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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B3636 - Identification of genetic determinants of dietary intakes by prioritizing obesity-related variants highly expressed in the brain - 19/10/2020

B number: 
B3636
Principal applicant name: 
Ming Ding | Harvard T.H. Chan School of Public Health (United States)
Co-applicants: 
Title of project: 
Identification of genetic determinants of dietary intakes by prioritizing obesity-related variants highly expressed in the brain
Proposal summary: 

Dietary intakes have important genetic determinants, however, the genetic variants affect dietary intake is unclear. A large GWAS with body mass index (BMI) identified 97 variants and found that nearly half of them has expression in the brain, the key site of central appetite regulation. We hypothesize that these brain variants contain important genetic information associated with dietary intakes, and will explore this hypothesis using data from ALSPAC and Harvard cohorts. We will further assess whether the associations of these variants with dietary intakes change with age and explore the mechanism using ALSPAC DNA methylation data.

Impact of research: 
Our proposal will provide critical preliminary data for a planned proposal to the NIH. By focusing on obesity-related variants highly expressed in the brain, we will identify genetic variants significantly associated with dietary intakes. In the near future, we will investigate how these variants, together with family environment, play a role in development of childhood obesity in the Grown-up Today Study (GUTS). The GUTS have sibling design within families and collection of biological samples are going on. It is also of our high interest to investigate how these variants affect emotion and eating behaviors using functional magnetic resonance imaging (fMRI).
Date proposal received: 
Thursday, 15 October, 2020
Date proposal approved: 
Monday, 19 October, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Eating disorders - anorexia, bulimia, GWAS, Epigenetics

B3585 - Qualitative review of ALSPAC recruitment and virtual visits by QuinteT Qualitative Research Integrated within Trials - 19/10/2020

B number: 
B3585
Principal applicant name: 
Marcus Jepson | University of Bristol
Co-applicants: 
Title of project: 
Qualitative review of ALSPAC recruitment and virtual visits by QuinteT (Qualitative Research Integrated within Trials)
Proposal summary: 

ALSPAC has received funding to complete a data collection sweep for original ALSPAC participants that was due to commence in September 2020 and to continue data collection with the ALSPAC-G2 (children of the children cohort). The original objective of bringing QuinteT into ALSPAC was to learn from their trials activity and to deploy techniques for engagement, measurement, update/change of approach to improve study performance. ALSPAC also aims to improve recruitment in key groups; Males, low SES, disengaged and ethnic minorities. A proposal was funded by the CRN for QuinteT to review ALSPAC engagement activities with a subset of male participants involved in the FIT substudy.
Due to the Covid-19 pandemic, ALSPAC has had to cease all face to face data collection activities. ALSPAC is now looking to develop a “virtual visit” and would like to use the CRN funding for QuinteT evaluate the effectiveness of our messaging around these virtual visits and to help evaluate the success of these visits from the participant perspective.

Impact of research: 
Improve documentation to participants, which we hope will improve the participant experience
Date proposal received: 
Friday, 16 October, 2020
Date proposal approved: 
Monday, 19 October, 2020
Keywords: 
Epidemiology, Cohort studies - attrition, bias, participant engagement, ethics

B3638 - Pathways to eating disorders and self-harm the role of memory and self-esteem - 19/10/2020

B number: 
B3638
Principal applicant name: 
Naomi Warne | University of Bristol (United Kingdom)
Co-applicants: 
Dr Helen Bould, Dr Jon Heron, Professor Paul Moran
Title of project: 
Pathways to eating disorders and self-harm: the role of memory and self-esteem
Proposal summary: 

Eating disorders and self-harm are serious health problems in young people, and are associated with poor outcomes. Rates of self-harm and eating disorders increased over adolescence and young adulthood. Further research on mechanisms occurring early in life that underlie the development of both self-harm and eating disorders in adolescence are required to inform potential preventative measures and treatment interventions.
Adverse Childhood Experiences (ACEs) are robustly associated with both eating disorders and self-harm and may act as a common risk factor for both. However, not everyone who has a stressful experience in childhood goes on to develop psychopathology, and it is unclear what factors may predispose an individual to develop self-harm or eating disorders following an ACE.

Subjective experience has been shown to be more important than objective reports in predicting psychopathology following ACEs. Therefore, two candidate mechanisms via which ACEs may lead to eating disorders and self-harm are 1) how individuals remember events in their past, their autobiographical memory, and 2) how people perceive themselves and their self-worth, their sense of self and self-esteem.

This project will investigate whether different features of autobiographical memory, as well as self-esteem, are on the pathway from ACEs to self-harm and eating disorders.

Impact of research: 
This project will lead to a greater understanding of the processes involved in the development of self-harm and disordered eating in adolescents and young adults. This analysis represents one research strand of three where we hope to identify whether memory and self-esteem could be novel intervention targets for individuals with self-harm and eating disorders.
Date proposal received: 
Monday, 19 October, 2020
Date proposal approved: 
Monday, 19 October, 2020
Keywords: 
Epidemiology, Eating disorders - anorexia, bulimia, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function

B3637 - Lifecycle paper WP314 Multi-behavioral patterns in European preschoolers - 16/10/2020

B number: 
B3637
Principal applicant name: 
Marie-Aline Charles | INSERM (France)
Co-applicants: 
Mr Maxime Cornet, Dr Patricia Dargent-Molina, Dr Sandrine Lioret
Title of project: 
Lifecycle paper, WP3.1.4: Multi-behavioral patterns in European preschoolers
Proposal summary: 

There are multiple evidences in the literature that there is a clustering of energy balance related behaviors in children, however, the link with obesity related outcomes is not always consistent across the studies. Our goal is mobilize several European cohorts, all part of the lifecycle consortium, to achieve greater statistical power, and compare results across European countries.

