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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B3460 - The power of the environment Environmental mediation of genetic liability - 03/02/2020

B number: 
B3460
Principal applicant name: 
Moritz Herle | Kings College London (UK)
Co-applicants: 
Prof Andrew Pickles, Prof Bianca De Stavola
Title of project: 
The power of the environment: Environmental mediation of genetic liability
Proposal summary: 

The consequences of childhood obesity remain one of the biggest public health burdens in the UK. 1 in 3 children are already overweight or obese by age 10 years. This is especially problematic because obesity has been linked to many health conditions, such as diabetes, cancer and depression. There is now substantive evidence that obesity runs in families, but genetics alone cannot explain the current rise of obesity in the population. So environmental factors have been proposed to be causal for this development. It is this dual determination, that remains paradoxical:
How is it possible that obesity is explained by both genes and environments and what does this complexity mean for public health interventions?
For childhood obesity, we already know that genetic and environmental factors are
important. However, it is not known how environmental factors might be protective of genetic
liability.
The main questions are:
1. Do parental feeding practices, such as offering food to soothe, enhance or buffer the
association between genetic liability and later childhood BMI, and what could be
achieved if we changed parental feeding strategies?
2. Does the child’s physical activity mediate the association between childhood genetic
liability and later BMI, and what would happen if levels of physical activity increased?
3. Can maternal genetic risk influence the child’s body size, even though the genetic liability
are not passed on?
4. What is the association between genetic liability and the built environment of the family
home, such as access to green spaces and public transport?

Impact of research: 
The proposed research is timely, and of great public interest. Polygenic scores for common disease are increasingly available through commercial providers. However, their association with environmental factors is not fully understood. This project brings together methods form genetic epidemiology and mediation analysis, highlighting a novel way to address complex questions, which can be adopted by other health researchers.
Date proposal received: 
Monday, 3 February, 2020
Date proposal approved: 
Monday, 3 February, 2020
Keywords: 
Epidemiology, Obesity, Statistical methods, BMI, Childhood - childcare, childhood adversity, Development, Environment - enviromental exposure, pollution, Genetic epidemiology, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Parenting, Physical - activity, fitness, function, Statistical methods

B3456 - Exploring causal effects of health behaviours on mental health and wellbeing - 28/01/2020

B number: 
B3456
Principal applicant name: 
Robyn Wootton | MRC IEU and School of Psychological Science
Co-applicants: 
Dr Hannah Sallis, Dr Adele Wang
Title of project: 
Exploring causal effects of health behaviours on mental health and wellbeing
Proposal summary: 

Poor mental health affects all domains of life, including work, relationships and physical health. Prevalence of mental illness in the UK is increasing, with 1 in 6 people experiencing mental health problems each week. One way of tackling this mental illness epidemic is through prevention. We can achieve this by maintaining and improving people's general mental health and wellbeing, before they reach a clinical diagnosis of mental illness. In this project we are interested in identifying behaviours in ones life that can be modified to improve mental health and wellbeing.

One possible predictor of mental health is our health behaviours. For example, our diet, how much physical activity we do, how much alcohol we consume and whether or not we smoke. While this may seem intuitive, there are many gaps in the research literature. First, it is commonly thought that these behaviours influence our mental health and wellbeing, but little research has been done to assess whether this is a causal effect rather than just a correlation. In order to identify effective intervention targets, it is critically important to ensure that these are causal. We will use complementary methods, allowing us to approach our research question through a number of different lenses. If we can draw consistent results, then we will be able to obtain the strongest and most informative evidence. Second, there is little research that has looked at the nuances of these health behaviours. For example, does the length or intensity of physical activity matter when considering its effect on mental health? We will use the wealth of secondary data available to us to untangle these specific details. Third, these health behaviours do not occur in isolation, therefore, we will investigate how they work together to affect
mental health. And finally, early intervention (i.e. in childhood) is an important aspect of prevention. We will use novel methods to understand how parental health behaviours influence the child's mental health. This can inform us about whether it is better to intervene on the parents or on the child's health behaviours.

