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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B3926 - What is the relationaship between biological markers of adversity and chronic inflammation to psychiatric outcomes at age 24 - 29/11/2021

B number: 
B3926
Principal applicant name: 
David Cotter | RCSI (Ireland)
Co-applicants: 
Prof Stan Zammit, Prof Mary Cannon, Dr David Mongan, Meike Heurich, Melanie Focking
Title of project: 
What is the relationaship between biological markers of adversity and chronic inflammation to psychiatric outcomes at age 24
Proposal summary: 

A wealth of data implicates inflammation in the pathophysiology of psychiatric and many other disorders. Childhood adversity is a risk factor for later psychiatric disorder and it is associated chronic inflammation as measured by the soluble urokinase-type plasminogen activator receptor [suPAR]). We have shown that suPAR is elevated among ALSPAC participants who have psychotic experiences and psychotic disorder at age 24. We have also shown that the complement pathway in the blood, which contributes to inflammation, is upregulated in the blood 6 years prior to the identification of psychotic disorder (PMID 29036721). Similarly we have shown that people at clinical high risk for psychosis who later develop a psychotic disorder show increased baseline levels of markers of the complement pathway (PMID 32857162). Most recently we have shown (preliminary data) that the complement pathway is upregulated among those in the first episode of psychosis who respond well to antipsychotic drugs. These findings implicate the complement pathway in psychosis. Of the members of the complement pathway that have been shown to be dysregulated, C1r, has been most consistently and strongly altered and has been validated using ELISA (PMID 32857162; PMID 32857162). C1r is linked to the activation of C4A variant implicated so strongly in schizophrenia genomic studies (PMID: 26814963) and is associated with other medical diseases such SLE and Hereditary Angioedema.
What is not known is:

1. what is the relationship of this marker of chronic inflammation [suPAR] and this plasma marker of the complement pathway, C1r, at age 24 to adversity in childhood and adolescence

2. what is the relationship between plasma suPAR and plasma C1r.

3. do measures of suPAR and C1r at age 24 mediate the relationship between adversity in childhood and adolescence and psychiatric outcomes at age 24.

We propose to answer these questions by quantifying these markers of chronic inflammation and complement activation in all young people who gave bloods in the ALSPAC clinics at age 24 to investigate the relationship to adversity and psychiatric outcomes at age 24.

We note that chronic inflammation and complement pathway function is an important contributing factor to many medical diseases and that this information can therefore be applied broadly and will find relevance far beyond the field of psychiatry.

Impact of research: 
This study will provide unique and clinically important data on the longitudinal pattern of markers of chronic inflammation and complement activation within all available plasma EDTA samples of the ALPAC cohort at age 24. Thus, while our own focus is the relationship between these markers and psychiatric outcomes at age 24, this data will be equally relevant to the very many general medical disorders of inflammation is a part. The impact will be significant.
Date proposal received: 
Thursday, 11 November, 2021
Date proposal approved: 
Friday, 12 November, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc.

B3878 - Play and Child Development Role of Parent and Child Genes and the Environment - 12/11/2021

B number: 
B3878
Principal applicant name: 
Gill Althia Francis | University of York (United Kingdom)
Co-applicants: 
Dr Umar Toseeb
Title of project: 
Play and Child Development: Role of Parent and Child Genes and the Environment
Proposal summary: 

To better understand the function of play, its origin, and purpose in child development; developmental psychology, and behavioural genetics methodologies are uniquely combined in an original approach to studying children's play. Variables related to children, their parents, and the genetic propensities of both will be combined to explore linkages between home environments, play, and children’s social/cognitive outcomes, in a cross-cohort-longitudinal approach. Data from three UK longitudinal studies will be used in a holistic attempt to tap into the construct of play given it is a multidimensional construct. The study addresses the call for novel approaches to studying how play relates to child development.

Impact of research: 
This study presents an innovative approach to better understanding the function of play, its origin, and its purpose in child development. It remains unclear the extent to which children’s and parent’s genetic propensities interact with and create environments that are conducive to playful behaviours. The findings from this study will add new knowledge as no previous study has tried to tease apart these factors.
Date proposal received: 
Tuesday, 9 November, 2021
Date proposal approved: 
Friday, 12 November, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Speech/language problem, Statistical methods, Statistical methods

B3879 - Gene-environment interactions in mental health trajectories of youth - 12/11/2021

B number: 
B3879
Principal applicant name: 
Sinan Guloksuz | Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University (Nederland)
Co-applicants: 
Dr Lucy Riglin, Prof Dr Bart Rutten, Dr Karim Lekadir
Title of project: 
Gene-environment interactions in mental health trajectories of youth
Proposal summary: 

This work aims to improving our understanding of the emergence of mental health problems across childhood, adolescence and young adulthood. We will investigate how different biological and environmental factors interact to drive or prevent the onset of mental ill-health.

