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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B3971 - The combined role of physical activity and dietary factors for musculoskeletal health during growth - 24/01/2022

B number: 
B3971
Principal applicant name: 
Dimitrios Vlachopoulos | University of Exeter (United Kingdom)
Co-applicants: 
Ms Rong Huang, Ms Annie Constable, Dr Alan Barker, Dr Luis Gracia-Marco , Maria Papageorgiou, Prof Krasimira Tsaneva-Atanasova , Dr Karen M. Knapp
Title of project: 
The combined role of physical activity and dietary factors for musculoskeletal health during growth
Proposal summary: 

Osteoporosis increases the risk of fracture due to decreased bone mass and deterioration of its structure which causes bone fragility. Low peak bone mass (PBM) at the end of adolescence or at the early stage of adulthood is a risk factor of osteoporosis. Bone development during growth is crucial for bone health throughout the whole life. Although the variation in bone outcomes is determined by heredity, lifestyle-related factors including physical activity (PA) and dietary habits can explain up to approximately 30% of the variation in PBM. It is known that sufficient moderate-to-vigorous PA levels and sufficient nutritional intakes, such as calcium, protein and vitamin D are needed to promote bone development. However, only a few studies focused on the combined and interactive effects between the dietary intakes and PA on bone health during growth. In addition, body mass is an important predictor of bone mineral content, according to previous studies, lean mass has a positive association with bone development, while the role of fat mass to bone is still controversial. Previous paediatric studies indicate the partial influence of endocrine markers on bone growth and especially during puberty, but the mediating role of endocrine markers on the relationship between body composition and PA with bone growth requires further research. Therefore, the overall objective of this research project is to assess the combined role of physical activity and dietary factors with bone development and examine the role of endocrine markers and body composition from childhood to early adulthood.

Impact of research: 
It is hoped to provide novel evidence about the balance of body composition components for bone health and the combined role of physical activity and diet for bone development from childhood to early adulthood. These results may bring a new perspective to public bone health improving recommendations.
Date proposal received: 
Monday, 17 January, 2022
Date proposal approved: 
Monday, 24 January, 2022
Keywords: 
Epidemiology, Bone disorders - arthritis, osteoporosis, Medical imaging, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Childhood - childcare, childhood adversity, Nutrition - breast feeding, diet, Physical - activity, fitness, function, Puberty

B3973 - Maternal vitamin D status during pregnancy and the risk of congenital heart disease in the offspring - 17/03/2022

B number: 
B3973
Principal applicant name: 
Deborah A Lawlor | University of Bristol
Co-applicants: 
Mr. Kurt Taylor, Ms Karen Christina Walker
Title of project: 
Maternal vitamin D status during pregnancy and the risk of congenital heart disease in the offspring
Proposal summary: 

Congenital heart disease (CHD) is a group of diseases with defects in the heart that occur during fetal life when the heart is formed. CHD occurs in 1% of births each year with causes not fully known. Most cases are believed to be caused by effects of both genes and risk factors that could be changed to prevent CHD (1,2). We are interested in identifying these modifiable risk factors. Several risk factors have been suggested including maternal diet intake (3). We would like to investigate the possible association between maternal vitamin D status and the risk of CHD in the child. A study from 2018 found that low maternal vitamin D was associated with a higher risk of CHD in the offspring (2). That study used blood markers of vitamin D measured approx. 15-months after birth as a proxy for mother’s vitamin D in early pregnancy. Because of the strong effects of sunlight and season on vitamin D levels the measures might not be a good indicator of the mother’s vitamin D in early pregnancy. We would like to use ALSPAC data to investigate the association of mother’s blood vitamin D in early pregnancy on their child’s risk of CHD. ALSPAC is an ideal study to improving our understanding of whether ensuring pregnant women have sufficient vitamin D could prevent CHD. It has measures of blood vitamin D (4), details of all cases of CHD including those that were diagnosed after birth (5), and information on factors that could confound the results.

Impact of research: 
Knowledge from the present study will contribute with valuable insights into risk factors for congenital heart disease.
Date proposal received: 
Friday, 14 January, 2022
Date proposal approved: 
Monday, 17 January, 2022
Keywords: 
Epidemiology, Congenital abnormalities, Statistical methods, Mendelian randomisation

B3968 - Contributions of fat and lean mass to structural vascular adaptations in the young - 17/01/2022

B number: 
B3968
Principal applicant name: 
Scott Chiesa | UCL (UK)
Co-applicants: 
Priyanka Iyer
Title of project: 
Contributions of fat and lean mass to structural vascular adaptations in the young
Proposal summary: 

In the absence of hard CVD endpoints in the young, early structural changes within the heart and arteries - such as an increase in left ventricular mass or a thickening or stiffening of the major arteries - are often used in early prevention research as surrogate measures of early disease. Many studies have related changes in these phenotypes at a young age to increases in either BMI or body fat %, suggesting that excess adiposity at an early age may drive pathophysiological changes within the heart and vessels. Both of these are crude measures of adiposity, however, with the former unable to separate fat from lean mass, and the latter unable to quantify absolute levels of each tissue type. The extent to which these phenotypic changes are driven by fat mass per se rather than a combination of fat and lean mass remains equivocal.