Impact of research: 
Date proposal received: 
Monday, 27 January, 2020
Date proposal approved: 
Tuesday, 28 January, 2020
Keywords: 
Epidemiology, Mental health, Statistical methods, Mendelian randomisation

B3457 - The association between traumatic brain injury and emotion recognition - 28/01/2020

B number: 
B3457
Principal applicant name: 
Robyn Wootton | School of Psychological Science and MRC IEU
Co-applicants: 
Maren Muller-Glodde, Professor Ian Penton-Voak, Professor Marcus Munafo
Title of project: 
The association between traumatic brain injury and emotion recognition
Proposal summary: 

It is relatively well established that having a traumatic brain injury is associated with subsequent deficits in emotion recognition from facial expressions (Babbage et al., 2011) and these deficits are thought to be relatively stable over time (Ietswaart, Milders, Crawford, Currie, & Scott, 2008). Changes in emotion recognition do not seem to be limited to people with moderate or severe injuries (Ietswaart et al., 2008; Kubu, 1999; Kubu et al., 1993), although there has been little research on specifically mTBI in this field. Léveillé, Guay, Blais, Scherzer, and De Beaumont (2017) after multiple concussion injuries suggested that males but not females show impaired emotion recognition. Further mood disorders, such as anxiety (Attwood et al., 2017) and depression (Dalili, Penton-Voak, Harmer, & Munafo, 2015) have been shown to impact emotion recognition. The aim of the current study is to investigate the effect of mTBI on emotion recognition in ALSPAC, whilst exploring the potential impact of factors such as sex, general cognitive ability, and mood.

Impact of research: 
Date proposal received: 
Monday, 27 January, 2020
Date proposal approved: 
Tuesday, 28 January, 2020
Keywords: 
Epidemiology, mild traumatic brain injury, Statistical methods, Cognition - cognitive function

B3451 - Markers of infection within Twins - - 28/01/2020

B number: 
B3451
Principal applicant name: 
Fergus Hamilton | MRC IEU / North Bristol NHS Trust / PHS (Avon)
Co-applicants: 
Ruth Mitchell, Nic Timpson
Title of project: 
Markers of infection within Twins -
Proposal summary: 
Impact of research: 
1. Publications in peer-reviwewed journals 2. Grant application to TwinsUK to perform serology within their (much larger!) cohort of Twins 3. A greater understanding of how infection works, and how heritable it is.
Date proposal received: 
Thursday, 23 January, 2020
Date proposal approved: 
Tuesday, 28 January, 2020
Keywords: 
Immunology, Infection, Classic Twin Study., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Twins

B3452 - Physical activity and prediabetes in adolescents and young adults - 28/01/2020

B number: 
B3452
Principal applicant name: 
Soyang Kwon | Ann & Robert H Lurie Children's Hospital of Chicago (USA)
Co-applicants: 
Title of project: 
Physical activity and prediabetes in adolescents and young adults
Proposal summary: 

This proposed project is to examine whether inactive youth are more likely to have prediabetes in adolescents and young adults.

Impact of research: 
A recent U.S. surveillance data revealed that 18% of adolescents and 24 % of young adults are pre-diabetic, which is alarming in public health. The likely impact of this research will be to provide direct evidence to support that an active lifestyle can prevent prediabetes in youth and young adults.
Date proposal received: 
Thursday, 23 January, 2020
Date proposal approved: 
Tuesday, 28 January, 2020
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Diabetes, Biological samples -e.g. blood, cell lines, saliva, etc., Physical - activity, fitness, function

B3453 - Exploring candidate gene mechanisms in atopic eczema - 28/01/2020

B number: 
B3453
Principal applicant name: 
Sara Brown | University of Dundee (UK)
Co-applicants: 
Dr Lavinia Paternoster
Title of project: 
Exploring candidate gene mechanisms in atopic eczema
Proposal summary: 

Eczema is an itchy skin condition that is caused by a combination of genetics – our DNA – and environmental effects, eg allergens and irritants. Eczema and other allergic conditions often run in families, showing that the effects of our DNA are important, but we are not sure which specific genes are responsible for causing eczema. If we could understand genetic mechanisms we may be able to use this knowledge to develop better treatments.
Studies carried out in large populations (including ALSPAC participants) have shown which regions of DNA may contribute to causing eczema. We have tested these regions in the lab and shown, using skin samples grown in an incubator, that genes which are switched on or off in skin can cause eczema or protect against eczema. We now need to explore whether these findings are important in childhood, comparing children with and without eczema. We would like to do this using the results of analyses from blood and skin samples collected in ALSPAC.
We hope that the results of our work will give valuable clues to how an individual’s DNA contributes to their risk of suffering from eczema.