Impact of research: 
Description and test of Lifecycle harmonized data, better knowledge of the association between BMI and the clustering of sleep / Physical Activity / sedentary and diet behaviors.
Date proposal received: 
Friday, 16 October, 2020
Date proposal approved: 
Friday, 16 October, 2020
Keywords: 
Epidemiology, Obesity

B3614 - Hypertensive disorders of pregnancy and cognition - 12/10/2020

B number: 
B3614
Principal applicant name: 
Abigail Fraser | MRC IEU (United Kingdom)
Co-applicants: 
Prof Janet Catov, Dr Kate Birnie, Dr Emma L Anderson
Title of project: 
Hypertensive disorders of pregnancy and cognition
Proposal summary: 
Impact of research: 
This work will add to understanding the heart-brain axis. It will also provide evidence as to whether women with HDP are at increased risk of log term cognitive decline and would benefit from monitoring/interventions to prevent this.
Date proposal received: 
Wednesday, 7 October, 2020
Date proposal approved: 
Monday, 12 October, 2020
Keywords: 
Epidemiology, Hypertension, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Ageing, Cognition - cognitive function

B3633 - GWAS on longitudinal pubertal traits in Chilean adolescents - 12/10/2020

B number: 
B3633
Principal applicant name: 
Susana Eyheramendy | Universidad Adolfo Ibáñez (Chile)
Co-applicants: 
Title of project: 
GWAS on longitudinal pubertal traits in Chilean adolescents
Proposal summary: 

In a current project, we are trying to identify genetic factors associated with pubertal traits in Chilean Children. We are also interested on how genetic ancestry affects these traits. In order to know whether our results on Chileans are unique, we need to replicate the same analyses using a European cohort like ALSPAC.

Impact of research: 
Identifying novel genetic variants involved in longitudinal pubertal traits and how genetic ancestry affects these traits
Date proposal received: 
Friday, 9 October, 2020
Date proposal approved: 
Monday, 12 October, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Puberty, GWAS, BMI GWAS Genetic Epidemiology Puberty Metabolic markers

B3634 - Curating UK COVID-19 diagnostics data to catalyse research and innovation - 19/10/2020

B number: 
B3634
Principal applicant name: 
Phil Quinlan | Computer Science, University of Nottingham (UK)
Co-applicants: 
Prof Nicholas Timpson
Title of project: 
Curating UK COVID-19 diagnostics data to catalyse research and innovation
Proposal summary: 

The UK has rich, globally important COVID-19 datasets, including large serology cohort studies funded by UKRI, Wellcome, DHSC/NHS, NIHR and the devolved administrations. However, this breadth of data creates a risk of fragmentation, inconsistent structure and access processes, severely limiting utility, timeliness and impact.
Our vision is to transform UK COVID-19 diagnostic datasets to be Findable, Accessible, Interoperable and Reusable (FAIR) and couple this with expert data engineering, enabled by Health Data Research (HDR) UK, to catalyse responsible and trustworthy use of the data for research and innovation.
We propose to support PIs and data custodians to link COVID-19 cohort, serology and other health and non-health datasets. This longitudinal linkage is vital to derive new scientific insights and deliver informed decisions about how best to control the spread of SARS-CoV-2. At present there are >30 independent studies with no streamlined approach to linkage to other health and non-health related datasets, lack of data standardisation, and no strategic approach to synthesise analyses across studies.
SAGE (9th June) requested HDR to work with partners to develop the UK-wide serology and testing data research asset that is linkable to other data sources.
This proposal has been prepared in response to this request. We have bought together 41 leaders from 29 different organisations and 44 data sources to address a major data engineering challenge by building upon existing UKRI investments, including the HDR BREATHE Hub, to create a ‘one-stop’ service for trustworthy, multi-stakeholder utilisation of curated COVID-19 data for public, private and third sector benefit.

Impact of research: 
Importance: The UK has >30 relevant research funded datasets (Table 1). Currently, these are held by multiple data controllers with different governance models. A key ambition is the standardised capture of granular data within NHS laboratory systems, permitting uniform analysis that adds value. Common data asset structures are vital if we are to deliver maximum research and innovation potency. Deliverables: We will deliver four new capabilities: (i) a platform for discoverability and feasibility analyses to understand if the required data and/or populations can answer research questions; (ii) the ability for researchers to perform meta-analysis and exploratory analysis UK-wide; (iii) the ability to link COVID-19 UK cohorts to multi- dimensional health and non-health related datasets UK-wide; (iv) development of the robust UK health data infrastructure to enable long-term impact beyond COVID-19. Expertise: We have brought together the PIs of research cohorts, NHS system leaders in diagnostic testing. the expertise and infrastructure of the HDR BREATHE Hub (Director Sheikh) and the HDR Gateway, the scalable global software of BC Platforms, the UKCRC Tissue Directory (200 tissue banks) and the four NHS national trusted research environments (TREs). Resources: We will develop the ability to discover, request access and analyse data from 44 data sources through: (i) improving access to new serology cohorts, including SIREN; (ii) existing cohorts that have been augmented with serology and other COVID-19 related data; and, (iii) NHS serology resources, to drive new insights into COVID-19. The HDR BREATHE Hub already has 17 COVID-19 related research cohorts registered in the HDR Innovation Gateway.
Date proposal received: 
Friday, 9 October, 2020
Date proposal approved: 
Monday, 12 October, 2020
Keywords: 
Health Services Research/Health Systems Research, Infection, Data management, COVID19