Impact of research: 
Conferences presentations and combination with other analyses to generate paper in high-impact journal.
Date proposal received: 
Thursday, 6 January, 2022
Date proposal approved: 
Monday, 17 January, 2022
Keywords: 
Epidemiology, Obesity, population study, Cardiovascular

B3969 - Contributions of fat and lean mass to blood pressure phenotypes in the young - 17/01/2022

B number: 
B3969
Principal applicant name: 
Scott Chiesa | UCL (United Kingdom)
Co-applicants: 
Valerie Mok
Title of project: 
Contributions of fat and lean mass to blood pressure phenotypes in the young
Proposal summary: 

Using a recall-by-genotype design, we have recently shown increases in BMI to be causally related to elevations in systolic - and to a lesser extent - diastolic blood pressure. While these changes are often attributed to the effects of excess adiposity, increases in BMI are known to arise from increases in both fat and underlying lean tissue, both of which may drive changes in blood pressure. This student project aims to investigate the extent to which these differing tissue types may contribute to changes in blood pressure commonly observed in the young.

Impact of research: 
Conferences presentations and combination with other analyses to generate paper in high-impact journal.
Date proposal received: 
Thursday, 6 January, 2022
Date proposal approved: 
Monday, 17 January, 2022
Keywords: 
Epidemiology, Hypertension, Obesity, population study, Blood pressure, BMI, Cardiovascular

B3972 - The relationship between the timing of prenatal alcohol exposure DNA methylation and depressive symptom trajectories - 17/01/2022

B number: 
B3972
Principal applicant name: 
Alexandre Lussier | Massachusetts General Hospital (United States)
Co-applicants: 
Dr. Erin C. Dunn
Title of project: 
The relationship between the timing of prenatal alcohol exposure, DNA methylation, and depressive symptom trajectories
Proposal summary: 

Prenatal alcohol exposure (PAE) is a potent risk factor for depression, with several studies showing that moderate levels of PAE can more than double depression risk. However, the biological mechanisms linking alcohol exposure to long-term vulnerability for depression remain poorly understood. One possibility is that PAE reprograms the epigenome through DNA methylation (DNAm), epigenetic modifications that do not change the sequence of the genome, but can alter gene expression. Both animal and human studies suggest that PAE can induce lasting DNAm changes in the brain and periphery, including in blood and buccal epithelial cells, and that these DNAm profiles are associated with disease risk. Despite these known links between PAE, DNAm, and depression, there are three main gaps in the literature.

First, most human epigenetic studies are cross-sectional and cannot evaluate the causal links between PAE, epigenome-wide DNAm, and depression. As such, it remains unknown whether the relationship between PAE and depression is causal, requiring additional genetic and environmental analyses to parse this relationship.

Second, nearly all studies define PAE as any exposure to alcohol between conception and birth, despite recent evidence that the effects of early-life exposures may have vary depending on when they occur. As such, it remains unknown whether there are specific trimesters or sensitive periods when children are more vulnerable, PAE differentially affects DNAm patterns, and prevention efforts might be most effective.

Third, depression can manifest through different time-dependent patterns after its initial onset, varying with regards to symptom levels, recurrence, and length. Given that a single timepoint cannot fully capture this time-dependent variability, we recently harnessed repeated measures of depressive symptoms to characterize a set of unique depressive symptom trajectories across childhood and adolescence (Lussier 2020; Hawrilenko 2020). However, it remains unclear when and how prenatal risk factors, such as alcohol, influence the manifestation of depressive symptoms across development.

As such, we seek to extend our prior work, which focused on sensitive periods for childhood adversity, to further investigate the relationship between prenatal alcohol exposure, DNAm, and depressive symptom trajectories across development. The central hypothesis we will test is that PAE has causal and time-dependent influences on depression heterogeneity across development, with measurable effects on depressive symptom trajectories and epigenetic processes from age 4 to 24.

