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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B3056 - Later-life health consequences in women with hypertensive disorders of pregnancy who carry a functional IGF1R gene variant - 07/02/2018

B number: 
B3056
Principal applicant name: 
Christopher Benz | Buck Institute for Research on Aging (USA)
Co-applicants: 
Mark Powell, MD MPH, Debbie Lawlor
Title of project: 
Later-life health consequences in women with hypertensive disorders of pregnancy who carry a functional IGF1R gene variant
Proposal summary: 

Pregnancy has long been known to have a major impact on the developing breast and the future risk of breast cancer. Many studies have shown that hypertensive disorders of pregnancy (HDP) are associated with lower risk of breast cancer; and one major study has also demonstrated a significant reduction in risk of other types of cancer. Although this lower risk may be modest in the overall population of women who experience HDP, our recent research has shown that this reduction for breast cancer can be as high as 90% in a subgroup with HDP that carry a common variant in a key growth factor receptor gene (IGF1R). This study’s initial objectives are to reconfirm the above cancer associations, examine if the risk reduction extends to women with milder increases in blood pressure during pregnancy, and to examine whether these reductions are modified by other pregnancy factors such as prematurity, maternal age, or offspring gender.

Interestingly, HDP has also been shown to be associated with increased later life risk of hypertension and heart disease, indicating that experiencing HDP can have both good and bad long-term health outcomes. Therefore, a second objective is to further explore this association and determine if the same IGF1R gene variant that predicts breast cancer risk also predicts future risk of developing cardiovascular disease.

This study could improve the ability to predict future risk of developing the two most significant age-associated health outcomes that women face, thereby leading to more effective personalized screening and novel prevention strategies.

Impact of research: 
Despite significant research accomplishments in breast cancer diagnosis and treatment, there continues to be limited progress in breast cancer prevention. Our recent epidemiologic evidence (recently validated in the large California Teachers Study cohort) showing dramatically lower later-life breast cancer risk in women with a history of a hypertensive disorder of pregnancy (HDP) who also carry a common, but functionally blunted variant of the physiologically critical insulin-like growth factor-1 receptor (IGF1R) gene helps explain why certain pregnancy events can lead to life-long breast cancer resistance in some but not all women. Our first objectives are to confirm this protective effect in another cohort, determine if it also applies to other common types of cancer, and if it is modulated by other pregnancy factors. These findings will not only lead to more personalized risk assessment for women, but could potentially lead to novel cancer prevention strategies applicable to all women. The initial risk reducing associations found in our work have recently been adopted by the Athena WISDOM Study, a multicenter University of California study that is individualizing breast cancer screening for women across the state of California. Further improvement in risk prediction for women with HDP represents an initial, and impactful application of this research. However, our ultimate goal is to clarify the cellular and molecular mechanisms underlying this natural form of breast cancer protection and, with this understanding, devise new cancer prevention strategies that could be offered to all women, not just those with HDP and the protective IGF1R genotype. Our second objective is to determine if the known increase in cardiovascular risk that has been demonstrated in women with HDP is modulated by inheritance of our functional IGF1R SNP, as IGF-1 and IGF1R activation have been shown to impact cardiovascular risk in non-HDP women. This determination could improve the precision of cardiovascular risk prediction in women who have experienced HDP, which would be expected to impact both screening and management of these women throughout their life, potentially improving later life outcomes from this leading cause of female death and disability.
Date proposal received: 
Sunday, 28 January, 2018
Date proposal approved: 
Monday, 29 January, 2018
Keywords: 
Epidemiology, Cancer, Hypertension, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Cardiovascular risk, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Blood pressure, BMI, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Genetic epidemiology, Hormones - cortisol, IGF, thyroid, Mothers - maternal age, menopause, obstetrics, Statistical methods

B3053 - Childhood diet and nutrition and respiratory and allergic outcomes a longitudinal study - 31/01/2018

B number: 
B3053
Principal applicant name: 
Seif Shaheen | Barts and The London School of Medicine, Queen Mary University of London (UK)
Co-applicants: 
Dr Chuanbo Xi, Prof John Henderson, Dr Kate Northstone
Title of project: 
Childhood diet and nutrition and respiratory and allergic outcomes: a longitudinal study.
Proposal summary: 

There are clues that childhood diet may influence respiratory health and risk of asthma and allergies, but the evidence to date only comes from 'snap-shot' studies at one point in time. In order to get a clearer picture of whether diet in early childhood influences the development of respiratory and allergic disorders later in childhood we need large studies which have collected data from the same individuals more than once over time. ALSPAC has collected detailed information about the children’s diet at age 3, and about asthma and allergies when the children were age 7 and older. This dataset will allow us to discover whether children who developed asthma had a different diet when they were younger, compared to children who did not get asthma. In particular, we will investigate whether children who eat a ‘healthier’ diet (higher intake of fruit, vegetables and oily fish, rich in antioxidants and omega-3 fatty acids) are less likely to develop asthma and lower lung function, especially if they have a particular genetic make-up and are exposed to high levels of tobacco smoke and air pollution.

