EpiFASSTT: Epigenetic effects on children's psychosocial development in a randomised trial of Folic Acid Supplementation in Second and Third Trimester

Lead Research Organisation: University of Ulster
Department Name: Sch of Biomedical Sciences

Abstract

Increasingly accurate surveys of human health throughout the course of life has led experts to propose that stresses on the child while still in the mother's womb can affect its health much later in life. While many factors can potentially act as stressors, the majority of these are difficult to examine thoroughly in human populations and so findings are based largely on observational work. Among concrete factors known to affect child health is the essential nutrient folate, which has been proven to play a role in preventing neural tube closure defects (e.g. Spina bifida) when deficient during the first three months (first trimester) of pregnancy. Current UK guidance is therefore to supplement with folate during first trimester only. However other observational studies suggest that folate deficiency in trimesters two and three also affects children's brain development. Proof for this can only be provided by the gold standard test which is a Randomised Control Trial, where half the participants take folate in trimesters 2 and 3 and half do not, with participants assigned randomly to supplement or no supplement. We recently conducted such a trial (Folic Acid Supplementation in the Second and Third Trimester (FASSTT)) and showed that folate levels in blood were substantially improved in mothers receiving the supplement and in their children. Follow-up work with the children at age seven showed improved outcomes with regard to several measures of intellectual and emotional development, including verbal reasoning ability and emotional resilience. Such long-term effects on health are thought to be mediated by a semi-permanent trace on the genes of the affected person called an epigenetic mark (from epi- (above) and gene). Here we plan to do a thorough search for possible epigenetic marks in the children from the FASSTT trial and their mothers. The levels of such marking detected, and the genes affected by it, will tell us much about the extent to which environmental stressors can affect a person's future health. Likewise it will give us concrete markers for assessing the impact of factors such as nutritional inputs on the health of the child. The results of our study will also inform policy regarding food supplements and pregnancy/early life social care, with tangible benefits for children, their mums, and in the wider sphere the social and health services which provide them with support.

Planned Impact

First and foremost, we will address the scope of the call, by combining psychological and biological approaches to investigate the underlying epigenetic changes linking early life experiences with later psychological and physical health outcomes. The overall outcome of the proposed project will be the scientific evidence needed to inform future health policy in relation to nutrition, pregnancy and early life psychosocial development. This will be achieved through an in-depth investigation combining expertise from psychology, nutrition, epigenetics and computing, and applying innovative and emerging technologies to generate new knowledge in an area of current public health importance. We will actively engage with key stakeholders to ensure that we maximise the opportunity for our project outcomes to influence policy and alter behaviour. This includes initiatives such as an Advisory Board for our trial consisting of participants and members of the public; engagement with policy makers at regional government level and in NGOs and use of Open days and Public Lectures. Enhanced multidisciplinary capacity will be built which will extend well beyond the lifetime of the current project. Each project outcome will also be reported as a paper for submission to high impact factor journals in the relevant disciplines, including those focused on public health, as well as presentations at prestigious international conferences and workshops. The excellent training opportunities afforded by this interdisciplinary project in the emerging area of early life influences and epigenetics are further enhanced by a clear program of training for staff and students, such as the Masterclass, as well as events with broader appeal like the Open Day. Participants and public on the Advisory Board will also receive training and gain experience in research studies, and interaction with the Board will be invaluable for the academic staff. The combined expertise described in this proposal will provide added value and considerably enhance the overall impact achievable by any one group alone.
We represent a multidisciplinary team involving three distinct Research Institutes (Biomedical Sciences, Psychology and Intelligent Systems), each with a strong track record of scientific excellence and published work. Of note the current proposal builds substantially on an long history of successful folate research at Ulster, which was recently the focus of a Research Impact Case Study in REF2014 on Folate (folic acid), health policy and the consumer http://ulster.ac.uk/ref2014/Impact/3B_5.pdf This is one demonstration of how international outputs for some of the team to date have provided a scientific foundation for developing evidence-based policy in this area and its translation to consumers. This new proposal has the potential for further concrete impact in terms of influencing policy on food fortification, dietary recommendations and support during pregnancy. Our findings are likely to have a real chance of improving the cognitive and socio-emotional development of children during the first years of life and the quality of life and well-being for mothers. Given the strength of the evidence that childhood development has significant impacts for adult health and well-being the outcomes of this study have major implications for long term impact. Further, the potential benefits to children in general if this work is supported could have a major public health impact within a relatively short timescale. Early intervention and prevention also has economic implications for health care.