Impact of research: 
Previous reports estimate that 10-15% of children are exposed to alcohol during pregnancy; numbers that are expected to rise due to the increases in alcohol use during the ongoing COVID-19 pandemic. By identifying the causal link between PAE and depression, this research will highlight the importance of PAE as a key modifiable and targetable factor in the prevention of depression. Through this work, we will also identify the molecular mechanisms that drive risk for depression across development and determine the optimal trimesters when interventions can be implemented to reduce the impact of prenatal alcohol exposure on depression risk. Specifically, we will identify a set of epigenetic biomarkers influenced by prenatal alcohol exposure and that predict the manifestation of depressive symptoms across development, as well as determine the trimesters when alcohol is most likely to causally affect these DNAm marks. Ultimately, this work will identify the specific periods when PAE can influence depression, which will help target interventions to the individuals who are at higher risk for early-onset depression.
Date proposal received: 
Thursday, 13 January, 2022
Date proposal approved: 
Monday, 17 January, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Computer simulations/modelling/algorithms, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Birth outcomes, Environment - enviromental exposure, pollution, Epigenetics, Genetic epidemiology, Genetics, Mendelian randomisation, Nutrition - breast feeding, diet, Parenting

B3967 - Epigenetics of changing traits - 17/01/2022

B number: 
B3967
Principal applicant name: 
Andrew Simpkin | NUI, Galway (Ireland)
Co-applicants: 
Anna Grossbach
Title of project: 
Epigenetics of changing traits
Proposal summary: 

The last decade has seen a dramatic improvement in our understanding of how our genes affect our height, body mass index (BMI), mental health, cancer risk, and many other traits. This has been facilitated by technological developments which allow us to measure a persons’ epigenetic data accurately and economically. Almost all epigenetic studies investigate traits collected at a single timepoint (e.g. adult height), and the epigenetic sites associated with these traits are then found using an epigenome-wide association study (EWAS). However, some traits such as BMI change over time, and the epigenetics of these repeatedly measured traits remain poorly understood. This project will apply new approaches for epigenetic analysis of longitudinal traits - in particular BMI measured repeatedly from birth to adulthood and depressive symptoms from later childhood through adolescence.

Impact of research: 
This research has major potential. The epigenetic analysis of changing/longitudinal phenotypes has yet to be developed, while methods are available in the GWAS context. Therefore, strong results in this study could lead to discoveries across a range of changing phenotypes, as longitudinal and epigenetic data continue to be collected more regularly. With ALSPAC/ARIES a leading cohort for epigenetic data analysis, these developments will open lots of pathways for research using data from Bristol.
Date proposal received: 
Thursday, 13 January, 2022
Date proposal approved: 
Monday, 17 January, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Mental health, Obesity, Statistical methods, Development, Epigenetics, Growth, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3949 - Assessing the hidden gateways into gambling and policies to reduce problem gambling - 10/01/2022

B number: 
B3949
Principal applicant name: 
Jonathan Cave | Supervisor (or University of Warwick) (United Kingdom)
Co-applicants: 
Ben Ho
Title of project: 
Assessing the hidden gateways into gambling and policies to reduce problem gambling
Proposal summary: 

This research paper will look at the gateways into gambling and in particular, problem gambling. Through a quantitative and statistical approach, we hope to identify the behavioural characteristics that may be associated with problem gamblers. Once identified, potential policies will be suggested to dissolve the issue of problem gambling.

Impact of research: 
Contribution to understanding of correlates and causal patterns behind problem gambling (also as a model for other 'addicitive' behaviours with societal reinforcers).
Date proposal received: 
Wednesday, 5 January, 2022
Date proposal approved: 
Monday, 10 January, 2022
Keywords: 
Economics, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Intelligence - memory, Social science, Statistical methods

B3965 - Can heavy menstrual bleeding be used to improve the prediction and prevention of cardiovascular disease in women - 05/01/2022

B number: 
B3965
Principal applicant name: 
Gemma Sharp | MRC IEU
Co-applicants: 
Title of project: 
Can heavy menstrual bleeding be used to improve the prediction and prevention of cardiovascular disease in women?
Proposal summary: 

Cardiovascular disease (CVD, e.g. heart attack, stroke) is the leading cause of death in women. Yet women with CVD remain understudied, under-recognised, underdiagnosed and undertreated. Therefore, women have not experienced the same decline in CV rates that has occurred in men in recent decades.
General practitioners currently use CVD risk prediction tools that use traditional risk factors such as blood pressure and cholesterol. We propose that a CVD risk assessment tool which incorporates menstrual data could improve the prediction/prevention of CVD in women.
Recent research suggests that menstrual symptoms such as heavy periods may predict future CVD. Examination of our local electronic health records revealed that women having surgery for heavy menstrual bleeding (HMB) had a seven times greater risk of death from a heart attack than the general female population. Women undergoing hysterectomy for benign causes (e.g. HMB) also had increased CVD, even if the ovaries were not removed.(2).
There are many underlying causes of HMB. These may be non-structural (normal womb at scan) or structural (fibroids/adenomyosis) causes and may be influenced by genetics. However, the relationship between the symptom of HMB, its underlying cause and CVD risk has not been systematically evaluated.
This project will evaluate: (1) if there is an association between the symptom or underlying cause of HMB and future CVD by examining anonymised electronic health records and longitudinal population-based cohort studies of women across the life-course. This will determine if menstrual data would be useful in the prediction of future CVD. (2) if inclusion of relevant menstrual data (informed by our population data studies) and/or other female-specific risk factors (from published literature) in current CV risk prediction tools improves their prediction of CVD. We will use two independent population studies from the UK and Australia to validate our findings. (3) if adoption of a CV risk prediction tool that incorporates female-specific risk factors is feasible in clinical practice to improve the prevention of CVD. We will ask three general practices to use the new female-specific tool on pre-menopausal women. We will assess the number of women it is used in, how user friendly the tool is and also examine the anonymised electronic health records of those it is used in to determine the rate of prescription of CV preventative medicines (e.g. blood pressure medications, statins). These results will inform the design of a future, larger trial to assess the effectiveness of this new tool versus the currently used tools.
This project combines the expertise of gynaecologists, cardiologists and epidemiologists to analyse data from populations to inform clinical practice. We aim to inform the inclusion of relevant menstrual data in CVD risk assessment tools and inform future studies to evaluate their performance in the identification of pre-menopausal women at risk of CVD, allowing early implementation of effective preventative strategies to reduce CV disease and death in women.