Impact of research: 
This project will provide the most rigorous evidence to date on the possible causal role of diet and nutrition in the development of childhood asthma, because of the longitudinal study design. We hope that our results will inform the design of a multicentre randomised trial aimed at the prevention of childhood asthma; a successful trial would be ground breaking.
Date proposal received: 
Wednesday, 24 January, 2018
Date proposal approved: 
Wednesday, 24 January, 2018
Keywords: 
Epidemiology, Respiratory - asthma, Statistical methods, Nutrition - breast feeding, diet

B3044 - The longitudinal relationship between technology and mental health Adolescence to young adulthood - 30/01/2018

B number: 
B3044
Principal applicant name: 
Cara Booker | Unviersity of Essex (England)
Co-applicants: 
Laurie James-Hawkins, PhD
Title of project: 
The longitudinal relationship between technology and mental health: Adolescence to young adulthood
Proposal summary: 

Adolescents are the heaviest users of technology. The proliferation of the types of technology have allowed for greater access and use among adolescents. One potential impact of the use of technology is changes in levels of mental health. How technology use affects levels of mental health in adolescences and later in life has not been fully answered by current research. Additionally, use of technology and levels of mental health differ by type of technology, gender and age. This project will explore how use of technology and mental health are related as adolescents’ transition into adulthood. We will look at gender differences as well as explore whether the type of technology affects mental health differently.
The UK has many high quality datasets of children and adolescents that may be able to address these questions. We will catalogue the use of technology questions employed in these datasets. Using those questions we will group individuals based on their use of technology and levels of mental health change during adolescence. We will then examine how levels of mental health and use of technology in early adulthood are associated with the adolescent groupings. Both technology use and mental health have been associated with educational attainment and entry into the labour market. Therefore we will extend our analysis to explore the relationships between use of technology, levels of mental health and educational attainment/entry into the labour market.
The findings from this project will inform future policy decisions, research and intervention development.

Impact of research: 
Trends in the levels of mental health of adolescents in the UK have shown a decline in mental health. There are gender differences in these levels and the decreasing trends of mental health appear to be increasing among females. One possibility for this worsening mental health trend is the concurrent increase in use of technology among this group, specifically social networking sites. Research on the links between technology and mental health among adolescents is mixed. Furthermore, few studies have addressed how technology use in adolescence is related to mental health in young adulthood and beyond. This project will expand on current research by identifying trajectories of technology use in adolescence and how those trajectories are associated with levels of mental health in adolescence and young adulthood. We will examine these relationships by gender and explore possible mechanisms. Technology and its use may only increase among adolescents, thus the importance of fully understanding its impacts, both positively and negatively on mental health are important. Additionally, we will look at educational attainment and entry into the labour market with respect to technology and mental health. Some forms of technology use have been linked to increased connectedness which may in turn be associated with better educational outcomes and delayed entry into the labour marked which may in turn lead to better mental health in later life.
Date proposal received: 
Monday, 15 January, 2018
Date proposal approved: 
Wednesday, 17 January, 2018
Keywords: 
Social Science, Mental health, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Sex differences, Social science, Statistical methods

B3047 - FUT2 secretor status infections and auto-immune disease role of maternal genotype and breastfeeding - 30/01/2018

B number: 
B3047
Principal applicant name: 
Meghan Azad | University of Manitoba (Canada)
Co-applicants: 
Nic Timpson
Title of project: 
FUT2 secretor status, infections and auto-immune disease: role of maternal genotype and breastfeeding
Proposal summary: 

About 20% of people have an inactive FUT2 gene and cannot secrete particular antigens in their body fluids or intestinal tract. These “non-secretors” are more resistant to pathogens that use FUT2 antigens to infect cells, but they are more susceptible to some other pathogens. Non-secretors also have a lower diversity of “healthy” gut bacteria, and may be at increased risk for autoimmune diseases including type 1 diabetes, psoriasis and inflammatory bowel disease. However, these associations are unclear because most studies rely on self-reported information rather than firm diagnoses or biological test results.

FUT2 antigens are also secreted in breast milk. They are attached to breast milk sugars that are not digested by babies, but provide a specialized food source for the babies’ gut bacteria. These bacteria influence the baby’s growth, immunity and metabolism throughout life. A mother’s secretor status therefore affects her baby’s gut bacteria, which in turn affects the baby’s development and health, including its susceptibility to infections and autoimmune disease later in childhood.

Thus, both maternal and infant FUT2 secretor status can affect the health of breastfed children. However, few studies examining FUT2 have accounted for breastfeeding or maternal secretor status, so it is unclear how a ‘match’ or ‘mismatch’ in mother/baby secretor status might impact the baby’s gut bacteria and risk of infections or autoimmune disease. We will address this intriguing issue using available information, genetic data, medical diagnoses and biological test results from the ALSPAC cohort.