Publications

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Matusheski NV (2021) Diets, nutrients, genes and the microbiome: recent advances in personalised nutrition. in The British journal of nutrition

 
Description Periconceptional folic acid (FA) has an established protective effect in preventing neural tube defects (NTDs), leading to global recommendations for FA supplementation before and in early pregnancy. However, it was unclear whether there were any benefits for offspring brain health arising from continued maternal FA supplementation beyond the first trimester. The aim of this project was to investigate the role of maternal folate nutrition during pregnancy in relation to brain health in the offspring and to examine the role of DNA methylation changes as potential mediators of these effects.

The children of mothers who had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) were investigated, providing a unique opportunity to more robustly examine offspring cognitive health in relation to maternal folate. Our findings from standardised cognitive tests were that we saw improved performance in specific cognitive domains (but not Full Scale IQ) in children at 11 years whose mothers had been randomised to receive FA during pregnancy. Furthermore, girls from the FA group scored significantly higher in verbal IQ than those in the placebo group. The current results in the FASSTT offspring at 11 years provide further substantiation of earlier results from the same children at 3 and 7 years, which showed improved cognition and word reasoning (verbal IQ) scores, respectively, in response to maternal FA supplementation through trimesters two and three of pregnancy (work now published in BMC Medicine 2020). In another study we showed that children from the supplemented group show significantly greater resilience and emotional intelligence than those from the control group (now published in Acta Paediatrica 2018), a finding which garnered a lot of interest at the British Psychological Society annual meeting, including a press interview.

One possible mechanism which might explain how folic acid can affect cognitive health is through affecting DNA methylation, as it feeds into the one-carbon cycle which supplies methyl groups. Two of our studies looked at possible changes in DNA methylation. In the first, we looked at candidate genes which have been implicated from the literature as important for brain development/responsive to folate and found small but significant differences at some, including two imprinted genes, which are a class of gene often involved in neural processes and which are known to respond to changes in DNA methylation. This study was published in 2018 in the American Journal of Clinical Nutrition and was the subject of an editorial article. Our second methylation study involved looking at the whole genome using an array technique and led to us identifying changes at an imprint controller, a specific gene which controls imprinting. Further work has shown that this gene appears to respond to changes in folate and in methylation, suggesting a mechanistic link. This was has also been published (Cinical Epigenetics, 2019).

A unique feature of this work was the application of magnetoencephalography (MEG) to assess brain activity in a subset of children. The results showed that offspring of the FA-treated mothers compared to placebo had better brain functioning at resting state and also demonstrated more efficient language processing abilities (in press Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial Caffrey A, McNulty H, Rollins M, Prasad G, Gaur P, Talcott JB, Witton C, Cassidy T, Marshall B, Dornan J, Moore AJ, Ward M, Strain JJ, Molloy AM, McLaughlin M, Lees-Murdock DJ, Walsh CP, Pentieva K, BMC Med). This is one of the first applications of MEG in nutrition research and specifically in children, as an objective measure of functional brain activity in response to nutrition intervention.

There are potentially important impacts arising from all this work. The findings so far provide scientific evidence that continuing FA supplementation beyond the early period that is protective against NTDs, may be beneficial for brain health in the offspring.

In clear recognition of the value of this work, we have received further funding through the HDHL/BBSRC co-funded call on epigenetics and nutrition to look at effects of B-vitamins such as folic acid on both early and late life "EpiBrain", 2 years, £266k (UK), consortium with Canada and Spain. Further, our work has led to a new collaboration with colleagues in Stratified Medicine and the Mental Health Institute to look at the epigenetics of anxiety and depression in young adults "CHITIN", 3yrs, E600 (UK), consortium with Ireland. Most recently, we have started to apply the same analysis techniques to look at methylation as a possible marker for severe versus mild response to SARS-CoV-2 with colleagues in Trinity College Dublin - COVRES: Understanding the Host-Virus Response in Patients with Mild versus Serious Disease Bjourson AJ (PI) Walsh CP, Gibson D, Rai TS, Murray E 2020-2021 £354k .
Exploitation Route Our findings lend support to the idea of fortifying food with low levels of folic acid to ensure folate sufficiency during pregnancy and optimal prenatal growth and postnatal development, and that this is a safe and effective means of both protecting against neural tube defects and improving psychosocial development. The work has infuenced policy changes within the UK and one of the team has chaired the national consultation on folate in Ireland.
Sectors Agriculture, Food and Drink,Healthcare,Government, Democracy and Justice

URL https://www.ulster.ac.uk/research/topic/biomedical-sciences/research/genomic-medicine-research-group
 
