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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B3691 - Influence of the month of birth on persistence of ADHD in prospective studies an individual patient data meta-analysis - 06/01/2021

B number: 
B3691
Principal applicant name: 
Stephan Collishaw | Cardiff University (United Kingdom)
Co-applicants: 
Thomas Broughton, Dr Kate Langley, Prof Kate Tilling, Professor Samuele Cortese, Corentin Gosling
Title of project: 
Influence of the month of birth on persistence of ADHD in prospective studies: an individual patient data meta-analysis
Proposal summary: 
Impact of research: 
The study will provide useful information for interpreting apparent low persistence of ADHD across development The study will likely lead to a high impact scientific publication The study will provide training and opportunity for international collaboration for a PhD student (project B3410)
Date proposal received: 
Saturday, 19 December, 2020
Date proposal approved: 
Wednesday, 6 January, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Developmental disorders - autism, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Development, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3693 - Understanding the developmental associations between stress and self-harm - 06/01/2021

B number: 
B3693
Principal applicant name: 
Annekatrin Steinhoff | University of Zurich, Jacobs Center for Productive Youth Development (Switzerland)
Co-applicants: 
Title of project: 
Understanding the developmental associations between stress and self-harm
Proposal summary: 

Self-harm among adolescents and young adults is a widespread public health problem. Self-harm is often a maladaptive coping strategy used to alleviate severe emotion dysregulation following stressful events. Adolescence is a period of marked development in the realm of social relationships and socio-emotional competencies. However, the developmental associations between social stress and self-harm across the adolescent years are poorly understood. In particular, the mechanisms linking social stress and self-harm are largely understudied. Better knowledge about these processes is urgently needed, in order to identify promising targets for interventions designed to support adolescents with self-harm and help them cease from this self-destructive behavior.

Therefore, the aim of this project is to investigate how social stress and self-harm are interrelated between early adolescence and early adulthood. A particular focus will be on the mechanisms underlying these associations. Candidate mediators are a) biological manifestations of stress (e.g., inflammation) and b) physical health and health behaviors (e.g., sleep patterns). Potential gender differences will also be considered.

The findings will provide novel insights into the developmental precursors of adolescent self-harm and help improve intervention programs designed to reduce the enormous burden that self-harm can entail for individuals and society.

Impact of research: 
The findings will provide new insights into the mechanisms linking stress and self-harm, and inform a holistic understanding of the developmental antecedents and consequences of self-harm. The findings will also help identify youth at risk for self-harm and improve intervention programs designed to reduce the enormous burden that self-harm can entail for individuals and society.
Date proposal received: 
Sunday, 3 January, 2021
Date proposal approved: 
Wednesday, 6 January, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Statistical methods, Development

B3685 - Diagnostic prediction model for coeliac disease - 06/01/2021

B number: 
B3685
Principal applicant name: 
Martha Elwenspoek | University of Bristol (United Kingdom)
Co-applicants: 
Penny Whiting
Title of project: 
Diagnostic prediction model for coeliac disease
Proposal summary: 

Coeliac disease (CD) is an autoimmune disorder, triggered by the protein gluten, and affects 1% of the UK population. Some patients with CD may be asymptomatic, others present with non-specific symptoms, making the diagnosis difficult. Only 30% are thought to be diagnosed. Treatment for CD is lifetime adherence to a gluten free diet. Untreated CD may lead to malnutrition, anaemia, osteoporosis, infertility in women, lymphoma and small bowel cancer. Guidelines recommend that adults and children “at high risk” of CD should be offered testing. However, it is not clear which groups are at sufficiently high risk to justify routine testing.
We have performed a systematic review to identify symptoms and risk factors related to CD. We will use ALSPAC data from children who were tested for CD to determine which combination of symptoms and risk factors best predict CD diagnosis. The results from this study may help GPs decide who should be offered testing for CD.

Impact of research: 
Appropriate identification and treatment of CD can have significant benefits for patients in terms of symptoms, quality of life, and long-term health outcomes, as well as reducing healthcare and societal economic costs.
Date proposal received: 
Thursday, 17 December, 2020
Date proposal approved: 
Thursday, 17 December, 2020
Keywords: 
Epidemiology, Coeliac disease, Computer simulations/modelling/algorithms, Statistical methods, Coeliac disease

B3681 - From Social Cognitive Deficits to Later Emotional and Behavioural Problems The Roles of Cortisol and Inflammatory Cytokines - 17/12/2020

B number: 
B3681
Principal applicant name: 
Marta Francesconi | University College London (UK)
Co-applicants: 
Dongying Ji, Ms, Steven Papachristou, Eirini Flouri
Title of project: 
From Social Cognitive Deficits to Later Emotional and Behavioural Problems: The Roles of Cortisol and Inflammatory Cytokines
Proposal summary: 

