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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B3844 - MR-PREG Consortium 26-07-2021 - 103144 - 20/09/2021

B number: 
B3844
Principal applicant name: 
Amy Taylor | University of Bristol (United Kingdom)
Co-applicants: 
Carolina Borges, Deborah Lawlor, Alice Carter, Marwa Al Arab, Nancy Mcbride, Ana Luiza Soares, Qian Yang, Alba Fernandez-Sanles, Fanny Kilpi
Title of project: 
MR-PREG Consortium (26-07-2021 - 10:31:44)
Proposal summary: 

ALSPAC contributes to a group of studies called MR-PREG which aims to investigate the impact of maternal exposures during pregnancy (such as BMI, smoking, blood pressure) on pregnancy complications, perinatal outcomes and later offspring outcomes. MR-PREG uses genetic data to explore whether associations between maternal exposures and these outcomes are likely to be causal.

Impact of research: 
There are already several papers in progress from the initial MR-PREG analyses. This work will be important for identifying the impact of maternal exposures during pregnancy and possible targets for intervention (e.g. healthy BMI ranges for pregnant women to prevent preterm birth).
Date proposal received: 
Monday, 6 September, 2021
Date proposal approved: 
Monday, 20 September, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., GWAS, Mothers - maternal age, menopause, obstetrics

B3865 - Global Lung Function Initiative Exhaled Nitric Oxide FENO Data Request - 20/09/2021

B number: 
B3865
Principal applicant name: 
Raquel Granell | MRC Integrative Epidemiology Unit (IEU) (United Kingdom)
Co-applicants: 
Prof Steve Turner, Dr Sadia Haider, Dr Cole Bowerman, Dr Sanja Stanojevic
Title of project: 
Global Lung Function Initiative Exhaled Nitric Oxide (FENO) Data Request
Proposal summary: 

The Global Lung Function Initiative (GLI) has collected measures of respiratory function from researchers and health care professionals from around the world and has produced reference equations for:

-Spirometry (respiratory testing) which take into account age, sex, height and race or ethnic origin;
-The Transfer Factor for Carbon Monoxide (TLCO) in the Caucasian population;
-Lung Volumes

The ERS has now approved a GLI Task Force for developing GLI reference equations for exhaled nitric oxide (FENO).

These reference equations allow studies to compare their values againts 'normal' values to aid diagnosis.

For more information about the FENO Task Force or to keep up to date with the GLI activities, you can visit the GLI website http://www.lungfunction.org/.

Impact of research: 
The equations will be published and made available to all clinicians and researchers for future studies; This publication will be referenced in most future papers involving analyses with FENO data. The ERS initiative may be newsworthy and suitable for any ALSPAC participant bulletin/website.
Date proposal received: 
Friday, 17 September, 2021
Date proposal approved: 
Monday, 20 September, 2021
Keywords: 
Epidemiology, Respiratory - asthma, Statistical methods, Statistical methods

B3872 - Genome wide association study of progression from impaired fasting glucose to type 2 diabetes - 20/09/2021

B number: 
B3872
Principal applicant name: 
April Hartley | Integrative Epidemiology Unit (UK)
Co-applicants: 
Professor Kate Tilling, Professor George Davey Smith, Dr Venexia Walker
Title of project: 
Genome wide association study of progression from impaired fasting glucose to type 2 diabetes
Proposal summary: 

Pre-diabetes is a condition where blood glucose levels are elevated above normal, but below the threshold to be defined as type 2 diabetes. It is estimated that 70% of those meeting the criteria for pre-diabetes will eventually progress to type 2 diabetes, which is a chronic, incurable condition associated with various other comorbidities. It is therefore important to understand why some individuals progress from pre-diabetes to type 2 diabetes, so that we can develop interventions to stop this happening. We therefore aim to identify the genetic basis for why some individuals progress from pre-diabetes to type 2 diabetes.

Impact of research: 
The ALSPAC data will contribute to a larger GWAS meta-analysis which will hopefully identify genes involved in progression from pre-diabetes to type 2 diabetes. The resulting summary statistics will also be used for two-sample Mendelian randomization analyses to identify non-genetic risk factors. Identifying risk factors for progression from pre-diabetes to diabetes may aid the development of interventions to prevent diabetes onset in those at high risk.
Date proposal received: 
Tuesday, 7 September, 2021
Date proposal approved: 
Monday, 20 September, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Diabetes, GWAS, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Genetic epidemiology, Genetics, Genomics, Genome wide association study, Mendelian randomisation, Metabolic - metabolism, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods

B3877 - Immuno-Metabolic Predictors of Anhedonic Depression and Treatment Response The IMPACT Programme - 16/09/2021

B number: 
B3877
Principal applicant name: 
Golam Khandaker | University of Bristol - MRC IEU (UK)
Co-applicants: 
Title of project: 
Immuno-Metabolic Predictors of Anhedonic Depression and Treatment Response: The IMPACT Programme
Proposal summary: 

The current work looks to examine the underpinnings of anhedonic depression - i.e. depression associated with an inability to feel pleasure. This is an important group and little is know about the factors that characterise and are important for this outcome. The work will use detailed questionnaires to examine the likely presence or absence of this presentation in ALSPAC participants and there will be extremely detailed followup of a sub-set of participants likely to have this condition. This work will be in parallel with that in a study called NESDA in The Netherlands - providing important replication and sample size.