Description We have had meetings with participants and with practitioners, all of whom have been impressed with the findings so far and report being influenced in their awareness of the need for folic acid during late pregnancy. Findings have been highlighted at conferences, in the media and through the web, including media interviews. The work published during the grant has already influenced UK policy on folic acid fortification and our team have played a key role in National consultation and policy in Ireland.
First Year Of Impact 2016
Sector Agriculture, Food and Drink,Communities and Social Services/Policy,Education,Healthcare,Government, Democracy and Justice
Impact Types Societal,Policy & public services

 
Description Chairing of National Committee on Food standards
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact We have played an important role in translating the science concerning folate and related B-vitamins through the lifecycle, and disseminating scientific evidence into practice for: 1. health professionals (to ensure that the patients they care for can benefit) and 2. policy makers in public health and food sectors (so that consumers in the general population can benefit). Notably, Prof Helene McNulty chaired the Folic Acid Review Committee at the Food Safety Authority of Ireland (2014-2016), the outcome of which was an extensive policy document Folic Acid and the Prevention of Birth Defects in Ireland
URL https://www.fsai.ie/news_centre/press_releases/folic_acid_report_04052016.html
 
Description ESRC/BBSRC Epigenetics Showcase
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact The showcase was held at Church House, Westminster and was aimed at a broad audience of academics, industrial representatives and policymakers. There were talks on the eight interdisciplinary projects funded via a joint call for research in the area of social and behavioural epigenetics in 2015. These collaborative projects between biological and social scientists aimed to understand the complex interactions between social phenomena, human biology and behaviour; and the impact of early life experiences on future health. The location of the showcase and the invitee list were designed to maximise the chances of influencing policymakers and future funders as well as patient advocates.
URL https://bbsrc.ukri.org/news/events/2019/1905-epigenetics-showcase/
 
Description Epigenetics in Health and Disease Workshop
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Approx. 100 participants including clinical practitioners, principal investigators, postgraduate students and visiting researchers. Talks were on a range of topics including psychology, nutrition, genomics, brain imaging, and epidemiology. There was uniformly positive feedback from participants and we have had numerous requests to repeat the workshop.
 
Description Influence on food policy
Geographic Reach National 
Policy Influence Type Citation in other policy documents
Impact Research developed by Ulster in folic acid (aka folate) has had direct impacts on policy and policy implementation in the health and food sectors, and contributed to translation of the evidence into practice for health professionals and policy makers. Our research has underpinned impacts in the following two areas in particular with this grant: 1) Developing national and international health policy on folic acid for women of reproductive age to prevent NTD Our research findings showed that naturally-occurring food forms of folate have poor stability and bioavailability, but that folic acid supplementation can greatly enhance the ability to achieve optimal folate status because it provides a highly bioavailable source of the vitamin. The research has had direct impacts on public health policy to prevent NTDs and related food policy in the UK [Scientific Advisory Committee on Nutrition (SACN) guidance 2017] 2) informing the risk-benefit controversy concerning food policy for folic acid-fortification The food policy of mandatory folic acid-fortification of staple foods with folic acid (to reduce pregnancies affected by NTD) is controversial. Despite being adopted by over 85 countries worldwide including North America and Australia, this policy has not yet been implemented in the UK, Ireland or elsewhere in Europe owing to concerns about potential adverse health effects. Research at Ulster has informed scientists and policy makers on important risk-benefit issues in relation to folic acid-fortification and provided evidence that unmetabolised folic acid (UMFA), considered a potential risk from having too high a dose of folic acid, was not found in cord blood of infants whose mothers had received supplements. This research paper has informed national health services and food regulatory authorities on the risk-benefit considerations related to folic acid fortification food policy
URL https://www.gov.uk/government/publications/folic-acid-updated-sacn-recommendations
 
Description MEG training
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Training for team members in the use and interpretation of magnetoencephalographic data (brain imaging)
 
Description Pyrosequencing training course
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Trained 10+ researchers from diverse backgrounds in the theory and practice of pyrosequencing for analysis of DNA methylation
 
Description Department for Employment and Learning Northern Ireland (DELNI): - PhD studentship SJT (£ 30000; 2016 - 2019)
Amount £30,000 (GBP)
Organisation Government of Northern Ireland 
Department Department for Employment and Learning Northern Ireland (DELNI)
Sector Public
Country United Kingdom
Start 09/2016 
End 09/2019
 
Description Department for Employment and Learning Northern Ireland (DELNI): PhD studentship AC (£ 30000; 2016 - 2019)
Amount £30,000 (GBP)
Organisation Government of Northern Ireland 
Department Department for Employment and Learning Northern Ireland (DELNI)
Sector Public
Country United Kingdom
Start 01/2016 
End 12/2018
 
