated with lower educational attainment and poorer life chances. There are clues that a poor diet in pregnancy may increase the risk of a child developing ADHD and cognitive difficulties, but the evidence is patchy and inconsistent, and sometimes based on small studies. Also, the role of childhood diet has been little studied, and we do not know whether effects of early nutrition on these conditions depend on genetic make-up.
We will investigate whether a poor diet in pregnancy and childhood is associated with a higher risk of developing ADHD and lower cognitive ability in childhood, and a healthier diet is associated with a lower risk, after allowing for background factors. We will also see whether effects of early diet and nutrition on risk of these conditions depends on the genetic make-up of the mother and/or the child. ALSPAC has all the data we need to investigate these hypotheses to a high standard. We are particularly interested in the role of healthy versus unhealthy dietary patterns, various foods (fruit, vegetables, oily fish), sugar, and specific nutrients including vitamins, folic acid, omega-3 fatty acids and choline. We will also analyse associations with blood vitamin D levels in pregnancy and childhood.
B4133 - Examining the relationship between working memory and other key outcomes - 13/09/2022
Working memory refers to an individual’s ability to store and process a limited amount of information for a brief period of time. It is considered crucial to many everyday activities, including reading, mental arithmetic and following instructions. In recent years, there has been a focus on examining how working memory operates in classroom settings. This research has revealed that working memory is an important predictor of academic achievement. For instance, Alloway and Alloway (2011) found that working memory at 5 years of age predicted educational attainment in key subject areas 6 years later. These studies have also identified that children with poor working memory often exhibit inattention, but rarely show high levels of hyperactivity (e.g. Alloway et al.., 2009). This research has developed our understanding of working memory and its importance during childhood and adolescence. However, there are three key limitations with existing research:
1) Few studies have examined classroom behaviours associated with poor working memory – Although working memory has been linked to the broad construct “inattention”, very little research has examined individual classroom behaviours in children with poor working memory (Gathercole et al., 2008). To date, only relatively small-scale study has examined this. However, within this study, the behaviours observed were not compared to a typically developing sample with typical working memory. Moreover, although approximately 1/3 of the sample received special educational needs (SEN) support, this was not controlled for when conducting the analysis. As such, further large-scale research is needed to identify the classroom behaviours that are associated with poor working memory. There is also very little understanding of the behaviours that adults with poor working memory are likely to show.
2) Little research has examined the outcomes associated with poor working memory – Existing research has revealed important relationships between working memory and academic achievement. However, these studies have tended to either assess working memory and academic achievement concurrently, or follow children for only a few years. To date, only one study has examined the relationship between working memory in childhood and academic achievement in adolescence (Evans et al., 2020). This study (which used ALSPAC data) found that working memory in childhood predicted maths attainment at Key Stage 2 and progress during secondary school. Although this study does advance our understanding of the relationship between working memory and academic achievement, it is not possible to conclude from this study whether working memory predicts GCSE outcomes per se. Furthermore, this study did not examine whether working memory predicts GCSE outcomes overall (e.g. whether or not the individual achieves 5 A*-C at GCSE Level including English and maths) or performance in other subjects (e.g. English, Science). As such, further research is needed to examine the relationships between working memory during childhood predicts academic achievement during adolescence. Finally, whilst previous research in adults has revealed important associations between working memory and other cognitive constructs (e.g. intelligence; Conway et al., 2003), it is unclear whether working memory in either childhood or adulthood is predictive of employment outcomes.
3) Little understanding of how individuals with poor working memory can be identified –It is not currently recommended that all adults or children undergo routine screening of working memory. Instead, individuals who are suspected of having difficulties may be referred for working memory assessments. However, a critical issue with this approach is that difficulties associated with poor working memory (e.g. behaviours associated with inattention) are rarely attributed to working memory (Gathercole et al., 2006). As such, more objective methods for identifying individuals who may benefit from working memory assessments would be useful. One method for identifying such individuals may be through use of routine data that schools and workplaces/adults already have access to (e.g. prior academic achievement). However, the extent to which routine data can be used to identify individuals at high risk of having poor working memory is currently unknown.
The planned project will address these questions by examining:
• Which individual inattentive and hyperactive behaviours are associated with poor working memory in adults and children
• Whether working memory during childhood predicts academic outcomes in childhood and adolescence
• Whether working memory measured childhood and adulthood predicts employment outcomes in adulthood
• Whether inattentive and hyperactive behaviours drive the effect of working memory on academic and employment outcomes
• whether routinely collected data (e.g. prior academic achievement and special educational needs status) can be used to identify adults and children at high risk of having poor working memory.
B4130 - Cognihoods Measuring our mental maps of the mosaic of social worlds - 08/09/2022
This project will transform our understandings of how neighborhoods “work” by developing a systematic and representative national study to understand neighborhood structure, function, and evolution, the first of its kind in the world. Neighborhoods are fundamental social and built environments for cities. They form the backbone of place-based policy and urban planning, nucleate our urban social communities, and have profound effects on peoples’ health, wealth, voting, and beyond. Often, policymakers and social scientists use administrative areas to stand in for our “neighborhoods,” but studies persistently show that these areas do not reflect peoples’ actual lived experiences. This mismatch between concept and measure reduces the effectiveness of place-based policy and confounds social science. Convenience samples (e.g. hoodmaps.com) or small-scale focus groups have sought to resolve this, but these are often unrepresentative—challenging to validate, reproduce, and generalize.
