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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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

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

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

B3905 - Developmental origins of thyroid function regulation in the Avon Longitudinal Study of Parents and Children ALSPAC birth cohor - 10/12/2021

B number: 
B3905
Principal applicant name: 
Alexandra Alvergne | CNRS (French National Centre for Research) (France)
Co-applicants: 
Ms. Sarai Keestra, Mr. Austin Argentieri , Prof. T. J. Roseboom, Dr Martijn Finken, Dr Vedrana Högqvist Tabor
Title of project: 
Developmental origins of thyroid function regulation in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohor
Proposal summary: 

Thyroid dysfunction due to hypo- or hyperthyroidism affects 200 million people worldwide and is a major health burden. Thyroid hormones are vital for healthy metabolism, tissue differentiation, neurodevelopment, growth, immune function, reproduction, and ageing, yet the relative contribution of environmental exposures (e.g. nutrition, psycho-socio-economic adversity, etc.) in shaping thyroid function regulation remains unknown. The thyroid axis is especially important for the health of (pregnant) women and their children , but currently there is a lack of intergenerational data that can help understand the complex interplay between environment and genetics in thyroid function regulation. We aim to fill that gap by analysing thyroid function related variables in the ALSPAC data. Specifically, we will (1) investigate critical periods in which environmental and life-history influence thyroid function regulation, (2) analyse the impact of thyroid function on reproductive health outcomes, and (3) explore the epigenetic pathways by which thyroid function affects health outcomes in mothers and children. Within these analyses we will look at both natural variation in thyroid function parameters as well as pathological variation due to thyroid dysfunction. Identifying critical periods of thyroid function plasticity may have significant implications for the optimal timing of comprehensive public health interventions that can decrease the burden of thyroid dysfunction and its health consequences over the life course.

Impact of research: 
Thyroid dysfunction affects 200 million people worldwide and is major health burden (Kuyl, 2015). Few studies have considered the comprehensive impact of environmental exposures on the thyroid function and reproductive health outcomes of mothers and their offspring, and none take a longitudinal life course approach. Identifying environmental risk factors for developing thyroid dysfunction can inform efforts at prevention and early identification of thyroid disease. Since thyroid hormones can play fundamental roles in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, understanding plasticity in healthy thyroid function also has the potential to help better understand natural variation in these neuroendocrine axes in face of adversity and its effects on reproductive health outcomes. Ultimately, we seek to determine the critical periods throughout the life course in which thyroid function is most flexible and plastic, which will help inform optimal timing for comprehensive public health interventions that address thyroid dysfunction and its health consequences. Using an evolutionary ecology framework we suggest that by understanding the role of thyroid function in regulating the energetic trade-offs between the functions of reproduction, growth, and somatic maintenance, an evolutionary medicine approach can contribute to clinical medicine by reinterpreting natural variation in thyroid function within an ecological context (Keestra et al., 2020). By investigating the effect of normal thyroid function variation during the life span on timing of maturation, we can enhance our understanding regarding the role of thyroid function in translating early life environmental exposures into differential developmental tempos. In this context, we also consider how variation in thyroid hormone levels in pregnant women affect incidence of pregnancy disorders and influence obstetric and neonatal health outcomes. Finally, we aim to develop a novel approach to understanding healthy thyroid function in later life by characterising the interactions between women’s reproductive history, thyroid function, and epigenetic markers of cellular ageing. By taking an experimental approach as outlined in this proposal, we seek to stimulate a new research programme that reconsiders thyroid function as an important pathway by which energy investments over the life course are regulated, utilising thyroid evolutionary ecology as a new predictive framework. Thyroid dysfunction has significant ramifications for the regulation of body temperature, metabolism, fertility, foetal neurological development, intellectual performance of school-aged children, adult mental health, and overall quality of life (Keestra et al., 2020). Even at subclinical levels, thyroid hormone imbalances are associated with psychiatric disorders, stroke risk, and altered cardiac function, and are thereby a significant source of ill health worldwide. Identifying environmental risk factors and biomarkers that associate with development of thyroid dysfunction can inform prevention efforts and enable early identification of thyroid disease. To reduce the disease burden of thyroid dysfunction and its associated comorbidities, chronic disease prevention must start at the earliest beginning (Klimek et al., 2014). Appreciating the way genetics, environment, and early life experiences give shape to organisms throughout their life span opens up new avenues towards personalised medicine in the prevention, diagnosis, and treatment of disease (Wells et al., 2017). By utilising the birth cohort’s longitudinal and diverse datasets, it is possible to study human beings in all their bio-psycho-social complexity, whilst bridging the gap between epidemiological studies and animal model research to elucidate the epigenetic mechanisms underlying environmental exposures and chronic disease risk (Thalabard et al., 1996). It is at these interfaces that interdisciplinary teams such as ours, consisting of medical anthropologists, evolutionary biologists, epigeneticists, and clinicians, can make the greatest contribution towards science and our understanding variation in health and disease across different contexts.
Date proposal received: 
Friday, 10 December, 2021
Date proposal approved: 
Friday, 10 December, 2021
Keywords: 
Endocrinology, Thyroid disease, Statistical methods, Hormones - cortisol, IGF, thyroid