Impact of research: 
Discovery science re. this presentation with likely information re. augmented therapeutic strategies.
Date proposal received: 
Sunday, 12 September, 2021
Date proposal approved: 
Thursday, 16 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Questionnaires, imaging (MRI), biosamples, possible randomised sub study intervention allocation. , Psychiatry, Imaging, Trial, Experimental Medicine

B3842 - Creating ALSPAC polygenic indexes for the SSGAC Polygenic Index Repository - 16/09/2021

B number: 
B3842
Principal applicant name: 
Tim Morris | University of Bristol (United Kingdom)
Co-applicants: 
Dr Aysu Okbay, Professor Daniel Benjmain, Dr Alexander Young, Hariharan Jayashankar, Seyed Moeen Nehzati, Tanner Bangerter , Jonathan Jala
Title of project: 
Creating ALSPAC polygenic indexes for the SSGAC Polygenic Index Repository
Proposal summary: 

In this project we will create "polygenic indexes" for the ALSPAC participants. Polygenic indexes are summaries of a persons known genetic predisposition to a particular trait, such as height. We will create these indexes for up to 47 different traits, which can then be use by other researchers.

Impact of research: 
Wide use by other researchers in research projects.
Date proposal received: 
Friday, 13 August, 2021
Date proposal approved: 
Monday, 13 September, 2021
Keywords: 
Genetics, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Obesity, GWAS, Statistical methods, Genetics, Genomics

B3869 - Development of standardised virus pseudotype assay to quantify SARS-CoV-2 neutralising antibodies in saliva and serum - 21/09/2021

B number: 
B3869
Principal applicant name: 
Ore Francis | University of Bristol (United Kingdom)
Co-applicants: 
Title of project: 
Development of standardised virus pseudotype assay to quantify SARS-CoV-2 neutralising antibodies in saliva and serum
Proposal summary: 

SARS-CoV-2 neutralising antibody (nAb) correlates with protection against SARS-CoV-2 infection and COVID-19, and measuring nAbs is crucial for COVID-19 patient management, vaccine trials and mechanistic research. I have developed a VPNA to measure nAbs, that does not require the high biosafety levels or time-consuming protocols necessary for using live SARS-CoV-2. This assay correlates with assays that measure abundance and live SARS-CoV-2 neutralisation ability of S-protein specific antibodies from sera. However, initial SARS-CoV-2-cell entry and subsequent shedding occurs in the upper-respiratory tract, so it is important to characterise immune responses in mucosae and blood. I plan to develop the anti-S-protein VPNA for saliva samples and standardise serum and saliva VPNAs to WHO reference samples. This updated VPNA will be used to characterise mucosal and systemic nAb responses in individuals who have had a natural SARS-CoV-2 infection with a focus on infection within families and to assess the efficacy of vaccination protocols.

Impact of research: 
A robust, high-throughput VPNA, optimised for serum and saliva samples and scaled to international standards is not yet available. The University of Bristol has identified patient samples from individuals before and after SARS-CoV-2 emergence and samples from patients undergoing different vaccination regimens. Characterisation of humoral immune responses, particularly nAbs, from the ALSPAC cohort will reveal local transmission dynamics in a detail not yet available. This work may reveal whether mucosal or systemic nAbs correlate best with differences observed in SARS-CoV-2 infection across demographics such as regional location or profession, metrics that may inform future pandemic-mediated policy (i.e., lockdowns). Additionally, samples from vaccinated individuals will reveal patterns corresponding to dose and timing of available vaccines. This could be vital in optimising current vaccination/booster policy. Additionally, VPNAs based on emerging VOCs will determine efficacy of current vaccines against new VOCs.
Date proposal received: 
Friday, 3 September, 2021
Date proposal approved: 
Monday, 13 September, 2021
Keywords: 
Immunology, COVID-19, Cell culture, Viral assay, Biological samples -e.g. blood, cell lines, saliva, etc., Immunity, SARS-CoV-2 COVID-19 Antibody

B3860 - Identifying markers for brain signatures of adolescent depression and depression risk - 13/09/2021

B number: 
B3860
Principal applicant name: 
Heather Whalley | University of Edinburgh
Co-applicants: 
Miss Amelia Edmonson-Stait, Dr Alex Kwong
Title of project: 
Identifying markers for brain signatures of adolescent depression and depression risk
Proposal summary: 

We currently have another proposal (B3421) investigating the brain signatures of adolescent depression and depression risk. In order to fully examine this project, we are running some initial analysis to define the most robust markers of depression across adolescence. From preliminary analysis and other research, we have found that trajectories of depressive symptoms may be robust markers for some brain signatures. Additionally, these trajectories could mediate the relationship between early risk factors and later brain signatures. Therefore, we are running additional analysis on the trajectories to validate these findings and we will examine them with the following methods. Please note, we already have access to the data, this is a student project using that data.

Depression can take on the shape of different trajectories. For some individuals symptoms of depression may appear in childhood and persist into adulthood, whereas for others symptoms may not appear until adolescence or later in life and may either persist or diminish with time. It remains unclear what risk factors influence these different trajectories. One potential risk factor of interest is inflammation as this has been shown to associate with depression, as well as brain structure and function.
Unlike traditional cross-sectional studies analysing trajectories of depression allows investigation of how individuals change over time. We aim to investigate how inflammation in childhood may influence depression trajectories across development. This is a time period of critical brain development in which symptoms of depression typically first occur. First, we will test for associations between markers of inflammation in childhood with depression trajectories using latent growth curve modelling. Secondly, we will test for potential causality of these associations using Mendelian randomisation.
This will aid our understanding of how early life biomarkers, such as inflammation, influence trajectories of depression, which in turn may be related to altered brain development. These findings will further develop the project (B3421) investigating the causes and timings of brain changes related to depression. We will eventually link these trajectories to the brain related changes and examine how trajectories mediate the relationship between early biomarkers and later brain related changes.