Impact of research: 
Date proposal received: 
Thursday, 30 December, 2021
Date proposal approved: 
Wednesday, 5 January, 2022
Keywords: 
Epidemiology

B3964 - High neighbourhood-level deprivation collective efficacy and conduct disorder behaviours A network analysis - 23/12/2021

B number: 
B3964
Principal applicant name: 
Ted Barker | King's College London (United Kingdom)
Co-applicants: 
Yi An Liao
Title of project: 
High neighbourhood-level deprivation, collective efficacy and conduct disorder behaviours: A network analysis
Proposal summary: 

High neighbourhood-level deprivation and low levels of neighbourhood collective efficacy (social cohesion and informal social control) are believed to work together to increase the development of conduct disorder (CD) behaviours, such as lying, fighting, stealing. However, in practice, neighbourhood deprivation has typically not been examined longitudinally and deprivation has often been solely based on neighbourhood-level socioeconomic status rather than a wide range of objective census-level indicators. In addition, CD behaviours have typically been examined using a summed score of behaviours, rather than assessing what particular CD behaviours (e.g., physical aggression) interact with low levels of social cohesion, informal social control and associated risks (e.g., affiliating with deviant peers) under varying levels of longitudinal deprivation exposures.

Impact of research: 
A peer reviewed publication at a decent impact factor (IF > 6.0)
Date proposal received: 
Thursday, 23 December, 2021
Date proposal approved: 
Thursday, 23 December, 2021
Keywords: 
Social Science, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Childhood - childcare, childhood adversity

B3963 - Timing of adolescent growth and maturation and related in utero stressors - 05/01/2022

B number: 
B3963
Principal applicant name: 
Ahmed Elhakeem | MRC IEU
Co-applicants: 
Title of project: 
Timing of adolescent growth and maturation and related in utero stressors
Proposal summary: 

The aim of this paper is to leverage repeated measurements from the ALSPAC birth cohort to describe the timing, chronological sequence, and interrelationships between the maturational processes and events of puberty, and to investigate the associations of key prenatal stressors with these derived indicators of puberty timing (i.e., with all early to late signs of puberty).

Impact of research: 
This work will be of interest to researchers, clinicians, policymakers, and the wider public
Date proposal received: 
Wednesday, 22 December, 2021
Date proposal approved: 
Wednesday, 22 December, 2021
Keywords: 
Endocrinology, Statistical methods, Development

B3944 - Ribosomal DNA copy number influences birth weight - 21/12/2021

B number: 
B3944
Principal applicant name: 
Vardhman Rakyan | Queen Mary University of London
Co-applicants: 
Dr Fran Rodriguez-Algarra
Title of project: 
Ribosomal DNA copy number influences birth weight
Proposal summary: 

Ribosomal DNA is a part of our DNA that is present as many copies (most genes are only present as two copies). Because of this reason, the rDNA is typically ignored in large scale genetic studies. We believe that the number of copies of rDNA influences a babies birth weight.

Impact of research: 
An improved understanding of the genetic basis of birth weight variation.
Date proposal received: 
Monday, 20 December, 2021
Date proposal approved: 
Tuesday, 21 December, 2021
Keywords: 
Genetics, Birth weight, DNA sequencing, Birth outcomes, BMI, Genetics, Whole genome sequencing

B3961 - Integrating genetics epigenetics and metabolomics to identify early life origins of adult disease - 05/02/2022

B number: 
B3961
Principal applicant name: 
Joel Hirschhorn | Boston Children's Hospital/Broad Institute of MIT and Harvard (United States)
Co-applicants: 
Dr. Mary Elizabeth Patti, Dr. Anders Eliasen
Title of project: 
Integrating genetics, epigenetics and metabolomics to identify early life origins of adult disease
Proposal summary: 

We will use multiple types of data from children in ALSPAC and other childhood cohorts to ask what factors, already evident in children, are causal precursors of future disease. We will focus on molecules that circulate in the blood (metabolites), factors inherited in the genome (genetic variants), and special modifications of the genome (epigenetics, methylation). By combining data from children for genetic variants, epigenetics and metabolites, we can ask whether there are particular metabolites or epigenetic factors that are causal precursors of diseases like obesity, coronary artery disease (CAD), and type 2 diabetes (T2D). Understanding the early causal factors of future disease could guide earlier and therefore potentially more effective interventions.