Impact of research: 
The main aim is to identify molecular mechanisms which may be targetable for eczema therapy – to bring about much needed improvements in the treatment of this disease. If we are not successful in identifying targetable mechanisms, the findings will still be of fundamental scientific value.
Date proposal received: 
Thursday, 23 January, 2020
Date proposal approved: 
Tuesday, 28 January, 2020
Keywords: 
Genetics, Allergy, Eczema, DNA sequencing, RNA, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Childhood - childcare, childhood adversity, Dermatology, Epigenetics, Genetic epidemiology, Genetics

B3454 - Exploring the effects of twin birth and prematurity on school readiness and early academic outcomes - 04/02/2020

B number: 
B3454
Principal applicant name: 
Amy Atkinson | Born in Bradford, Bradford Institute for Health Research (West Yorkshire)
Co-applicants: 
Professor Mark Mon-Williams, Dr Liam Hill, Dr Katherine Pettinger
Title of project: 
Exploring the effects of twin birth and prematurity on school readiness and early academic outcomes
Proposal summary: 

The project will explore how being born as part of a twin birth or being born premature affects school readiness (performance on entry assessments) and academic outcomes during the early primary school years (Key Stage 1).

There is evidence that twins have poorer academic outcomes during early adulthood relative to singletons (Tsou, Tsou, Wu, & Liu, 2008). It is possible that this is actually a consequence of the increased probability of twins being born preterm or small for gestational age.
In addition, this finding is not consistently observed; a large scale Danish study found no significant differenes in adolescents’ academic outcomes between twins and singletons (Christensen, Petersen, Skytthe, & Hersking, 2006). We aim to explore whether being born as a twin affects school readiness and early academic outcomes relative to being an only child or having one older non-twin sibling and if so, whether this effect persists after controlling for factors known to affect academic outcomes (e.g. birth weight, maternal education).

The second research question aims to examine whether the birth order of twins affects academic outcomes. There is some evidence that first born twins weigh more than second born twins (Yokoyama et al., 2016). Whilst first born twins can be delivered in much the same way as a singleton, there are many more opportunities for obstetric complications (and therefore perinatal compromise) for second born twins, particularly if delivered vaginally. Intrapartum monitoring of the second twin can be challenging, there may be a malpresentation of the second twin requiring internal cephalic version and breech delivery; if these manouveres fail an emergency caesarean section may be required (Leung 2002, Leung 2004). The analysis will therefore explore whether first born twins perform better academically during the primary school years, and whether this effect differs depending on the mode of delivery. Also of interest is whether any effects are reduced or eliminated once controlling for factors such as birth weight and gestational age.

A final analysis will be completed to explore whether children born preterm have worse academic performace relative to their term born siblings. Pettinger et al. (2019) found that gestational age was a significant predictor of whether a child attained a good level of development on the early years foundation stage profile (EYFSP) (e.g. Pettinger et al., 2019). The EYFSP is a mandatory assessment carried out in all state-funded schools at the end of reception year, and is seen as a measure of ‘school readiness’.
However, it is possible that this effect may be (in part) explained by the home environment. Although Pettinger et al. (2019) controlled for factors such as maternal education and receipt of means tested benefits, there may be other unknown environmental factors that affect school readiness. Comparing preterm children to term born siblings would allow us to control for these factors. There is published evidence from Scandinavian studies using sibling matching, which shows that extreme prematurity (<27 weeks gestation) is associated with increased mortality, autism and low educational attainment (D’Onofrio BM, 2013; Risnes KR, 2016). Our work could add significantly more than this, since this study only reported on ‘years in education’ and ‘failing’ education.

These analyses have been completed on the Born in Bradford data already (approval code: SP335). However, the number of children in each analysis is small, limiting the conclusions that can be drawn. We are therefore seeking to replicate our findings using the ALSPAC database, as this would allow us to strengthen our conclusions if the outcomes are replicated. If possible, we also plan to run a set of analyses on a combined dataset, which would allow us to increase the statistical power.

Impact of research: 
Date proposal received: 
Friday, 24 January, 2020
Date proposal approved: 
Friday, 24 January, 2020
Keywords: 
Social Science, Statistical methods, Childhood - childcare, childhood adversity, Development, Offspring, Siblings, Twins

B3450 - Predicting comprehensive smoking behaviours using epigenetic risk scores - 24/01/2020

B number: 
B3450
Principal applicant name: 
Ryan Langdon | ICEP (UK)
Co-applicants: 
Dr Matthew Suderman, Dr Paul Yousefi, Dr Rebecca Richmond
Title of project: 
Predicting comprehensive smoking behaviours using epigenetic risk scores
Proposal summary: 

The negative health risks of exposure to cigarette smoke are well known; including personal, second-hand and foetal exposure during pregnancy.
These health risks, in addition to a high prevalence in the UK and worldwide, make accurate measurement of smoking status an important factor in most epidemiological studies.