Impact of research: 
Shed light on biological mechanisms underpinning depression
Date proposal received: 
Saturday, 28 August, 2021
Date proposal approved: 
Monday, 13 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition

B3862 - The impact of child mental health on subsequent maternal mental health - 16/09/2021

B number: 
B3862
Principal applicant name: 
Faith Martin | Centre for Intelligent Healthcare, Coventry University
Co-applicants: 
Dr Cain Clark
Title of project: 
The impact of child mental health on subsequent maternal mental health
Proposal summary: 

Research has shown that there is a link a mother's and a child's mental health. There is a pattern that where mothers have poor mental health, their children are at risk of developing mental health difficulties also. Research with parents of children with mental health difficulties has shown how distressing this can be for parents. For example, parents of young people who self-harm report significant distress related to their child's difficulties. We seek to explore the link between child mental health and subsequent maternal mental health. We focus on the mother as this is where there is most available data within ALSPAC. This will help us understand whether mothers are at risk of developing significant distress after their child has reported clinical levels of mental health difficulties.

We will also look at variables that describe family structure and characteristics of the mother and child. For example, we want to understand if child mental health problems are more likely to be linked to maternal mental health problems if family have a lower income or if the mother does not live with a partner. We are interested in factors that increase stress or reduce available support for mothers. This will help us identify if there may be characteristics that make a mother more likely to have poor mental health in relation to their child's distress. If so, this will help us make recommendations for how services may need to be made available to best support families.

Impact of research: 
1) One of few academic papers to explore this topic, examining the potential impact of child mental health on maternal mental health. This contributes to the academic field by further developing a narrative of the importance of considering different/ bi-directional relationships and viewing parents as part of a family that may need support. 2) Working with our funder, the local CCG, if relationships are identified, we will have direct impact by reporting to them any findings relating to social and demographic variables that are associated to greater risk of mothers reporting mental health problems after their child has developed difficulties. This has potential impact to inform the CCG about any characteristics that may be important for planning services that are accessible to these families - for example, should we identify that mothers who work full-time are at greater risk of developing significant distress, we could recommend the importance of ensuring support for families is made available outside of working hours.
Date proposal received: 
Tuesday, 31 August, 2021
Date proposal approved: 
Monday, 13 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Mothers - maternal age, menopause, obstetrics, Parenting, mental health; family; maternal mental health;

B3861 - Determinants of social inequalities in respiratory health Findings from the EU Child Cohort Network - 16/09/2021

B number: 
B3861
Principal applicant name: 
Angela Pinot de Moira | University of Copenhagen
Co-applicants: 
Anne Vedelsdal Aurup
Title of project: 
Determinants of social inequalities in respiratory health: Findings from the EU Child Cohort Network
Proposal summary: 

Asthma disproportionately affects children from disadvantaged backgrounds. Few studies have estimated and compared how early years risk factors explain the social inequalities in childhood asthma across different countries. This study will examine the social distribution and prevalence of asthma and investigate how specific early years risk factors might underpin any observed social inequalities in childhood asthma in LifeCycle cohorts.

Impact of research: 
This study will help to identify interventions that could potentially reduce observed social inqualities in respiratory health.
Date proposal received: 
Monday, 30 August, 2021
Date proposal approved: 
Monday, 13 September, 2021
Keywords: 
Epidemiology, Respiratory - asthma, Statistical methods, Childhood - childcare, childhood adversity, Environment - enviromental exposure, pollution, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods

B3852 - Exploring intergenerational risk transmission using network analysis - 08/09/2021

B number: 
B3852
Principal applicant name: 
Aja Murray | University of Edinburgh (UK)
Co-applicants: 
Dr Bonnie Auyueng, Chad Lance Hemady, Dr Franziska Meinck, Dr Deborah Fry, Professor GJ Melendez-Torres
Title of project: 
Exploring intergenerational risk transmission using network analysis
Proposal summary: 

Prenatal mental and physical health are important factors associated with infant health and later child development. Previous research has identified a wide array of prenatal risk factors for poor infant outcomes, including sociodemographic factors (e.g., maternal education level, socioeconomic position), behavioural factors (e.g., substance use), biological factors (e.g., infections, gestational diabetes), psychosocial factors (e.g., exposure to interpersonal violence), and environmental factors (e.g., exposure to interpersonal violence, exposure to second-hand smoke), inter alia.1,2,3 Evidence also suggest that these risks factors and adverse outcomes are associated with maternal exposure to childhood maltreatment and abuse. 5,6 However, most empirical studies usually focus on exploring a specific pathway of intergenerational risk transmission rather than accounting for multiple dynamic factors and their interactive effects. To extend the methodological framework, this project aims to use graphical network analysis to: i) model dependencies between maternal childhood and prenatal risk factors and poor infant outcomes (in the form of infant prematurity and low birth weight); ii) and identify central risk factors that are likely to impact other types of risk factors and adverse health outcomes.
References:

1 De Bernabé, J.V., Soriano, T., Albaladejo, R., Juarranz, M., Calle, M.E., Martınez, D. and Domınguez-Rojas, V., 2004. Risk factors for low birth weight: a review. European Journal of Obstetrics & Gynecology and Reproductive Biology, 116(1), pp.3-15.