Impact of research: 
We hope to identify metabolic and/or epigenetic childhood markers that are associated with genetic risk of future cardiometabolic disease and to assess them for evidence of causality using Mendelian randomization. If successful, these biomarkers may be part of early screening to guide intervention, and if causal may give rise to new therapeutic hypotheses that are based in causal mechanisms.
Date proposal received: 
Tuesday, 21 December, 2021
Date proposal approved: 
Tuesday, 21 December, 2021
Keywords: 
Genetics, Diabetes, Obesity, coronary artery disease hyperlipidemia central adiposity nonalcoholic fatty liver disease metabolic syndrome hypertension, GWAS, Metabolomics, Statistical methods, Methylation (epigenetics), Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Mendelian randomisation, Metabolic - metabolism, Nutrition - breast feeding, diet, Statistical methods, Blood pressure, BMI, Cardiovascular, Epigenetics, Genetic epidemiology, Genetics, Genomics, Genome wide association study

B3951 - Recognising ADHD in ID - 20/12/2021

B number: 
B3951
Principal applicant name: 
Melanie Palmer | Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London
Co-applicants: 
Professor Emily Simonoff
Title of project: 
Recognising ADHD in ID
Proposal summary: 

Individuals with Intellectual Disability (ID) often have other neurodevelopmental conditions, such as Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), that lead to further impairments and reduced quality of life. This triad of conditions contributes to difficulties in teasing apart symptoms, adding diagnostic complexity. No ADHD screening tools have been developed specifically for ID populations and they do not take ASD into account. This project will use ALSPAC data to explore the manifestations of ADHD in children and young people with and without ID. The ultimate aim is to enhancing methods for detection of co-occurring ADHD in ID.

Impact of research: 
The ultimate outcome is to improve methods for ADHD recognition in CYP with ID, helping clinicians to arrive at a diagnostic decision about whether co-occurring ADHD is present or not with greater confidence. As ADHD is currently under-recognised in ID, it is likely that improving recognition will increase caseness. Better recognition and more accurate diagnosis of ADHD will be of significant clinical value as it will lead to more appropriate and tailored interventions, improving treatment choice, functional outcomes, and quality of life. The key outcome is to identify the accuracy of ADHD screeners for use with ID, which items are most discriminating, and whether a new measure, or further validation of an existing measure, is needed. Recommendations about recognising ADHD in ID and measurement of ADHD symptomology will be made for parents and clinicians.
Date proposal received: 
Monday, 13 December, 2021
Date proposal approved: 
Monday, 20 December, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Cognitive impairment, Learning difficulty, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Communication (including non-verbal), Psychology - personality, Statistical methods

B3959 - Rethinking mental health difficulties - 20/12/2021

B number: 
B3959
Principal applicant name: 
Jenny Retzler | University of Huddersfield
Co-applicants: 
Dr Chris Retzler
Title of project: 
Rethinking mental health difficulties
Proposal summary: 

The symptoms experienced by young people with mental health difficulties rarely fit neatly into one diagnosis. For more than half of young people with difficulties, the symptoms experienced can be divided into two, or even more, diagnoses, while for others, there is no diagnostic category into which they fit. These problems with our diagnostic categories make it difficult for researchers and doctors who want to know how and why, some people develop mental health difficulties, and how best to support them.

To solve these problems, we need to look at mental health difficulties in a different way. In the last five years, researchers have started using ‘person-centred’ statistical techniques, which produce an alternative to the diagnostic categories we use at the moment, to look at mental health difficulties in teenage groups. Person-centred techniques look for patterns in data that show how symptoms might group in certain ways for some individuals, and in different ways for others. For example, having poor concentration might be grouped together with feeling anxious and being withdrawn in some young people. In others, poor concentration might, instead, be grouped together with feeling restless and breaking rules. With traditional diagnoses, both sets of young people might be diagnosed with ADHD, but using a person-centred perspective we can find these different groupings that reflect the variety of difficulties being experienced. This should give researchers a better chance of understanding what might make it more (or less) likely that somebody has the problems they do, and what type of support might help them most.