Description Epigenome-wide associations of premature cardiovascular disease in a UAE population
Amount £300,000 (GBP)
Organisation American University of Sharjah 
Sector Academic/University
Country United Arab Emirates
Start 01/2022 
End 12/2024
 
Description Future Minds NI
Amount £100,782 (GBP)
Funding ID MR/T046562/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2020 
End 06/2021
 
Description HDHL EpiBrain: Epigenetic effects of B-vitamins on brain health throughout life
Amount £583,195 (GBP)
Funding ID BB/S020330/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2019 
End 12/2021
 
Description Improving mental health among at-risk young people in a challenging border region
Amount € 699,804 (EUR)
Funding ID CHI/5433/2018 
Organisation Northern Ireland HSC R&D 
Sector Public
Country United Kingdom
Start 03/2019 
End 03/2022
 
Description Interdisciplinary PhD studentship
Amount £36,750 (GBP)
Organisation Northern Ireland Office 
Sector Public
Country United Kingdom
Start 08/2017 
End 08/2020
 
Description Irish Student Wellbeing and ADHD project
Amount € 199,417 (EUR)
Organisation Letterkenny Institute of Technology 
Sector Academic/University
Country Ireland
Start 05/2022 
End 07/2024
 
Description Newton Mobility Grant
Amount £24,000 (GBP)
Funding ID IE160973 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2017 
End 02/2019
 
Description PhD studentship- MO
Amount £30,000 (GBP)
Organisation Ulster University 
Department Vice-Chancellor's Research Scholarship UU
Sector Academic/University
Country United Kingdom
Start 08/2017 
End 08/2020
 
Description Research Challenge Fund
Amount £24,996 (GBP)
Organisation Ulster University 
Sector Academic/University
Country United Kingdom
Start 02/2017 
End 01/2018
 
Description Seed Funding
Amount £10,000 (GBP)
Organisation Northern Ireland Clinical Research Facility (NICRF) 
Sector Public
Country United Kingdom
Start 11/2016 
End 10/2017
 
Description Training Grant- SJT
Amount £1,000 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2017 
End 12/2017
 
Title Development of Language Task Response Tool for use in Magnetoencephaology 
Description Our studies on children born to mothers who received folic acid supplementation in trimesters 2 and 3 of pregnancy have shown that these children perform better in standardised tests of verbal reasoning and other language tasks using standardised psychology tests such as WPPSSI. In order to gain greater insight into the biological underpinnings of this improved brain function, we wished to try and identify and quantitate and differences in brain activity between children in the placebo and folic acid supplement groups using a physical device. With colleagues in brain imaging and in collaboration with researchers at Aston University, we adapted existing computer-based tests to allow their use in a magnetoencephalography setting, which required substantial adaptation of both the questions and the format of delivery 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2019 
Provided To Others? No  
Impact The work has led to a number of exciting findings in terms of differences in brainwave activity in the placebo versus control children as measured by the superconducting quantum interference devices (SQUIDs) in the MEG, which can quantify changes in real-time in a non-invasive and relatively child-friendly setting. These results are currently being written up for submission as a further scientific paper by team members 
 
Title CandiMeth 
Description DNA methylation microarrays are widely used in clinical epigenetics and are often processed using R packages like ChAMP or RnBeads by trained bioinformaticians. However, looking at specific genes requires bespoke coding which wet-lab biologists or clinicians are not trained for. This leads to high demands on bioinformaticians, who in turn may lack insight into the specific biological problem. We therefore wished to develop a tool for mapping and quantification of methylation differences at candidate genomic features of interest, without using coding, to bridge this gap. We generated the workflow CandiMeth (CANDIdate METHylation) in the web-based environment Galaxy. CandiMeth takes as input any table listing differences in methylation generated by either of the popular R-based packages above and maps these to the human genome. A simple interface then allows the user to query the data using lists of gene names. CandiMeth generates 1)Tracks in the popular UCSC genome browser with an intuitive visual indicator of where differences in methylation occur between samples, or groups of samples 2) Tables containing quantitative data on the candidate regions, allowing interpretation of significance. In addition to genes and promoters, CandiMeth can analyse methylation differences at LINEs and SINEs. Cross-comparison to other open-resource genomic data at UCSC facilitates interpretation of the biological significance of the data and the design of wet lab assays to further explore methylation changes and their consequences for the candidate genes. CandiMeth (RRID:SCR_017974; Biotools:CandiMeth) allows rapid, quantitative analysis of methylation at user-specified features without the need for coding and is freely available, with extensive guidance, at CandiMeth GitHub repo. 
Type Of Material Computer model/algorithm 
Year Produced 2020 
Provided To Others? Yes  
Impact We use this extensively in our work, and it has helped underpin new grants with colleagues in other disciplines such as the JPI EpiBrain award. 
URL https://github.com/sjthursby/CandiMeth
 