Impact of research: 
Broadly, this research will improve our understanding of disease processes. It will provide new information about the potential interaction between breastfeeding and maternal and infant FUT2 secretor status, and their collective impact on infectious and autoimmune disease susceptibility. This will guide further research that could ultimately inform ‘personalized’ approaches to infant feeding and disease prevention or therapy, based on maternal and infant FUT2 genotypes.
Date proposal received: 
Wednesday, 17 January, 2018
Date proposal approved: 
Wednesday, 17 January, 2018
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Allergy, Diabetes, Eczema, Gastrointestinal, Infection, Respiratory - asthma, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Breast feeding, Epigenetics, Genetic epidemiology, Genetics, Immunity, Microbiome, Nutrition - breast feeding, diet

B3045 - Maths achievement over the primary-secondary school transition the role of psychological biological and social factors - 30/01/2018

B number: 
B3045
Principal applicant name: 
Andy Field | University of Sussex (UK)
Co-applicants: 
Danielle Evans, Dr. Darya Gaysina
Title of project: 
Maths achievement over the primary-secondary school transition: the role of psychological, biological and social factors
Proposal summary: 

The primary-secondary school transition is a pivotal moment in most children’s lives, often accompanied by feelings of worry, stress and anxiety. One factor that has been previously associated with the transition to secondary school is a loss in academic achievement. Previous research has suggested a number of factors are related to differing levels of educational success, however, it is unknown how these factors may interact when taking the school transition into consideration.
The academic ability this project is focusing on is maths attainment. Theoretical and empirical research has suggested that maths skills can be altered by mental health issues and memory deficits, as well as parent-child interactions and the schooling environment.
To assess which factors are the most important for maths achievement, the project is investigating biological, psychological, social and environmental factors over 3 stages: pre-school transition, during school transition, and post-school transition.
In the pre-school transition stage, early life factors including a healthy pregnancy and birth as well as the child’s psychological attributes and early parent-child interactions will be explored. Following this, during the transition to secondary school, the focus of investigation will be on the schooling environment and teacher characteristics. The child’s psychological wellbeing and peer relationships during this time will also be examined. After the transition, the variables discussed previously will be investigated to examine whether they can predict later maths attainment at age 16.
To investigate this the study will utilise data from over 14,000 mothers and their children followed up extensively since before birth to assess which prenatal, pre-transition, during transition, and post-transition factors are the most important for improving maths abilities at age 16. A wide range of biological, psychological, and social factors will be investigated. The study predicts that prenatal issues will negatively impact early maths abilities, while positive relationships with parents and peers will lessen their effects. It is predicted that positive school experiences and teacher attitudes will also decrease this impact. Furthermore, it is predicted that greater mental health issues and lower cognitive abilities will decrease attainment.

Impact of research: 
The potential impacts of this research are extensive. Should the results provide evidence for specific factors having high predictive power for maths achievement in later adolescence, it is possible for interventions to be tailored to individuals needs based on how they score on each variable. Thus, allowing interventions to be more effective taking into account each child’s risk and protecting factors. Identifying predictors in early childhood has the ability to improve a child’s proposed trajectory by recognising the weaker areas associated with lower maths performance and working to improve them. The University of Sussex already has well established links with local schools in the surrounding areas that would benefit from the potential impacts of this study. Prior interventions set up by the University of Sussex have already been undertaken. For example, the University frequently holds teacher conferences and has also previously set up workshops for parents to attend to provide evidence-based advice resulting from research conducted by the University.
Date proposal received: 
Tuesday, 16 January, 2018
Date proposal approved: 
Wednesday, 17 January, 2018
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Intelligence - memory, Parenting, Psychology - personality, Statistical methods

B3041 - Methods Measures of Context Consistency in Longitudinal Neighborhood Analysis - 05/02/2018

B number: 
B3041
Principal applicant name: 
David Manley | Geographical Sciences (UK)
Co-applicants: 
Dr Levi Wolf, Prof Richard Harris, Professor Kelvyn Jones
Title of project: 
Methods & Measures of Context Consistency in Longitudinal Neighborhood Analysis
Proposal summary: 

This would involve support to develop statistical methods to both characterize spatial-social volatility in neighbourhoods, as well as identify its potential impact on longitudinal models that incorporate contextual effects. This support also encompasses developing an open source implementation of these statistical methods to serve as the reference-in-praxis, made freely available to all scholars. Further, example data sets constructed to both illustrate the potential for instability and geographies to correct for these problems will be generated. In addition, travel support to discuss, develop, and collect professional feedback on these methods & questions is requested, as well as a postgraduate research assistant to conduct a significant portion of the work in collaboration with the requesting committee.

Impact of research: 
Potentially provide a new tool for understanding how neighbourhood impacts individuals. It could provide the basis for better neighbourhood representations in the ALSPAC data specifically and in contextual research in general.
Date proposal received: 
Wednesday, 10 January, 2018
Date proposal approved: 
Wednesday, 10 January, 2018
Keywords: 
Statistics/methodology, Obesity, BMI / ABSI, Statistical methods

B3039 - Physical activity in early adulthood Analysis of the ALSPAC cohort to identify influences on physical activity that can inform - 18/01/2018

B number: 
B3039
Principal applicant name: 
Russ Jago | School for Policy Studies
Co-applicants: 
Professor Debbie Lawlor, Professor Nic Timpson, Professor Kate Tilling, Dr Simon Sebire
Title of project: 
Physical activity in early adulthood: Analysis of the ALSPAC cohort to identify influences on physical activity that can inform
Proposal summary: 