Impact of research: 
The project will have impacts across multiple domains: scientific, clinical practice, and policy-making by providing accessible knowledge platform for better understanding of trajectories of mental health and illness, prediction tools for early intervention to improve health care for young people, reduce suffering, disability and socioeconomic consequences.
Date proposal received: 
Tuesday, 2 November, 2021
Date proposal approved: 
Friday, 12 November, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Genetic epidemiology

B3925 - Networks of Adversity in Childhood and Adolescence and their Relationship to Adult Mental Health - 17/11/2021

B number: 
B3925
Principal applicant name: 
Edward Dylan Barker | Institute of Psychiatry, King's College London (United Kingdom)
Co-applicants: 
Ayla Pollmann
Title of project: 
Networks of Adversity in Childhood and Adolescence and their Relationship to Adult Mental Health
Proposal summary: 

Adverse events before the age of eighteen are common and include diverse experiences ranging from sexual abuse to parental divorce. These stressful events have been linked to physical and mental health issues. Previous research has focused mainly on childhood adversity and adverse experiences in the family environment, and little consideration has been given to what types of adversity may be particularly harmful in adolescence.

Impact of research: 
Published peer reviewed paper.
Date proposal received: 
Tuesday, 9 November, 2021
Date proposal approved: 
Friday, 12 November, 2021
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Childhood - childcare, childhood adversity

B3924 - Novel diagnostic and therapeutic pathways and improved exacerbation prediction in asthma and COPD - 19/11/2021

B number: 
B3924
Principal applicant name: 
James Dodd | University of Bristol (United Kingdom)
Co-applicants: 
Raquel Granell, Nic Timpson
Title of project: 
Novel diagnostic and therapeutic pathways and improved exacerbation prediction in asthma and COPD.
Proposal summary: 

Respiratory disease, the third largest cause of death in England, affects one in five people. Hospital admissions for lung diseases drive NHS winter pressures, costing £11billion annually. Reducing the impact of respiratory disease and associated health inequalities is a UK Government priority (UK Life Sciences Vision 2021).
In collaboration with ALSPAC we will focus on
• Workstream 2: Asthma and chronic obstructive pulmonary disease (COPD)

Impact of research: 
Our research will inform later phase trials and generate evidence needed for phase 2 and 3 trials of novel therapeutics designed to alter the natural history of obstructive lung diseases and transform digital self-management. We will seek funding for these through NIHR i4i, RfPB and HTA schemes. These findings will inform clinical guidelines and national policy including clinical commissioning and NICE technology appraisals.
Date proposal received: 
Monday, 8 November, 2021
Date proposal approved: 
Monday, 8 November, 2021
Keywords: 
Clinical research/clinical practice, Allergy, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Cognitive impairment, Mental health, Respiratory - asthma, Statistical methods, Ageing, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cardiovascular, Cognition - cognitive function, Development, Environment - enviromental exposure, pollution, Mendelian randomisation

B3921 - Sugar Sweetened Beverages and adiposity - 04/11/2021

B number: 
B3921
Principal applicant name: 
David Benton | Swansea Univeristy (United Kingdom)
Co-applicants: 
DR Hayley Yound
Title of project: 
Sugar Sweetened Beverages and adiposity
Proposal summary: 

It has been repeated suggested that drinking sugar sweetened drinks is a major risk factor for obesity. The role of pure fruit is controversial as although it contains natural sugar it also provides beneficial polyphenosl and vitamin C. The project will compare the drinking sugar sweetened drinks, sugar sweetened fruit containing drinks and pure fruit juice by the mother during pregnancy and during the firts year of age. The effects on the weight gain during the first ten years of life will be examined.

Impact of research: 
Will answer the question whether fruit juice should be viewed in a similar way to sugar sweetened beverages
Date proposal received: 
Monday, 1 November, 2021
Date proposal approved: 
Thursday, 4 November, 2021
Keywords: 
Developmental biology, Obesity, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics

B3920 - The connectomics of Alzheimers risk characterising brain temporal network dynamics in young adults - 04/11/2021

B number: 
B3920
Principal applicant name: 
Jiaxiang Zhang | Cardiff University (UK)
Co-applicants: 
Mr Andrea Vergallo, Professor Kim Graham, Professor Andrew Lawrence
Title of project: 
The connectomics of Alzheimer’s risk: characterising brain temporal network dynamics in young adults
Proposal summary: 

Using advanced imaging and novel mathematical approaches, we will identify spatio-temporal brain networks that show altered dynamics in young adults with genetic risk for Alzheimer's disease. The PhD will provide grounding in network neuroscience — an evolving field using network theories to study the brain across multiple scales and modalities.