Title EPIC array datasets from an RCT 
Description DNA methylation data in the form of EPIC array datasets form part of our publication in Clinical Epigenetics 2019 and are available from us on request, as stated in the paper. These were obtained from analysis of DNA derived from cord blood at term, where the mothers participated in a randomized controlled trial involving folic acid supplementation in second and third trimester of pregnancy. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact Publication (Clinical Epigenetics 2019) on the outcomes 
 
Title Supporting data for "CandiMeth: Powerful yet simple visualization and quantification of DNA methylation at candidate genes" 
Description DNA methylation microarrays are widely used in clinical epigenetics and are often processed using R packages like ChAMP or RnBeads by trained bioinformaticians. However, looking at specific genes requires bespoke coding which wet-lab biologists or clinicians are not trained for. This leads to high demands on bioinformaticians, who in turn may lack insight into the specific biological problem. We therefore wished to develop a tool for mapping and quantification of methylation differences at candidate genomic features of interest, without using coding, to bridge this gap.
We generated the workflow CandiMeth (CANDIdate METHylation) in the web-based environment Galaxy. CandiMeth takes as input any table listing differences in methylation generated by either of the popular R-based packages above and maps these to the human genome. A simple interface then allows the user to query the data using lists of gene names. CandiMeth generates 1)Tracks in the popular UCSC genome browser with an intuitive visual indicator of where differences in methylation occur between samples, or groups of samples 2) Tables containing quantitative data on the candidate regions, allowing interpretation of significance. In addition to genes and promoters, CandiMeth can analyse methylation differences at LINEs and SINEs. Cross-comparison to other open-resource genomic data at UCSC facilitates interpretation of the biological significance of the data and the design of wet lab assays to further explore methylation changes and their consequences for the candidate genes.
CandiMeth (RRID:SCR_017974; Biotools:CandiMeth) allows rapid, quantitative analysis of methylation at user-specified features without the need for coding and is freely available, with extensive guidance, at CandiMeth GitHub repo. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Extensive use of the software within the group and by our collaborators 
URL http://gigadb.org/dataset/100753
 
Description Collaboration with Caroline Relton and colleagues in Bristol 
Organisation University of Bristol
Department MRC Integrative Epidemiology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We are providing information on the EPiFASSTT study and our outcomes to the team in Bristol, who have a similar study called AFAST which looks at effects in adults (rather than children). The aim is to cross-validate our findings.
Collaborator Contribution Caroline and her team are providing us with advice on how they proceeded with their analyses, and what other tools and approaches may be useful for us. Their bioinformatician Matt Suderman has shown us his new R package meffil which they are using to allow comparison across different studies and which may be able to allow us to integrate the two datasets, or at least analyse in a comparable fashion.
Impact Seminar at Bristol (C Walsh). Research visit (R. Irwin to Bristol) Paper - Clinical Epigenetics 2019 -see outputs This is an interdisciplinary collaboration involving epigenetics, epidemiology, statistics and bioinformatics
Start Year 2016
 
Description Collaboration with Center for Research and Development, Region Gävleborg/Uppsala University 
Organisation Region Gävleborg
Country Sweden 
Sector Public 
PI Contribution Joint funding application "Post covid-19 follow up in Region Gävleborg with focus on the elderly population- an interdisciplinary research proposal" submitted March 15 2022 submitted to the Swedish Natural Sciences Foundation, aiming to carry out long-term follow up on elderly patients who contracted covid-19 to clarify symptoms as well as monitor health status and psychological well-being.
Collaborator Contribution We provide advice on data analytics based on our experience with our own datasets, as well as cross-comparisons between our cohorts and those in Sweden.
Impact Joint funding application through the Science Research Council of Sweden to look at mental health consequences of long covid. Multidisciplinary team including a clinical epidemiologist, clinical psychologists and a data analyst.
Start Year 2022
 
Description Newton mobility exchange 
Organisation Chinese Academy of Sciences
Department Shanghai Institutes for Biological Sciences
Country China 
Sector Academic/University 
PI Contribution Exchange of personnel to learn techniques and scientific approaches
Collaborator Contribution Training in pyrosequencing for assessing DNA methylation
Impact Four exchange visits have already occurred, two to China and two from China, involving the PIs, an RA and a PhD. We are currently working on a number of outputs as a result.
Start Year 2017
 