Social cognition, the ability to understand the mind of other people, is essential for successful social
interaction. Children with emotional and behavioural problems are more likely to have a history of poor
social cognition ability. However, the path from poor social cognition to emotional and behavioural problems
in childhood and adolescence is unclear. The possibility I will explore in this PhD project is that social
cognitive deficits increase stress (i.e., hypothalamus-pituitary-adrenal dysregulation and flattened cortisol
rhythm and/or chronic inflammation), leading to emotional and behavioural problems. Cortisol and
inflammatory cytokines are thought to be promising biomarkers of various stressed-related behavioural and,
particularly, emotional disorders, yet existing evidence in children and adolescents is little and mixed, and
is mostly about clinical disorders. Additionally, it is not known yet how cortisol and inflammatory cytokines
work when facing stress caused by social cognition deficits, especially in the general population. The aim
of the project is to explore the role of these biomarkers in the interplay mechanism of social cognition deficits
and emotional and behavioural problems in children and adolescents, using longitudinal data from a large
general population study, the Avon Longitudinal Study of Parents and Children. Analytically, the project will
explore three relationships: a) the longitudinal association between deficits in core aspects of social
cognition (emotion recognition & theory of mind) and emotional and behavioural problems, b) the role of
cortisol in explaining the association and c) and the role of inflammatory cytokines in explaining the
association. The relationship between inflammation and cortisol is complex so the final analysis exploring
the role of both will consider this complexity fully.

Impact of research: 
Academic and policy. We think our findings will be of use and value to the following 4 groups. The first group are those making decisions about preventive and early treatment interventions. A second group to whom results will be addressed are the general public, especially parents and expectant parents. Academic researchers are a third category of users, including those with a substantive interest in child emotional and behavioural development, those interested in stress ‘effects’ and those interested in advanced longitudinal modelling. Finally, we hope to inform those commissioning research in child development, who, to a large extent, continue to underestimate or neglect the interaction between the body and the mind.
Date proposal received: 
Tuesday, 15 December, 2020
Date proposal approved: 
Thursday, 17 December, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Statistical methods, Birth outcomes, BMI, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Immunity, Intelligence - memory

B3680 - NCS Cohort Project ARQ1 COVID-19 and Mental Health Outcomes - 16/12/2020

B number: 
B3680
Principal applicant name: 
Gareth Griffith | University of Bristol (UK)
Co-applicants: 
Dr Jazz Croft, Dr Alex Kwong, Dr Ruth Mitchell, Dr Kate Northstone, Professor Nic Timpson
Title of project: 
NCS Cohort Project, ARQ1, COVID-19 and Mental Health Outcomes
Proposal summary: 

The COVID-19 pandemic has affected daily life across the UK from early March 2020. Viral suppression measures, including nationwide social distancing laws and the imposition both local and national lockdowns are likely to have had a large scale but heterogeneous impact on individual mental health outcomes over this period. Research published using ALSPAC COVID-19 questionnaire data has suggested that whilst depressive symptoms did not increase amongst respondents, anxiety symptoms increased considerably (Kwong et al. 2020). The distribution of these effects are currently poorly understood. This project aims to contextualise how individuals' mental health has changed over the course of the pandemic, and how subsequent economic and health outcomes have been moderated by prior mental health difficulties. Understanding how existing inequalities in mental health prevalence interact with, and are amplified by, the pandemic and associated viral suppression measures is of critical public health importance in helping to identify vulnerable groups in need of further support to aid in reducing health inequalities and promote wellbeing.

Using data from Children of the 90s, we can investigate participants' mental health status, employment, housing, and health behaviours before and during the pandemic, to enable us to make inference about mental health impacts conditional on prior health status.

Impact of research: 
Findings will contribute to the limited evidence base of the impacts of COVID-19 and viral suppression measures on mental health outcomes. It will help target funding at those most vulnerable to the negative outcomes of the pandemic, and inform the need for nuanced mental interventions to alleviate adverse impacts of viral suppression measures.
Date proposal received: 
Tuesday, 15 December, 2020
Date proposal approved: 
Wednesday, 16 December, 2020
Keywords: 
Epidemiology, Mental health, Statistical methods

B3678 - Consortium Against Pain InEquality CAPE - The impact of adverse childhood experiences on chronic pain responses to treatment - 17/12/2020

B number: 
B3678
Principal applicant name: 
Gary Macfarlane | University of Aberdeen (United Kingdom)
Co-applicants: 
Professor Tim Hales, Dr Line Caes
Title of project: 
Consortium Against Pain InEquality (CAPE) - The impact of adverse childhood experiences on chronic pain & responses to treatment
Proposal summary: 

The World Health Organisation describes adverse childhood experiences (ACEs) including abuse, neglect, violence and other household dysfunction, as the commonest and most intense childhood stressors. About half of us experience at least one and those exposed to several are likely to experience more health problems later in life, including chronic pain. There is a strong relationship between exposure to multiple ACEs and social deprivation, and additional associations with having a young mother or being male. Although there is increasing evidence that ACEs contribute to health inequalities, there is no widespread screening to identify interventions. Reasons for this include the limited range of ACEs in existing methods of assessment and little consideration of other factors that may contribute to vulnerability.