Impact of research: 
This research will advance our understanding of the effect of genotypes on brain temporal networks.
Date proposal received: 
Wednesday, 3 November, 2021
Date proposal approved: 
Thursday, 4 November, 2021
Keywords: 
Neurology

B3899 - Developmentally-induced DNA methylation changes in response to maternal tobacco and cannabis use during pregnancy - 03/11/2021

B number: 
B3899
Principal applicant name: 
Amy Osborne | University of Canterbury (New Zealand)
Co-applicants: 
Dr Alexandra Noble, Professor Jack Satsangi, Dr Alex Adams
Title of project: 
Developmentally-induced DNA methylation changes in response to maternal tobacco and cannabis use during pregnancy
Proposal summary: 

Substance use during pregnancy is a large driver of health inequalities in exposed children, and despite the known impacts on infant health that accompany its use, tobacco use during pregnancy is still prevalent. Additionally, cannabis use in pregnant women is increasing. Tobacco use during pregnancy is associated with low birth weight, respiratory distress, and an increased risk of neurodevelopmental disorders and Irritable Bowel Disease (IBD) in exposed offspring. Developmentally-induced health inequalities are often driven by environmentally-induced genetic change, and our recent research has shown a link between DNA methylation and neurodevelopmental disorders. Interestingly, exposure to cannabis during development shows similar phenotypic patterns to tobacco, however, the molecular links between exposure and phenotype have not yet been explored.

Thus, in addition to data derived from our current cohorts (the Christchurch Health and Development Study [CHDS], Southampton Trio Cohort of the UK & Ireland Paediatric IBD Genetics Group) which both have well documented maternal tobacco and cannabis exposure measures, and manifestations of disease in the offspring, we seek to include DNA methylation data from ALSPAC to determine whether maternal tobacco and cannabis use impacts the genome of exposed offspring at genes involved in neurodevelopment and immune regulation, which may help explain the observed link between developmental exposure and offspring outcomes.

This research addresses the knowledge gaps around the association of maternal substance use and health outcomes in children, clarifying the potential risks of substance use, particularly maternal cannabis use, and indicate what this might mean for the health outcomes of exposed children.

Impact of research: 
Our research will be high impact because it will assess the robustness and longevity of developmentally-induced differential methylation, across multiple cohorts, and its association with disease and offspring health. Additionally, there is a paucity of research that seeks to probe the molecular basis of associations between developmental exposures and offspring phenotype, on this level, and across multiple phenotypes. Specifically, currently there is the gap between cannabis and tobacco use during pregnancy and the impacts on offspring phenotype. Prevalence rates suggest that there is an increase in detrimental health outcomes for offspring due to both exposures. Furthermore, maternal cannabis use during pregnancy has been hypothesised to have neurological impacts on offspring. Whereas maternal tobacco use during pregnancy is thought to impact childhood IBD. However, we don't know whether this relationship is causal, partly causal or only correlational. To tackle this question, it is important that we use an adequate number of individuals in our study design. As this is unable to be undertaken in our cohort samples, we propose that the use of the ALSPAC data will add vital numbers to adequately answer our hypotheses, building a robust and high impact research programme. This research pipeline will begin to address this knowledge gap by identifying the precise molecular targets of cannabis and tobacco in developing offspring, which will aid in the understanding of the safety of these two substances for pregnant mothers. Furthermore, we want to assess the differences exhibited by the different exposure groups. Although very little work has thus been undertaken on cannabis only exposure, recent observations from our group using adult cannabis users has revealed distinct methylation differences compared to adult tobacco smoking exposure. Hence, why we are also intrigued to assess these two exposures and the different disease phenotypes. We have previously applied Illumina methylation array technology successfully in other studies (insert a range of citations here), this shows that we are uniquely placed to successfully deliver this important project. We will ensure the impact of our research via a broad dissemination programme. The cannabis in utero findings for this study will be communicated to the New Zealand and UK public via the Canterbury District Health Board maternal drug screening programme (NZ), and through education of other District Health Boards, community organisations, and addiction services both in New Zealand and in the UK. We anticipate at least two high impact manuscripts from this research. Importantly, the IBD findings will be incorporated into relatively new technology (Nanopore adaptive sequencing) to allow us to measure DNA methylation and examine the accuracy of these tests in several cohorts of children. This will allow us to develop our diagnostic test in a platform which would be easy to establish and allow us to test in children the markers for diagnosis, disease aggressiveness and treatment response we have been developing in adults. Furthermore, we hope that the development of these tests will allow us to reduce the need for invasive investigations including colonoscopy in children.
Date proposal received: 
Thursday, 28 October, 2021
Date proposal approved: 
Wednesday, 3 November, 2021
Keywords: 
Genetics, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cognitive impairment, Gastrointestinal, DNA methylation, Birth outcomes, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Environment - enviromental exposure, pollution, Epigenetics

B3915 - Smoking induced newborn DNA methylation and early childhood caries experience - 01/11/2021

B number: 
B3915
Principal applicant name: 
Aderonke Akinkugbe | Virginia Commonwealth University
Co-applicants: 
Title of project: 
Smoking induced newborn DNA methylation and early childhood caries experience
Proposal summary: 

Dental caries a complex chronic disease of multifactorial etiology that affects a children worldwide. Its risk factors include a susceptible tooth, fermentable sugars and caries bacteria. Certain upstream factors have also been implicated in the etiology of dental caries and they are those that promote a favorable oral environment for dental caries susceptibility and progression. One of such upstream factors is prenatal smoking. The prenatal period is a sensitive time for fetal growth and development, including the development of the primary tooth germ that commences at the end of the 5th week of gestation. Exposure to prenatal smoking during this critical period not only affects the health and wellbeing of the developing fetus but also the quality of the developing tooth. Previous studies that have found an association between prenatal smoking and dental caries in the child relied on self-reported smoking during pregnancy, and thus, susceptible misreporting and recall bias of actual smoking status. This current study utilizes an objective measure of exposure to smoking in-utero in the form of newborn DNA methylation (DNAm) measured in cord blood collected at birth.