Description Patient Stratification in major depressive disorder 
Organisation Western Health and Social Care Trust
Country United Kingdom 
Sector Public 
PI Contribution Based on our experience working with the 450k arrays and our new skills in processing these, and following on from talks we have given on the EpiFASSTT grant, we were invited to participate in a new collaborative project between Stratified Medicine at Ulster and the Adult Psychiatry team at the Trust. This resulted in a successful seed grant (see further funding) to pursue a project called "Evaluating the effectiveness of DNA methylation patterns for patient stratification in major depressive disorder", which is ongoing. There was also an (unsuccessful) bid for a grant on Self-harm with additional colleagues from Psychology, and then for a successful bid to the HSC R&D office/INTERREG for a 3 year grant (see further funding).
Collaborator Contribution The Western Trust provide clinical advice and access to patient data; Stratified medicine provide expertise in major depressive disorder, recruit participants and collect samples.
Impact Successful seed grant (see further funding). Successful larger grant (CHITIN- see further funding) Assembled MS to be submitted soon Multidisciplinary- Epigenetics, Stratified Medicine, Pyschiatry, Psychology, Bioinformatics
Start Year 2016
 
Title To determine whether taking folic acid during the later stages of pregnancy has any beneficial effects of the cognitive development and growth of the offspring 
Description The Trial has shown, using a variety of measures including clinical psychology tools, brain imaging, cognitive assessment, biomarker evaluation and epigenetic analysis, that continued supplementation of pregnant mothers beyond the first trimester (current recommendations in UK) has positive impacts on the offspring psychosocial and cognitive development. Through our champions on the FSA Ireland (McNulty) and European FSA (Pentieva) Committees this evidence is contributing to ongoing consultation on food fortification with folic acid. Through follow-on funding from the HDL/BBSRC we are now extending this work to look at epigenetic correlates of b-vitamin intervention in different countries as well as at different stages of the life course (see further funding section). 
Type Preventative Intervention - Nutrition and Chemoprevention
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2018
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Consultation on food fortification with folic acid in the UK is still on-going, but the results of our Trial have been reported in high-ranking journals in our respective fields as evidenced in the Publications attributed to the award 
URL http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/research-projec...
 
Title CandiMeth- a software tool for quantifying and visualising DNA methylation changes 
Description DNA methylation microarrays are widely used in clinical epigenetics and are often processed using R packages like ChAMP or RnBeads by trained bioinfomaticians. However, looking at specific genes requires bespoke coding which wet-lab biologists or clinicians are not trained for. This leads to high demands on bioinfomaticians, who in turn may lack insight into the specific biological problem. We therefore wished to develop a tool for mapping and quantification of methylation differences at candidate genomic features of interest, without using coding, to bridge this gap. We therefore generated the workflow CandiMeth (CANDIdate METHylation) in the web-based environment Galaxy. CandiMeth takes as input any table listing differences in methylation generated by either of the popular R-based packages above and maps these to the human genome. A simple interface then allows the user to query the data using lists of gene names. CandiMeth generates 1)Tracks in the popular UCSC genome browser with an intuitive visual indicator of where differences in methylation occur between samples, or groups of samples 2) Tables containing quantitative data on the candidate regions, allowing interpretation of significance. In addition to genes and promoters, CandiMeth can analyse methylation differences at LINEs and SINEs. Cross-comparison to other open-resource genomic data at UCSC facilitates interpretation of the biological significance of the data and the design of wet lab assays to further explore methylation changes and their consequences for the candidate genes. CandiMeth allows rapid, quantitative analysis of methylation at user-specified features without the need for coding and is freely available through Github 
Type Of Technology Webtool/Application 
Year Produced 2020 
Open Source License? Yes  
Impact The software has been used in a number of our published papers (many listed against this award), done in collaboration with colleagues from a range of disciplines, and is empowering those in the life sciences to carry out their own analyses of epigenetic alterations without the need for extensive bioinformatics support. 
URL https://github.com/sjthursby/CandiMeth
 
Description 20th Annual Irish Society of Human Genetics Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I presented a short talk at the 20th Annual Irish Society of Human Genetics Conference in Croke Park, Dublin. The audience was >100; a mix of medical practitioners, researchers and postgraduate/undergraduate students.
Year(s) Of Engagement Activity 2017
URL http://irishsocietyofhumangenetics.blogspot.co.uk/2017/08/2017-ishg-conference-programme.html
 