Physical activity is associated with reduced risk of depression, heart disease, stroke, type 2 diabetes and many forms of cancer. Physical inactivity has been estimated to cost the NHS £1.06 billion per year in direct costs, with a further £6.5 billion in lost work productivity. Thus, inactivity is a major drain on the physical, mental and economic health of the UK and understanding the key factors that influence physical activity is the critical first phase of developing strategies to change behaviour at the population level. This application focusses on assessing the physical activity patterns of young adults (age 28-30) in the ALSPAC cohort and the aspects of their current life and their development that help to explain why they adopt their current pattern of physical activity behaviour. This is potentially a very important time for the establishment of future disease risk but for which there is a lack of information on physical activity or how to transition to adulthood well

Impact of research: 
A key goal of this project is to increase understanding of physical activity behaviours in young adults and then use that information to generate new strategies to help this largely ignored group to be more active more often. As such a key goal of this work is to move forward the development of new intervention approaches that are specifically targeted for young adults.
Date proposal received: 
Wednesday, 10 January, 2018
Date proposal approved: 
Wednesday, 10 January, 2018
Keywords: 
Epidemiology, Diabetes, Hypertension, Mental health, Obesity, Statistical methods, BMI, Cardiovascular, Physical - activity, fitness, function, Social science

B3036 - Expansion of Andhra Pradesh Children Parents Study APCAPS to esablish an Urbanizing Population Laboratory - 18/01/2018

B number: 
B3036
Principal applicant name: 
Sanjay Kinra | London School of Hygiene & Tropical Medicine (UK)
Co-applicants: 
Prof George Davey Smith, Dr Nic Timpson
Title of project: 
Expansion of Andhra Pradesh Children & Parents Study (APCAPS) to esablish an Urbanizing Population Laboratory
Proposal summary: 

Andhra Pradesh Children and Parents Study (www.apcaps.lshtm.ac.uk) is a cohort of households which took part in a mother-child nutritional supplementation trial (1987-90). Located in vicinity of Hyderabad city, an emerging technology hub in south India, the study district is undergoing rapid uneven urbanisation, providing a unique window of opportunity (analogous to a stepped-wedge design) to investigate of health effects of urbanisation. So far, we have collected data on built environment and air quality of study villages, and serial longitudinal data for chronic disease risk factors on cohort participants (n=7000). We now propose to expand clinical data collection, on a wide range of health outcomes (e.g. chronic diseases, mental health, ageing, injuries, infectious diseases), making extensive use of wearable sensors and other digital technologies, to all remaining residents (N=100,000) of the 29 study villages. The resulting Urbanising Population Laboratory – a complete eco-system of health data, including bio-repository, on all individuals, their inter-relationships/networks, and their environment (natural, physical, social) – set within a backdrop of rapid uneven urbanisation, will offer the global research community unparalleled opportunities to investigate how environment shapes human health. We will establish a linked electronic health surveillance system to enable ongoing data collection. Collaboration with an established LPS (ALSPAC) will add further value to both cohorts.

Impact of research: 
It will provide unique data for disease/health for India (similar to what ALSPAC has achieved in the UK) and also strengthen causal inferences across both settings.
Date proposal received: 
Friday, 5 January, 2018
Date proposal approved: 
Wednesday, 10 January, 2018
Keywords: 
Epidemiology, Chronic non-communicable diseases., Statistical methods, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics

B3035 - ALSPAC MRI-II - 22/01/2018

B number: 
B3035
Principal applicant name: 
Anthony David | King's College London
Co-applicants: 
Prof Stan Zammit, Porf Glyn Lewis, Andy Boyd, Professor Derek Jones
Title of project: 
ALSPAC MRI-II
Proposal summary: 

The Avon Longitudinal Study of Parents and Children (ALSPAC) has shown that over 9% of 18 year olds have psychotic experiences (PEs) such as hallucinations and delusions, verified by trained psychologists and using strict criteria. When persistent, PEs increase the likelihood of a person developing psychotic disorders such as schizophrenia, other psychiatric conditions (eg depression) and poor psychosocial outcomes such as unemployment. PEs can sometimes recede as people pass from adolescence to adulthood but we don't know how changes in the brain, which continues to develop and mature through these years, underlie and affect PEs. Thanks to grants from the MRC, we have recently shown, using magnetic resonance imaging (MRI) brain scans, that at age 20+, individuals from ALSPAC with PEs have small changes in regional brain volumes, and global and local connectivity which cannot be ascribed to the consequences of having a psychiatric diagnosis or treatment with medication. We have also shown that individuals from ALSPAC who may be at a slightly increased risk of psychosis due to their genetic makeup (using a ‘risk score’ made out of the contribution of the many genes which when added together, are associated with a small but significantly increased risk of schizophrenia) also have subtle changes in brain thickness and volume.
Our objective is to re-scan these same individuals, numbering about 450 in total, at age 26 using the full range of MRI scanning techniques. This will enable us to test the hypothesis that persistent PEs are underpinned by anomalous pathways or trajectories of brain development and abnormalities in function, as compared with those without PEs and against their original baseline scans. Additional objectives are to plot changes in cognition (using IQ tests) which we expect might show some decline in those with persistent PEs. We will make use of the latest genetic risk for schizophrenia scores from genome-wide association studies available in ALSPAC to examine the potential of our brain measures to be used as intermediate links between genes and clinical outcomes. Finally we will see if blood markers of inflammation which can act on the brain, measured in the same individuals when they were children and again when adults, might explain the brain changes we see on MRI.
We will use a powerful 3 Tesla MRI brain scanner located in Cardiff to obtain detailed structural images and measures of grey and white matter volumes and a particular variant of scanning called diffusion tensor imaging which picks up the integrity of white matter tracts - nature's wires - that connect together groups of brain cells. Functional MRI, which picks up those parts of the brain that are active during a task, will be carried out while participants are trying to remember a sequence of letters and also while they are at rest (although their brains will still be working). This will help us to determine the degree of physiological compromise/compensation evident in the brain in those with PEs and structural changes. This will also help us look at how the different specialised parts of the brain are working together as a coherent unit.
This project will enable us to map the change in brain development in young people with and without potentially important psychotic experiences (PEs) taken from ALSPAC, one of the most well-studied epidemiological samples available to medical science. Because there is such a wealth of information available, it means that when we analyse the brain scans we can take into account lots of other factors which might otherwise obscure or falsely exaggerate the effects of PEs such as cannabis and alcohol misuse. The project as a whole has the potential to advance in our understanding of the biological basis of psychotic and related disorders and to help guide the development of primary prevention and early intervention strategies in mental health care.