B3945 - Coming of Age in a Pandemic Transitions to Adulthood and Long-Term Mental Health - 17/12/2021

B number: 
B3945
Principal applicant name: 
Annie Herbert | Population Health Sciences, University of Bristol
Co-applicants: 
Dr Michael Green
Title of project: 
Coming of Age in a Pandemic: Transitions to Adulthood, and Long-Term Mental Health
Proposal summary: 

The COVID-19 pandemic has disrupted the lives of many people in many ways. For young people who were becoming adults, it may have disrupted or delayed moves out of education and into employment, or from living with parents to forming families. This may have long-term implications for their lives and mental health. We will combine information from three surveys that followed people from their youth into adulthood before the pandemic, with information from a survey of young people who were just becoming adults as the COVID-19 pandemic happened. In doing so, we aim to find out what impact the COVID-19 pandemic has had on the economic and family situations of this generation of young adults, and what the longer- term impacts of this on their mental health could be.

Impact of research: 
The findings will provide a better understanding of how the pandemic has affected young people's working and living patterns in a critical period of their life for transitioning to adult roles, and the potential knock-on effects on mental health. Findings can be inform as to mental health needs among this unique group of young people.
Date proposal received: 
Monday, 6 December, 2021
Date proposal approved: 
Friday, 10 December, 2021
Keywords: 
Epidemiology, Mental health, Social science

B3947 - A deep clinical phenotyping study of a group of participants on a low lung function trajectory - 16/12/2021

B number: 
B3947
Principal applicant name: 
George Nava | University of Bristol; Academic Respiratory Unit, Southmead Hospital; NIHR-funded position (UK)
Co-applicants: 
Dr James Dodd, Dr Raquel Granell, Professor Nicholas Timpson
Title of project: 
A deep clinical phenotyping study of a group of participants on a low lung function trajectory.
Proposal summary: 

Chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) are incurable but potentially preventable. Studies in cohorts such as ALSPAC have identified that everyone’s lung capacity increases in childhood, peaks in their early 20s and declines from the age of 30. Some groups never reach a normal peak, and some decline more quickly than others. Those on low lung function trajectories are at higher risk of developing lung diseases, diseases of other organs and dying younger. The reasons that these different trajectories exist are not fully understood. Without addressing this question, we cannot improve outcomes for patients with poor lung health and reduce the burden of chronic lung disease. This project aims to improve this understanding and identify potential targets for future interventions.

We will undertake a series of detailed assessments on a small group of ALSPAC Generation 1 participants to look for evidence of early lung disease. We will compare those on a low lung function trajectory with those on a normal one. The assessment will include an interview with a respiratory doctor, breathing tests and a state-of-the-art scan of the lungs at the University of Sheffield, which is a safe new technique of looking in detail at the structure and function of the lungs. This will complement the lung function tests that are aiming to collect data for >4000 participants in the Clinic at 30.

This study will have a range of applications and create future research opportunities to improve our understanding of normal and abnormal lung function development and finding ways of improving everyone’s lung health.