DNA methylation appears to provide reliable and long-term markers of tobacco smoke exposure. In fact, it is possible to use combinations of methylation levels at smoking-associated CpG sites to not only differentiate among current, former and never smokers but to also detect smoking intensity, number of smoking years and time since cessation. These aspects of smoking aren't necessarily captured in questionnaire-based responses for a given study. Even if they were, they might not be reliable and may even be misreported. For example, saying you smoke 20 cigarettes a day doesn't say how deep you inhale those cigarettes or whether the brand matters. Moreover, you might be a current smoker but say you're not a smoker out of guilt. Methylation provides a continuous measure (0-100%) in response to various aspects of smoking (rather than "yes/no"), and objectively shows a response to smoking, so can overcome these issues.

Recently, a study by Leffondre found a comprehensive measure of smoking history that incorporated intensity, duration, and time since cessation (including the half-life of the effect of stopping smoking). We will use ARIES DNA methylation data to develop predictors of smoking behaviour using this index, which we will compare against self-reported smoking behaviour from questionnaires and ALSPAC cotinine data. We hope to derive a comprehensive prediction model of smoking which can be applied to other cohorts. Methylation may be able to be used in the absence of self-report data, or more importantly, help improve prediction of diseases which are caused by smoking.

Impact of research: 
This research aims to investigate the efficacy of using DNA methylation as an objective biomarker for comprehensive smoking history, potentially being used as tool for estimating the extent of misreporting in self-reported smoking behaviours and, to a greater extent, to be used to improve prediction of smoking-related adverse health outcomes where methylation data is available.
Date proposal received: 
Wednesday, 22 January, 2020
Date proposal approved: 
Wednesday, 22 January, 2020
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Environment - enviromental exposure, pollution, Epigenetics, Fathers, Mothers - maternal age, menopause, obstetrics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Offspring, Statistical methods

B3449 - Moving from self-harm or violence towards others to dual harm predictors of transition in early adulthood - 21/01/2020

B number: 
B3449
Principal applicant name: 
Sarah Steeg | University of Manchester
Co-applicants: 
Dr Peter Taylor
Title of project: 
Moving from self-harm or violence towards others to dual harm: predictors of transition in early adulthood
Proposal summary: 

‘Dual harm’ is a term that has been used to describe the co-occurrence of self-harm and violence to others. Young people engaging in dual harm are likely to have specific clinical and support needs. However, very little is known about their characteristics and how individuals who have dual harmed differ from those who self-harm and those who are violent. Understanding the characteristics of people with dual harm experiences will help design services to meet their needs.
We will use data from the ALSPAC to look at differences between young people reporting self-harm, violence towards others, dual harm and neither behaviours at age 16. We are interested in differences in depression, attitudes towards violence, being exposed to self-harm and violence in the home or among peers, impulsivity, self-esteem, callous-unemotional traits, behavioural and emotional dysregulation and body image. We will then look at young people who report either self-harm or violence at age 16 and go on to report dual harm in young adulthood. We expect that their characteristics will differ from those who do not transition to dual harm.

Impact of research: 
Young people engaging in dual harm have particularly raised risks of premature mortality (3) and higher rates of psychiatric disorder (1). While there has been extensive research into characteristics and risk factors among young people who have self-harmed, very little is known about young people who move from engaging in self-harm or violence towards others to dual harm. The findings of this study will help shed light on this highly vulnerable population. Understanding the distinct characteristics of this group is the first step in developing appropriate support and clinical interventions. Reference list 1. Richmond-Rakerd LS, Caspi A, Arseneault L, et al. Adolescents Who Self-Harm and Commit Violent Crime: Testing Early-Life Predictors of Dual Harm in a Longitudinal Cohort Study. The American journal of psychiatry 2019: appiajp201818060740-appiajp. 2. Mars B, Heron J, Klonsky ED, et al. What distinguishes adolescents with suicidal thoughts from those who have attempted suicide? A population-based birth cohort study. Journal of Child Psychology and Psychiatry 2019; 60(1): 91-9. 3. Steeg S, Webb RT, Mok PLH, et al. Risk of dying unnaturally among people aged 15-35 years who have harmed themselves and inflicted violence on others: a national nested case-control study. Lancet Public Health 2019; 4(5): E220-E8. 4. Slade K. Dual harm: the importance of recognising the duality of self-harm and violence in forensic populations. Medicine Science and the Law 2019; 59(2): 75-7. 5. Mars B, Heron J, Crane C, et al. Clinical and social outcomes of adolescent self harm: population based birth cohort study. Bmj-British Medical Journal 2014; 349: G5954-G. 6. Latzman R.D, Lilienfeld S.O, Latzman N.E, Clark L.A. Exploring Callous and Unemotional Traits in Youth via General Personality Traits: an Eye Towards DSM-5. Personality Disorders: Theory, Research, and Treatment 2013; 4(3): 191-202.
Date proposal received: 
Monday, 20 January, 2020
Date proposal approved: 
Tuesday, 21 January, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Violence, Statistical methods, Psychology - personality