Impact of research: 
This project has the potential to deliver important advances in our understanding of the biological basis of psychotic disorders, and perhaps to inform the development of primary prevention and early intervention strategies, a key priority for the MRC and NHS. The cohort is going through the main age of risk for schizophrenia and non-affective psychoses so if this study is not carried out now an opportunity will be lost.
Date proposal received: 
Thursday, 4 January, 2018
Date proposal approved: 
Tuesday, 9 January, 2018
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Allergy, Eating disorders - anorexia, bulimia, Eczema, Epilepsy, Fertility/infertility, Gastrointestinal, Hypertension, Incontinence, Infection, Learning difficulty, Mental health, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Obesity, Pain, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Respiratory - asthma, Sexually transmitted diseases, chlamydia, gonorrhoea, Speech/language problem, Bone disorders - arthritis, osteoporosis, Developmental disorders - autism, Cancer, Chronic fatigue, Cognitive impairment, Congenital abnormalities, Diabetes, NMR, Immunity

B3031 - Predictors and patterns of GP contacts for young people who have self-harmed - 09/01/2018

B number: 
B3031
Principal applicant name: 
Rosie Cornish | Population Health Sciences, Bristol Medical School (UK)
Co-applicants: 
Dr Becky Mars, Dr Alison Teyhan, Mr Andy Boyd, Professor David Gunnell, Professor Ann John
Title of project: 
Predictors and patterns of GP contacts for young people who have self-harmed
Proposal summary: 

Self-harm in young people is a major problem. As many as 1-in-6 teenagers have self-harmed at some point in their lives, and self-harm is particularly common between the ages of 10 and 16 years. Young people who self-harm seem to be more likely to do poorly in a number of ways in early adulthood, including being more likely to have a mental health problem, and to use substances like alcohol and drugs. It is also the strongest known risk factor for suicide. Although self-harm is very common in young people, most do not seek help. In this project we plan to investigate whether individuals who self-harm are visiting their GP and, if so, what they are visiting the GP for and how often. We would also like to identify what proportion of teenagers who have self-harmed are picked up by their GP and whether there are important differences between those who are picked up by their GP and those who are not.

Impact of research: 
The proposed research will increase our understanding about the predictors and patterns of GP service use among young people who self-harm. This information will have the following mental health implications: • Answer the question as to whether young people who self-harm are not visiting the GP, or whether they are attending and their self-harm is being missed • Help GPs to recognise adolescents who may be self-harming (by understanding what they are presenting with, and by identifying associated factors) • Highlight characteristics of individuals who are unlikely to be identified by GP • Provide information about the early-adult outcomes of young people who self-harm, and whether this is moderated by help-seeking
Date proposal received: 
Wednesday, 3 January, 2018
Date proposal approved: 
Thursday, 4 January, 2018
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health

B3026 - Cellular phenotyping of Placentas and Prediction of outcomes - 08/01/2018

B number: 
B3026
Principal applicant name: 
Cecelia Lindgren | BDI University of Oxford (United Kingdom)
Co-applicants: 
Prof Debbie Lawlor, Dr Susan Ring
Title of project: 
Cellular phenotyping of Placentas and Prediction of outcomes
Proposal summary: 

This project aims to use state of the art analysis technology to look at placenta with the aim to characterize the cells that make up the placenta and see if any features of them are related to pregnancy outcomes for mom and child.

Impact of research: 
Better understanding of the role of the placenta in maternal and fetal health and well-being in the short and longer term
Date proposal received: 
Monday, 18 December, 2017
Date proposal approved: 
Wednesday, 3 January, 2018
Keywords: 
Biochemistry/structural biology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Machine learning applied to histological slides, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3027 - Placental pathology linking the health of two generations - 08/01/2018

B number: 
B3027
Principal applicant name: 
Abigail Fraser | MRC IEU (United Kingdom)
Co-applicants: 
Dr Sue Ring, Prof William Anthony Parks, Prof Janet Catov
Title of project: 
Placental pathology: linking the health of two generations
Proposal summary: 

Problems with the placenta can cause preeclampsia, preterm delivery and small babies.
These problems with how the placenta develops to support a pregnancy may be linked with heart disease in both mothers and their children.
We plan to characterise existing placentas in order to gain a better understanding of what a healthy and a non-healthy placenta looks like and how these characteristics relate to pregnancy outcomes but also to long tern health of mothers and offspring.