Impact of research: 
Ability to quantify the extent of misclassification from self-reported prenatal smoking using newborn DNAm as gold standard, and definitive conclusions on the association between prenatal smoking and offspring caries experience.
Date proposal received: 
Thursday, 28 October, 2021
Date proposal approved: 
Monday, 1 November, 2021
Keywords: 
Epidemiology, Oral health, Statistical methods, Dental, Epigenetics, Offspring, Statistical methods

B3918 - Modelling longitudinal trajectories of lung function using UNICORN cohorts - 28/10/2021

B number: 
B3918
Principal applicant name: 
Anhar Ullah | National Heart and Lung Institute Imperial College London. (UK)
Co-applicants: 
Dr Raquel Granell , Dr Sadia Haider, Dr Sara Fontanella
Title of project: 
Modelling longitudinal trajectories of lung function using UNICORN cohorts
Proposal summary: 

Introduction: Several studies have reported that lung function in early adulthood is a significant predictor of mortality and COPD and that childhood events in part determine lung function in adult life. Multiple birth cohort’s studies support these findings; these studies have shown different lung function growth trajectories in the population. Most of the studies reported parallel lung function trajectories with two to four trajectories, except Tasmanian longitudinal health study. Tasmanian longitudinal health study identifies six trajectories, besides persistently high, average, below average, persistently low they also reported trajectories with early below average, accelerated decline and early low, accelerated growth, normal decline, the reason for this may be due to long follow-up time (up to age 53 years).
Hypothesis: We hypothesised that besides the parallel trajectories already reported in the literature, there are trajectories with both declining and increasing trends. We have already found some interesting findings to support our initial hypothesis using the MAAS and IOW data, which need validation using a similar cohort but larger sample size. Furthermore, using MASS and IOW, we are modelling other spirometry patterns derived from actual spirometry measures; these new derived markers are more clinically relevant and easily interpretable.
Methods: We will use a latent process mixed model for multivariate markers and latent transition analysis to support our hypothesis. After deriving the trajectories, we will identify early-life predictors for these trajectories; we will also use the genotyping data to see whether these trajectories have genetic bases. To Validate our findings from MAAS and IOW, we need a larger cohort, and ALSPAC is vital for this validation due to its larger sample size.

Impact of research: 
To show how individual-level patterns of lung function deviate from group-level trajectories derived using data-driven techniques. In particular, we wish to identify children with lung function decline and improved growth. Anhar has expertise in methodologies to identify these patterns, which have not been identified n previous studies. We believe this research will advance the literature and understanding of lung function development in a clinically meaningful and important way.
Date proposal received: 
Friday, 22 October, 2021
Date proposal approved: 
Thursday, 28 October, 2021
Keywords: 
Bioinformatics, Allergy, Respiratory - asthma, Statistical methods, Development, Growth, Sex differences, Statistical methods

B3919 - Investigating the mechanisms underlying sleep problems and links to mental ill health in autistic children and adolescents - 01/11/2021

B number: 
B3919
Principal applicant name: 
Daniel Smith | University of Edinburgh (United Kingdom)
Co-applicants: 
Ms. Reesha Zahir, Prof. Sue Fletcher-Watson
Title of project: 
Investigating the mechanisms underlying sleep problems and links to mental ill health in autistic children and adolescents
Proposal summary: 

Disordered sleep is commonly reported in autism from a young age, as are symptoms of mental illness. Mental health and sleep are known to influence each other in a bidirectional manner within the general population, but the nature of the association between sleep and mental health problems in autism is poorly understood. Moreover, the underlying causes of sleep problems in autism are unknown. Thus, current treatments for sleep problems are largely ineffective in autistic people, and they also face severe consequences of mental ill health, such as high rates of suicidality and in-patient care. We aim to characterise the relationship between sleep problems and mental ill health, and identify factors underpinning the sleep problems in autism and in people with autistic traits. We will focus specifically on childhood and adolescence as this comprises the typical age-range of onset for problems in both sleep and mental health. Our approach to answering these questions will involve statistical modelling of longitudinal data on sleep and mental health in ALSPAC.