2 Murray, A.L., Kaiser, D., Valdebenito, S., Hughes, C., Baban, A., Fernando, A.D., Madrid, B., Ward, C.L., Osafo, J., Dunne, M. and Sikander, S., 2020. The intergenerational effects of intimate partner violence in pregnancy: mediating pathways and implications for prevention. Trauma, Violence, & Abuse, 21(5), pp.964-976.

3 Miranda, Marie Lynn, Pamela Maxson, and Sharon Edwards. "Environmental contributions to disparities in pregnancy outcomes." Epidemiologic reviews 31, no. 1 (2009): 67-83.

4 Nesari, M., Olson, J.K., Vandermeer, B., Slater, L. and Olson, D.M., 2018. Does a maternal history of abuse before pregnancy affect pregnancy outcomes? A systematic review with meta-analysis. BMC pregnancy and childbirth, 18(1), pp.1-11.

5 Racine, N., Plamondon, A., Madigan, S., McDonald, S. and Tough, S., 2018. Maternal adverse childhood experiences and infant development. Pediatrics, 141(4).

Impact of research: 
Date proposal received: 
Wednesday, 25 August, 2021
Date proposal approved: 
Wednesday, 8 September, 2021
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Statistical methods

B3857 - COVID-19 vaccine effects on the menstrual cycle - 02/09/2021

B number: 
B3857
Principal applicant name: 
Gemma Sharp | University of Bristol, IEU
Co-applicants: 
Dr Kate Northstone, Prof Nic Timpson
Title of project: 
COVID-19 vaccine effects on the menstrual cycle
Proposal summary: 

Accumulating online discussions suggest some women have experienced menstrual changes after receiving the COVID-19 vaccine. This is important and potentially concerning, as a large proportion of people menstruate and menstrual health is increasingly recognised as an important indicator and determinant of broader health and quality of life. The extent, nature, and mechanism of COVID-19 vaccine-related menstrual changes is currently unclear. The menstrual cycle is regulated by a complex interplay of hormones that can interact with the immune system to influence menstrual bleeding and premenstrual symptoms; vaccines cause huge immune disruptions and so could plausibly affect menstrual features. Questions about menstruation were added to the most recent questionnaire sent to ALSPAC participants. In this project, we will explore 1) the prevalence of different types of vaccine-associated menstrual disruptions, 2) demographic and life history factors associated with experiencing menstrual disruptions, 3) through future ALSPAC planned follow-ups, the duration of menstrual disruptions and future reproductive health outcomes.

Aim(s) and objective(s)
We would like to propose adding a set of questions around menstruation and pandemic-related menstrual changes to the ALSPAC questionnaires. The resulting data would enable us and others to:
1) estimate the prevalence and extent of menstrual changes during the pandemic and describe the demographic of people experiencing these changes;
2) study the potential bidirectional relationship between menstruation and COVID symptoms,
3) study the relationship between menstrual changes and stress and lifestyle changes;
4) study the longer term effects of pandemic-related menstrual changes on later health and reproductive outcomes (for example, fertility, pregnancy outcomes and timing of menopause).
Methods (including an overview of statistical methods)
The questions we are proposing to add were developed for a large online survey of menstrual changes during the pandemic. The questions were developed by Alexandra Alvergne's group at the University of Oxford with input from clinical gynaecologists and PPI input from long-covid sufferers and women with menstrual disorders. The survey is currently live.
Exposures, outcomes and confounders to be considered (justifying particular types of data as necessary)
If/when the data from our proposed questions are collected, we will put in another proposal for a project to address specific research questions.

That research will likely require access to ALSPAC data on stress, lifestyle changes and COVID symptoms from the COVID questionnaires and longitudinal data on menstruation from the G1 and G0 questionnaires. Follow-up ALSPAC questionnaires will allow us to see variations in fertility and timing of menopause according to responses to our questions. Covariates of interest will include socioeconomic position, chronic health conditions, age and BMI.
Reasons for using ALSPAC
ALSPAC has detailed prospectively collected longitudinal data on experiences before and during the COVID pandemic. It is also unique in terms of the availability of data on menstruation prior to the pandemic. Some cohorts have collected data on cycle length, but ALSPAC appears to be the only cohort to have asked about pre-menstrual symptoms like irritability and fatigue.
What do you think the likely impact of your research will be?
Judging by the interest in news stories and blog posts about the small number of survey studies we identified in our systematic review, we estimate that this research will be of wide public interest.
Stigma and a lack of knowledge about what is ‘normal’ means menstrual disorders are often under-reported and under-diagnosed, but they affect a large proportion of the population. For example, in the UK, 5% of women aged 30-49 years (>439,380 women) consult their GP each year due to excessive uterine bleeding. Our systematic review suggests that the number of women suffering from menstrual disorders has likely increased. Therefore, in addition to patients themselves, the research will be of interest to clinicians providing care to menstruating women. Recent years have seen an exponential interest in menstrual health and an appreciation of its role as an indicator and determinant of broader health and wellbeing. This is reflected by very recent policy changes to reduce tax on menstrual products. We anticipate that our research will contribute to further policy changes around improving population menstrual health and quality of life for menstruating women.

