Proposal summaries

These are research proposals that have been approved by the ALSPAC exec. The titles include a B number which identifies the proposal and the date on which the proposals received ALSPAC exec approval.

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B4141 - Comparisons of brain structure and microstructure in individuals with and without clinical or genetic risk for psychosis - 26/09/2022

B number: 
B4141
Principal applicant name: 
Christian K. Tamnes | University of Oslo (Norge)
Co-applicants: 
Nasimeh Naseri, Alexandra Havdahl, Dr.
Title of project: 
Comparisons of brain structure and microstructure in individuals with and without clinical or genetic risk for psychosis
Proposal summary: 

The current project is a student project that is linked to the already approved project: B3840 Developmental pathways to mental health problems. All needed data are available through B3840.

Psychotic disorders are often severe and have high heritability. Despite a small proportion of the population being affected by psychotic disorders, they have the highest disability weight. Beside impairing health in their own, these disorders further increase risks for other health outcomes such as suicide. To understand the mechanistic pathways leading to development of psychotic disorders, it is important to study individuals with at risk, either individuals at clinical risk or individuals with genetic risk. Clinical risk refers to the presence of symptoms, but that the full diagnostic criteria are not met. Genetic risk is in an ALSPAC MRI substudy operazationalied as high polygenic risk for schizophrenia. Further, studying individuals at risk reduces confounding for medication or chronic illness to some extent.

Substantial efforts have been dedicated to identify neural factors associated with risk for psychotic disorders. Despite these efforts, the picture of how psychotic disorders develop is not clear and our knowledge about which factors contribute to this development is limited. There is thus a demand for further research to identify the brain structural and microstructural correlates associated with psychosis risk. Moreover, directly comparing individuals with clinical (symptom-based) risk for psychosis and individuals with genetic risk for psychosis can possibly reveal both shared and distinct neural mechanisms.

Impact of research: 
Date proposal received: 
Tuesday, 20 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Neuroimaging, Psychosis, schizophrenia, psychotic disorders

B4147 - Religious or spiritual beliefs/behaviours RSBB and COVID infection - 26/09/2022

B number: 
B4147
Principal applicant name: 
Raquel Granell | MRC Integrative Epidemiology Unit (IEU)
Co-applicants: 
Prof James Dodd, Dr Caitlin Morgan, Prof Jean Golding, Isaac Halstead
Title of project: 
Religious or spiritual beliefs/behaviours (RSBB) and COVID infection
Proposal summary: 

The COVID-19 pandemic has had an irrevocable impact on healthcare both in the UK and worldwide. To date, almost 20 million cases had been recorded in the England and 164,000 deaths[1]. As we make advances in understanding how we manage this disease clinically, it is also important that we use this time to better understand who is more susceptible to COVID infection and why. Understanding the impact of religion and spiritual beliefs/behaviours (RSBB) is a novel assessment of factors that may influence COVID-19 transmission and therefore incidence. In this study we will determine whether (and how) behaviours associated with religion or spiritual beliefs such as attending a place of worship, attending a faith school or belief in a divine power has any impact on COVID incidence in our cohort. Our analysis will be conducted using data collected before and after covid from mothers and partners from the ALSPAC cohort and classes of religiosity determined by latent class analysis on the same population (highly religious, moderately religious, agnostic, and atheist)[2]. These four groups have been determined using a range of religious belief indicators and socioeconomic risk factors. By conducting this analysis, we hope to contribute to the emerging description of COVID populations alongside other known risk factors such as social deprivation and co-morbidity.