Impact of research: 
By increasing our understanding of the mechanisms underpinning sleep problems in autism, this research could help inform treatment approaches, as well as the development of new interventions to improve sleep in autistic people. Moreover, characterising the contribution of sleep to mental health in autism could also help address mental illness in autism more effectively, thus improving both mental health and quality of life outcomes for autistic people
Date proposal received: 
Wednesday, 27 October, 2021
Date proposal approved: 
Thursday, 28 October, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Developmental disorders - autism, Statistical methods, Statistical methods

B3909 - The tempo of childhood growth and physical and neurocognitive development - 27/10/2021

B number: 
B3909
Principal applicant name: 
Yee-Ming Chan | Boston Children's Hospital (United States)
Co-applicants: 
Title of project: 
The tempo of childhood growth and physical and neurocognitive development
Proposal summary: 

In our research and clinical experience, we have found that children with delayed puberty often have delays in other aspects of childhood growth and development, including later emergence of adult teeth (secondary tooth eruption), slower growth in childhood, and delayed appearance of changes driven by hormones from the adrenal glands, such as pubic hair, underarm hair, and body odor. These observations suggest that some "master" mechanism (currently unknown) dictates the tempo of childhood growth and development.

This master mechanism may also affect aspects of neurocognitive development, as we have observed high rates of attention-deficit/hyperactivity disorder in children with delayed puberty - over 35%, compared to 5% to 10% in the general population. Alternatively, it has been proposed that ADHD medications may affect the timing of puberty (perhaps through suppression of appetite, or by stimulating production of the hormone cortisol), though studies that have formally examined this possibility have not found evidence for this.

Our above studies focused on children with delayed puberty. In this project, we seek to examine relationships between these childhood milestones in a more general population. We also seek to identify the genetic factors that control the tempo of childhood growth and development.

Impact of research: 
As a pediatric endocrinologist, I routinely evaluate children with concerns about rapid or slow growth and with concerns about precocious and delayed puberty. However, we have an extremely limited understanding of the mechanisms that regulate childhood growth and development, and this hampers our ability to distinguish benign variation from pathological conditions and, in turn, to decide whether reassurance vs. intervention is needed. A more complete understanding of determinants of the tempo of childhood growth will not only shed light on a fascinating and mysterious process, it will also permit a more physiologically informed approach to evaluation and management of children with atypical growth and/or pubertal timing. We also intend to use findings from this project to develop clinical tools, such as a tool to estimate when a child with delayed puberty will eventually enter puberty, which would in turn help to guide management decisions. The connection between growth, pubertal timing, ADHD, and ADHD medications has long been discussed, but the mechanisms underlying all of these - much less linking all of these - remain elusive. Understanding these mechanisms may lead to new approaches to diagnose and manage these concerns.
Date proposal received: 
Friday, 15 October, 2021
Date proposal approved: 
Wednesday, 27 October, 2021
Keywords: 
Endocrinology, Learning difficulty, Puberty, growth, adrenarche, other developmental milestones, ADHD, Statistical methods, Latest class/factor/trajectory analyses, polygenic risk score analysis, Mendelian randomization, BMI, Cognition - cognitive function, Development, Genetics, Genomics, Growth, Hormones - cortisol, IGF, thyroid, Mendelian randomisation, Puberty, Sex differences

B3793 - Clusters of exposome components and their association with lung function evolution during the youth - REMEDIA project - 19/11/2021

B number: 
B3793
Principal applicant name: 
Sophie Lanone | INSERM (France)
Co-applicants: 
Pr Etienne Audureau, Pr Ralph Epaud, Pr Isabelle Coll, Matthieu Ortala
Title of project: 
Clusters of exposome components and their association with lung function evolution during the youth - REMEDIA project
Proposal summary: 

The concept of exposome refers to the totality of the environmental exposures (diet, lifestyle, occupational and environmental factors, …) from conception onwards, including its external and internal components. Among non-communicable respiratory diseases, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are two highly debilitating diseases that are of particular interest to consider in parallel in a human exposome study. The overall objective of the REMEDIA project is to determine how and to what extent the exposome affects the severity and morbidity of COPD and CF throughout the progression of disease, thus providing key elements to design more tailored prevention and care programs. We assess exposome and health data from several cohorts and population registers to determine, at various times of life, whether specific exposome(s) is(are) associated with particular phenotypes of COPD/CF in terms of severity, morbidity, exacerbations and co-morbidities. Yet, lung function development starts in utero and continue up to early adulthood, when a maximal lung function is reached. It is therefore of crucial importance to understand the impact of exposome on this key determinant of adult pulmonary health.

We hypothesize that lung diseases occurrence and lung function development during the youth is both influenced directly by individual/contextual components of the exposome and indirectly (mediated) via more complex pathways. Human research on this topic has generally focused on single exposure–health effect relationships. Our objective is to consider a broader definition to the exposome accounting for its multiple facets at the individual/contextual levels, also taking into account the potential clustering of exposures which may often be observed in combination (e.g. air pollution, socioeconomic indicators and individual health-related behaviours).

Consequently, the specific objective to be addressed using the ALPSAC cohort is to investigate whether there are specific exposome components, in isolation and/or in combination (clusters), linked to lung function trajectories and maximal achieved lung function at early adulthood, taken as an early determinant of COPD and CF outcome.