The challenge we face is that person-centred techniques are still quite new and we don’t yet know whether the new groupings they produce are consistent, or any more representative or useful than the current ways we diagnose. This is what this project aims to assess. At the same time, we want to get input from young people with experience of mental health difficulties as we do this. Phase 1 will start by understanding more from young people about their experiences of mental health difficulties and the diagnostic journey. We want to know what has been important to them, what they think might have influenced the symptoms they live with, and what sorts of things help make life easier. Researchers will use the understanding we gain from these sessions to plan how they will do the statistical analysis in phase two to make sure that it captures what is important to young people. Phase 2 will be the statistical analysis, shaped by Phase 1. We will use ALSPAC data, which has followed up thousands of people from childhood and through the teenage years, and use person-centred techniques to find new groupings with shared patterns of symptoms. We will then test the statistical strength and consistency of the new groupings, and use understanding gained from Phase 1 to see whether the new groupings can help us to learn more about the factors that impact mental health. In Phase 3, we want to come back to young people to see how far they feel the new perspectives on mental health difficulties that were generated in Phase 2 fit with their experiences. They can help us to see what will and won’t be an improvement over existing diagnoses, and can consider with us how the findings can be used to improve the diagnostic journey. During this phase, we also want to discuss the findings with groups who make decisions about how CAMHS runs, to identify positive ways to use the knowledge that has been generated.

Impact of research: 
This project will benefit young people living with mental health conditions in a number of ways. In the short-term it would give those in charge of mental health services some ideas about what is important to consider during diagnosis and management, and a new way to look at mental health difficulties. Longer term, this can be used to inform a diagnostic process that truly reflects the pattern of difficulties individuals have. From a research perspective, we hope that in the short-term, our project will make any benefits of using person-centred techniques to define mental health difficulties clearer to researchers, so that they can use them effectively. With this understanding, knowledge of new ways to prevent and support these difficulties will be possible long-term. Adolescent mental health research will also benefit from the way this project combines the experiences of young people with complicated statistical analysis. Usually, these two parts of research are kept separate, but we want to show how much more we can understand if we bring the two together, and give other researchers an example that they can follow of how to do this effectively.
Date proposal received: 
Thursday, 16 December, 2021
Date proposal approved: 
Monday, 20 December, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cognitive impairment, Eating disorders - anorexia, bulimia, Mental health, Computer simulations/modelling/algorithms, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Statistical methods

B3952 - Orienting causal relationships between sleep and adiposity traits using genetic risk scores and mendelian randomisation - 20/12/2021

B number: 
B3952
Principal applicant name: 
Rebecca Richmond | University of Bristol (United Kingdom)
Co-applicants: 
Miss Bryony Hayes
Title of project: 
Orienting causal relationships between sleep and adiposity traits using genetic risk scores and mendelian randomisation
Proposal summary: 

Poor sleep and obesity are problem that permeates though much of the UK population. Up to 67% of UK adults report disturbed sleep, 26 – 36% experience insomnia and 23% sleep for < 5 hrs per night1. Furthermore, a 2019 health survey for England found that 28.0% of adults in England are obese and a further 36.2% are overweight2. Similarly, obesity is a growing problem in the UK, amongst both children and young people. In 2019, a study by the National Child Measurement Programme (NCMP) found that by the age of five, 13.1% of children were overweight and 9.9% were obese. Between 2007 and 2019, the same study found that prevalence of obesity in year six children had increased from 17.5% to 21.0% 2.
Sleep traits such as chronotype (morning- or evening-preference), insomnia (difficulty initiating or maintaining sleep) and sleep duration (length of time spent sleeping) have previously been studied in relation to adiposity. In previous studies, increased odds of obesity has been associated with evening-preference chronotype4, occurrence of insomnia symptoms 5, and both short (<6h) and long (>9h) sleep duration5. Many studies have also found that individuals involved in night shift work are more likely to become overweight or obese6,7. In addition, associations have been found between increased obesity and both sleep apnoea8 and restless leg syndrome9, both of which may result in poor quality sleep10,11. However, it is often difficult to determine causal relationships and direction of effects in many of these studies, given the observational and often cross-sectional nature of the data.
We have recently performed preliminary Mendelian randomization to establish direction of effects between adiposity- and sleep-traits using summary data from genome-wide associations studies. We wish to follow up these findings using data from the Avon Longitudinal Study of Parents and Children (ALSPAC).
References:
1. Aviva. Aviva health check UK report. (2016).
2. Baker, C. Inside: 1. Obesity in adults, England 2. Obesity in children. 3336, (2021).
3. Cole, T. J., Freeman, J. V. & Preece, M. A. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat. Med. 17, 407–429 (1998).
4. Sun, X., Gustat, J., Bertisch, S. M., Redline, S. & Bazzano, L. The association between sleep chronotype and obesity among black and white participants of the Bogalusa Heart Study. Chronobiol. Int. 37, 123–134 (2020).
5. Cai, G.-H. et al. Insomnia symptoms and sleep duration and their combined effects in relation to associations with obesity and central obesity. Sleep Med. 46, 81–87 (2018).
6. Liu, Q. et al. Is shift work associated with a higher risk of overweight or obesity? A systematic review of observational studies with meta-analysis. Int. J. Epidemiol. 47, 1956–1971 (2018).
7. Brum, M. C. B. et al. Night shift work, short sleep and obesity. Diabetol. Metab. Syndr. 12, 13 (2020).
8. Romero-Corral, A., Caples, S. M., Lopez-Jimenez, F. & Somers, V. K. Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest 137, 711–719 (2010).
9. Gao, X., Schwarzschild, M. A., Wang, H. & Ascherio, A. Obesity and restless legs syndrome in men and women. Neurology 72, 1255–1261 (2009).
10. Bogan, R. K. Effects of restless legs syndrome (RLS) on sleep. Neuropsychiatr. Dis. Treat. 2, 513–519 (2006).
11. Miyahara, L. K. et al. Evaluation of sleep quality and risk of obstructive sleep apnea in patients referred for aesthetic rhinoplasty. Sleep Sci. (Sao Paulo, Brazil) 12, 126–131 (2019).