CAPE will develop a thorough questionnaire for assessing ACEs to enrich large population cohort data. This information will be linked to prescribing, social care records, neuroimaging, genetics and tissue samples, enabling identification of biopsychosocial factors that create vulnerability to chronic pain and adverse responses to treatment.

Impact of research: 
We will create a richly phenotyped datasets linking ACE exposure to pain, prescribing and adverse outcomes. Within CAPE, we will examine whether the increased burden of chronic pain, which disproportionately affects those exposed to multiple ACEs, leads to higher levels of opioid prescribing and associated adverse events. We anticipate that this will enable development of personalised pain management approaches and inform prescribing guidelines. We will engage with the Drug Deaths Task Force (https://www.gov.scot/groups/drug-deaths-task-force/) to develop evidence-based public health policy.
Date proposal received: 
Monday, 14 December, 2020
Date proposal approved: 
Tuesday, 15 December, 2020
Keywords: 
Epidemiology, Pain, Childhood - childcare, childhood adversity

B3677 - Does sleep quality and quantity during the early years having lasting effects on educational outcomes - 06/01/2021

B number: 
B3677
Principal applicant name: 
Amy Atkinson | Centre for Applied Education Research (United Kingdom)
Co-applicants: 
Dr Lisa Henderson, Professor Gareth Gaskell, Dr Liam Hill, Professor Mark Mon-Williams
Title of project: 
Does sleep quality and quantity during the early years having lasting effects on educational outcomes?
Proposal summary: 

Several studies have demonstrated that sleep during the early years (i.e. prior to formal school entry) can predict later language skills, cognition and wellbeing during childhood and adolescence. However, these studies have typically only examined a few sleep parameters (e.g. Dionne et al., 2011; Knowland et al., in press;), with some mixed findings emerging (Kocevska et al., 2017; Touchette et al., 2007). Moreover, research exploring the effects on later mental wellbeing have generally relied on a composite ‘sleep problems’ variable (reflecting various individual sleep parameters; e.g. frequent wakings, early wakings, nightmares; e.g. Gregory & O’Connor, 2002), making it difficult to conclude which sleep parameters are important. Further research is therefore needed to systematically examine the effects of early sleep on these critical cognitive and wellbeing outcomes. Nevertheless, based on existing evidence, it appears that sleep quality and quantity parameters can predict key outcomes during childhood and adolescence.

However, the effects of early sleep have only been considered on a limited number of outcomes to date. Notably, extant investigations into the effects of sleep on cognitive outcomes have relied on standardised test performance. It is therefore unclear whether early sleep parameters predict real-world cognitive outcomes, such as educational performance. Although there is evidence that sleep parameters are predictive of school readiness and academic achievement (e.g. Drake et al., 2003; Tso et al., 2016), these studies have either been cross-sectional in nature (measuring sleep close in time to the educational assessments) or longitudinal studies that commenced at or after the point of school entry. Longitudinal investigations of the effects of early sleep (i.e. before school entry) on later educational outcomes are lacking. The planned research will address these questions, by examining whether sleep during early development (i.e. at 6-42 months of age) predicts performance on a school entry assessment and academic achievement.

The project will also investigate factors that drive the effects of early sleep on later educational outcomes. As school readiness and academic achievement are closely linked to language abilities, cognitive skills, and mental wellbeing (e.g. Agnafors et al., 2020; Duncan et al., 2007; Romano et al., 2010), these factors may mediate the relationship between early sleep and educational outcomes. Alternatively, or additionally, it is possible that the longitudinal effects on educational outcomes may be driven by persistent sleep patterns. Indeed, there is some evidence that sleep parameters show continuity throughout childhood and adolescence (e.g. Stein et al., 2001). As such, it is possible that early sleep patterns may predict sleep parameters measured close in time to the school readiness and academic assessments, with sleep at these latter timepoints affecting educational performance. The current research will investigate these research questions by: (i) further examining how early sleep relates to language, cognitive, and wellbeing outcomes at school entry; and (ii) investigating whether these factors drive the relationship between early sleep and later educational outcomes.

Finally, from both a theoretical and practical perspective, the project will examine whether effects of sleep are equivalent for different groups of children. As cross-sectional studies have found that sleep is particularly important for cognitive functioning and academic outcomes in children from disadvantaged backgrounds (e.g. Wetter et al., 2019), this analysis will focus on examining whether the longitudinal effects of early sleep are moderated by maternal education and self-reported financial difficulties.