B3448 - Genome-wide association studies of prenatal depression in ALSPAC - 21/01/2020

B number: 
B3448
Principal applicant name: 
Jian Zhao | MRC Integrative Epidemiology Unit, University of Bristol (UK)
Co-applicants: 
Prof Deborah Lawlor
Title of project: 
Genome-wide association studies of prenatal depression in ALSPAC
Proposal summary: 

Prenatal depression has been reported to have associations with adverse pregnancy/ birth outcomes in previous observational studies. However, due to residual confounding, the causal effect of prenatal depression on these outcomes still remain unclear. Mendelian randomisation works well as a novel causal inference approach with utilising genetic variants as instrument variables. This aim of this project is to conduct genome wide association studies (GWAS) of prenatal depression to facilitate Mendelian randomisation studies in perinatal epidemiology area.

Impact of research: 
The results from ALSPAC will contribute to the knowledge on genetic effect on prenatal depression. Furthermore, causal evidence between prenatal depression and adverse pregnancy/ birth outcomes will be enhanced after Mendelian randomisation studies.
Date proposal received: 
Friday, 17 January, 2020
Date proposal approved: 
Tuesday, 21 January, 2020
Keywords: 
Epidemiology, Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., GWAS, Genome wide association study

B3443 - Physical activity and mental health among adolescents and young adults A novel approach using multivariate pattern analysis - 17/01/2020

B number: 
B3443
Principal applicant name: 
Matteo Christian Sattler | NIHR Bristol Biomedical Research Centre - Nutrition Theme, Bristol Dental School, University of Bristol (United Kingdom)
Co-applicants: 
Nicola Wiles, PhD, Sam Leary, PhD, Andy Ness, PhD, Eivind Aadland, PhD, Olav Martin Kvalheim, PhD, Mireille van Poppel, PhD, Rodrigo Antunes Lima, PhD, Lars Bo Andersen, PhD
Title of project: 
Physical activity and mental health among adolescents and young adults: A novel approach using multivariate pattern analysis
Proposal summary: 

The benefits of physical activity (PA) for mental health are well established. However, little longitudinal evidence is available in adolescents regarding the association between PA and anxiety and depressive symptoms. Especially problematic is our lack of knowledge about the intensity of PA that is needed to prevent or treat clinically relevant symptoms in this critical period of life. This lack of knowledge can be strongly attributed to the way we currently analyze the intensity information from accelerometry. Data are ‘simplified’ and collapsed into only a few intensities (e.g. light, moderate-to-vigorous), which are then included in statistical models. This causes substantial loss of information and challenges the detection of the relative importance of specific intensities. However, using a larger number of intensities is not possible since traditional models (i.e. multiple linear regression) cannot handle their closed structure and multicollinearity. A novel approach is multivariate pattern analysis (MPA) (specifically: partial least squares regression [PLSR]) which was introduced to PA research by Aadland et al. in 2018. MPA overcomes these shortcomings and can be used to describe the PA spectrum with many intensities (e.g. > 20 variables) while determining most important ones. This study uses MPA to investigate the association between the entire PA intensity spectrum at age 14 years and future anxiety and depressive symptoms throughout adolescence and young adulthood.

Ref: Aadland E, Kvalheim OM, Anderssen SA, Resaland GK, Andersen LB. The multivariate physical activity signature associated with metabolic health in children. Int J Behav Nutr Phys Act. 2018;15(1):77.

Impact of research: 
Accelerometers capture detailed but complex PA information. In practice, researchers only use a fraction of the available information (e.g. time spent in moderate-to-vigorous physical activity [MVPA]) to establish associations with health outcomes. MPA allows us to use the entire intensity spectrum of PA which results in a more accurate description of PA behaviors. MPA will help us to use the intensity information from accelerometry more appropriately and to derive more reliable conclusions about how different PA intensities relate to mental health. Regarding anxiety and depressive symptoms, there is a lack of evidence for the most relevant intensities. Thus, this will be the first study worldwide applying MPA in a longitudinal setting to identify PA intensities most strongly associated with future anxiety and depressive symptoms in adolescents and young adults. Both PA guidelines for the general population and clinical practice would strongly benefit from this knowledge.
Date proposal received: 
Wednesday, 15 January, 2020
Date proposal approved: 
Friday, 17 January, 2020
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Statistical methods, Physical activity, Epidemiology, Mental health, Statistical analysis