[1]coronavirus.data.gov.uk.(n.d.).Official UK Coronavirus Dashboard. [online]Available at: https://coronavirus.data.gov.uk/details/deaths?areaType=nation&areaName=....
[2]Halstead I, Heron J and Joinson C. Identifying patterns of religiosity in adults from a large UK cohort using latent class analysis[version 1; peer review: awaiting peer review].Wellcome Open Res 2022, 7:192(https://doi.org/10.12688/wellcomeopenres.17969.1)

Impact of research: 
High impact journal publication, presentations at national/international conferences
Date proposal received: 
Tuesday, 13 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Epidemiology

B4148 - Examining the bidirectional association between emotion recognition and social wellbeing and school outcomes - 26/09/2022

B number: 
B4148
Principal applicant name: 
Zoe Reed | University of Bristol
Co-applicants: 
Dr Angela Attwood, Professor Marcus Munafò
Title of project: 
Examining the bidirectional association between emotion recognition and social, wellbeing and school outcomes
Proposal summary: 

Emotion recognition is an important part of social interaction, and difficulties in recognising others’ emotions can have a negative impact on this. In addition, these difficulties may subsequently impact social function and mental health. It is also possible that difficulties in this area e.g., social anxiety, could disrupt school attendance in children. Previous studies which have examined these relationships tend to be small and cross-sectional. We propose using a large existing cohort with data at multiple timepoints to overcome these limitations and allow the direction of association to be examined as well. It is important to further understand these relationships particularly given that poorer emotion recognition is observed in autistic individuals, or those with more autistic traits, and therefore these relationships will be particularly relevant for autistic individuals with emotion recognition difficulties.

We will examine the bidirectional association between emotion recognition and outcomes related to social traits, wellbeing/mental health and school attendance. Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) will be used for this. Data will be used from different time points to attempt to understand the direction of any associations found. This work would be useful in informing what downstream effects there may be with interventions targeting emotion recognition, for example, in autistic individuals.

Impact of research: 
This research will lead to a better understanding of relationship between emotion recognition and social, wellbeing and school attendance outcomes. We hope to use this information to strengthen the evidence base around these relationships which will be useful for other work we are doing around emotion recognition interventions for autistic children, in terms of identifying potential downstream effects.
Date proposal received: 
Thursday, 15 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Epidemiology, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Communication (including non-verbal), Emotion recognition

B4149 - Identifying the genetic markers associated with within-individual variability in blood pressure mini-project - 26/09/2022

B number: 
B4149
Principal applicant name: 
Richard Parker | University of Bristol (UK)
Co-applicants: 
Dr April Hartley, Prof Kate Tilling, Dr Jessica Barrett, Helen Natukunda
Title of project: 
Identifying the genetic markers associated with within-individual variability in blood pressure (mini-project)
Proposal summary: 

Evidence suggests that erratic (highly-variable) blood pressure, as well as high mean average blood pressure, could be associated with cardiovascular disease (CVD). As such, a better understanding of the associations of genes with blood pressure variability could provide further insight into the development of CVD. However, whilst there has been considerable research identifying the genetic factors associated with mean average blood pressure, little is known about the associations of genetic factors with blood pressure variability. The project aims to address this by analysing data from ALSPAC to investigate associations between blood pressure variability and genes.

Impact of research: 
Identify genetic variants associated with within-individual blood pressure variability, which could provide insight into the development of cardiovascular disease.
Date proposal received: 
Thursday, 15 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Hypertension, GWAS, Statistical methods, Blood pressure, Cardiovascular, Genetic epidemiology, Genome wide association study, Statistical methods

B4143 - LoF MC3R coding mutations in cohorts of patients with delayed puberty - 20/09/2022

B number: 
B4143
Principal applicant name: 
Stephen O'Rahilly | Wellcome MRC Institute of Metabolic Science (UK)
Co-applicants: 
Professor Nicholas Timpson, Dr Ahmed Elhakeem, Laura Corbin, Ruby Tsang
Title of project: 
LoF MC3R coding mutations in cohorts of patients with delayed puberty
Proposal summary: 

We are currently writing a follow-up MC3R paper where we have found and characterised LoF MC3R coding mutations in cohorts of patients with delayed puberty, in collaboration with Dr Yee-Ming Chan, a member of the Delayed Puberty Genetics Consortium based in Boston, and Prof Peter Clayton from Manchester University. 
 
We have found 3/268 heterozygous individuals total in these cohorts carrying LoF MC3R mutations and we have compared this to the number of individuals in ALSPAC carrying both partial or complete LoF MC3R mutations, to see if there is any enrichment in the delayed puberty cohorts compared to ALSPAC as a control cohort.
 