Impact of research: 
The MHRA has identified this as an area of interest. Our results will be fed directly back to them, as well as published in a peer-reviewed journal articles.
Date proposal received: 
Thursday, 26 August, 2021
Date proposal approved: 
Thursday, 2 September, 2021
Keywords: 
Epidemiology, Fertility/infertility, Menstrual health COVID, COVID Reproductive health Menstruation

B3867 - Integration of genetic transcriptomic and clinical data provides insight into the development of eating disorders - 14/09/2021

B number: 
B3867
Principal applicant name: 
Samuel Chawner | Cardiff University (United Kingdom)
Co-applicants: 
Professor Peter Holmans, Professor Marianne van den Bree, Prof Sir Michael Owen, Professor Cynthia Bulik
Title of project: 
Integration of genetic, transcriptomic, and clinical data provides insight into the development of eating disorders
Proposal summary: 

Eating disorders have a serious impact on an individual’s wellbeing and physical health. Individuals with eating disorders are up to 6 times more likely of dying prematurely, compared to healthy adults with no eating disorders. It is therefore crucial that we better understand the reasons why young people develop eating disorders. However, it is difficult to study the early signs of eating disorders because teenagers only see a doctor when they are already seriously ill. We need research into child development to identify early signs of eating disorders and to understand how eating disorders develop.

We want to understand how the genes influence risk of eating behaviour and eating disorders in the general population. We will use sophisticated genetic analyses to investigate if any subtle genetic changes are linked with weight, eating behaviours, and eating disorder symptoms in the general population. These analyses will also reveal which biological mechanisms are linked to eating disorders. We will also investigate overlap between my findings for eating disorders and those for other mental health conditions.

Impact of research: 
What do you think the likely impact of your research will be? My research proposal aims to understand the role of genetics in the development of eating disorders and related traits, and identify the biological processes that underly these traits. Greater knowledge of the biology of eating disorders has the potential to identify new biomarkers and inform new treatments and precision medicine approaches for patients.
Date proposal received: 
Thursday, 2 September, 2021
Date proposal approved: 
Thursday, 2 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Congenital abnormalities, Mental health, Obesity, DNA sequencing, RNA, Development, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Growth

B3864 - Variable antibody response to SARS-CoV-2 and the effects of vaccination career - 02/09/2021

B number: 
B3864
Principal applicant name: 
Richard Stanton | University of Cardiff (UK)
Co-applicants: 
Prof Nic Timpson, Ass Prof Kate Northstons, Dr Sue Ring
Title of project: 
Variable antibody response to SARS-CoV-2 and the effects of vaccination career.
Proposal summary: 

This project sets out to use existing samples (on N=4 participants) collected as part of the UKCiC initiative to examine the ability of SARS-CoV-2 vaccination to recover variable immunological response to wild infection. Data on continuously assessed antibody response to wild infection will be used to identify those with low response and then biological samples available over a schedule of first and second vaccinations will be used to examine the impact of these interventions.

Impact of research: 
Our underlying hypothesis is that the type of humoral response generated from natural infection is superior to vaccination, in terms of the ability of non-neutralising antibodies to activate cellular immunity. If this is true, and we can establish why it occurs, it may provide a means to enhance the efficacy of vaccine-induced responses.
Date proposal received: 
Wednesday, 1 September, 2021
Date proposal approved: 
Wednesday, 1 September, 2021
Keywords: 
Immunology, Infection, Biological sample analysis of immunological response to SARS-CoV-2, Immunity

B3859 - Analysis of 3D body scans genetics of body morphology correlation with measure of adiposity and cardiometabolic consequences - 08/09/2021

B number: 
B3859
Principal applicant name: 
Christoffer Nellåker | NDWRH, University of Oxford (United Kingdom)
Co-applicants: 
Michael Suttie, Abigail Fraser, Professor, Cecilia Lindgren, Professor
Title of project: 
Analysis of 3D body scans: genetics of body morphology, correlation with measure of adiposity and cardiometabolic consequences.
Proposal summary: 

Obesity is a major risk factor for diseases ranging from diabetes, heart conditions and even cancers. However, it is also well established that it is not only the amount of fat in the body that confers risk for various diseases but where the fat is distributed. There are a number of ways adiposity and body composition can be measured, but it is an ongoing area of research as to what measures are best for understanding the risk of disease and the genetic underpinnings of why this happens.
Body mass index (BMI) is a measure of body size but is a crude indicator of body composition, taking into account only a height-weight ratio. The gold standards to measure specific adipose tissue distribution and body composition involve either MRI, which is costly, or CT imaging, which requires unnecessary exposure to ionising radiation. 3D imaging is a non-invasive, cost-effective method of capturing surface geometry. Whole-body 3D scans can provide a detailed, geometrically accurate representation of body morphology and physical composition. We propose to analyse 3D body scan data collected as part of the ALSPAC study to examine how body shapes can be used to investigate genetics and the risk of cardiometabolic diseases.

Impact of research: 
We hope to elucidate if 3D body scan data could become a valuable anthropometric tool for health outcome predictions in the future. These instruments are being explored for non-medical purposes such as the fashion and online retailer industries, and could constitute a minimally invasive clinical tool in the future.
Date proposal received: 
Tuesday, 24 August, 2021
Date proposal approved: 
Wednesday, 1 September, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Obesity, Computer simulations/modelling/algorithms, Cardiovascular

B3836 - Bidirectional effects of educational attainment/intelligence on brain morphology - 26/08/2021

B number: 
B3836
Principal applicant name: 
Emma Anderson | IEU
Co-applicants: 
Roxanna Korologou-Linden
Title of project: 
Bidirectional effects of educational attainment/intelligence on brain morphology
Proposal summary: 

We aim to examine how educational attainment and intelligence (predicted by genetics) affect brain morphology (cortical surface area, thickness and volumes of subcortical structures) in individuals across the life course. We are aiming to examine how early we can observe the effects of educational attainment and cognitive ability on brain morphology by using cohorts of different ages, such as ABCD, Generation R, ALSPAC, IMAGEN, and UK Biobank. This can indicate whether brain plasticity exists in response to changing educational attainment/intelligence levels. We will also investigate how differences in brain morphology can affect one's educational attainment and/or intelligence, using summary-level data from the ENIGMA consortium.