Impact of research: 
This work will have important theoretical implications by delineating the extent to which early sleep predicts performance on meaningful assessments of school readiness and academic achievement. It will provide further insights into the effects of early sleep on later language skills, cognitive abilities, and mental wellbeing. The work may also be important practically, potentially identifying a novel way in which educational outcomes and mental wellbeing can be enhanced during childhood and adolescence. Furthermore, by investigating whether the effects of early sleep are particularly pronounced in children from disadvantaged backgrounds, this project might identify a novel way in which the socioeconomic status gap in educational performance could be reduced.
Date proposal received: 
Saturday, 12 December, 2020
Date proposal approved: 
Tuesday, 15 December, 2020
Keywords: 
Social Science, Cognitive impairment, mental health - e.g. anxiety, depression, psychosis, etc, speech/language problems, Statistical methods, • Childhood - childcare, childhood adversity • Cognition – cognitive function • Communication (including non-verbal) • Development • Sleep • Speech and language

B3676 - NCS ARQ6 Identifying cases of COVID-19 in the ALSPAC cohort - 15/12/2020

B number: 
B3676
Principal applicant name: 
Kate Northstone | University of Bristol (United Kingdom)
Co-applicants: 
Professor Nic Timpson, Ruth Mitchell
Title of project: 
NCS ARQ6: Identifying cases of COVID-19 in the ALSPAC cohort
Proposal summary: 
Impact of research: 
Provide a resource for other cohort studies to assist them in identifying cases.
Date proposal received: 
Friday, 11 December, 2020
Date proposal approved: 
Tuesday, 15 December, 2020
Keywords: 
Epidemiology, Infection, Immunity

B3674 - Childcare attendance and age of introductions on respiratory infections allergy and asthma - 15/12/2020

B number: 
B3674
Principal applicant name: 
Rachel Foong | Telethon Kids Institute (Australia)
Co-applicants: 
Professor Graham Hall, Associate Professor Rae-Chi Huang
Title of project: 
Childcare attendance and age of introductions on respiratory infections, allergy and asthma
Proposal summary: 

Studies examining the effects of attendance at childcare on the development of asthma are conflicting. There are studies that report a protective effect, no effect and an increased risk of respiratory symptoms and allergic disease. Risks associated with asthma are however influenced by age of childcare attendance and family history of asthma. Children attending childcare also have more frequent infections than those who stay at home, and infections are a known risk factor for asthma. This study aims to investigate if attendance at childcare is associated with increased risk of allergies and asthma, and if the age of introduction and respiratory infections play a role.

Impact of research: 
In the Lifecycle consortium, we will be available to better determine the effects of early childcare attendance on respiratory outcomes in Europe, the UK and Australia with more certainty given the large sample size.
Date proposal received: 
Thursday, 10 December, 2020
Date proposal approved: 
Tuesday, 15 December, 2020
Keywords: 
Physiology, Allergy, Infection, Respiratory - asthma, Statistical methods, Childhood - childcare, childhood adversity

B3675 - Myopia in Young Adults - 15/12/2020

B number: 
B3675
Principal applicant name: 
Jeremy A. Guggenheim | School of Optometry & Vision Sciences Cardiff University (United Kingdom)
Co-applicants: 
Dr Cathy Williams, Professor Ian Flitcroft, Professor Stan Zammit, Professor Russ Jago, Professor Peter Blair, Dr Anna Pease
Title of project: 
Myopia in Young Adults
Proposal summary: 

Myopia (short-sightedness) is an eye condition in which distance vision is blurry. People with myopia need to wear glasses or contact lenses, or have laser refractive surgery, to achieve sharp distance vision. When people with myopia get older, they are at a higher-than-average risk of developing permanent sight problems such as macular disease. Myopia typically develops during school age. The reason it develops is not understood, however both genes and lifestyle factors are known to play a role. Children whose parents have myopia inherit a genetic predisposition to develop myopia themselves. In clinical studies, children who are randomly assigned to spend extra time outdoors each day have a lower incidence of myopia, suggesting that spending too little time outdoors is a risk factor. Individuals who spend more years at school also tend to develop a higher level of myopia. Around the world, the prevalence rate of myopia varies widely. This is thought to be related to the variation in the ‘intensity’ of school work and the pressure to do well at school. Myopia has also been linked to mental health problems such as depression and to levels of physical activity. However, for most of these links, it is unclear if myopia is a cause or a consequence of the association.