B3444 - LUNG DEVELOPMENT GENES AND ADULT LUNG FUNCTION REPLICATION in ALSPAC - 17/01/2020

B number: 
B3444
Principal applicant name: 
Raquel Granell | University pf Bristol
Co-applicants: 
Dr Cosetta Minelli, Prof Seif Shaheen
Title of project: 
LUNG DEVELOPMENT GENES AND ADULT LUNG FUNCTION: REPLICATION in ALSPAC
Proposal summary: 
Impact of research: 
Date proposal received: 
Wednesday, 15 January, 2020
Date proposal approved: 
Friday, 17 January, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation)

B3446 - Chronic Airway Diseases Early Stratification CADSET - 17/01/2020

B number: 
B3446
Principal applicant name: 
Raquel Granell | MRC Integrative Epidemiology Unit (IEU)
Co-applicants: 
Erik Melén, Professor of pediatrics, Anke-Hilse Maitland van der Zee, Professor
Title of project: 
Chronic Airway Diseases Early Stratification (CADSET)
Proposal summary: 
Impact of research: 
Date proposal received: 
Thursday, 16 January, 2020
Date proposal approved: 
Friday, 17 January, 2020
Keywords: 
Epidemiology

B3447 - Polygenic predictions of blood pressure traits - 17/01/2020

B number: 
B3447
Principal applicant name: 
Karsten Øvretveit | Norwegian University of Science and Technology
Co-applicants: 
Dr. Kaitlin Wade, PhD
Title of project: 
Polygenic predictions of blood pressure traits
Proposal summary: 

Essential hypertension (HTN) is a leading, preventable risk factor for cardiovascular morbidity and mortality. Recent genome-wide association studies (GWAS) have provided major insight into the genetic architecture of blood pressure (BP) traits, in part due to increasingly large sample sizes. Moreover, novel approaches to genetic risk quantification have been shown to improve upon traditional methods by more accurately incorporating the growing number of genetic markers with observable effects on common complex traits into a single construct, leading to greater predictive power and clinical translation. This project aims to derive and validate risk scores for BP traits and assess their predictive power for HTN and related morbidity and mortality.

Impact of research: 
We expect our research to make important contributions to the calculation of ORS in the field of genetic research. Additionally, our adult sample span 35 years, allowing us to look at not only cross-sectional BP measurements, but also changes over time. This by itself represents a unique opportunity to investigate genetic susceptibilities to complex traits and the addition of the ALSPAC cohort would allow us to follow genetic markers with an observed effect on BP from the beginning to the end of life.
Date proposal received: 
Friday, 17 January, 2020
Date proposal approved: 
Friday, 17 January, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Hypertension, DNA sequencing, Blood pressure, Cardiovascular, Genetic epidemiology, Genetics

B3445 - Placentas and health across the life-course of two generations - 17/01/2020

B number: 
B3445
Principal applicant name: 
Abigail Fraser | Population Health Sciences, Bristol Medical School (United Kingdom)
Co-applicants: 
Mr Joseph Gilbody, Dr Gemma Clayton, Prof Deborah Lawlor
Title of project: 
Placentas and health across the life-course of two generations
Proposal summary: 

Placental size directly correlates with its ability to provide developing feotues with the nutrients needed for growth while in the womb, differing placenta size has been linked with health issues both during pregnancy and for both the child and the mother later in life. In this project we propose to study the effect of placenta size on health outcomes of the child and mother both post pregnancy and throughout their lifespans.

Impact of research: 
This project will help to increase our understanding of the relationship between placental variation and diseases throughout the life course, potentially leading to the development of preventative treatments for negative health outcomes in later life associated with placental variation.
Date proposal received: 
Thursday, 16 January, 2020
Date proposal approved: 
Friday, 17 January, 2020
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Offspring

B3441 - Changing causes and consequences of underweight overweight and obesity a historical comparison of the UK and Norway 1984-202 - 14/01/2020

B number: 
B3441
Principal applicant name: 
Amanda Hughes | University of Bristol (United Kingdom)
Co-applicants: 
Title of project: 
Changing causes and consequences of underweight, overweight, and obesity: a historical comparison of the UK and Norway, 1984-202
Proposal summary: 