Impact of research: 
A better understanding of the causal direction between sleep traits and adiposity may be used to inform futures studies that explore the causal pathways between adiposity, sleep and health outcomes such as breast cancer, and may also be used to inform patient-based intervention studies.
Date proposal received: 
Wednesday, 15 December, 2021
Date proposal approved: 
Monday, 20 December, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Obesity, Sleep traits such as chronotype, insomnia, sleep duration, napping during the day, daytime dozing, ease of getting up in the morning, GWAS, Statistical methods, Genetic risk scores, observational analyses, longitudinal analyses, BMI, Genetic epidemiology, Genetics, Genome wide association study, Mendelian randomisation, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods

B3960 - Replication of trans-ancestry adiposity genetic scores - 20/12/2021

B number: 
B3960
Principal applicant name: 
Robin Walters | University of Oxford (UK)
Co-applicants: 
Gibran Hemani
Title of project: 
Replication of trans-ancestry adiposity genetic scores
Proposal summary: 

There is a growing interest in the use of "genetic scores" to investigate the contribution of traits such as obesity and blood pressure to disease and disease risk. However, scores developed using individuals of one ancestry (e.g. Europeans) typically are less useful when applied to populations from another (e.g. East Asians). We are investigating the performance of scores generated using data from multiple ancestries, compared with those from a single ancestry, and have found that there can be substantial improvements. As part of this, to make sure that our results are reproducible, we need to do analyses in sets of individuals who were not used in generating the scores. This project tests how our "improved" scores perform in ALSPAC mothers and fathers.

Impact of research: 
Improved understanding of the limitations of using genetic scores across ancestries, and of the improvements that can be gained from trans-ancestry meta-analyses.
Date proposal received: 
Thursday, 16 December, 2021
Date proposal approved: 
Monday, 20 December, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Obesity, Statistical methods, BMI, Genetic epidemiology, Genetics

B3950 - Identifying the genetic markers associated with within-individual variability in blood pressure - 21/12/2021

B number: 
B3950
Principal applicant name: 
Richard Parker | University of Bristol (UK)
Co-applicants: 
Dr April Hartley, Prof Kate Tilling, Dr Jessica Barrett, Prof George Leckie, Prof George Davey Smith, Prof Laura Howe, Dr Jon Heron, Prof Alun Hughes
Title of project: 
Identifying the genetic markers associated with within-individual variability in blood pressure
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: 
Friday, 10 December, 2021
Date proposal approved: 
Monday, 20 December, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Hypertension, GWAS, Statistical methods, Blood pressure, Cardiovascular, Genetic epidemiology, Genome wide association study, Statistical methods

B3946 - Maternal diabetes in pregnancy and developmental programming of neurodevelopment disorders An inflammatory Hypothesis - 24/01/2022

B number: 
B3946
Principal applicant name: 
Rachelle Pretorius | Telethonkids Institute (Western Australia )
Co-applicants: 
Prof Rae-Chi Huang
Title of project: 
Maternal diabetes in pregnancy and developmental programming of neurodevelopment disorders: An inflammatory Hypothesis
Proposal summary: 

Cognitive and behavioral disorders among children are on the increase. Exposures to metabolic disorders during pregnancy may influence the offspring’s psychopathology and neurodevelopment. This project will assess the relationship between diabetes before and during pregnancy on various aspects of child cognitive and behavioral development

Impact of research: 
Using the extensive data available form a large number of mother-children pair will assist in our understanding of the role of maternal metabolic health and childhood mental health outcomes. Findings from the studies will directly impact implementation activities and improve health outcomes of future generations
Date proposal received: 
Tuesday, 7 December, 2021
Date proposal approved: 
Monday, 20 December, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Cognitive impairment, Congenital abnormalities, Diabetes, Learning difficulty, Mental health, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Birth outcomes, Intelligence - memory, Mothers - maternal age, menopause, obstetrics, Metabolic - metabolism, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Nutrition - breast feeding, diet, Offspring, Psychology - personality, Speech and language, Statistical methods, Blood pressure, BMI, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Endocrine - endocrine disrupters, Environment - enviromental exposure, pollution