The ALSPAC cohort is unique in the scale and breadth of the information that has been collected about vision problems in childhood. This includes information about myopia development. In previous studies of ALSPAC participants, our research group has documented the time-course of myopia development and exposure to risk factors or protective factors such as time spent outdoors. For example, children from the ALSPAC cohort who spent relatively less time outdoors than their peers at age 7-years-old were found to have an increased risk of developing myopia by the age of 15. Here, we propose to build on our previous findings. Our primary aim is to discover if myopia is the cause or consequence of its associations with other lifestyle factors and health or wellbeing characteristics. To do this, we will use a technique called Mendelian randomisation, which uses random inheritance of subtle genetic features in a way similar to randomisation of participants in a clinical trial. Usually, Mendelian randomisation studies require very large cohorts of participants – larger than the ALSPAC cohort. However, myopia and many of the related conditions we plan to investigate are highly heritable, which means there is a good prospect of successfully answering our research questions using data collected in a sample the size of the ALSPAC cohort. Our secondary aims are extensions of the primary aim. We will compare the eye characteristics and lifestyle of children growing up in the UK with those of children elsewhere, to investigate if the risks for myopia are similar or different in countries with high or low prevalence rates of myopia. We will also extend our previous studies into the genetics of myopia. The exceptionally high level of detail that the ALSPAC research team has collected about genetics will allow us to test the role of specific genes in conferring a predisposition to myopia, and how this varies depending on the lifestyle risk factors that children are exposed to.

Impact of research: 
As regards lifestyle risk factors, we will seek to confirm previous observational associations and, where possible, use Mendelian randomisation to assess the direction of causality. The findings may aid the design of future randomised controlled trials for interventions designed to reduce myopia progression. As regards genetic risk, our studies may help identify novel genes that confer a risk of myopia. This knowledge may aid the development of drugs capable of slowing myopia progression.
Date proposal received: 
Thursday, 10 December, 2020
Date proposal approved: 
Tuesday, 15 December, 2020
Keywords: 
Ophthalmology, Gene mapping, GWAS, Microarrays, RNA, Statistical methods, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Growth, Mendelian randomisation, Physical - activity, fitness, function, Sleep, Vision

B3671 - Urban exposome during pregnancy and early childhood and child cognitive and motor function - 15/12/2020

B number: 
B3671
Principal applicant name: 
Monica Guxens | ISGlobal
Co-applicants: 
Anne-Claire Binter
Title of project: 
Urban exposome during pregnancy and early childhood and child cognitive and motor function
Proposal summary: 
Impact of research: 
Date proposal received: 
Tuesday, 15 December, 2020
Date proposal approved: 
Tuesday, 15 December, 2020
Keywords: 
Epidemiology, Cognitive impairment, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Cognition - cognitive function, Statistical methods

B3672 - Urban exposome during pregnancy and early childhood and child emotional and behavioural problems - 15/12/2020

B number: 
B3672
Principal applicant name: 
Monica Guxens | ISGlobal
Co-applicants: 
Anne-Claire Binter, Dr
Title of project: 
Urban exposome during pregnancy and early childhood and child emotional and behavioural problems
Proposal summary: 
Impact of research: 
Date proposal received: 
Tuesday, 15 December, 2020
Date proposal approved: 
Tuesday, 15 December, 2020
Keywords: 
Epidemiology

B3673 - Maternal exposure to urban environmental stressors and depression in the postnatal period - 09/12/2020

B number: 
B3673
Principal applicant name: 
Tim Cadman | Integrate Epidemiology Unit (UK)
Co-applicants: 
Dr Marie Pedersen, Katrine Strandberg-Larsen, Deborah Lawlor
Title of project: 
Maternal exposure to urban environmental stressors and depression in the postnatal period
Proposal summary: 

Maternal postnatal depression is estimated to affect 6 – 38% of women in high income countries. Not only is it by nature distressing, it is also associated with health risks to the child. We need to know more about what causes postnatal depression in order to inform policy to prevent it.

One set of factors which could be important are aspects of the city environment such as noise, air polution and access to natural spaces. The period following birth is a particular vulnerable time and these factors could have a negative impact on maternal mental health. For example, air polution could affect the brain which could lead to an increased risk of depression. Road traffic noise could disrupt sleep leading to increased stress, and a lack of access to natural spaces could reduce opportunities to socialise and relax.

Whilst there is some evidence that these aspects of the city environment are related to depression in adults, very few studies have explored their relevance for postnatal depression. In this study we aim to use a large data resource including many European cities to investigate whether exposure to these different aspects of the city environment increases the risk of postnatal depression.