Description Cell Symposia Stem Cell Epigenetics Conference - Sitges, Barcelona 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact The conference brought together experts who work broadly over a diverse range of epigenetic topics and stem cell types, providing a forum in which interdisciplinary discussions promoted cross-collaboration between experts in these areas and sparked new ideas that will hopefully accelerate progress in the field. The purpose was to engage with attendees at all career levels, to discuss and present research and as a networking opportunity.
Year(s) Of Engagement Activity 2015
URL http://cell-symposia-stem-cell-epigenetics.com/
 
Description Conference - Effect of folic acid supplementation during pregnancy on cognitive development of children aged 10 years: early results from the FASSTT Offspring study 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Titled presentation: Effect of folic acid supplementation during pregnancy on cognitive development of children aged 10 years: early results from the FASSTT Offspring study
Nutrition Society Irish Section Postgraduate Meeting held at QUB, Northern Ireland
Year(s) Of Engagement Activity 2018
 
Description Conference - Faculty of Life & Health Sciences: UU, Northern Ireland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Effect of folic acid supplementation during pregnancy on gene specific DNA methylation in the child: evidence from a randomised controlled trial held at UU
Year(s) Of Engagement Activity 2016
 
Description Conference - Nutrition Society Irish Section Postgraduate Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Nutrition Society Irish Section Postgraduate Meeting at UUC Ireland - Effect of maternal folic acid supplementation on gene specific DNA methylation in the child: evidence from a randomised controlled trial
Year(s) Of Engagement Activity 2016
 
Description Departmental Seminar- Shanghai Institutes for Biological Sciences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave an overview of our work and results from the MRC and ESRC/BBSRC grants with a few to the collaborative work to be undertaken as part of our Royal Society Newton Exchange grant
Year(s) Of Engagement Activity 2017
 
Description Dr Aoife Caffrey: 13th European Nutrition Conference, Federation of European Nutrition Societies (FENS) 2019 in Dublin, Ireland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Aoife Caffrey presented her PhD thesis titled 'Maternal folate nutrition and offspring brain health' at the 13th European Nutrition Conference, Federation of European Nutrition Societies (FENS) 2019 in Dublin, Ireland; 15-18 October 2019.
Year(s) Of Engagement Activity 2019
URL https://www.dsm.com/corporate/science-innovation/bright-science-awards/phd-graduate-awards.html#aoif...
 
Description ESRC/BBSRC Epigenetics Initiative initial meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Workshop and seminars for grantees who were awarded funding under the scheme. Gave talk and interacted with other funded teams and representatives from the funding body.
Year(s) Of Engagement Activity 2016
 
Description ESRC/BBSRC Epigenetics Initiative second meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Workshop and reporting on progress for grant-holders
Year(s) Of Engagement Activity 2017
 
Description ESRC/BBSRC Epigenetics Initiative third meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Third workshop including reporting on several published outcomes, as well as discussion of possible new funding opportunities for the group. Some new collaborations for funding proposals were initiated.
Year(s) Of Engagement Activity 2018
 
Description EpiFASSTT biannual team meetings 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Six-monthly formal team meetings with representatives from all of the disciplines
Year(s) Of Engagement Activity 2016,2017
 
Description Epigenetics and Inheritance - Miroslava Ondicova 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Poster presentation in Zurich relating to molecular work on the grant
Year(s) Of Engagement Activity 2019
 
Description Epigenomics of Common Disease 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This meeting focused on epigenomic studies across of a wide range of common and other diseases including cancer, and included approaches from a variety of different disciplines. It explored technological and methodological developments and provided a forum to present and discuss recent advances in epigenomics of relevance to human disease. This meeting allowed our research team to integrate knowledge with experts in the field, presentation of out work and networking opportunity.
Year(s) Of Engagement Activity 2016
URL http://www.globaleventslist.elsevier.com/events/2016/11/epigenomics-of-common-diseases/
 
Description Invited Talk at the British Psychological Society Annual Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A short talk given by Prof Cassidy at the BPS annual meeting on 4 May 2017, which resulted in a lot of interest and a press release (see separate entry).
Year(s) Of Engagement Activity 2017
 
Description Invited seminar, University of Exeter 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Visit to Exeter to discuss our findings and possible future collaborations with Prof Jon Mill and Dr. Therese Murphy, which had led to further engagement and joint organisation of a section of a large conference.
Year(s) Of Engagement Activity 2017
 
Description Invited short talk- European Congress on Personalised Medicine 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited short talk at the Congress, a broad forum for practitioners, patients, policymakers and media as well as the professional scientist
Year(s) Of Engagement Activity 2017
 