B3632 - Air pollution and childhood asthma potential role of common allergies as mediators - 19/10/2020

B number: 
B3632
Principal applicant name: 
Tiffany Yang | Bradford Institute for Health Research (United Kingdom)
Co-applicants: 
Title of project: 
Air pollution and childhood asthma: potential role of common allergies as mediators
Proposal summary: 

Asthma is a major non-communicable disease affecting over 12% of children and estimated to affect 339 million people worldwide (1,22). It is a multifaceted and heterogeneous disease with different patterns of incidence and prevalence between children and adults and between males and females (3). Its etiology is thought to be a complex interplay between environmental exposures (such as air pollution, mold, pollen, and the weather), genetic susceptibility, and host factors (such as infections and nutrition); the underlying mechanisms, while not fully understood, may include airway inflammation and control of reactivity and airway tone (4).

Exposure to outdoor air pollutants such as particulate matter (PM) and nitrogen dioxide (NO2) have been associated with both childhood asthma and allergies (5–12). However, whether allergies such as atopic dermatitis (eczema) and allergic rhinitis (hay fever) mediate the relationship has not been well-characterized.

The atopic march, the linear progression starting with eczema with subsequent allergic rhinitis and asthma in later childhood is a well-known concept but it may not capture the trajectories of most children (13–15). Asthma often co-occurs with allergies like eczema and allergic rhinitis but the causal nature of this progression is unknown. Studies suggest that a dysfunctional skin barrier may be a site for allergic sensitization and contributes to the onset of eczema and progression to allergic rhinitis and childhood asthma (16). Eczema has often been found to precede development of asthma, but this is not always the case, with only an estimated 1-in-3 children with eczema developing childhood asthma later on (17,18). Similarly, asthma often co-occurs with allergic rhinitis due to shared common physiology such as heightened reactivity and bronchial hyperresponsiveness (19,20). It is considered a risk factor for asthma, with a 23-year follow-up finding allergic rhinitis three times more likely to develop asthma than those without allergic rhinitis (14,15). However, the evolution of the two appear to be bidirectional; a study in Italy following 99 patients with only allergic rhinitis or allergic asthma over 10 years found that 31.8% of participants with allergic rhinitis developed asthma, while 50% of those with asthma went on to develop allergic rhinitis (21).

In this proposal, we hypothesize that relationships between early-life stressors such as exposure to air pollutants and childhood asthma are at least partly mediated by common allergies and allergic diseases.

REFERENCES
1. Lai CKW, Beasley R, Crane J, Foliaki S, Shah J, Weiland S. Global variation in the prevalence and severity of asthma symptoms: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax. 2009;64(6):476-483. doi:10.1136/thx.2008.106609
2. Global Asthma Network. Global Asthma Report.; 2018. www.globalasthmanetwork.org
3. Dharmage SC, Perret JL, Custovic A. Epidemiology of asthma in children and adults. Front Pediatr. 2019;7(JUN):1-15. doi:10.3389/fped.2019.00246
4. Eder W, Ege MJ, von Mutius E. The Asthma Epidemic. N Engl J Med. 2006;355(21):2226-2235. doi:10.1056/NEJMra054308
5. Hsu HHL, Chiu YHM, Coull BA, et al. Prenatal particulate air pollution and asthma onset in urban children: Identifying sensitive windows and sex differences. Am J Respir Crit Care Med. 2015;192(9):1052-1059. doi:10.1164/rccm.201504-0658OC
6. Khreis H, Kelly C, Tate J, Parslow R, Lucas K, Nieuwenhuijsen M. Exposure to traffic-related air pollution and risk of development of childhood asthma: A systematic review and meta-analysis. Environ Int. 2017;100:1-31. doi:10.1016/j.envint.2016.11.012
7. Bowatte G, Lodge C, Lowe AJ, et al. The influence of childhood traffic-related air pollution exposure on asthma, allergy and sensitization: A systematic review and a meta-analysis of birth cohort studies. Allergy Eur J Allergy Clin Immunol. 2015;70(3):245-256. doi:10.1111/all.12561
8. Hehua Z, Qing C, Shanyan G, Qijun W, Yuhong Z. The impact of prenatal exposure to air pollution on childhood wheezing and asthma: A systematic review. Environ Res. 2017;159:519-530. doi:10.1016/j.envres.2017.08.038
9. Patel MM, Quinn JW, Jung KH, et al. Traffic density and stationary sources of air pollution associated with wheeze, asthma, and immunoglobulin E from birth to age 5 years among New York City children. Environ Res. 2011;111(8):1222-1229. doi:10.1016/j.envres.2011.08.004
10. Deng Q, Lu C, Li Y, Sundell J, Dan Norbäck. Exposure to outdoor air pollution during trimesters of pregnancy and childhood asthma, allergic rhinitis, and eczema. Environ Res. 2016;150:119-127. doi:10.1016/j.envres.2016.05.050
11. Morgenstern V, Zutavern A, Cyrys J, et al. Atopic diseases, allergic sensitization, and exposure to traffic-related air pollution in children. Am J Respir Crit Care Med. 2008;177(12):1331-1337. doi:10.1164/rccm.200701-036OC
12. Granum B, Oftedal B, Agier L, et al. Multiple environmental exposures in early-life and allergy-related outcomes in childhood. Environ Int. 2020;144:106038. doi:10.1016/j.envint.2020.106038
13. Belgrave DCM, Granell R, Simpson A, et al. Developmental Profiles of Eczema, Wheeze, and Rhinitis: Two Population-Based Birth Cohort Studies. PLoS Med. 2014;11(10). doi:10.1371/journal.pmed.1001748
14. Settipane RJ, Hagy GW, Settipane GA. Long-term risk factors for developing asthma and allergic rhinitis: a 23-year follow-up study of college students. Allergy Proc. 15(1):21-25. doi:10.2500/108854194778816634
15. Wright AL, Holberg CJ, Martinez FD, Halonen M, Morgan W, Taussig LM. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics. 1994;94(6 Pt 1):895-901. http://www.ncbi.nlm.nih.gov/pubmed/7971008
16. Bantz SK, Zhu Z, Zheng T. The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma. J Clin Cell Immunol. 2014;5(2):707-708. doi:10.4172/2155-9899.1000202
17. Burgess JA, Dharmage SC, Byrnes GB, et al. Childhood eczema and asthma incidence and persistence: A cohort study from childhood to middle age. J Allergy Clin Immunol. 2008;122(2):280-285. doi:10.1016/j.jaci.2008.05.018
18. van der Hulst AE, Klip H, Brand PLP. Risk of developing asthma in young children with atopic eczema: a systematic review. J Allergy Clin Immunol. 2007;120(3):565-569. doi:10.1016/j.jaci.2007.05.042
19. Khan DA. Allergic rhinitis and asthma: Epidemiology and common pathophysiology. Allergy Asthma Proc. 2014;35(5):357-361. doi:10.2500/aap.2014.35.3794
20. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108(5 Suppl). doi:10.1067/mai.2001.118891
21. Lombardi C, Passalacqua G, Gargioni S, et al. The natural history of respiratory allergy: a follow-up study of 99 patients up to 10 years. Respir Med. 2001;95(1):9-12. doi:10.1053/rmed.2000.0945