Impact of research: 
Date proposal received: 
Monday, 18 December, 2017
Date proposal approved: 
Tuesday, 19 December, 2017
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Medical imaging, Biological samples -e.g. blood, cell lines, saliva, etc.

B3021 - Linking financial and retail data with ALSPAC to uncover causes of mental health illness and routes to wellbeing - 08/01/2018

B number: 
B3021
Principal applicant name: 
Anya Skatova | Experimental Psychology
Co-applicants: 
Dr Claire Haworth
Title of project: 
Linking financial and retail data with ALSPAC to uncover causes of mental health illness and routes to wellbeing
Proposal summary: 

Each of us leaves many digital traces. For example, when we buy things in supermarkets and use loyalty cards to get benefits the supermarket records our purchases, creating a representation of our habits and preferences. Companies have been using aggregates of these data to track sales of their products, and to understand aspects of context that can impact sales levels, and to target marketing and promotions. But can these data be utilized for higher public impact helping individuals, economies and society at large? For example, can we learn about causes and consequences of mental health illnesses and routes to wellbeing through objectively tracked real world behaviours and choices? Up to now longitudinal cohort studies – like ALSPAC – allowed to use rich genetic, biomedical and early environment data to explain real world outcomes such as mental health illnesses and wellbeing. However, these outcomes often are self-reported which makes it challenging to unpick relationships in the data. This project aims to link objective measures of behaviour traced through retail and banking data to provide a set of variables reflecting objectively measured real world behaviours and decisions. These can be then linked to rich genetic, bio-medical and early environment data already collected on longitudinal cohorts and allow to investigate causes and consequences of real world outcomes such as mental health issues and wellbeing.

Impact of research: 
Linking objective patterns of real word choices reflected in retail and banking data with a well-characterised cohort sample like ALSPAC will provide ground-breaking insights into causes and outcomes of wellbeing and mental health issues, as well as help to unpick mechanisms by which they develop. Understanding the causal pathways between decision-making patterns and psychological outcomes will contribute to policy helping to reduce behaviours which are harmful to mental health and wellbeing. Finally, building an ethical framework for linking transactional data with longitudinal cohorts data will uncover new ways of studying patterns and causes of population health and prosperity.
Date proposal received: 
Wednesday, 13 December, 2017
Date proposal approved: 
Thursday, 14 December, 2017
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Chronic fatigue, Cognitive impairment, Eating disorders - anorexia, bulimia, Learning difficulty, Mental health, Obesity, Pain, Computer simulations/modelling/algorithms, Qualitative study, Statistical methods, Data linkage , Cohort studies - attrition, bias, participant engagement, ethics, Linkage, Psychology - personality, Social science, Statistical methods

B3019 - Mitochondrial DNA haplogroups and trajectories of cardiometabolic risk factors across childhood and adolescence - 15/12/2017

B number: 
B3019
Principal applicant name: 
Linda O'Keeffe | Integrative Epidemiology Unit
Co-applicants: 
Emily Aubrey, Santiago Rodriguez, Evie Stergiakouli
Title of project: 
Mitochondrial DNA haplogroups and trajectories of cardiometabolic risk factors across childhood and adolescence
Proposal summary: 

Mitochondrial DNA encodes for key functions of the mitochondria directly related to the creation of energy in the cell. Therefore, genetic variation in mitochondrial DNA could potentially be related to anthropometric and cardiovascular traits. Mitochondrial DNA haplogroups have been derived in ALSPAC and we have previously examined the association of these haplogroups with psychiatric traits.

Impact of research: 
This research will make an important contribution to the understanding of how mitochondrial DNA haplogroups are associated with cardiometabolic risk factors.
Date proposal received: 
Tuesday, 12 December, 2017
Date proposal approved: 
Tuesday, 12 December, 2017
Keywords: 
Epidemiology, Statistical methods, Cardiovascular

B3014 - Pilot study exploring feasibility of measuring hba1c using frozen hba1c prepared hemolysates - 08/01/2018

B number: 
B3014
Principal applicant name: 
Nicholas TImpson | Integrative Epidemiology Unit (IEU), University of Bristol (United Kingdom)
Co-applicants: 
Dr Vanessa Tan, Dr Susan Ring
Title of project: 
Pilot study exploring feasibility of measuring hba1c using frozen hba1c prepared hemolysates
Proposal summary: 

The measurement of circulating Haemoglobin A1C (glycated haemoglobin; Hba1c) is a good proxy of the mean plasma glucose concentration over a period of the past 2 months. Haemoglobin A1C levels are commonly used as a screening test for diabetes diagnosis and monitoring. Using freshly collected blood samples, circulating levels of Hba1c can be accurately measured by Boronate affinity high performance liquid chromatography (HPLC). However, it is currently unclear if this method can measure levels of Hba1c accurately using frozen hemolysates. Hba1c prepared hemolysates have previously been collected from ALSPAC mums at various clinics (FOM1, FOM2, FOM3 and FOM4). This proposal is for a pilot study to test the feasibility of measuring Hba1c using frozen Hba1c prepared hemolysates. This project will enable the assessment of whether Hba1c can be measured in frozen Hba1c hemolysates. If this is feasible, Hba1c levels of mums in ALSPAC can be measured and will be useful for future research linked to different health outcomes such as diabetes and cancer.