Impact of research: 
Better understand the relation between specific exposome components and specific evolution patterns in lung function and phenotypes of the diseases of interest.
Date proposal received: 
Friday, 24 September, 2021
Date proposal approved: 
Wednesday, 27 October, 2021
Keywords: 
Epidemiology, COPD & CF - interest in lung function trajectories as determinants of lung function at adult age, Statistical methods, Birth outcomes, BMI, Childhood - childcare, childhood adversity, Development, Environment - enviromental exposure, pollution, Growth, Nutrition - breast feeding, diet, Physical - activity, fitness, function, Statistical methods

B3908 - Longitudinal associations of DNA methylation and sleep in children - 26/10/2021

B number: 
B3908
Principal applicant name: 
Rebecca Richmond | University of Bristol (United Kingdom)
Co-applicants: 
Dr Sara Sammallahti
Title of project: 
Longitudinal associations of DNA methylation and sleep in children
Proposal summary: 

Sleep is important for healthy functioning in children. However, the biological factors underlying sleep development in childhood remain unclear. Epigenetic processes may serve as a biological mechanism that underlie differences in child sleep characteristics.

Impact of research: 
DNA methylation patterns associated with childhood sleep characteristics may provide insights into mechanisms by which genetic and environmental exposures in early life influence sleep.
Date proposal received: 
Monday, 25 October, 2021
Date proposal approved: 
Tuesday, 26 October, 2021
Keywords: 
Epigenetics, Sleep, Epigenetics, Epigenetics, Sleep

B3916 - Physical and mental health multimorbidity across the lifespan LIfespaN multimorbidity research Collaborative LINC - 19/11/2021

B number: 
B3916
Principal applicant name: 
Marianne van den Bree | Cardiff University (United Kingdom)
Co-applicants: 
Prof Golam Khandaker, Prof Nic Timpson, Prof Peter Holmans, Prof James Walters, Prof Michael Owen, Prof George Kirov, Prof John MacLeod, Prof Mark Mon-Williams, Prof Sarah Finer, Dr Andres Ingason
Title of project: 
Physical and mental health multimorbidity across the lifespan (LIfespaN multimorbidity research Collaborative: LINC).
Proposal summary: 

Multimorbidity (MM) happens when two or more different diseases are present at the same time in an individual. This is
common between physical and psychiatric diseases with almost half of people with a psychiatric disease also having a
physical disease. As well as about a third of people with a physical disease also having a psychiatric disease. These
patients have worse quality of life than those with a single disease, they often struggle to get the best care and are at risk of
living less long. A common and serious type of MM is between internalizing diseases (depression and anxiety) and
cardiovascular disease (ICV-MM). Still, very little is understood as to how ICV-MM develops and why it happens. We do
know however that both internalizing disease and cardiovascular risk (e.g., obesity, cholesterol) tend to begin before
adulthood.
To really understand how ICV-MM risk develops, we need large studies of people of all ages whose health has been followed
over time. Studies of children are crucial because they can tell us about early risks for development of ICV-MM later in life.
This is important for developing better plans to prevent at-risk children developing ICV-MM.
We know that genes influence risk of both internalizing and cardiovascular disease and that some people are at high
genetic risk. We also know that certain conditions that start early in life (neurodevelopmental conditions) such as
intellectual disability, autism and ADHD increase risk of developing ICV MM later. Children's environments can also
increase this risk, for example, stressful experiences such as poverty and physical or sexual abuse. But how exactly genes,
neurodevelopmental conditions and early environmental risks influence the development of ICV-MM over the lifespan is still
not understood.
Certain groups are known to be at increased risk of ICV-MM, such as people of South Asian heritage and women, but we
don't know why this is. Better understanding of how ICV-MM develops in different groups in society will help doctors give
patients care that is matched to their specific needs. It will also help doctors, governments and schools prevent ICV-MM in
at-risk children in ways that work best for them.
To really understand the complexities of ICV-MM development, a team of researchers with a wide range of expertise is
needed who together understand physical and psychiatric diseases as well as how genetics, neurodevelopmental
conditions and the environments people live in influence them throughout their lives.
Our LIfespaN multimorbidity research Collaborative (LINC) combines wide-ranging medical and research expertise in
physical and psychiatric diseases. We have brought together five very large studies in which the health of many people has
been followed over time. Rich medical data is available, including from medical records. Genetic information is also
available for these people. Other important information has also been collected such as on people's living environments,
life events and lifestyles.
These studies follow the health over time of children, adolescents and adults. We can therefore study how internalizing and
cardiovascular disease happen together in adulthood. Importantly we can then also study early risk factors in the children
before they develop these conditions. Because our child and adult samples differ in ethnicity and economic situation, we
can also study how the development of ICV-MM differs for different groups in society. Finally, because we have genetic
data, we can study how genes influence ICV-MM development in people at risk.
Our study will help us understand how ICV-MM develops and which circumstances influence this. What we learn will be
important for the prevention of ICV-MM in children who are at risk because of genetics, their sex, or ethnic or economic reasons. We will work with patients, doctors and charities to develop specific health advice in order to reduce ICV-MM in at
risk groups in the future.