Impact of research: 
The large sample size available as a result of the harmonization process carried out by LifeCycle cohorts will help increase the precision of our estimates and we hope the impact of this will be a better understanding of the relationships between our exposure and outcome and whether allergies play a role in mediating this relationship.
Date proposal received: 
Thursday, 8 October, 2020
Date proposal approved: 
Monday, 12 October, 2020
Keywords: 
Epidemiology, Allergy, Respiratory - asthma, Statistical methods, Environment - enviromental exposure, pollution

B3620 - Genetics of Stuttering - 12/10/2020

B number: 
B3620
Principal applicant name: 
Simon Fisher | Max Planck Institute for Psycholinguistics (Netherlands)
Co-applicants: 
Prof Melanie Bahlo, Prof Angela Morgan, Dr Vicki Jackson, Dr Beate St Pourcain, Dr Yvonne Wren, Dr Else Eising
Title of project: 
Genetics of Stuttering
Proposal summary: 

Stuttering is a complex communication disorder, characterized by dysfluent speech, that can have a profound effect on an individual’s social and mental wellbeing. Up to 11% of children commence stuttering by 4 years of age. Whilst stuttering resolves for many, a third will develop a persistent stutter. Stuttering interventions are effective for some in the preschool years; yet, there are no effective treatments for older children, adolescents or adults, and it is not possible to predict who will develop persistent stuttering. The exact causes of stuttering are still unknown, but genetic factors play an important role.

We hypothesize that common genetic variation makes a substantial contribution to the risk of stuttering and propose that this is most effectively investigated by undertaking a genome-wide association study (GWAS), using a large population-based sample of people who stutter (PWS), recruited via an online questionnaire. Crucially, so far there is no published GWAS for stuttering, a clear gap in our genetic understanding of this disorder.

We are building a global collection of PWS, recruiting adults and children through a concerted media recruitment campaign. Alongside our efforts to recruit PWS directly, we are building a global network of cohorts with information on stuttering via the GenLang Consortium. We intend to combine data from both approaches, in a large-scale GWAS meta-analysis.

Understanding the genetics of stuttering will provide insights into the underlying biology, potentially leading to stratification of stuttering into clinically relevant subtypes, targeted treatment and drug targets. This will lead to better health and socioeconomic outcomes for PWS.

Impact of research: 
The ALSPAC data will contribute to a large-scale GWAS meta-analysis of stuttering. To date no GWAS for stuttering has been published, giving high chance of novel findings. Understanding the genetics of stuttering will provide insights into the underlying biology, potentially leading to stratification of stuttering into clinically relevant subtypes, targeted treatment and drug targets. This will lead to better health and socioeconomic outcomes for PWS.
Date proposal received: 
Tuesday, 22 September, 2020
Date proposal approved: 
Monday, 12 October, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Speech/language problem, GWAS, Communication (including non-verbal), Genetic epidemiology, Genome wide association study, Speech and language

B3630 - Prenatal and early-life exposure to heavy metals and childhood neurodevelopment - 09/10/2020