Impact of research: 
It will increase understanding on the extent to which the urban environment affects postnatal depression, which could inform preventative policies.
Date proposal received: 
Friday, 4 December, 2020
Date proposal approved: 
Tuesday, 8 December, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics

B3667 - Predicting pubertal timing in boys and girls using clinical data and polygenic risk scores - 02/12/2020

B number: 
B3667
Principal applicant name: 
Despoina Manousaki | Research Center of the CHU Sainte Justine, University of Montreal (Canada)
Co-applicants: 
Nahid Yazdan Panah, Mojgan Yazdan Panah, Nicholas Timpson, Ken Ong, John Perry, Brent Richards
Title of project: 
Predicting pubertal timing in boys and girls using clinical data and polygenic risk scores
Proposal summary: 

Children with precocious puberty are defined as girls with breast development before age 8 years and boys with testicular enlargement before age 9 years (which corresponds to minus 2 standard deviations (SD) compared to the average age of these changes in both sexes). Earlier age at pubertal start has been associated with earlier age at first vaginal bleeding (menarche) in girls and earlier age at voice change in boys, and with long-term consequences, including shorter adult height and psychosocial adverse effects. Although more frequent in certain ethnicities, the prevalence of precocious puberty in girls is constantly increasing worldwide, following the increase in cases of pediatric obesity. Most children with precocious puberty do not present any endocrine, metabolic, neurologic or neurosurgical condition explaining their earlier pubertal start (these cases are defined as “idiopathic” precocious puberty), but extensive work up (including specific hormone measurements and radiological exams) is routinely performed to eliminate such conditions. An important portion of children with precocious puberty will be considered for treatment with puberty-blocking pharmacological agents, without clear evidence that these treatments will increase their adult height.
Late puberty is defined as an absence of breast development by age 13 in girls (or absence of menarche by age 15), and an absence of testicular enlargement before age 14 in boys. This phenomenon is more frequent in boys, in most of which no pathological cause is detected, and these children will end up developing a spontaneous puberty and achieve a normal adult height. Nonetheless, these children are often referred for endocrine evaluation and investigated to eliminate an underlying medical condition.
Given that age at pubertal start in the population follows a Gaussian distribution, 2.3% of normal healthy children will start their puberty at and age below 2 SD below the mean for each sex, and another 2.3% will start their puberty above 2SD above this mean. Defining which children with precocious or late puberty correspond to these 2.3% of the general population is important, since this would avoid unnecessary investigations and treatment in these patients.
Pubertal traits (age at breast development and menarche in girls, testicular enlargement and voice change in boys, age at pubertal growth spurt in both sexes), have a polygenic nature, and an overlapping genetic architecture in boys and girls. It has been estimated that about 50% of variation in age at menarche can be attributed to genetics. Polygenic risk scores (PRS) have been demonstrated to have an improving ability to identify individuals at significantly high/low predisposition towards complex diseases. Therefore, it has become possible to identify individuals who will lie at the extreme distribution of a trait, such as age at menarche in girls or age at voice change in boys.
Therefore, we posit that PRS for age at menarche in girls or age at voice change in boys, in combination with clinical risk factors (such as increased body mass index) may be able to effectively predict children diagnosed as having idiopathic precocious puberty and in which no further investigation or treatment would be required to achieve a normal adult height (within their parental target height). Also, the same scores could identify children in the opposite extreme of the normal distribution, ie children with late puberty.

Impact of research: 
Our study can potentially stratify for risk of IPP or late puberty among children, based on a score derivable at no risk and low cost. Such a stratification is likely to substantially reduce the socioeconomic burden on many families whose children have IPP or late puberty while optimizing allocation of medical resources. Our study may also illustrate whether the genetic factors captured by the PRS are constantly associated with pubertal development stages since early childhood, or when they start to become associated. Finally, by objectifying the portion of the variance in pubertal traits explained by genetic factors, we will draw interesting conclusions on the “nature vs nurture” of precocious puberty- since it is has been shown that lower socio-economic status and exposure to environmental chemicals predispose to earlier pubertal start. This is likely to shed new light upon investigations on puberty, growth and development.
Date proposal received: 
Friday, 27 November, 2020
Date proposal approved: 
Wednesday, 2 December, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation)

B3668 - The relationship between parenting and mental health the role of genetic nurture and child evocative effects across contexts - 02/12/2020

B number: 
B3668
Principal applicant name: 
Marcus Munafò | University of Bristol
Co-applicants: 
Miss Amy Campbell, Dr Hannah Sallis, Dr Rebecca Pearson
Title of project: 
The relationship between parenting and mental health: the role of genetic nurture and child evocative effects across contexts
Proposal summary: 

There are known links between parenting behaviour and mental health outcomes in children. However, it is not known the extent to which the genetics of the mother and the child independently interact to influence children’s future mental health. Genetics can influence child outcomes in multiple different ways:
1. Genetic variants which increase the risk of developing a mental health disorder can be passed directly from mother to child
2. A mother’s genetics can affect the way that she parents her child
3. A child’s genetics can cause them to behave in certain ways which evoke certain responses from their mother
Across four studies, I will investigate the role of genetics in the relationship between parenting and mental health outcomes.