Impact of research: 
Potentially high, informing policy, clinical practice
Date proposal received: 
Thursday, 21 October, 2021
Date proposal approved: 
Tuesday, 26 October, 2021
Keywords: 
Epidemiology, Mental health, Statistical methods, Cardiovascular

B3912 - Measurement of Genic Constraint via Reproductive Success - 01/11/2021

B number: 
B3912
Principal applicant name: 
Eugene Gardner | MRC Epidemiology Unit, University of Cambridge (United Kingdom)
Co-applicants: 
Title of project: 
Measurement of Genic Constraint via Reproductive Success
Proposal summary: 

New genetic variants arise in the germline due to mutation. While the majority are genetically neutral and have no effect on organismal phenotype, some variants confer either an advantage and proceed towards fixation via positive selection, or a disadvantage and are removed from the gene pool by negative selection. The context of where a given variant arises in the genome strongly predicts whether it is eliminated or becomes fixed, with the function of the gene impacted perhaps the most predictive for coding variation. Genes that are depleted of deleterious genetic variation (DGV) due to negative selection are said to be “constrained”. Why most genes are under significant constraint remains a mystery, but in recent work using data from the UK Biobank we identified a link between DGV burden within constrained genes and increased childlessness.

We also found that a combination of having a partner at home and presence of various mental health disorders played a significant role in the relationship between DGV and childlessness. We hypothesized that DGV burden is associated with behaviours attributable to mental health disorders that in turn decrease the likelihood of finding a reproductive partner. However, we were unable to test this hypothesis due to limitations in the phenotyping of our original data. Using the rich, longitudinal phenotyping and genetic data provided by ALSPAC, we now wish to explore how individual feelings about having children, mental health disorders, and behaviours interact to create selective pressure on DGV within constrained genes.

Impact of research: 
My hope is that our research will be used to develop a better understanding of why some genes are depleted for deleterious genetic variation and the mechanisms of how deleterious genetic variation burden leads to increased childlessness.
Date proposal received: 
Monday, 18 October, 2021
Date proposal approved: 
Tuesday, 26 October, 2021
Keywords: 
Genetics, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Cognitive impairment, Fertility/infertility, Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Computer simulations/modelling/algorithms, DNA sequencing, Gene mapping, Statistical methods, Ageing, Birth outcomes, Parenting, Sex differences, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Genetic epidemiology, Genetics, Genomics, Growth, Offspring

B3903 - Does Fetal Alcohol Spectrum Disorders FASD classification predict engagement in adolescent Multiple Risk Behaviours MRBs - 26/10/2021

B number: 
B3903
Principal applicant name: 
Caroline Wright | University of Bristol (United Kingdom)
Co-applicants: 
Dr Luisa Zuccolo, Dr Cheryl McQuire, Dr Laura Tinner, James Parsonage
Title of project: 
Does Fetal Alcohol Spectrum Disorders (FASD) classification predict engagement in adolescent Multiple Risk Behaviours (MRBs)?
Proposal summary: 

To explore the associations between fetal alcohol spectrum disorder (FASD) / Prenatal alcohol exposure (PAE) and adolescent multiple risk behaviours (MRBs). We are interested in exploring the prospective associations between prenatal alcohol exposure and MRBs, such as self-harm, drug use, tobacco smoking and alcohol consumption which are known to increase through adolescence and may persist into adulthood leading to multiple and composite adverse health outcomes. Identifying at risk adolescents could be used to aid the development of interventions and preventative policy.

Impact of research: 
An MSc dissertation and possibly a peer-reviewed paper
Date proposal received: 
Monday, 25 October, 2021
Date proposal approved: 
Tuesday, 26 October, 2021
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Learning difficulty, Mental health, Obesity, Sexually transmitted diseases, chlamydia, gonorrhoea, Statistical methods, Birth outcomes

B3913 - The causal role of the human gut microbiome in cancer aetiology - 26/10/2021

B number: 
B3913
Principal applicant name: 
Kaitlin Wade | Integrative Epidemiology Unit and Integrative Cancer Epidemiology Programme (United Kingdom)
Co-applicants: 
Alec McKinlay
Title of project: 
The causal role of the human gut microbiome in cancer aetiology
Proposal summary: 

The human gut microbiome, home to a range of bacteria and various other microorganisms, is a diverse and complex feature of human homeostasis. Its specific composition varies between individuals due to pre-determined characteristics, i.e. our genetics, and modifiable factors including diet, lifestyle and probiotic consumption. The differences between individuals have highlighted its role in mediating a range of pathologies including obesity, metabolic syndrome, inflammatory disorders, and alterations in stress responses and behaviour. More recently, a relationship to cancer has been highlighted, where variations in the metabolites produced from these microorganisms is likely to have differential risk to cancer aetiology between individuals. The bacteria within the microbiome therefore has the potential for pharmaceutical intervention (through pro/prebiotics), if specific metabolites produced from these microbes are robustly associated to cancer outcomes.
Observational epidemiological studies have tried to quantify this relationship; however, they will often lack in overall certainty of causal inference and further be prone to biases, confounding and reverse causation. Mendelian randomisation (MR) has therefore been used as a tool within the field to improve the weakness pertinent to observational studies. The aim of the methodology is to utilise genetic polymorphisms, with well-characterised biological functions, as a proxy measurement for environmental exposures to provide evidence for causation. These germ line variants are independently and randomly assorted, allow for objective measurements to the degree of exposure and show a lack of association to behavioural, social or physiological factors, therefore allowing MR to be comparable to that of a randomised controlled trial (RCT) within the hierarchy of evidence – if done correctly.