We currently have an estimate (from previous sequence data in ALSPAC) of the number of carriers in ALSPAC for the pLoF R220S mutation - 29 het individuals - based on the frequency of coverage of this variant within the pooled target capture sequencing data performed for MC3R. However as we never broke these pools we do not have a validated number of carriers for this variant (chr20_56249501_C_A).

Impact of research: 
Better understanding of rare variants in the MC3R locus.
Date proposal received: 
Monday, 5 September, 2022
Date proposal approved: 
Tuesday, 20 September, 2022
Keywords: 
Genetics, Growth, development, maturation., DNA sequencing, Development

B4144 - Ability of adult blood pressure-related CpGs to predict blood pressure in childhood and adolescence - 20/09/2022

B number: 
B4144
Principal applicant name: 
Hannah Elliott | University of Bristol (UK)
Co-applicants: 
Dr Paul Yousefi, Mr Mohammed el Sharkawy, Dr Leanne Kupers
Title of project: 
Ability of adult blood pressure-related CpGs to predict blood pressure in childhood and adolescence
Proposal summary: 

Hypertension is one of the strongest risk factors for cardiovascular disease, which is the leading cause of death worldwide (1). Early-life exposures have been associated with blood pressure and the development of hypertension (2), with differential DNA methylation suggested as a potential underlying mechanism (3). Two large epigenome-wide association studies (EWAS) on systolic and diastolic blood pressure in adults have identified associations with DNA methylation (DNAm) levels of multiple Cytosine-phosphate-Guanine (CpG) sites (4,5). In the CHARGE consortium, one large-scale multi-ethnic EWAS on blood pressure in n=9,828 adults identified 13 CpGs annotated to 8 genes that were associated with blood pressure (4). A DNAm risk score based on these CpGs explained 1.4% and 2.0% of the inter-individual variation in systolic and diastolic BP, respectively. Another, more recent, EWAS on 4,820 multi-ethnic adults (6), identified 33 CpGs that explained an additional 3.3% and 4.0% of the inter-individual variation in systolic and diastolic blood pressure, respectively, beyond the traditional blood pressure risk factors age, sex, and body mass index (BMI), with 3 CpGs overlapping with the CHARGE study. The majority of the discovered CpG sites have been linked with other metabolic phenotypes including obesity, lipids, CRP, insulin resistance, and type 2 diabetes mellitus by previous epigenome-wide association studies (6), indicating that DNAm may be one of the common factors related to the concurrence of multiple cardiometabolic abnormalities.

Much less is known about the associations between DNAm and blood pressure in children. It is also not known if blood pressure associations with DNAm found in adults are already apparent in early childhood, late childhood and adolescence. Therefore, in this project, we aim to test the ability of a methylation risk score, developed using CpGs previously identified to be associated with SBP and DBP in adult EWAS meta-analysis by Richard (4) and Huang (6), to predict blood pressure at multiple timepoints in childhood and adolescence, and its added value compared to a risk score constructed only from the basic covariates age, sex and BMI.
This weighted methylation risk score was developed using the CpGs from the adult studies that survived a penalized elastic net regression in the ALSPAC adult data.