Impact of research: 
This PhD will contribute to the overall understanding of the intergenerational transmission of mental health, through parenting and genetic factors. This improved aetiological understanding can then facilitate identification of intervention targets and intervention design.
Date proposal received: 
Monday, 30 November, 2020
Date proposal approved: 
Wednesday, 2 December, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Mental health, Computer simulations/modelling/algorithms, Psychology - personality

B3665 - Early life exposure to cardiovascular risk factors and cerebral structure and function in young adults - 02/12/2020

B number: 
B3665
Principal applicant name: 
Scott Chiesa | UCL (UK)
Co-applicants: 
Dr Sana Suri, Professor Klaus Ebmeier, Professor John Deanfield, Georgios Georgiopoulos
Title of project: 
Early life exposure to cardiovascular risk factors and cerebral structure and function in young adults
Proposal summary: 

Certain behavioural (e.g. diet, smoking, physical activity) and physiological (e.g. obesity, cholesterol, glycaemic control, blood pressure) risk factors have long been known to increase risk of atherosclerotic CVD in later life. Although clinical events rarely occur prior to middle-age, our group have previously shown that early signs of damage to the vasculature can be detectable from as early as childhood (Charakida et al 2012 JACC; Dangardt et al 2019 Lancet Child and Adolescent Health; Chiesa et al JACC Imaging 2019), and that cumulative exposure to this damage across the lifespan likely represents one of the biggest causes of later-life events.

Intriguingly, recent research strongly suggests that these modifiable health behaviours and risk factors may also contribute to another of the world's most pressing global health crises – dementia. A wealth of recent research supports the concept that the development and progression of cognitive decline and eventual dementia can be slowed or perhaps even prevented by addressing various risk factors more commonly linked to CVD (Livingstone et al 2020 Lancet). The implementation of early-life prevention strategies to improve heart health may therefore also provide dual benefits for long-term brain health.

Our group and others have recently contributed to accumulating evidence suggesting that it is exposure to these CV risk factors earlier in the lifespan which appear to relate most strongly to risk of cerebral (i.e. brain) disease risk in later life. These findings suggest that although dementia diagnoses are almost exclusively made in older age, they may in fact represent the end result of cumulative damage to brain tissues which have been sustained over decades previously. However, how early this damage starts and what factors are responsible for its appearance is currently unknown, as very few populations are available in which detailed brain scans have been carried out on a young population with wide-ranging CVD risk factors.

Impact of research: 
It is currently not known how early in life adverse changes within the cerebral tissues and circulation begin to appear, and whether the brain may be negatively impacted by childhood and adolescent exposure to risk factors in the same way as we have previously shown in the arteries. This study will provide a unique opportunity to investigate the effect that cumulative exposure to these risk factors has on markers of cerebral damage which are known to link to cognitive decline in older populations, and may therefore provide the first evidence of an adverse impact on the brain from poor health behaviours in the earliest stages of life. These findings are likely to be of wide interest to the scientific community and may inform prevention strategies for cerebral health by identifying a previously unappreciated but crucial window for targeting poor health behaviours.
Date proposal received: 
Tuesday, 24 November, 2020
Date proposal approved: 
Wednesday, 2 December, 2020
Keywords: 
Epidemiology, Cognitive impairment, Hypertension, Obesity, CVD, Medical imaging, epidemiology, Ageing, Blood pressure, BMI, Cardiovascular, Cognition - cognitive function, Equipment - MRI, Neurology

B3670 - National Core Studies ARQ7 Investigating the socio-economic impact of COVID-19 - 02/12/2020

B number: 
B3670
Principal applicant name: 
Laura Howe | University of Bristol (United Kingdom)
Co-applicants: 
Dr. Kate Northstone , Professor Nicholas Timpson, Dr. Jazz Croft, Gareth Griffith, Dr. Alex Kwong
Title of project: 
National Core Studies ARQ7: Investigating the socio-economic impact of COVID-19
Proposal summary: 

The COVID-19 pandemic has affected daily life since the start of the pandemic in March 2020. The adoption of viral suppression measures, including social distancing and both localised and national lockdowns, has led to an increase in economic inactivity and changes to the labour market. According to Office of National Statistics estimates (ONS October 2020), since March 2020 the rate of economic growth in the United Kingdom has been slowing and unemployment has risen sharply with the most dramatic decline being during the early stages of the pandemic. The effect of these changes to employment status (increased/decreased hours, periods of furloughed employment, redundancy, change in employment) on physical and mental health and health behaviours (alcohol consumption, exercise, diet) during the pandemic is currently unclear. An important consideration is whether different social factors (e.g. gender, ethnicity, economic situation, clinical vulnerability to COVID-19) contribute to poorer health and wellbeing during the pandemic because of changes in employment status. Understanding how social inequalities may contribute to changes in employment and health outcomes can help to identify vulnerable groups for additional support to reduce health difficulties and promote wellbeing.

Using data from Children of the 90s, we can examine participants’ employment status, wellbeing, and health behaviours before and during the pandemic to help us answer these questions and inform social and economic policy.