B3933 - Understanding Genetic Risk for Externalizing across Development and in Conjunction with the Environment - 17/12/2021

B number: 
B3933
Principal applicant name: 
Danielle Dick | Virginia Commonwealth University (United States)
Co-applicants: 
Dr. Holly Poore, Maia Choi, Erin Gallert, Dr. Fazil Aliev, Dr. Sarah Brislin, Morgan Driver, Rebecca Smith, Nate Thomas, Dr. Amy Adkins, Emily Balcke
Title of project: 
Understanding Genetic Risk for Externalizing across Development and in Conjunction with the Environment
Proposal summary: 

Externalizing refers to a constellation of behaviors characterized by under-controlled or impulsive action and antagonism and which manifests in multiple psychiatric disorders (e.g., ADHD, substance use disorders) as well as personality, temperament, and behavioral traits. Twin and molecular genetic studies indicate that externalizing phenotypes are highly heritable and that multiple externalizing phenotypes are influenced by the same genetic factors. This project aims to characterize genetic risk for externalizing in longitudinal samples to better understand the spectrum of phenotypes associated with identified genetic variants, across development, across sex, and in conjunction with the environment.

Impact of research: 
Results from this project will further the goal of genomics research to enhance risk prediction of phenotypes associated with high disease burden and suffering. By taking genetic findings from GWAS into longitudinal, developmental studies like ALSPAC, we will be able to map the pathways by which genetic risk manifests across development, highlighting the early behavioral manifestations of risk, and studying how various individual characteristics and environments moderate the risk across developmental periods. The original externalizing GWAS, from which our polygenic scores were derived, was published in Nature Neuroscience (full citation below) and we anticipate that our follow-up analyses further characterizing risk will also be of high impact. Karlsson Linnér, R., Mallard, T.T., Barr, P.B. et al. Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction. Nat Neurosci 24, 1367–1376 (2021). https://doi.org/10.1038/s41593-021-00908-3
Date proposal received: 
Thursday, 9 December, 2021
Date proposal approved: 
Friday, 17 December, 2021
Keywords: 
Social Science, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, GWAS, Statistical methods, Genetic epidemiology, Genetics, Genomics, Psychology - personality, Social science, Statistical methods

B3940 - The DASH-style dietary pattern in childhood in relation to Cardiometabolic Risk in early adulthood in the ALSPAC cohort - 10/12/2021

B number: 
B3940
Principal applicant name: 
Genevieve Buckland | Bristol Medical, Centre for Academic Child Health (United Kingdom)
Co-applicants: 
Dr. Caroline Taylor, Dr. Pauline Emmett
Title of project: 
The DASH-style dietary pattern in childhood in relation to Cardiometabolic Risk in early adulthood in the ALSPAC cohort.
Proposal summary: 

The Dietary Approaches to Stop Hypertension (DASH) diet is considered a healthy dietary pattern that is associated with lower blood pressure, reduced risk of cardiovascular diseases, type 2 diabetes and related cardiometabolic risk factors in adults. However, research into the cardiometabolic benefits of this dietary pattern during childhood and adolescence is scarce, especially from large studies following-up children into adulthood.
We plan to use dietary data collected in ALSPAC when the children were 7 years, 10 years and 13 years old to assess how closely their diets aligned to a DASH-style dietary pattern. Apart from being low in salt, this dietary patter is high in fruits and vegetables, nuts and pulses, wholegrains, and low-fat dairy products and low in red and processed meat, sweetened drinks and saturated fat. We will explore whether the children with more DASH-style dietary patterns during childhood have better overall cardiometabolic health when they are 17 years and 24 years old, and if so which aspects of cardiometabolic health are benefited most. Overall cardiometabolic health will be measured using a Cardiometabolic Risk (CMR) score that takes into account each participants’ glucose, insulin, triglyceride and cholesterol levels, blood pressure and body composition.

Impact of research: 
This study will advance our understanding of the dietary determinants during childhood for the development of cardiometabolic risk factors in early adulthood. Research in this area from large prospective studies with long follow-up times are limited. Dietary habits are still evolving during childhood and adolescence and by studying dietary patterns at three time points we will also be able to assess if there are critical time point(s) when these dietary habits are more important for future cardiometabolic health. We expect our findings to contribute to the scientific evidence needed to develop effective preventative strategies and identify and manage at risk groups, where there is a particular shortfall in clinical and public health practice. For instance, the results could help when designing specific dietary interventions targeted at high-risk children and adolescents to reduce their risk of developing cardiometabolic diseases later in adulthood.
Date proposal received: 
Monday, 29 November, 2021
Date proposal approved: 
Friday, 10 December, 2021
Keywords: 
Epidemiology, Hypertension, Association analysis (using regression models) of dietary and cardiometabolic data. , Nutrition - breast feeding, diet

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