B number: 
B3630
Principal applicant name: 
Sarah Lewis | University of Bristol
Co-applicants: 
Kyle Dack, Dr Dheeraj Rai, Caroline Taylor
Title of project: 
Prenatal and early-life exposure to heavy metals and childhood neurodevelopment.
Proposal summary: 

Arsenic, cadmium, lead, and mercury (As, Cd, Pb, Hg), are toxic elements with no known biological functions. Long-term exposure to these elements is possible through the food chain, water contamination, and air pollution depending on local conditions. Arsenic appears to impair neurocognitive performance but not behavioural outcomes (Tolins et al, 2014), and the impacts on language or motor development are less clear. There have been few studies to date of cadmium and neurodevelopment (Rodriguez-Barranco et al, 2013), although previous work within ALSPAC found no association with motor skills (Taylor et al, 2018). Mercury at high-doses is known to delay neurodevelopment (Grandjean & Herz, 2011), but the evidence for an effect at more realistic low-levels is unclear. The strongest evidence of harm during childhood from heavy metals is exposure to lead which has been reliably linked to impaired cognitive, behavioural, and motor development (Sanders et al, 2009). For each of these elements there is a potential to strengthen the evidence base through the use of genetic methods unbiased from confounding factors, and to examine less-studied neurodevelopmental outcomes.

Impact of research: 
May have an important public health impact if strong evidence of an effect for a particular heavy metal. This could result in measures to restrict exposure even further and improve neurodevelopmental outcomes
Date proposal received: 
Tuesday, 6 October, 2020
Date proposal approved: 
Friday, 9 October, 2020
Keywords: 
Epidemiology, Developmental disorders - autism, Statistical methods, Genetic epidemiology

B3631 - The relationship of adverse pregnancy and perinatal outcomes with blood NMR metabolites in the offspring - 09/10/2020

B number: 
B3631
Principal applicant name: 
Ahmed Elhakeem | MRC IEU
Co-applicants: 
Deborah Lawlor
Title of project: 
The relationship of adverse pregnancy and perinatal outcomes with blood NMR metabolites in the offspring
Proposal summary: 

The aim of this study is to explore associations of common adverse pregnancy and perinatal outcomes with offspring plasma/serum-based NMR metabolites and compare associations between those conditions that might result in / reflect fetal undernutrition with those resulting in / reflecting fetal overgrowth. We will also assess whether associations differ by age at NMR measurement in the offspring.

Impact of research: 
Knowledge advancement
Date proposal received: 
Thursday, 8 October, 2020
Date proposal approved: 
Friday, 9 October, 2020
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Metabolomics, Cardiovascular

B3629 - Exposure to carbon monoxide in pregnancy and postnatalProject title not yet specified insert title here 06-10-2020 - 071950 - 07/10/2020

B number: 
B3629
Principal applicant name: 
Yasmin Iles-Caven | University of Bristol (United Kingdom)
Co-applicants: 
Professor Jean Golding
Title of project: 
Exposure to carbon monoxide in pregnancy and postnatalProject title not yet specified, insert title here (06-10-2020 - 07:19:50)
Proposal summary: 

Carbon monoxide (CO) is a highly toxic gas which, at high levels, can kill. Such lethal events are often accidental. When a pregnant women is involved in such an acute CO poisoning episode it can have demonstrable deleterious effects on the unborn child, with increased chance of stillbirth or the birth of a child with motor and/or mental abnormalities. Post-mortem examination of these stillbirths has indicated that the major effect of the acute CO event was on the central nervous system. This raises the question as to what effect chronic exposures might have on the brain of the unborn fetus or developing child. This project will use data already collected by ALSPAC: Prenatal and early life exposure to CO from domestic heating and cooking and proximity to busy roads.

Impact of research: 
Tightening up of regulations regarding gas heating/cooking and ventilation. Advice to mothers-to-be of the importance of adequate ventilation when cooking with gas.
Date proposal received: 
Tuesday, 6 October, 2020
Date proposal approved: 
Wednesday, 7 October, 2020
Keywords: 
Epidemiology, Addiction; cognitive impairment; developmental disorders; learning difficulties; mental health; pregnancy; speech/language (Sorry tick option isn't working), Epidemiological methods, Birth outcomes; cognition; communication; developmental; environment; intelligence; psychology; sex differences; speech & language (Sorry, the please tick direction doesn't work)

B3609 - Association between maternal thyroid dysfunction during pregnancy and thyroid dysfunction in offspring - 05/10/2020

B number: 
B3609
Principal applicant name: 
Gloria Li | The Hong Kong Polytechnic University (Hong Kong)
Co-applicants: 
Dr. Ching-Lung Cheung
Title of project: 
Association between maternal thyroid dysfunction during pregnancy and thyroid dysfunction in offspring
Proposal summary: 

Thyroid dysfunction is one of the most common clinical problems among pregnant women. Before the onset of foetal thyroid function in mid gestation, the foetus is completely dependent on the maternal supply of thyroid hormones, which play a crucial role in the foetal growth and development. The increased requirement of thyroid hormones by approximately 50% during pregnancy is a challenge for the maternal thyroid glands. Our recent systematic review and meta-analysis showed that maternal thyroid dysfunction is associated with neurodevelopmental disorders, such as attention deficit hyperactivity disorder and epilepsy. However, the association between maternal and offspring thyroid dysfunction were only investigated in single studies. The major disadvantage of existing studies included limited sample size and unavailability of confounding variables. This project aims to evaluate the association between maternal and offspring thyroid dysfunction in an individual cohort of larger sample size, with appropriate adjustment for confounding factors. It is expected that the results may provide insights on the clinical practice in handling thyroid dysfunction in pregnant mothers and their offspring.