1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessmentof burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet (London, England).2012;380(9859):2224-60.
2. Lackland DT. Fetal and Early Life Determinants of Hypertension in Adults. Hypertension. 2004;44(6):811-2.
3. Wang X, Falkner B, Zhu H, Shi H, Su S, Xu X, Sharma AK, Dong Y, Treiber F, Gutin B, et al.. A genome-wide methylation study on essential hypertension in young African American males. 2013; 8:e53938.
4. Richard MA, Huan T, Ligthart S, Gondalia R, Jhun MA, Brody JA, Irvin MR, Marioni R, Shen J, Tsai PC,Montasser ME, Jia Y, Syme C, Salfati EL, Boerwinkle E, Guan W, Mosley TH Jr, Bressler J, Morrison AC,Liu C, Mendelson MM, Uitterlinden AG, van Meurs JB; BIOS Consortium, Franco OH, Zhang G, Li Y, Stew-art JD, Bis JC, Psaty BM, Chen YI, Kardia SLR, Zhao W, Turner ST, Absher D, Aslibekyan S, Starr JM,McRae AF, Hou L, Just AC, Schwartz JD, Vokonas PS, Menni C, Spector TD, Shuldiner A, Damcott CM,Rotter JI, Palmas W, Liu Y, Paus T, Horvath S, O'Connell JR, Guo X, Pausova Z, Assimes TL, SotoodehniaN, Smith JA, Arnett DK, Deary IJ, Baccarelli AA, Bell JT, Whitsel E, Dehghan A, Levy D, Fornage M. DNAMethylation Analysis Identifies Loci for Blood Pressure Regulation. Am J Hum Genet. 2017 Dec7;101(1):888-902.
5. Kazmi N, Elliott HR, Burrows K, Tillin T, Hughes AD, Chaturvedi N, et al. (2020) Associations between highblood pressure and DNA methylation. PLoS ONE 15(1): e0227728.
6. Huang Y, Ollikainen M, Muniandy M, Zhang T, Dongen Jv, Hao G, et al. Identification, Heritability, and Re-lation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure. Hypertension.2020;76(1):195-205.
7. Gervin, K., Salas, L.A., Bakulski, K.M. et al. Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data. Clin Epigenet 11, 125 (2019).

Impact of research: 
This research will improve knowledge of the relationship between DNA methylation and BP across the lifecourse. This research will will improve current risk scores to predict blood pressure in children.
Date proposal received: 
Monday, 12 September, 2022
Date proposal approved: 
Tuesday, 20 September, 2022
Keywords: 
Epidemiology, Hypertension, Statistical methods, Methylation analysis, Blood pressure, Cardiovascular, Epigenetics

B4145 - Fatigue among adolescents and young people with psychotic experiences Results from the ALSPAC birth cohort - 20/09/2022

B number: 
B4145
Principal applicant name: 
Trudie Chalder | King's College London (United Kingdom)
Co-applicants: 
Ms Kim Poole-Wright, Fiona Gaughran, Mr Ismail Guennouni
Title of project: 
Fatigue among adolescents and young people with psychotic experiences: Results from the ALSPAC birth cohort
Proposal summary: 

The experience of psychotic-like experiences (PLE), such as hallucinations and delusions, are not uncommon in the general population. Previous studies have indicated that adolescents reported higher rates of approximately 13% for at least one symptom (Horwood et al., 2008) and 4.9% for ‘definite’ symptoms among 18 year olds. Research shows that those with PLE have lower global and social functioning outcomes (Pontillo, De Luca, Pucciarini, Vicari, & Armando, 2018), which become progressively impaired on the course to schizophrenia (Addington, 2003). Among these impairments, is a ‘marked lack of energy’. Fatigue becomes a factor in the prodrome phase of psychosis (Chen et al., 2019), and for those with a psychotic diagnosis (Poole-Wright, Gaughran, Murray, & Chalder, 2022). Although it is an important factor in these phases, not much is known about fatigue in those experiencing attenuated symptoms. Some research into sub-types of PLE, such as unusual perceptual experiences or ideas of reference, has been related to fatigue. For example, fatigue was found to mediate the relationship between adverse experiences with caregivers and ideas of reference in non-clinical participants (León-Palacios, Garrido-Fernández, Senín-Calderón, Perona-Garcelán, & Rodríguez-Testal, 2019). Young people at ultra-high risk were found to manage their fatigue by various strategies (Carney, Cotter, Bradshaw, & Yung, 2017). However, fatigue and its associations in those with PLE remain under-explored in the literature. This research will address this gap in the literature by examining the prevalence and associations of fatigue in adolescents and young people who experience psychotic-like symptoms.