Impact of research: 
Findings will contribute to the currently limited evidence base in this area. We will be able to identify groups that have particularly been affected by the pandemic and inform the need for responsive behavioural change interventions to alleviate adverse impacts.
Date proposal received: 
Tuesday, 1 December, 2020
Date proposal approved: 
Wednesday, 2 December, 2020
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Mental health, Obesity, Statistical methods, BMI, Physical - activity, fitness, function, Employment, COVID-19

B3669 - Exploring epigenetic and phenotypic associations with genetic liability to juvenile idiopathic arthritis - 02/12/2020

B number: 
B3669
Principal applicant name: 
Gemma Sharp | MRC IEU, UoB
Co-applicants: 
Dr Sarah Clarke
Title of project: 
Exploring epigenetic and phenotypic associations with genetic liability to juvenile idiopathic arthritis
Proposal summary: 

Juvenile idiopathic arthritis (JIA) is the most common rheumatic condition of childhood, but remains a relatively rare condition. Whilst there is growing knowledge about JIA disease management, we have very limited knowledge about the wider impacts of the condition, particularly in adolescence and adult life. For example observational data suggests that JIA patients have adverse educational attainment levels and employment outcomes. There is also growing concern about wider health implications of JIA such as cardiovascular disease risk, similar to that seen for adult rheumatoid arthritis patients, although long term follow-up data of JIA patients into adulthood is very limited. Within this PhD a range of different techniques are being used to explore causes and effects of JIA across the life course using observational and ‘omic data. Our earlier work has shown associations between JIA and a number of other health outcomes, however outcome datasets have all derived from older adult populations. Building on earlier work, this project aims to examine the association between the level of the genetic risk of JIA (using polygenic risk scoring) and a range of clinical (e.g. cardiovascular risk factors), biological (e.g. circulating CRP levels), metabolic (eg circulating lipids) and molecular (e.g. changes to DNA methylation) outcomes during childhood and early adulthood. This will allow us to identify potential JIA associated comorbidity earlier in disease to a) allow earlier risk stratification of patients and b) allow underlying mechanisms of comorbidity to be explored.

Impact of research: 
Understanding the wide health impact of JIA on patients with the condition will enable a more targeted and holistic approach to their care with regards to risk stratification and modification. This will be particularly important as JIA patient transition from paediatric to adult health services.
Date proposal received: 
Monday, 30 November, 2020
Date proposal approved: 
Wednesday, 2 December, 2020
Keywords: 
Epidemiology, Juvenile Idiopathic Arthritis, EWAS, pheWAS, Childhood - childcare, childhood adversity, Epigenetics, Genetic epidemiology, Mendelian randomisation

B3666 - Characterisation determinants mechanisms and consequences of long COVID providing the evidence base for health care services - 14/04/2021

B number: 
B3666
Principal applicant name: 
Nishi Chaturvedi | University College London (UK)
Co-applicants: 
Prof Nicholas Timpson, Prof jonathan Sterne, Prof John Macleod, Andy Boyd
Title of project: 
Characterisation, determinants, mechanisms and consequences of long COVID – providing the evidence base for health care services
Proposal summary: 

Over 95% of COVID-19 (C-19) infections are not admitted to hospital. Yet debilitating physical and mental health symptoms of long COVID are reported frequently, their degree not wholly related to symptom severity. The diagnosis of long COVID itself, the categorisation into distinct syndromes with implications for identification of high risk groups, tailoring of interventions, and likelihood of recovery or adverse outcomes are poorly described. Our proposal will address these gaps, and help inform guidelines.

Impact of research: 
The characterisation and recording of long COVID
Date proposal received: 
Thursday, 26 November, 2020
Date proposal approved: 
Wednesday, 2 December, 2020
Keywords: 
Epidemiology, Infection, Epidemiological definition and dissection of longCOVID, COVID epidemiology

B3658 - Evaluating longitudinal invariance in measures of child and adolescent mental health and wellbeing across development - 01/12/2020

B number: 
B3658
Principal applicant name: 
Aja Murray | University of Edinburgh (UK)
Co-applicants: 
Dr Tom Booth, Dr Graciela Muniz-Terrera, Dr Anastasia Ushakova
Title of project: 
Evaluating longitudinal invariance in measures of child and adolescent mental health and wellbeing across development
Proposal summary: 
Impact of research: 
The research will help inform improved measurement of mental health issues across childhood and adolescence by providing insights into how mental health manifests differently at different developmental stages as well as providing direct psychometric evidence relating to the performance of specific commonly used mental health measures. It can also enhance the use of the ALSPAC dataset by providing information on how to best use the mental health measures available to achieve scores that can be validly compared over developmental stages.
Date proposal received: 
Friday, 20 November, 2020
Date proposal approved: 
Tuesday, 1 December, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

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