Instead, I will develop a novel social survey method that is socially-representative, reproducible, and generalizable. First, I will develop an open and reproducible neighborhood survey module with the Avon Longitudinal Study of Parents and Children (ALSPAC). Respondents will be able to draw their neighborhoods, describe them, and relate them to other parts of respondents’ lives. Then, I will seek to understand how potential mis-matches between these lived neighbourhoods and zones used in urban planning may affect political, social, and health inequalities and outcomes. Finally, I will work with the Cohort and Longitudinal Enhancement Resources (CLOSER), the UK’s world-leading network of cohort and longitudinal studies, to deploy this nation-wide and examine both the generality and stability of these lived neighborhoods over time. In addition, I will seek to develop statistical learning techniques that can predict where these communities might arise directly from information on the built environment. Altogether, this will provide the first socially-representative longitudinal study of neighborhood structure and function in the world.
B4125 - Determining the association between trauma HPA axis dysregulation and mental health using robust measures - 01/09/2022
Poor mental health affects more than one billion people worldwide but despite this frequent occurrence and the potential personal burden, treatment options are scarce and not always effective. There is a need, therefore, for a better understanding of the environmental and biological causes of mental health problems, so that new treatments can be developed.
It is known that stressful or traumatic situations can increase an individual’s chance of developing a range of mental health problems. In response to a stressful situation, whether psychological or physical, the human body activates processes that aim to increase the chance of survival. These responses are referred to as “fight-flight-freeze” and can result in giving the body energy, making you feel more, and reducing the sensation of pain. One key hormone involved in this response is cortisol. Although the release of cortisol in response to stress is initially beneficial, evidence has shown that experiencing severe or ongoing stressful events can lead to abnormal cortisol levels, which in turn has been linked to harmful outcomes, including obesity, cancer, heart disease, susceptibility to infection, and poor mental health.
Mental health problems that have been linked to cortisol levels include psychosis, depression, anxiety, and post-traumatic stress disorder (PTSD). For example, studies have shown that individuals diagnosed with depression or schizophrenia have higher levels of cortisol in their blood or saliva when compared to individuals without a psychiatric illness, while individuals with PTSD have lower levels. Some studies also show that high cortisol levels in early life associate with developing a mental health problem later in life, indicating that stress response abnormalities may cause mental health problems. However, findings are not always consistent, and results are hard to compare as the time of day the cortisol measure is taken and the material used for measurement (e.g., saliva, blood, urine) vary across studies.
One way in which cortisol may be causally linked to mental health problems is through inflammation. In normal conditions, cortisol reduces inflammation (e.g., it’s commonly used to treat inflammatory diseases such as arthritis and asthma), however, studies have shown that under abnormal conditions (e.g., during ongoing stress), the relationship changes and high levels of cortisol are associated with increased inflammation. An increase in inflammation can be harmful to neurons in the brain by affecting neuron functioning and decreasing neuron repair. As such, studies have linked stress-related inflammation to poor mental health, however, the size of these studies are small and, again, studies are hampered by inadequate measures of cortisol and inflammation.
As can be seen, there is a need for large studies using improved measures of cortisol to investigate the causal link between stress response and mental health. In this project we therefore aim to generate reliable, robust measures of cortisol and inflammation using serum measures, genetic data and hair samples, to investigate whether cortisol levels lie on the pathway between early life trauma and mental health and whether they influence inflammation.
This work will inform whether interventions targeting the stress response system have the potential to prevent or treat psychiatric disorders.
B4126 - The ALSPAC variable search tool - 15/08/2022
Creating a search tool for researchers to browse the available data within ALSPAC, and to provide an R package for direct users to extract data in a reproducible manner
B4128 - Interplay between genetic risk for metabolic syndrome and mental illness on childhood development outcomes - 15/08/2022
Individuals with a mental health condition are more likely to develop metabolic syndrome, which is a collection of risk factors for heart disease like elevated blood sugar, cholesterol, and blood pressure. Conversely, those with metabolic syndrome are also at higher risk of mental illness. This relationship can be partially explained by factors like lifestyle and medication; however, shared biology also influences the cardiovascular system and brain. For example, there is emerging evidence that there are genetic risk factors that are related to both mental health and cardiovascular disease. The impact of this genetic risk for both disorders remains poorly understood in children and adolescents. Given early intervention is important for both mental illness and heart disease, understanding these relationships may assist to identify how best to implement early intervention. This study will investigate individuals with high genetic risk for both mental health conditions and heart disease to establish whether this impacts their psychological and physical development.