Impact of research: 
This research is intended to extend current understanding of fatigue symptoms in psychosis by investigating whether fatigue is implicated in adolescents with psychotic-like experiences, and if tiredness is an important factor in PLE. This could be significant in the continuum to a psychosis diagnosis by indicating that fatigue is a factor in the early alterations in functioning (alongside cognitive, social and communication declines) in those with PLE.
Date proposal received: 
Monday, 12 September, 2022
Date proposal approved: 
Tuesday, 20 September, 2022
Keywords: 
Epidemiology, Chronic fatigue, Statistical methods, psychotic experiences, fatigue, depression, anxiety, physical activity

B4139 - Childhood predictors of later-emerging ADHD among women - 13/09/2022

B number: 
B4139
Principal applicant name: 
Jessica Agnew-Blais | Queen Mary University London (UK)
Co-applicants: 
Title of project: 
Childhood predictors of later-emerging ADHD among women
Proposal summary: 

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.

Impact of research: 
Several lines of research point to under-recognition and underdiagnosis of ADHD among girls compared to boys; and even when girls are diagnosed, it tends to occur at older ages than boys. Women are also more likely to have received other diagnoses prior to their ultimate diagnosis of ADHD, and this later and potential misdiagnosis can result in years of poorer functioning, feelings of low self-worth, and higher risk for depression and anxiety. It is critical to identify factors in childhood that increase risk for adult ADHD among girls, to support earlier identification and intervention.
Date proposal received: 
Friday, 2 September, 2022
Date proposal approved: 
Tuesday, 13 September, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Psychology - personality

B4142 - Decision-Making Dashboard for Designing Diabesity Prevention Programmes for Children and Young People - 13/09/2022

B number: 
B4142
Principal applicant name: 
Jackie Blissett | Institute of Health and Neurodevelopment, Aston University (UK )
Co-applicants: 
Krishnarajah Nirantharakumar
Title of project: 
Decision-Making Dashboard for Designing ‘Diabesity’ Prevention Programmes for Children and Young People
Proposal summary: 

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.

Impact of research: 
Our analysis of the ALSPAC data is one fundamental aspect of the broader 'Diabesity Dashboard' programme, which has the potential for significant impact to the provision of diabesity prevention services for children and young people. Data analysis from ALSPAC will contribute to the modelling which will allow us to predict which prevention strategies would work for which groups and at what point in development these should be targeted for maximum efficacy to prevent T2D in CYP. Such a model will facilitate informed decision making by stakeholders invested in T2D prevention and will result in reduction of the substantial health inequalities associated with T2D.
Date proposal received: 
Monday, 5 September, 2022
Date proposal approved: 
Tuesday, 13 September, 2022
Keywords: 
Public health, medicine, computer science, psychology., Diabetes, Computer simulations/modelling/algorithms, BMI

B4138 - Financial difficulties and the cost of living crisis - 13/09/2022

B number: 
B4138
Principal applicant name: 
Nic Timpson | UoB
Co-applicants: 
Prof Kate Northstone
Title of project: 
Financial difficulties and the cost of living crisis
Proposal summary: 

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.

Impact of research: 
Date proposal received: 
Friday, 2 September, 2022
Date proposal approved: 
Tuesday, 13 September, 2022
Keywords: 
Social Science, Social science

B4137 - How and why does ADHD lead to depression in young people - 12/09/2022

B number: 
B4137
Principal applicant name: 
Lucy Riglin | Cardiff University (Wales)
Co-applicants: 
Title of project: 
How and why does ADHD lead to depression in young people?
Proposal summary: 

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.

Impact of research: 
Date proposal received: 
Sunday, 28 August, 2022
Date proposal approved: 
Monday, 12 September, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods

B4136 - The mechanisms underlying relative protection from diabetes in multiple islet autoantibody positive individuals who develop diab - 08/09/2022

B number: 
B4136
Principal applicant name: 
Kathleen Gillespie | University of Bristol (United Kingdom)
Co-applicants: 
Title of project: 
The mechanisms underlying relative protection from diabetes in multiple islet autoantibody positive individuals who develop diab
Proposal summary: 

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)

Impact of research: 
The World has suddenly realised that autoimmune diabetes is as often a condition of adults as children. Decades of research has improved our understanding of the natural history in children but very little is known in adults. The impact of this study will therefore be large.
Date proposal received: 
Saturday, 27 August, 2022
Date proposal approved: 
Wednesday, 7 September, 2022
Keywords: 
Immunology, Diabetes, Immunoassays, Immunity

B4140 - Estimating the causal effect of body mass index on platelet function - 08/09/2022

B number: 
B4140
Principal applicant name: 
Lucy Goudswaard | Population Health Sciences, University of Bristol (United Kingdom)
Co-applicants: 
Professor Nicholas Timpson, Dr Laura Corbin, Professor Ingeborg Hers
Title of project: 
Estimating the causal effect of body mass index on platelet function
Proposal summary: 

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.