Impact of research: 
There are a range of potential impacts of this research. Firstly, this research aims to address the issue the need to prevent the development of significant respiratory disease. Trends in across all of healthcare are moving towards early recognition and prevention of medical conditions. Millions of people suffer and die from respiratory diseases each year. Many chronic diseases remain subclinical for years, however once the symptoms emerge, the pathology is irreversible and advanced. This research will contribute to our understanding of the pathogenesis of lung disease and contribute to the search for biomarkers of early disease that could form the focus of interventions to prevent or limit disease progression. This could have significant impacts to populations across the world. For the ALSPAC G1 participants specifically, it is possible that we will identify undiagnosed respiratory disease, such as uncontrolled asthma, that we will be able to recommend management in line with current NHS treatment pathways. Furthermore, if aligned research is able to identify new interventions or treatments, then these participants would represent an ideal group to offer these to. For our research team and Bristol University as a whole, it will provide a deeper understanding of the subjects of current and future lung function trajectory studies. This could both enhance the ability to interpret gained from these studies, but it will also provide a wealth of legacy data from which future studies can be design. It will also act as pilot data from which a larger study could be expanded. In addition, we are currently in discussions with the POLARIS (Pulmonary, Lung and Respiratory Imaging Sheffield) research team at the University of Sheffield about developing the capabilities to perform hyperpolarised xenon-129 imaging in Bristol. This will be the first time that a study from Bristol has employed this exciting technology and this experience will strengthen future applications to bring this technique to our university. For other researchers in the field, it will be the first time that a birth cohort has had deep clinical phenotyping or cross-sectional imaging of the lungs at the critical timepoint in lung development. It will contribute to international collaborations such as CADSET and may help to mould research across other cohorts.
Date proposal received: 
Tuesday, 7 December, 2021
Date proposal approved: 
Wednesday, 8 December, 2021
Keywords: 
Epidemiology, Respiratory - asthma, Medical imaging, Clinical endotyping and phenotyping, Ageing, Equipment - MRI, Environment - enviromental exposure, pollution, Lung function

B3938 - Windows of vulnerability Sensitive periods for social adversity in adolescence - 02/12/2021

B number: 
B3938
Principal applicant name: 
Delia Fuhrmann | King's College London, UK
Co-applicants: 
Dr Kathryn Bates, Ms Amber Inman, Prof Rogier Kievit, Dr Amy Orben, Ms Ayla Pollman
Title of project: 
Windows of vulnerability: Sensitive periods for social adversity in adolescence
Proposal summary: 

A large body of research has shown adverse childhood experiences (such as parental neglect, mental and physical abuse) can impact children’s developmental trajectories and have lasting effects on their cognitive function and mental health. In comparison, there is little consensus as to what types of adversity affect adolescents and the timing at which young people are most vulnerable to different types of adversity. This impedes the development of effective policies for prevention and intervention. Initial evidence suggests that for adolescents, other types of adversity, such as social exclusion by peers, may be particularly detrimental. With respect to timing of adversity, protracted sensitive periods of brain development in areas underlying complex skills, e.g., flexible thinking and building relationships, could present a window of vulnerability where young people are particularly sensitive to adversity exposure. The aims of this research project are twofold. First, to investigate what types of adversity impact cognitive and mental health outcomes in adolescents, and secondly, to determine when different adversities have the greatest impact. This will provide an opportunity for informing policies on how we can prevent and alleviate adversity in youth.

Impact of research: 
This project will firstly advance current theories of adversity in developmental psychology by establishing the types and timing of adversity in a longitudinal design. Many studies to date focus on early childhood adversities and examine how this predicts later outcomes. Employing the rich ALSPAC dataset and advanced statistical methods outlined above will allow us to extend current knowledge to understand how adversity impacts cognition and mental health throughout each stage of development. This has important implications for policy and practice. Establishing when young people are most vulnerable to which types of adversity can be used to direct interventions to prevent adversity exposure in young people.
Date proposal received: 
Friday, 26 November, 2021
Date proposal approved: 
Wednesday, 1 December, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Cognition - cognitive function, Development, Environment - enviromental exposure, pollution, Statistical methods

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