Impact of research: 
The findings from this study will enable the assessment of whether Hba1c can be measured in frozen Hba1c hemolysates.
Date proposal received: 
Friday, 8 December, 2017
Date proposal approved: 
Tuesday, 12 December, 2017
Keywords: 
Clinical research/clinical practice, Diabetes, Measurement of Hba1c using boronate affinity high performance liquid chromatography. , Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc.

B3008 - Epigenome-wide association study of seizures - 06/12/2017

B number: 
B3008
Principal applicant name: 
Doretta Caramaschi | MRC IEU -- University of Bristol (United Kingdom)
Co-applicants: 
Dr Esther Walton, Ms Charlie Hatcher
Title of project: 
Epigenome-wide association study of seizures
Proposal summary: 

Epilepsy is a common disorder that presents with recurrent seizures often from early childhood. It can affect children’s learning and school achievement and it is often related to other conditions such as autism, while significantly inflicting a burden on the affected children and their families. Amongst the known causes are genetic factors and birth complications. However, the mechanism by which epilepsy develops is unclear. Recent studies have found epigenetic alterations being linked with several neurological and psychiatric diseases, including scarce evidence of a link with epilepsy. Epigenetic modifications are chemical changes in the DNA molecule that maintain intact the inherited genetic information while altering, sometimes permanently, the functionality of the interested genes. Investigating these changes in the peripheral blood of children that experience seizures might help develop early biomarkers and understand the biological mechanisms behind epilepsy. In this project we aim to investigate the link between the epigenome at birth, during childhood and adolescence with the experience of seizures and we will investigate its potential consequences for neurodevelopment and mental health.

Impact of research: 
This project will allow us explore an area that is currently under-investigated and will give us new insights into the area of epilepsy and child development. If the results are confirmed by replication in other cohorts, the results will be published in a peer-reviewed journal and communicated to health professionals and to the public where they will be particularly of interest to the families whose children have experienced seizures.
Date proposal received: 
Monday, 4 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Epidemiology, Epilepsy, Epigenetics, Development

B3011 - Investigating the performance of multiple imputation with increasing proportions of missingness - 06/12/2017

B number: 
B3011
Principal applicant name: 
Jon Heron | Bristol Medical School (PHS) (United Kingdom)
Co-applicants: 
Mr Paul Madley-Dowd, Dr Rachael Hughes, Professor Kate Tilling
Title of project: 
Investigating the performance of multiple imputation with increasing proportions of missingness
Proposal summary: 

Missing data is a common problem in epidemiology where participant drop out can substantially reduce the sample size of initially large cohorts. One method of dealing with missing data is to use multiple imputation (MI) in which copies of the dataset are created and missing values are replaced in each dataset using an imputation model. An analysis model is then fitted to each imputed dataset and the point estimates of model parameters are combined using Rubin’s Rules. Variables included in the imputation model but not the analysis model are known as auxiliary variables.

A common question among researchers and reviewers is what proportion of missing data warrants the use of MI. A lower threshold of 5% missingness has been suggested as a point below which MI provides negligible benefit. At the opposite end some reviewers suggest an upper threshold of 50% missingness above which MI should not be attempted.

The fraction of missing information (FMI) is a measure able to quantify the loss of information to missingness while accounting for the amount of information retained by other variables within the dataset. It can be thought of as the fraction of the total variance of a MI model that is attributable to the between imputation variance. The FMI can take values between 0 and 1 with low values being preferable.

In a simulation study proportions of missing data in a multivariate normal dataset were increased using a missing completely at random pattern. Multiple imputation was then used and its performance compared to complete case analysis. Imputation models with varying amounts of auxiliary information were investigated in terms of the bias and precision of parameter estimates, confidence interval coverage and FMI.

An empirical example, using ALSPAC data, will now be used to support the findings of the simulation study.

Impact of research: 
This research will advise epidemiologists and reviewers as to the limits of the proportions of missing data in an outcome variable that multiple imputation can be used. It will also advise on the importance of auxiliary variables to multiple imputation.
Date proposal received: 
Tuesday, 5 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Statistics/methodology, Cognitive impairment, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3012 - Using modern causal inference methods to investigate the role of inflammation in the aetiology of eating disorders - 06/12/2017

B number: 
B3012
Principal applicant name: 
Francesca Solmi | UCL (United Kingdom)
Co-applicants: 
Prof Glyn Lewis, Prof Cynthia Bulik, Prof Bianca De Stavola, Dr Golam Khandaker, Professor Christina Dalman, Dr Karoline Kuchenbaecker
Title of project: 
Using modern causal inference methods to investigate the role of inflammation in the aetiology of eating disorders
Proposal summary: 

Eating disorders are severe psychiatric conditions usually starting in adolescence. Their cause is
poorly understood.