Impact of research: 
To our knowledge, a recall study has not been performed to explore the effect of BMI on platelet function. The deep phenotypes that we will perform will complement our analyses using the Framingham Heart Study and will help us characterise the relationship between BMI and platelet function.
Date proposal received: 
Monday, 5 September, 2022
Date proposal approved: 
Monday, 5 September, 2022
Keywords: 
Epidemiology, Obesity, Recall study Platelet function , Metabolic - metabolism

B4135 - The role of maternal and childhood diet and nutrition in the development of childhood ADHD and impaired cognitive ability - 26/08/2022

B number: 
B4135
Principal applicant name: 
Seif Shaheen | Queen Mary University of London
Co-applicants: 
Professor Amanda Waterman, Dr Evie Stergiakouli, Dr Pauline Emmett
Title of project: 
The role of maternal and childhood diet and nutrition in the development of childhood ADHD and impaired cognitive ability
Proposal summary: 

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.

Impact of research: 
This project will provide important evidence on the role that poorer nutrition in pregnancy and childhood plays in the development of ADHD and impaired cognitive function in children. Our results could lead to a trial in pregnancy aimed at preventing ADHD and improving cognitive ability in the offspring by improving maternal diet and nutrition. Such a trial might be targeted at women with a particular genetic make-up, to maximise beneficial effects on the child. Ultimately this research could influence policy and lead to a reduction in ADHD and impaired cognitive function in the population. Results will be presented at an international conference by the early career researcher who will do the statistical analyses, and will be published in leading journals.
Date proposal received: 
Wednesday, 24 August, 2022
Date proposal approved: 
Friday, 26 August, 2022
Keywords: 
Epidemiology, Developmental disorders - autism, Statistical methods, Nutrition - breast feeding, diet

B4132 - Creating a healthy control sample for investigating the metabolomic footprint of weight loss - 08/09/2022

B number: 
B4132
Principal applicant name: 
Laura Corbin | University of Bristol (UK)
Co-applicants: 
Prof Nic Timpson, Maddy Smith, Dr David Hughes
Title of project: 
Creating a healthy control sample for investigating the metabolomic footprint of weight loss
Proposal summary: 

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.

Impact of research: 
By bringing this work together with our other projects conducted within N.Timpson’s Wellcome Trust Investigator Award, we hope to improve understanding of the metabolomic consequences of weight loss surgery and the downstream consequences of these in terms of long-term health. We will also hope to use this work to demonstrate the value of combining data across study designs at the individual data level over and above simply comparing results (summary statistics) across studies.
Date proposal received: 
Thursday, 25 August, 2022
Date proposal approved: 
Friday, 26 August, 2022
Keywords: 
Molecular genetics and genomics, Diabetes, Obesity, Metabolomics, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., BMI, Statistical methods

B4133 - Examining the relationship between working memory and other key outcomes - 13/09/2022

B number: 
B4133
Principal applicant name: 
Amy Atkinson | Lancaster University
Co-applicants: 
Professor John Towse
Title of project: 
Examining the relationship between working memory and other key outcomes
Proposal summary: 

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.

Impact of research: 
This work will have provide novel insights extent to the associations between working memory, inattentive/hyperactive behaviours and real world outcomes. The research may also have important practical implications, indicating which behaviours educational professionals and managers should monitor for, as well as identifying possible concurrent and longitudinal outcomes of poor working memory. Furthermore, the research will indicate whether routinely collected data can be used to identify children with poor working memory. We have built a series of dissemination activities into our grant proposal, including workshops for stakeholders, development of a training course, development of infographics, and presentations at non-academic conferences (e.g. ResearchEd).
Date proposal received: 
Tuesday, 23 August, 2022
Date proposal approved: 
Thursday, 25 August, 2022
Keywords: 
Social Science, Cognitive impairment, Learning difficulty, Statistical methods, Cognition - cognitive function, Development, Intelligence - memory, Social science, Statistical methods

B4130 - Cognihoods Measuring our mental maps of the mosaic of social worlds - 08/09/2022

B number: 
B4130
Principal applicant name: 
Levi John Wolf | School of Geographical Sciences
Co-applicants: 
Title of project: 
Cognihoods: Measuring our mental maps of the "mosaic of social worlds"
Proposal summary: 

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.