Impact of research: 
The study findings may provide insights on the clinical practice in handling thyroid dysfunction in pregnant mothers and their offspring.
Date proposal received: 
Wednesday, 2 September, 2020
Date proposal approved: 
Monday, 5 October, 2020
Keywords: 
Endocrinology, thyroid function, Epidemiology, Endocrine - endocrine disrupters

B3611 - Association of maternal hypothyroidism with bone health in offspring - 05/10/2020

B number: 
B3611
Principal applicant name: 
Gloria Li | The Hong Kong Polytechnic University (Hong Kong)
Co-applicants: 
Dr. Ching-Lung Cheung
Title of project: 
Association of maternal hypothyroidism with bone health in offspring
Proposal summary: 

Previous studies have demonstrated that maternal thyroid dysfunction is associated with a number of neurodevelopmental disorders, such as attention deficit hyperactivity disorder and epilepsy. However, the association between maternal thyroid dysfunction and other health outcomes in offspring were either investigated in single study, or not examined. Although it is known that hypothyroidism is associated with increased fracture risk in adults, as well as reduced bone mass during childhood, the association between maternal hypothyroidism and bone health in offspring has not been studied previously. This project aims to evaluate the observational and causal association between maternal hypothyroidism and bone health in offspring.

Impact of research: 
Date proposal received: 
Wednesday, 2 September, 2020
Date proposal approved: 
Monday, 5 October, 2020
Keywords: 
Endocrinology, Bone disorders - arthritis, osteoporosis, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Epidemiology Mendelian Randomization, Bones (and joints), Endocrine - endocrine disrupters, Genetic epidemiology, Genome wide association study, Mendelian randomisation, Offspring

B3626 - Does following a vegetarian/vegan/plant-based diet during pregnancy causally affect the health of offspring - 05/10/2020

B number: 
B3626
Principal applicant name: 
Gemma Sharp | MRC IEU, UoB
Co-applicants: 
Peiyuan Huang, Dr Laura Johnson, Dr Giulia Mancano
Title of project: 
Does following a vegetarian/vegan/plant-based diet during pregnancy causally affect the health of offspring?
Proposal summary: 

Partly because of perceived health benefits and environment concerns, vegetarian/vegan diets have become increasingly popular around the globe in recent years. Despite the possibility of low intakes of some nutrients such as protein, omega-3 fatty acids, vitamin D, vitamin B12, iron, calcium, zinc, and choline, evidence suggests that vegetarians have generally better long-term health than their omnivorous counterparts. Pregnancy is a special period in the lifecourse, when foetal development requires increased nutrient intakes and accelerates nutritional depletion, and adequate and balanced nutrition is critical for both maternal and foetal health. Two reviews have suggested that appropriately planned and well-balanced vegetarian/vegan diets during pregnancy may be considered safe for the women and their fetuses. However, little is known about whether these diets will have longer-term effects on offspring health throughout childhood. Vegetarianism is highly socially and culturally patterned, so there is a need to carefully control for confounding to infer causal effects. This PhD aims to study associations between maternal vegetarian diet and offspring health across several domains and to attempt to infer which associations are likely to be causal. It also aims to study the role of DNA methylation and circulating metabolites as mediators of any effects.

Impact of research: 
We hope to develop a better understanding of the offspring health effects of mothers following a plant-based diet during pregnancy. This is an under-researched area but plant-based diets are on the increase. Therefore there is a potential to inform public health messaging around maternal diet during pregnancy.
Date proposal received: 
Wednesday, 30 September, 2020
Date proposal approved: 
Monday, 5 October, 2020
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., GWAS, Metabolomics, Development, Epigenetics, Genetic epidemiology, Genome wide association study, Mendelian randomisation, Nutrition - breast feeding, diet, Offspring

B3627 - Untreated depression or antidepressant use during pregnancy which is worse for offspring health - 08/10/2020

B number: 
B3627
Principal applicant name: 
Gemma Sharp | MRC IEU, UoB
Co-applicants: 
Florence Martin, Dr Dheeraj Rai, Dr Kayleigh Easey, Harriet Forbes
Title of project: 
Untreated depression or antidepressant use during pregnancy: which is worse for offspring health?
Proposal summary: 

Depression is increasingly common in women of child-bearing age, with studies suggesting that 10 – 15% of pregnant women may suffer from depression during pregnancy (Gavin et al. 2005). Although observational studies have shown very little evidence that antidepressant use during pregnancy is associated with congenital malformations (Jordan et al. 2016, Ban et al. 2014, O’Brien et al. 2008), there is increasing evidence suggesting a potential neurodevelopmental impact (Sullivan et al. 2013, Rai et al. 2013, Boukhris et al. 2013).
Studying outcomes in this area is made particularly difficult not only by the inability and impracticality of performing randomised control trials in pregnant women, but also the confounding by indication of depression itself in observational studies (Källén, 2012). Another concern is the way risks regarding medication use in pregnancy are framed in the scientific literature and translations in the media, clinic and public health advice. This framing could contribute to mothers feeling guilty for treating their depression, thus potentially exacerbating their condition and its impact on their offspring.
In this project, we will use the Clinical Practice Research Datalink (CPRD) and epigenetic and genetic data from ALSPAC to triangulate evidence to examine and tease apart the potential links between untreated depression and antidepressant use with adverse pregnancy, birth and neurodevelopmental outcomes.