Impact of research: 
Date proposal received: 
Tuesday, 17 August, 2021
Date proposal approved: 
Thursday, 26 August, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Computer simulations/modelling/algorithms, Cognition - cognitive function

B3845 - Early-life factors for elevated blood pressure later in life - 26/08/2021

B number: 
B3845
Principal applicant name: 
Peige Song | Zhejiang University (China)
Co-applicants: 
Miss Leying Hou, Miss Qian Yi
Title of project: 
Early-life factors for elevated blood pressure later in life
Proposal summary: 

Elevated blood pressure, or hypertension, has become a major public health concern globally. Evidence shows that blood pressure tracks into adulthood. However, most epidemiology research to date on hypertension has focused on risk factors from single aspects, but it is becoming increasingly evident that early-life factors may come from multiple sources, such as society, community, family and individual. For example, a positive association between rapid weight gain and elevated blood pressure in both children and adults has been widely observed. Other community-based evidence shows that lower early-life environment exposure to residential greenness has been found to be independently associated with elevated blood pressure. Until recently, the combined effects and interplay of individual and community-level factors on the developmental programming of blood pressure are still limited, and further research is needed.

Impact of research: 
This research will expand its impact in the research field of public health, paediatric hypertension, environmental health.
Date proposal received: 
Monday, 16 August, 2021
Date proposal approved: 
Thursday, 26 August, 2021
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Diabetes, Eating disorders - anorexia, bulimia, Eczema, Hypertension, Mental health, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Respiratory - asthma, Metabolomics, Statistical methods, Ageing, Biological samples -e.g. blood, cell lines, saliva, etc., Childhood - childcare, childhood adversity, Development, Endocrine - endocrine disrupters, Environment - enviromental exposure, pollution, Epigenetics, Fathers, Genetic epidemiology, Growth, Hormones - cortisol, IGF, thyroid, Injury (including accidents), Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Intelligence - memory, Mothers - maternal age, menopause, obstetrics, Metabolic - metabolism, Nutrition - breast feeding, diet, Offspring, Psychology - personality, Physical - activity, fitness, function, Puberty, Sex differences, Siblings, Birth outcomes, Sleep, Social science, Statistical methods, Telomere, Vision, Blood pressure, BMI, Bones (and joints), Breast feeding, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics

B3846 - SocialPaths Sex-specific social pathways to cardiovascular disease risk across the life course - 26/08/2021

B number: 
B3846
Principal applicant name: 
Kate O'Neill | University College Cork
Co-applicants: 
Dr Linda O'Keeffe
Title of project: 
SocialPaths; Sex-specific social pathways to cardiovascular disease risk across the life course
Proposal summary: 

Heart disease remains the leading cause of death around the world and will continue to be so for the rest of the 21st century. After several decades of research, we know what causes heart disease but it remains a challenge globally to prevent it and much research is still required to inform new prevention strategies into the future. These prevention strategies require research that takes a different approach to the study of heart disease. In the past, much research on heart disease has focused on males and often ignored important differences between the sexes. This means that much of what we know about heart disease and how we go about preventing it today is based on research in males. As a result research which studies males and females separately and the differences between them is required.

In addition to the need to study differences between females and males, there is a need to study social differences in heart disease risk, since the risk of heart disease differs substantially by social factors such as education and income. However, though we know social inequalities in heart disease risk have existed for many decades and start as early as infancy and young childhood, reduction of social inequalities in health has proven challenging for society. This is because many social factors such as income or education are difficult to change. Thus research which focuses on the risk factors (smoking for example) which are easier to change and that link social risk factors like education and CVD across the life course is required.

Addressing key knowledge gaps in the sex-and social epidemiology of CVD across the life course, this project aims to improve understanding of the role of social risk factors in heart disease risk across a person’s life using a number of different approaches in world-leading studies of children and adults. Improving understanding of sex-specific heart disease risk can inform different, more effective preventions strategies in females and males than strategies informed by research which treat females and males the same. In addition, gaining a better understanding of the role social risk factors in the heart disease risk across the life course can inform realistic approaches for prevention of social inequalities in heart disease across a person’s life time.

Impact of research: 
SocialPaths will address three critical knowledge gaps which cross-cut limitations in understanding in the sex-specific aetiology of CVD and the role of social risk factors in CVD aetiology across the life course. Specifically, SocialPaths will focus on producing new knowledge with greater potential for translation to reduction of social inequalities in health using: •Life course approaches which can inform timing of intervention for social inequalities which takes account of the unique sex-specific aetiology of CVD across the life course; •Causal mediation methods which can be used for sex-specific investigation of modifiable pathways linking social risk factors and CVD risk and testing of hypothetical real world interventions for social inequalities in CVD risk across the life course.
Date proposal received: 
Wednesday, 18 August, 2021
Date proposal approved: 
Thursday, 26 August, 2021
Keywords: 
Epidemiology

B3847 - Allostatic load in childhood and the development of mental health disorders - 26/08/2021

B number: 
B3847
Principal applicant name: 
Zoltan Sarnyai | James Cook University (Australia)
Co-applicants: 
Sabine Finlay
Title of project: 
Allostatic load in childhood and the development of mental health disorders
Proposal summary: 