Impact of research: 
Understanding the relationship between individuals and their small urban communities is critical for place-based policy and urban planning. Particularly, things like political efficacy (ability to change community), belonging, and self-percieved segregation/homogenity are important for understanding how to design and deploy urban policy. Practically, if the FLF is successful, the survey module will be rolled out nationwide, allowing for the first socially-representative systematic study of urban neighborhoods. This would be a substantial advance in urban studies, and I would hope to anonymize and release these neighborhood boundary perceptions (depending on disclosure protocols) for planners to use in designing new policy and drawing new political boundaries (e.g. https://ljwolf.org/bce)
Date proposal received: 
Thursday, 18 August, 2022
Date proposal approved: 
Friday, 19 August, 2022
Keywords: 
Social Science, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Environment - enviromental exposure, pollution, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Psychology - personality, Physical - activity, fitness, function, Social science, Statistical methods

B4126 - The ALSPAC variable search tool - 15/08/2022

B number: 
B4126
Principal applicant name: 
Gibran Hemani | MRC Integrative Epidemiology Unit
Co-applicants: 
Dr Matthew Suderman
Title of project: 
The ALSPAC variable search tool
Proposal summary: 

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

Impact of research: 
Improve access and reproducibility to researchers
Date proposal received: 
Thursday, 11 August, 2022
Date proposal approved: 
Monday, 15 August, 2022
Keywords: 
Bioinformatics, All, Data science, Data science, reproducibility

B4128 - Interplay between genetic risk for metabolic syndrome and mental illness on childhood development outcomes - 15/08/2022

B number: 
B4128
Principal applicant name: 
William Reay | The University of Newcastle, NSW, Australia (Australia)
Co-applicants: 
Dr Dylan Kiltschewskij, Dr Kirrilly Pursey , L/Prof Clare Collins, Dr Erin Clarke, Professor Murray Cairns
Title of project: 
Interplay between genetic risk for metabolic syndrome and mental illness on childhood development outcomes
Proposal summary: 

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.

Impact of research: 
This study will further unravel the complex relationship between genetic risk for mental health conditions and heart disease. Specifically, these data will demonstrate whether there is an interplay between genetic risk for these two classes of disorders and clinically important outcomes in children/adolescents. These analyses using data from children and adolescents is particularly impactful as it may indicate markers of high genetic risk load that can be subjected to further investigation for risk stratification and precision intervention. Moreover, to our knowledge this study will be the first to test whether diet quality and specific nutrient intake can modify some of these associations, which would be valuable to inform future intervention studies to explore these hypotheses. This study also represents collaboration between clinical dieticians and geneticists, which are important relationships to increase the impact of genetic findings.
Date proposal received: 
Monday, 15 August, 2022
Date proposal approved: 
Monday, 15 August, 2022
Keywords: 
Genetics, Mental health, Polygenic risk scoring , Genetics

B4129 - Characteristics of Converters to and Deconverters from Traditional Religious Beliefs and Behaviours - 15/08/2022

B number: 
B4129
Principal applicant name: 
Jean Golding | UoB (United Kingdom)
Co-applicants: 
Professor Ralph Hood
Title of project: 
Characteristics of Converters to, and Deconverters from, Traditional Religious Beliefs and Behaviours
Proposal summary: 

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.

Impact of research: 
Difficult to say until we have completed the analyses.
Date proposal received: 
Monday, 15 August, 2022
Date proposal approved: 
Monday, 15 August, 2022
Keywords: 
Epidemiology, Mental health, Statistical methods, Psychology - personality

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