In high-income countries, underweight is largely ignored in health research, despite a clear link with worse health and higher mortality risk. But in the UK, where changes to welfare policy have been accompanied by an explosion in foodbank use, social differences in underweight must be reassessed. This project will be the first comprehensive investigation of present-day inequalities in low body weight in Britain. Considering adults, children and adolescents, we will describe the extent of inequalities, and identify the most vulnerable groups. We will shed light on causes, by comparing inequalities in present-day UK with inequalities in other policy contexts: the UK in the 1990s and 2000s, and Norway from the 1980s to the present day.
Starkly raised risk of underweight was recently found among British adult jobseekers, and higher risk of thinness among younger disadvantaged children. Reported after substantial changes to welfare policy, it is not clear if such inequalities existed before those changes, if similar patterns are seen in other countries, or which other disadvantaged groups are affected. We will find out when these patterns first emerged in the UK, by comparing data from the 1990s, 2000s and 2010s. To see if they only occur in certain policy contexts – strongly suggesting they are avoidable - we will also use data from Norway, which in the same period had different welfare policies and a lower poverty rate. To identify other vulnerable groups, we will look at underweight among adults in low-income employment, and children and adolescents in households affected by unemployment and low-income employment.
The project therefore fills three urgent needs: to describe the extent of inequalities in low body weight, to identify groups of vulnerable adults and children, and to understand the causes of these inequalities. Policymakers currently do not have the knowledge required to consider inequalities across the full body weight range, and this project will fill that gap.

Impact of research: 
1. Unlike with obesity, we simply do not know enough about inequalities in low body weight for decision-makers to consider them in policy. This project will provide that knowledge. 2. By providing the first large-scale evidence of social inequalities in body weight across the entire range, results can be used by non-profit groups aiming to reduce the impact of poverty on nutrition and health. 3. Through both routes, the people who ultimately stand to benefit most will be individuals and families affected by low income, unemployment, and changes to welfare policy.
Date proposal received: 
Friday, 10 January, 2020
Date proposal approved: 
Tuesday, 14 January, 2020
Keywords: 
Epidemiology, Obesity, Statistical methods, BMI, Childhood - childcare, childhood adversity, Social science

B3442 - The biological background of attention-deficit/hyperactivity disorder - 14/01/2020

B number: 
B3442
Principal applicant name: 
Hannah Sallis | MRC IEU
Co-applicants: 
Ville Karhunen, Gemma Sharp, Marcus Munafo, Claire Prince, Marjo-Riitta Järvelin
Title of project: 
The biological background of attention-deficit/hyperactivity disorder
Proposal summary: 

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by persistent patterns of inattention, hyperactivity and/or impulsivity, which interfere with normal functioning or development. ADHD is highly heritable, with heritability estimates from twin studies at around 75%. It is also suggested that epigenetic modifications – alterations in the DNA not changing the sequence itself – play a role in ADHD aetiology. In addition, there is known shared genetic liability between obesity and ADHD. Maternal obesity is a known risk indicator for offspring ADHD, however it is not clear whether this is due to the shared genetic predisposition, or possible intrauterine mechanisms.

Impact of research: 
Adding information to the biological background of attention-deficit/hyperactivity disorder.
Date proposal received: 
Monday, 13 January, 2020
Date proposal approved: 
Tuesday, 14 January, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Mental health, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Epigenetics, Genetic epidemiology, Statistical methods

B3419 - The relationship between cognitive and neural development and a childs environment - 10/01/2020

B number: 
B3419
Principal applicant name: 
Duncan Astle | University of Cambridge (United Kingdom)
Co-applicants: 
Ms Tess Smith, Mr Tochukwu Nweze, Dr Rogier Kievit
Title of project: 
The relationship between cognitive and neural development and a child's environment
Proposal summary: 

In the UK 14 million people live in poverty. Four million of these are children. The level of child poverty is rising, and the rate is projected to accelerate in coming years. Growing up in a deprived environment can have a profoundly negative effect on a child’s development. Children from deprived backgrounds are more likely to be placed in special education, fail courses, and complete fewer years of schooling. But the adversities children encounter extend well beyond economic hardship and incorporate multiple familial factors like chaotic home life, poor parental mental and physical health, lack of community support, poor schooling and communication difficulties. These factors have a well-documented impact on multiple child outcomes including educational attainment, mental health, and behaviour. This is a global problem. Up to 50% of children and adolescents growing up worldwide experience at least one episode of childhood adversity in early life: 30% of all mental health problems are attributable to such adversity. The effects are also persistent – early adversity can set a life-long trajectory associated with poor physical and mental well-being and significantly worse occupational and economic outcomes. This results in an inter-generational cycle of disadvantage where deprivation impacts each subsequent generation. Supporting young people who face adversity is one of the major modern challenges for educators, practitioners and policy-makers, as they work to reduce educational under-attainment, poor economic outcomes and address the burgeoning mental health crisis.