The increased wear and tear on the body, is the consequence of multisystem regulations in response to repeated challenges from the environment (McEwen & Stellar, 1993). This multisystem dysregulation can be objectively quantified by calculating the allostatic load index, a cumulative score of biological biomarkers in the cardiovascular, immune, neuroendocrine, and metabolic systems (Berger et al., 2018; McEwen, 2004). Elevated allostatic load has been shown to predict the risk of major health outcomes, both systemically and in the brain. Evidence suggests that the elevation of individual biomarkers can be observed in early childhood (9 years old) in people who later develop a mental health disorder, however only a few biomarkers (IL-6 and CRP) has been investigated (Khandaker et al., 2014).
We and others have shown that severe mental disorder, such as schizophrenia, bipolar disorder and psychosis is associated with increased allostatic load (Berger et al., 2018; Berger et al., 2020; Juster et al., 2018; Piotrowski et al., 2019). Furthermore, our group has established that elevated allostatic load predicts depression symptoms and may underlie higher mental health burden and shortened life expectancy of a population affected by considerable stress and trauma, the Indigenous Australian people (Berger et al., 2019; Ketheesan et al., 2020)
This project will expand on these earlier findings and include biological markers from the four major physiological systems to calculate the allostatic load index and identify whether there is an association between a multisystem dysregulation in childhood and the development of severe mental health disorders. If such association is detectable, that will raise the possibility that the allostatic load index could be applied for targeting interventions in populations at risk and aiming to reduce the risk of developing a mental health disorder in adulthood.

References:
Berger, M., Juster, R. P., Westphal, S., Amminger, G. P., Bogerts, B., Schiltz, K., Bahn, S., Steiner, J., & Sarnyai, Z. (2018). Allostatic load is associated with psychotic symptoms and decreases with antipsychotic treatment in patients with schizophrenia and first-episode psychosis. Psychoneuroendocrinology, 90, 35-42. https://doi.org/https://dx.doi.org/10.1016/j.psyneuen.2018.02.001
Berger, M., Lavoie, S., McGorry, P. D., Nelson, B., Markulev, C., Yuen, H. P., Schaefer, M., Sarnyai, Z., & Amminger, G. P. (2020). Relationship between allostatic load and clinical outcomes in youth at ultra-high risk for psychosis in the NEURAPRO study. Schizophrenia Research, 226, 38-43. https://doi.org/https://doi.org/10.1016/j.schres.2018.10.002
Berger, M., Taylor, S., Harriss, L., Campbell, S., Thompson, F., Jones, S., Sushames, A., Amminger, G. P., Sarnyai, Z., & McDermott, R. (2019). Hair cortisol, allostatic load, and depressive symptoms in Australian Aboriginal and Torres Strait Islander people [Research Support, Non-U.S. Gov't]. Stress, 22(3), 312-320. https://doi.org/https://dx.doi.org/10.1080/10253890.2019.1572745
Juster, R.-P., Sasseville, M., Giguère, C.-É., Consortium, S., & Lupien, S. J. (2018). Elevated allostatic load in individuals presenting at psychiatric emergency services. Journal of Psychosomatic Research, 115, 101-109. https://doi.org/10.1016/j.jpsychores.2018.10.012
Ketheesan, S., Rinaudo, M., Berger, M., Wenitong, M., Juster, R. P., McEwen, B. S., & Sarnyai, Z. (2020). Stress, allostatic load and mental health in Indigenous Australians* [Review]. Stress, 23(5), 509-518. https://doi.org/http://dx.doi.org/10.1080/10253890.2020.1732346
Khandaker, G. M., Pearson, R. M., Zammit, S., Lewis, G., & Jones, P. B. (2014). Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry, 71(10), 1121-1128. https://doi.org/https://dx.doi.org/10.1001/jamapsychiatry.2014.1332
McEwen, B. S. (2004). Protection and damage from acute and chronic stress: Allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Annals of the New York Academy of Sciences, 1032, 1-7. https://doi.org/10.1196/annals.1314.001
McEwen, B. S., & Stellar, E. (1993). Stress and the individual. Mechanisms leading to disease. JAMA Internal Medicine, 1(18), 2093-2101.
Piotrowski, P., Kotowicz, K., Rymaszewska, J., Beszlej, J. A., Plichta, P., Samochowiec, J., Kalinowska, S., Trzesniowska-Drukala, B., & Misiak, B. (2019). Allostatic load index and its clinical correlates at various stages of psychosis. Schizophrenia Research, 210, 73-80. https://doi.org/https://dx.doi.org/10.1016/j.schres.2019.06.009

Impact of research: 
The concept of allostatic load, the multi-system disregulation in response to repeated toxic stress and trauma, is moving to the centre of investigating pathomechanisms and diagnistic/predictive biomarkers in psychiatry. There have been several convincing cross-sectional studies, including ours, to show elevated allostatic load in a variety of severe psychiatric disorders. However, there has been no study involving a longitudinal birth cohort conducted in this field. We expect that the unique power of the ALSPAC study will allow us to uncover that early childhood adversity results in a long-lasting multisystem dysregulation, measured as elevated allostatic load, which, in turn contribute to the development of psychiatric disorders in young adulthood. Furthermore, such relationship will indicate that the measurement of allostatic load may have predicitve power for the future emergence of mental illness in toxic stress/trauma exposed, vulnerable individuals, which can guide the development of novel interventions. The development of new algorhythms, rooted in an etiologically and mechanistically plausible framework (stress-trauma-mental illness), with preditive power, will have a significant practical impact in psychiatric diagnosis and treatment monitoring.
Date proposal received: 
Wednesday, 18 August, 2021
Date proposal approved: 
Thursday, 26 August, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., BMI, Childhood - childcare, childhood adversity, Hormones - cortisol, IGF, thyroid, Metabolic - metabolism