Impact of research: 
A better understanding of the relative effect of depression and anti-depressants on offspring health will be important evidence in informing public health messaging around pregnancy.
Date proposal received: 
Wednesday, 30 September, 2020
Date proposal approved: 
Monday, 5 October, 2020
Keywords: 
Epidemiology, Developmental disorders - autism, Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Childhood - childcare, childhood adversity, Development, Epigenetics, Mothers - maternal age, menopause, obstetrics, Offspring

B3622 - Associations between sedentary time and physical activity with arterial function and structure from childhood to adulthood - 29/09/2020

B number: 
B3622
Principal applicant name: 
Alan Barker | University of Exeter (England)
Co-applicants: 
Miss Kate M. Sansum , Dr. Bert Bond, Dr. Richard Pulsford, Prof. Alison McManus, Dr. Andrew Agbaje, Prof. Tomi-Pekka Tuomainen
Title of project: 
Associations between sedentary time and physical activity with arterial function and structure from childhood to adulthood
Proposal summary: 

It is well established that cardiovascular disease (CVD) begins in childhood. Impairments in vascular function occur before the structural changes of CVD present in the arteries and the progression of CVD is related to CVD risk factors, such as cardiorespiratory fitness, physical activity, body composition and blood markers, in youth. Therefore, there is great interest in understanding how exposure to early lifestyle factors could be related to CVD risk in children and adolescents. Our current project utilising the ALSPAC data (B3455) is investigating the associations between early exposure to cardiorespiratory fitness and body composition with measures of arterial structure and function. However, physical activity and sedentary time are additional important markers of health, and warrant exploration for their potential associations with arterial structure and function at an early age.

Existing paediatric data examining associations between physical activity and/or sedentary time with measures of arterial structure and function are limited by small sample sizes and a subjective assessment of physical activity. Therefore, the current models are unable to account for a suitable number of confounding variables. Also, most studies have used cross-sectional design, and those which are longitudinal have a maximum follow up period of two years. Moreover, independent relationships of physical activity and sedentary time with arterial structure and function, may be altered by an existing interaction between physical activity and/or sedentary time.

Recent experimental data in prepubertal children has shown that the decline in arterial function during prolonged sitting can be prevented by performing 10 minutes of moderate intensity exercise each hour. There is evidence on the interaction between physical activity and/or sedentary time and traditional CVD risk factors, such as body composition and blood markers, in children and adolescents. However, there is a scarcity of data at a population level that examines how sedentary time and physical activity interact in children and how this relates to direct measures of vascular function and structure. Therefore, this project aims to examine the cross-sectional and longitudinal relationships between the early life exposure to physical activity and sedentary time with vascular function and structure from childhood to adulthood, while controlling for traditional CVD risk factors and cardiorespiratory fitness.

Impact of research: 
The findings of the project will be published in peer-reviewed journals and disseminated at conferences. The University of Exeter will also publish a press release on the project findings for the general public. Furthermore, it is hoped the findings will contribute to development of future interventions and policy surrounding sedentary behaviour guidelines that aim to delay the progression of sub-clinical arterial diseases in childhood.
Date proposal received: 
Wednesday, 23 September, 2020
Date proposal approved: 
Tuesday, 29 September, 2020
Keywords: 
Paediatric Exercise Medicine/Physiology and Epidemiology, Cardiovascular disease , Statistical methods, Allometric scaling, mixed-method , Ageing, Biological samples -e.g. blood, cell lines, saliva, etc., Blood pressure, BMI, Cardiovascular, Childhood - childcare, childhood adversity, Physical - activity, fitness, function, Puberty, Sex differences, Statistical methods, Cardiorespiratory fitness, endothelial function, metabolic health, carotid intima-media thickness, arterial distensibility, obesity, fat-free mass, fat mass, cardiovascular health, arterial stiffness, childhood, adolescence, early adulthood, atherosclerosis, cardiovascular diseases, public health.

B3624 - The effect of adverse childhood experiences on multiple functional domains - 30/09/2020

B number: 
B3624
Principal applicant name: 
Nichola Brydges (Thuvesholmen) | Cardiff University
Co-applicants: 
Title of project: 
The effect of adverse childhood experiences on multiple functional domains
Proposal summary: 

Research over the last decade has demonstrated that alongside genetic factors, childhood adversity plays a vital role in the development of psychiatric illnesses. Several meta-analyses have shown robustly that childhood adversity is a cross-diagnostic risk factor, increasing rates of depression and anxiety to schizophrenia and borderline personality disorder. Despite this association, the biological processes underlying this phenomenon are not well understood. Without this knowledge, development of effective therapeutics is impossible. The precise effects of childhood adversity on function per se (e.g. cognition, emotion, social function) are not well known. The aim of this research is investigate the links between adverse childhood experiences and later function, identifying domains which are most affected (both in psychiatric and clinically well populations). These domains will then be explored further using translational animal models and more focused human studies, uncovering underlying biological mechanisms and leading to novel treatment options for people affected by childhood adversity.

Not all individuals exposed to childhood adversity will develop psychiatric illness, and genetics is likely to play a role in determining susceptibility vs. resilience. The role that genetics plays in moderating the effects of childhood adversity on function will therefore also be explored.