Research has shown that infections in pregnancy and childhood, autoimmune disorders (e.g. type-1
diabetes), and inflammation (i.e. the body’s response to infection or injury) could increase a
person’s risk of developing mental health problems, including depression and psychosis. However,
little research has investigated the relationship between inflammation and eating disorders.
To address this question I will study whether: 1) exposure to infection during pregnancy or
childhood; 2) having high levels of inflammation in childhood; 3) carrying high genetic risk for
autoimmunity increase a person’s risk of developing an eating disorder.

The studies I will carry out use new approaches bringing together eating disorder data, biological markers of inflammation, and genes. This research will help to understand more about what causes eating disorders so that we can develop interventions to reduce the risk.

Impact of research: 
If my hypothesis of an association between inflammation and eating disorders is confirmed, it would justify: further research into anti-inflammatory treatments for EDs; studies linking inflammatory mechanisms to ED treatments; preventative strategies targeting ‘at-risk’ groups (e.g. those with autoimmune disorders).
Date proposal received: 
Wednesday, 6 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Epidemiology, Diabetes, Eating disorders - anorexia, bulimia, Eczema, Infection, Mental health, Respiratory - asthma, Genomics - structural variants, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Statistical methods, BMI, Cognition - cognitive function, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Hormones - cortisol, IGF, thyroid, Immunity, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Nutrition - breast feeding, diet, Offspring

B3013 - Intrauterine effects of maternal sex hormones on offspring DNA methylation and health outcomes - 06/12/2017

B number: 
B3013
Principal applicant name: 
Ryan Arathimos | MRC Integrative Epidemiology Unit (United Kingdom)
Co-applicants: 
Prof Caroline Relton, Dr Matthew Suderman
Title of project: 
Intrauterine effects of maternal sex hormones on offspring DNA methylation and health outcomes.
Proposal summary: 

Associations between circulating sex hormones in blood serum and DNA methylation have previously been found in ALSPAC children in both childhood and adolescence. Such associations may tag biological pathways involved in endocrine-related diseases, with important implications for the study of hypo- or hyper- gonadism, as well as various metabolic disorders known to be regulated by sex hormones. Whether such associations also exist between maternal levels of sex hormones and the mothers growing foetus is not known. The project will look at the effects of sex hormones in mothers on DNA methylation in children, using both observational and genetic evidence. Maternal sex hormone genotype will be used as a proxy of circulating sex hormone levels in genetic analyses enabling true causal associations to be unpicked from those due to confounding. Paternal genotype will be used as negative control to determine whether associations are due to in utero exposure to maternal sex hormones or simply shared genotype between mother and offspring.

Impact of research: 
The results of this research could be used to identify children at risk of outcomes linked to exposure to extreme intrauterine sex hormone levels. High risk individuals would be candidates for preventative interventions. Inclusion of DNA methylation will allow generation of exposure biomarkers (as a methylation score) reflecting exposure to intrauterine sex hormones that may be informative in risk prediction of future adverse health outcomes, in cases where pregnancy hormone levels are not available. Methylation itself could also be investigated as a mediator of in utero sex hormone and later life health outcomes, with potential for intervention. The results of this project will be of particular interest to endocrinologists, studying the biological effects of sex hormones, as well as researchers (epidemiologists and epigeneticists) involved in investigating the developmental origins of health and disease hypothesis.
Date proposal received: 
Wednesday, 6 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Endocrinology, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3010 - Causal analysis of maternal substance use during pregnancy and offspring neurodevelopmental outcomes 24-10-2017 - 165436 - 07/12/2017

B number: 
B3010
Principal applicant name: 
Dheeraj Rai | Centre of Academic Mental Health, University of Bristol (United Kingdom)
Co-applicants: 
Mr Paul Madley-Dowd, Prof Stan Zammit, Dr Jon Heron, Dr Luisa Zuccolo, Mr Andrew Boyd, Prof Marcus Munafo
Title of project: 
Causal analysis of maternal substance use during pregnancy and offspring neurodevelopmental outcomes (24-10-2017 - 16:54:36)
Proposal summary: 

Alcohol and tobacco use during pregnancy have been shown to influence fetal brain development. These exposures have also been associated with intellectual disability, learning difficulties, autism spectrum disorder (ASD) and schizophrenia. Although such associations may be biologically plausible, whether they are causal or not is unclear. As a part of this project we aim to further investigate whether substance use by mothers during pregnancy is causally associated with childhood neurodevelopmental outcomes. To do this we will use a variety of statistical techniques which may improve our understanding. These techniques include comparison of mother and father’s substance use behaviours and the use of genetic methods which help to determine causality. These analyses will be undertaken in several large population based birth cohorts, including ALSPAC, in conjunction with other techniques such as sibling designs. The project will help to expand our understanding of the non-genetic causes of ASD, learning/intellectual disability and psychosis. Our research will provide a stronger evidence base to help future guidelines or policy regarding substance use during pregnancy.

Impact of research: 
If causal associations are detected and found to be robust following investigation using other cohorts, this would provide evidence supporting conservative governmental policy regarding the use of alcohol and tobacco use during pregnancy.
Date proposal received: 
Tuesday, 5 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Developmental disorders - autism, Cognitive impairment, Learning difficulty, Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Epigenetics, Statistical methods, Birth outcomes, Cognition - cognitive function, Development, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Linkage, Intelligence - memory, Mothers - maternal age, menopause, obstetrics, Offspring, Siblings

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