B3855 - Predicting Illness Trajectories after Adolescent Psychotic Experiences - 26/08/2021

B number: 
B3855
Principal applicant name: 
William W. Eaton | Johns Hopkins Bloomberg School of Public Health (USA)
Co-applicants: 
Katrina Rodriguez
Title of project: 
Predicting Illness Trajectories after Adolescent Psychotic Experiences
Proposal summary: 

Psychotic experiences, such as hearing voices or seeing things others cannot see or hear, and delusions, are not unusual in adolescents, with a large population-based study finding a cumulative incidence proportion of 8.1% in the period between 12 and 24 years of age (Sullivan et al., 2020). Psychotic experiences are a risk factor for multiple disorders including psychotic disorders, anxiety disorders, and depressive disorders (Fisher et al., 2013; Kaymaz et al., 2012). Additionally, compared to adolescents who do not report psychotic experiences, those who do have higher odds of suicidal behavior, independently of depressive symptoms (S. A. Sullivan et al., 2015; Yates et al., 2019). It is well established that longer durations of untreated psychosis, which is commonly defined as the time from the first psychotic experience to the initiation of appropriate treatment, lead to worse outcomes, including more relapses and hospitalizations and lower functioning (Marshall et al., 2005). However, there are currently no well-established methods of identifying those who will go on to be diagnosed with a mental disorder or exhibit suicidal behaviors. Prediction of those who are most at risk of being later diagnosed with mental disorders or suicidal behaviors would provide both targets for intervention as well as more precise treatments, positively affecting prognosis and saving lives.
In this study our primary aim is to identify the cumulative incidence of schizophrenia spectrum, anxiety, depressive disorders, and suicidal behaviors in young adults who had reported psychotic experiences in adolescence and to compare incidence rates to those adults who did not report psychotic experiences in adolescence. Our secondary aim is to identify the biopsychosocial characteristics that predict outcomes such as mental disorders and/or suicidal behavior, as well as persistent psychotic experiences in the absence of mental disorders, after psychotic experiences in adolescence; and to develop an algorithm for prediction. Longitudinal studies of incidence of mental disorders beginning at birth have been conducted using population health registers (Byrne et al., 2007), but unlike the ALSPAC research, these studies fail to capture the range of occurrences which do not lead to treatment in the health care system and they do not have the capability of measuring psychotic experiences in the absence of mental disorder. Also, this area of research does not appear to have been fully explored using the ALSPAC data; however ALSPAC’s inclusion of prenatal factors and a longitudinal follow-up from birth to adulthood provides the ideal study design to answer these questions in a holistic manner.

Impact of research: 
Early intervention is the best modifiable risk factor for mental disorders. Developing the ability to predict who may or may not go on to develop specific disorders in such a critical developmental period as adolescence can inform treatment and dramatically lessen the burden of mental disorders. The applicant has reviewed a wide range of research in the field of early psychosis, yet none involve both a population-based sample and such a holistic range of predictors ranging from birth to young adulthood as we propose to study here. Examining this critical period of development will not only inform treatment but also provide insight into the etiology of mental disorders.
Date proposal received: 
Wednesday, 18 August, 2021
Date proposal approved: 
Thursday, 26 August, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Statistical methods, Statistical methods

B3858 - Student Project The role of the human gut microbiome in cancer aetiology - 26/08/2021

B number: 
B3858
Principal applicant name: 
Kaitlin Wade | Integrative Epidemiology Unit and Integrative Cancer Epidemiology Programme (United Kingdom)
Co-applicants: 
Miss Rebecca Scanlan
Title of project: 
Student Project: The role of the human gut microbiome in cancer aetiology
Proposal summary: 

A burgeoning field of research has highlighted the role of the human microbiome in mediating a range of pathologies including obesity, metabolic syndrome, inflammatory disorders, and alterations in stress responses and behaviour. Furthermore, the progression of certain cancers may be driven by microbial interactions and possess distinct microbial signatures which may contribute towards tumour inflammation. The gut microbiome of an individual has potential to be modified in order to improve health outcomes given recent therapeutic developments.

Whilst observational epidemiological studies have provided evidence that the gut microbiome may play a role in cancer risk, such studies typically suffer forms of bias such as reverse causation and residual confounding. In recent years, Mendelian randomization has been increasingly utilised to unravel the connections between various exposures and cancer outcomes, using genetic variants as instruments for risk factors to overcome such biases. This technique is well-suited to analysing cancer due to a number of factors, including the long latency period of many cancers which makes reverse causation a common downfall of previous findings, as well as overcoming the time- and expense-related limitations of randomised controlled trials.

The hypothesis of this project is that the gastrointestinal microbiome is a causative factor in breast cancer incidence and progression. Key aims are to test this hypothesis with the use of epidemiological methods including Mendelian randomisation techniques to improve causality, utilising GWAS and individual-level data to investigate the associations between composition of the gut microbiome and the aetiology of breast cancer.

Impact of research: 
The gut microbiome is a modifiable risk factor for disease that may have clinical importance in terms of breast cancer incidence and progression, and potentially facilitate therapeutic development to improve health and reduce the burden of the disease.
Date proposal received: 
Tuesday, 24 August, 2021
Date proposal approved: 
Thursday, 26 August, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Cancer, GWAS, Mass spectrometry, Metabolomics, NMR, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Genetic epidemiology, Genetics, Genome wide association study, Mendelian randomisation, Microbiome, Statistical methods

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