B4129 - Characteristics of Converters to and Deconverters from Traditional Religious Beliefs and Behaviours - 15/08/2022
Our Co-investigator, Ralph Hood, has undertaken studies of individuals who have left their religion and those who have stayed or converted using longitudinal data in two countries – Germany and the USA. ALSPAC provides a valuable data set to investigate whether the factors that predict such events are similar in the UK, and whether the individual that makes such a change benefits psychologically in the longer term.
B4123 - Climate change sustainable diets and religion - 09/08/2022
Human activity is having a dramatic impact on our planet's climate, and measures to reduce carbon emissions to limit to extent of this climate change are urgently needed. In this project, using the recently-collected climate change data in ALSPAC we aim to explore the factors associated with climate change beliefs and behaviours, with a specific focus on both behaviours relating to sustainable diets (i.e., reduction of meat and/or dairy consumption) and religious/spiritual beliefs and behaviours (RSBB).
B4115 - Adverse Childhood Experiences and Violent Offending - 09/08/2022
Our proposed project is primarily centred on the research topic of diversion away from the criminal justice system. Specifically, we will chart the developmental interplay between person-centred clusters of adverse childhood experiences (ACEs) and violent offending (assault and use of a weapon) during adolescence. In doing this we hope to identify which clusters of ACEs are most salient for subsequent violent offending. We will also investigate whether these differ for marginalised groups.
B4122 - AMOUNT An investigation of changes in young peoples substance use - 15/08/2022
Substance use (SU) by young people (YP; YPSU) can lead to short- and long-term harms. Although YPSU has been falling over the past 20 years in the UK, evidence suggests that it is now increasing again among some groups. Studies suggest that these changes may depend on where YP live, how they socialise, the health/social challenges that they face, and the ways in which they access and use substances.
This project is part of a larger study that is working with YP and other experts to understand in what ways and for which groups of YP SU is changing. We are developing and testing new theories to help us understand the most important factors that underpin these increases. Some factors relate to individuals, including mental health or experiences of the care system; others will relate to wider contexts such as communities, policy, and youth culture, including how drug markets have changed, changes in leisure and recreation, or shifts in attitudes towards SU; and others depend on the interactions between all of these.
In this project we will first examine whether there is evidence that YP may be using drugs to help cope with mental health problems. We will then explore whether YP who use alcohol and have mental health problems have worse outcomes if they also use drugs such as cannabis.
B4124 - Utilising Epigenetics as a Platform for Precision Medicine - 15/08/2022
Complex disorders such as psychiatric conditions often arise from varying combinations of genetic and environmental factors. This represents a major problem for drug development, as the cause of the disease is highly variable from person to person, and as such, drug response rates vary significantly. By examining an individual’s unique genetic risk factors, treatment response rates could theoretically be increased by improving subcategorization of individuals and personalising the administration of appropriate medications. Although genetic risk scores have been developed for this purpose, the use of epigenetic information in the form of DNA methylation remains relatively underexplored, despite the fact this epigenetic modification can simultaneously index both genetic and environmental risk factors. In this study, we will examine whether DNA methylation can be used to refine the classification individuals with complex disorders and better match affected individuals to personalised medications. In addition, we will also explore the relationship between epigenetic risk for complex disorders and measures of biochemical and metabolic traits to determine whether the epigenetic component of complex disorders is associated with changes in druggable, blood-based biomarkers.
B4121 - Mechanisms linking the natriuretic peptide receptor-C gene to elevated blood pressure Genetic epidemiology study - 01/08/2022
Previous research has identified several regions of the human genome associated with high blood pressure. One such region is the NPR3 gene, encoding the natriuretic peptide receptor-C. Whilst genetic variants in this region are associated with high blood pressure, it is not known which variant/s drive the association or whether the effect on blood pressure occurs through altered expression of the NPR3 gene. This study will use existing ALSPAC data to investigate the association between the NPR3 gene and high blood pressure.
B4114 - Social determinants of mental health and cognition in adolescence - 01/08/2022
One quarter of the world’s population is affected by a mental or neurological disorder at some point in their life (WHO, 2001), and depression alone is predicted to be the leading burden of disease globally by 2030 (Malhi & Mann, 2018). These disorders typically manifest early in life, with 74% of diagnoses first occurring under the age of 18 years, and 50% before 15 years (Kim-Cohen et al., 2003). Understanding risk and protective factors underlying mental ill-health, and how these might develop over time, is crucial for the creation of effective prevention and intervention.
As children mature into adolescents, they increasingly interact with, and become more sensitive to evaluation and rejection by peers. Increased sensitivity to social rejection during this period has been associated with decreased mental health (Gao et al., 2017), while the opposite has been found for increased social support (van Harmelen et al., 2017). The environment in which these interactions occur is also changing, with adolescents spending an average of 6 hours each day online, the majority of which is spent on social media sites (Anderson & Jiang, 2018). Exploring these effects cross-sectionally, we found that increased social rejection sensitivity and decreased perceived social support were associated with increased negative mood in adolescents (11-24 years; Grunewald, Deng, Wertz & Schweizer, Under review), and now seek to further investigate these effects longitudinally.