Whilst MR may improve causality within this field, it is however prone to its own limitations. Specifically in the context of the microbiome, whereby, identifying variants to proxy for our trait of interest becomes increasingly more difficult. The project will therefore aim to test the relationship between the microbiome and cancer outcomes, through triangulating finding from both observational and genetic evidence. It will focus specifically on cancer outcomes that have not previously been robustly studied within this context, including (but not limited to) lung cancer.

Impact of research: 
The gut microbiome is a modifiable risk factor for disease that may have clinical importance in terms of cancer incidence and progression, and potentially facilitate therapeutic development to improve health and reduce the burden of the disease.
Date proposal received: 
Monday, 18 October, 2021
Date proposal approved: 
Tuesday, 26 October, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Cancer, Gastrointestinal, GWAS, Genetic epidemiology, Genetics, Mendelian randomisation, Microbiome

B3898 - ASSOCIATIONS BETWEEN CERTAINTY OF COVID-19 INFECTION STATUS AND REPORTING OF LONG COVID SYMPTOMS THE ROLE OF NOCEBO - 25/10/2021

B number: 
B3898
Principal applicant name: 
Catherine Macleod-Hall | Bristol Medical School (United Kingdom)
Co-applicants: 
Dr Maddy Dyer, Professor Marcus Munafò
Title of project: 
ASSOCIATIONS BETWEEN CERTAINTY OF COVID-19 INFECTION STATUS AND REPORTING OF LONG COVID SYMPTOMS: THE ROLE OF NOCEBO
Proposal summary: 

Some people experience symptoms caused by COVID that last longer than the original infection and these can be severe or disabling (COVID Symptom Study, 2020). This study aims to better understand why some people develop ‘long COVID’ – symptoms lasting longer than four weeks (National Institute for Health and Care Excellence, 2020) – and others do not. We will be comparing long COVID symptoms between those who have had COVID confirmed by a test, and those who believe they have had COVID but have not had a positive test. We will then explore whether this relationship is different between men and women, and between those who reported anxiety and those who didn’t. We hope that this research will help us to understand better whether psychological mechanisms contribute to the development of long COVID.

Impact of research: 
Long COVID is a new phenomenon that is still poorly understood, and a better understanding of the pathogenesis of the syndrome is required to shape future research and therapies. The influence of nocebo and negative expectations will have implications for the communication around diseases by the media and medical profession, particularly those of significant socio-political consequence such as COVID-19.
Date proposal received: 
Friday, 8 October, 2021
Date proposal approved: 
Monday, 25 October, 2021
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Chronic fatigue, Mental health, Respiratory - asthma, Statistical methods, Mental health Wellbeing Epidemiology Psychology COVID-19 Long COVID

B3904 - Comparison of blood pressure measures for assessing risk of adverse outcomes in pregnancy - 25/10/2021

B number: 
B3904
Principal applicant name: 
Amy Taylor | University of Bristol (United Kingdom)
Co-applicants: 
Professor Abigail Fraser
Title of project: 
Comparison of blood pressure measures for assessing risk of adverse outcomes in pregnancy
Proposal summary: 

Blood pressure is routinely measured during pregnancy and is important for determining the risk of experiencing adverse pregnancy outcomes including pre-eclampsia, gestational hypertension, preterm birth, having a small for gestational age baby, and gestational diabetes. There is evidence that measurement early in pregnancy of integrative measures of systolic and diastolic blood pressure may be more important than individual blood pressure measures for predicting which women may go on to experience hypertensive disorders of pregnancy (preeclampsia and gestational hypertension). For example, mean arterial pressure (MAP) calculated as (systolic blood pressure + 2 x diastolic blood pressure)/3 has been shown to be a better predictor of pre-eclampsia than systolic blood pressure (SBP) or diastolic blood pressure (DBP). However, to our knowledge, there have been no direct comparisons of a range of different measures of blood pressure (SBP, DBP, MAP, pulse pressure (PP), mid blood pressure) on all of these adverse pregnancy outcome (APO) subtypes at a the same timepoint early in pregnancy. This research aims to look at which measures/derived measures of blood pressure best predict pre-eclampsia, gestational hypertension, preterm birth, small for gestational age (SGA) and gestational diabetes.

Impact of research: 
A direct comparison of blood pressure measures taken at the same time during pregnancy should give a clearer picture to clinicians of which blood pressure measures are most informative for determining risk of APOs.
Date proposal received: 
Monday, 11 October, 2021
Date proposal approved: 
Monday, 25 October, 2021
Keywords: 
Epidemiology, Hypertension, Statistical methods, Blood pressure

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