Impact of research: 
This research will give us deeper insights into the type of functional domains that are affected by adverse childhood experiences, irrespective of psychiatric diagnosis. It will also illuminate the moderating effect of genetic polymorphisms, providing potential mechanisms of risk vs. resilience to mental illness following adverse childhood experiences. This is extremely important in terms of identifying new therapeutic avenues, and will guide the development of translational animal models, aimed at uncovering the biological mechanisms linking childhood adversity with impairments in function (animal work is a second component of my broader fellowship application). This will lead to informed therapeutic treatments.
Date proposal received: 
Friday, 25 September, 2020
Date proposal approved: 
Tuesday, 29 September, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Childhood - childcare, childhood adversity

B3623 - The impact of Adverse Childhood Experiences on social and health inequalities a life course perspective - 06/10/2020

B number: 
B3623
Principal applicant name: 
Laura Howe | MRC Integrative Epidemiology Unit at the University of Bristol (United Kingdom)
Co-applicants: 
Gwen Fernandes, Jon Heron, Liz Washbrook, John Macleod, Hugh McLeod
Title of project: 
The impact of Adverse Childhood Experiences on social and health inequalities: a life course perspective
Proposal summary: 

Adverse Childhood Experiences (ACEs) are stressful events that occur during childhood and adolescence, and include child maltreatment (i.e. emotional, physical, and sexual abuse and neglect) as well as measures of family dysfunction (e.g. parental divorce/separation, intimate partner violence, substance misuse, mental illness, and imprisonment). People who experience ACEs are less likely to do well in school, more likely to become unemployed, and more likely to have poor health. Furthermore, since people who live in socioeconomic deprivation are more at risk of experiencing ACEs, and also more at risk of poor health, ACEs are one mechanism that could drive socioeconomic inequalities in health. However, most of the research to date has looked at ACEs as a whole, and not asked whether experiencing ACEs at different points during infancy, childhood and adolescence might have different impacts. This is important, because it affects decisions about how we best support people who experience ACEs. If ACEs in infancy have the biggest effect on later outcomes, then focusing support on the early years will be most beneficial. Whereas if ACEs at older ages also cause problems, potentially ‘derailing’ people from their previous educational level for example, that would imply that continued support across the whole of childhood and adolescence is important. At a time when local government budgets are severely stretched, generating evidence to help support the justification and prioritisation of interventions is crucial. At present, our ability to carry out high-quality cost-effectiveness analysis of interventions to mitigate the effects of ACEs is limited by a lack of good evidence on the effects of ACEs on key economic outcomes, and how these effects differ across the life course. In this project, we will plug this gap, using extremely detailed data about experiences of ACEs across the life course, linked with detailed family and socioeconomic data, and repeated measures of educational attainment, employment, and health. We will explore the links between ACEs and education and employment, whether these are affected by the timing, duration and recency of ACE exposure, and the mechanisms underlying the associations.
The 2020 SARS-Cov-2 pandemic is likely to have severe implications for children experiencing ACEs and adults who have experienced ACEs. The ‘lockdown’ measures are likely to lead to increased occurrence of ACEs. Missed schooling is likely to be more detrimental for already vulnerable children, and many children who were entitled to continue attending school during lockdown did not do so. Job losses and reductions in income have been concentrated in the already disadvantaged, and the uncertain job market going forwards will pose a greater risk to young adults without the cushioning of a stable family environment and educational success. Using new data collected during the pandemic, we will assess whether young adults who have experienced ACEs are more vulnerable to the economic consequences of the pandemic, e.g. reduced income, furlough, or job loss. This evidence could provide support to the continued and increased need for the provision of services for people experiencing ACEs at this time.
We will work with key academic and non-academic collaborators to ensure that the results from this project are used to support the case for services designed to support people who have experienced ACEs, including with our results being used directly to improve the quality of cost-effectiveness analyses for interventions.

Impact of research: 
A key route for non-academic dissemination will be via the local government teams in the West of England (Bristol, North Somerset, Bath and North East Somerset, South Gloucestershire, Gloucestershire, Wiltshire and Swindon) with whom the team already have strong links. The local teams have expressed an interest in modelling the cost-effectiveness of interventions to mitigate the adverse effects of ACEs, in order to support the ‘business case’ for their planned initiatives, at a time when local government budgets are under severe pressure. The results from this project will be used to directly feed in to the modelling of specific interventions of interest to local teams by the team at the NIHR Applied Research Collaboration (ARC) West.
Date proposal received: 
Thursday, 24 September, 2020
Date proposal approved: 
Tuesday, 29 September, 2020
Keywords: 
Social Science, Childhood - childcare, childhood adversity, Social science

B3618 - The role of genetics in body size at different life stages longitudinal study in ALSPAC - 29/09/2020

B number: 
B3618
Principal applicant name: 
Joshua Bell | MRC IEU, University of Bristol (United Kingdom)
Co-applicants: 
Scott Waterfield, Dr Linda O'Keeffe, Dr Tom Richardson, Prof George Davey Smith
Title of project: 
The role of genetics in body size at different life stages: longitudinal study in ALSPAC
Proposal summary: 
Impact of research: 
The likely output of this research will be at least one publication in a general medical or epidemiology journal, the impact of which may be theoretical advancement in obesity research and recommendations for clinical and population screening.
Date proposal received: 
Friday, 18 September, 2020
Date proposal approved: 
Wednesday, 23 September, 2020
Keywords: 
Epidemiology, Obesity, GWAS, Genetics

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