Yet not all children who face adversity go on to experience poor outcomes: certain factors appear to insulate children from hardship, such that they demonstrate resilience (broadly defined as succeeding in a particular domain, such as education, despite experiencing adversity). Resilience within mental health is an increasingly recognised phenomenon, but our knowledge about which factors foster resilience across a broader range of outcomes, different populations and in response to diverse sources of adversity is currently limited. Understanding the cross-domain factors that promote resilience is vital to drive the development of interventions that improve the outcomes of child and adolescent victims of adversity. This is the purpose of our project. We want to explore how different environmental factors interact with cognitive and brain development, whether particular features of a child's environment are most strongly linked with these outcomes, and whether some factors foster resilience.

Impact of research: 
The research will benefit national policy-makers, practitioners working in educational and clinical practice, those responsible for child welfare in other institutions, and ultimately children and families who are at risk.
Date proposal received: 
Tuesday, 7 January, 2020
Date proposal approved: 
Friday, 10 January, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Cognitive impairment, Statistical methods, Development

B3437 - Examining the association between alcohol use cognitive functioning and self-harm - 10/01/2020

B number: 
B3437
Principal applicant name: 
Liam Mahedy | University of Bristol
Co-applicants: 
Prof. Marcus Munafo, Miss Daisy Drummond, Miss Kajal Shah, Miss Maddy Cooper
Title of project: 
Examining the association between alcohol use, cognitive functioning and self-harm
Proposal summary: 

Alcohol use during adolescence is a major public health concern, in particular because the brain is still developing and undergoing considerable structural and functional changes. Identifying risk factors that influence adolescent alcohol use is important to appropriately target prevention programs. One area of research that has received considerable attention is the role cognitive functioning (e.g., working memory and inhibition) play as risk for involvement in adolescent alcohol use. There is also a large literature showing a relationship between substance use and self-harm. It is possible that alcohol may increase the risk of self-harm by lowering inhibitions and impairing working memory, which is central to decision making. There is also evidence to suggest that there may be a bi-directional relationship, as several longitudinal studies have reported an association between adolescent self-harm and alcohol problems in adulthood. Although previous prospective studies have examined this association, they are often limited by the use of small sample size, different alcohol use phenotype (i.e. bingeing vs frequency), different follow-up periods, or lack of control for relevant confounders.

Impact of research: 
This research project has the potential to inform the development of cognitive training as intervention/prevention strategies aimed at reducing alcohol initiation and self-harm.
Date proposal received: 
Wednesday, 8 January, 2020
Date proposal approved: 
Friday, 10 January, 2020
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Cognitive impairment, Mental health, Statistical methods, Cognition - cognitive function, Statistical methods, Alcohol use, self-harm

B3438 - Novel statistical methods for the analysis of high-dimensional epigenetic data - 10/01/2020

B number: 
B3438
Principal applicant name: 
Haeran Cho | University of Bristol (United Kingdom)
Co-applicants: 
Prof Kate Tilling, Dr Josine Min, Dr Claire Gormley, Prof Jonathan Rougier
Title of project: 
Novel statistical methods for the analysis of high-dimensional epigenetic data
Proposal summary: 

We propose to address the problem of handling large-scale genome-wide DNA methylation data. To this end, we will develop a novel technique for clustering DNA methylation (DNAm) sites which will aid reducing the complexity of the subsequent EWAS. For example, a DNAm site that is hypo-methylated in the smoker cohort but hyper-methylated in non-smoker one merits further analysis for significant association with smoking, while those sites exhibiting no difference in the two cohorts does not.
We will investigate the use of algorithms for large matrix factorisation under constraints to provide a natural clustering of DNAm sites, and study what statistical guarantee is achievable under which conditions. To verify the suitability of the proposed method, we propose to use the DNA methylation data available from ARIES.

Impact of research: 
The findings from the proposed study will help lay a solid foundation for addressing the additional challenges brought on by epigenetic data analysis include (i) handling of continuous exposures beyond discrete variables (e.g., smoker/non-smoker), and (ii) accounting for cell heterogeneity. In particular, further research into (ii) is highly relevant since samples are measured at bulk rather than at the single-cell level and the methylome obtained for each sample contains the signals aggregated from distinct cell types. Few existing methods can identify the risk-DNAm sites for each individual cell type, missing the opportunity to obtain finer-scale results in EWAS. We plan to address the above problems based on the insights gained from the proposed research.
Date proposal received: 
Thursday, 9 January, 2020
Date proposal approved: 
Friday, 10 January, 2020
Keywords: 
Statistics/methodology, DNA sequencing, Statistical methods, Genetic epidemiology, Genome wide association study, Statistical methods

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