Description Invited speaker 3rd Annual Epigenetics Discovery Congress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Delivered a talk to this audience, consisting of researchers, clinician scientists and industry representatives, as well as postdocs and PhD students. There were a number of questions and useful interactions and we are now engaged in writing a grant with a colleague we met there.
Year(s) Of Engagement Activity 2017
 
Description Irish Society of Human Genetics - Poster Presentation - Miroslava Ondicova 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Poster presentation showcasing molecular work from the grant
Year(s) Of Engagement Activity 2019
 
Description Meeting with the public at the Portrush Airshow (2-3 September 2017) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Nutrition health promotion activity which gave us the opportunity to discuss with the general public our research and to make people aware for the results of our work.
Year(s) Of Engagement Activity 2017
 
Description Mental Health Initiative 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Presented some of the results of the EpiFASSTT study to Clinical Psychology team in the Western Trust, which sparked much interest and several requests for follow-up activities and potential collaborations
Year(s) Of Engagement Activity 2017
 
Description Molecular Biology Techniques - Pyrosequencing Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact A workshop was held in the Walsh laboratory to introduce new students, existing staff and other interested members of the University to participate in a week long event of seminars focused on background to molecular biology, techniques involved in analysis of DNA methylation and pyrosequencing alongside lab-based workshops with a work booklet provided to all attendees and also on-hand help as and when required.
Year(s) Of Engagement Activity 2015
 
Description Nutrition Society Irish Postgraduate Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact The team contributed to the Nutrition Society Summer Conference held in Dublin 16-17 February 2017. There were approximately 120 attendees. Aoife Caffrey from Ulster University presented 'Effect of maternal folic acid supplementation on gene specific DNA methylation in the child: evidence from a randomised controlled trial.'

The conference is designed to provide postgraduate students at all stages of their research with the opportunity to present their work, attend career sessions and network with peers.The programme is comprised mainly of oral communication sessions, chaired by postgraduate students. It is supported by social functions and guest talks to encourage networking and career development.

Aoife Caffrey from Ulster University presented 'Effect of maternal folic acid supplementation on gene specific DNA methylation in the child: evidence from a randomised controlled trial.'
Year(s) Of Engagement Activity 2016,2017
URL https://www.nutritionsociety.org/events/irish-postgraduate-conference
 
Description Nutrition Society Summer Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The EpiFASSTT: Epigenetic effects on children's psychosocial development in a randomised trial of folic acid supplementation in second and third trimester team contributed to the Nutrition Society Summer Conference held in Dublin 11-14 June 2016. There were approximately 400 attendees.

The conference focus was 'New technology in nutrition research and practice'. New and emerging technologies have the potential to advance nutrition science; examples of such technologies include nutrigenomic approaches to enhance molecular phenotyping, the use of metabolomics in dietary biomarker discovery and the use of epigenetics to understand gene-environment interactions.

Aoife Caffrey from Ulster University (EpiFASSTT) presented 'Effect of folic acid supplementation in pregnancy on gene specific DNA methylation in the child: evidence from a randomised controlled trial.' The abstract will be published in the Proceedings of the Nutrition Society.
Year(s) Of Engagement Activity 2016
URL http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/news/2016/nutri...
 
Description Presentation at Inuternational Union of Nutritional Sciences 21st International Congress of Nutrition, Argentina 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact International Union of Nutritional Sciences 21st International Congress of Nutrition (IUNS 21st ICN), Buenos Aires, Argentina.
Oral presenation: "Offspring DNA methylation changes in response to maternal folic acid supplementation in the second and third trimesters: evidence from a randomized controlled trial"
Year(s) Of Engagement Activity 2017
 
Description Presentation at the Nutrition Society Irish Section Conference, Northern Ireland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Nutrition Society Irish Section Conference, Ulster University, Northern Ireland.
PhD presentation: "Mandatory folate nutrition and offspring health: evidence and current controversies"
Winner of the Postgraduate Review Competition
Year(s) Of Engagement Activity 2018
URL https://www.nutritionsociety.org/node/392/postgraduate-competition
 
Description Presentation of poster at International Conference on Homocysteine and One-Carbon Metabolism, Denmark 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact International Conference on Homocysteine and One-Carbon Metabolism, Denmark.
Poster presentation: "Gene-specific DNA methylation in the offspring in response to folic acid supplementation during the second and third trimesters of pregnancy: evidence from a randomised controlled trial"
Year(s) Of Engagement Activity 2017
 
Description Presentation of poster at The Nutrition Society Irish Section Conference, Northern Ireland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The Nutrition Society Irish Section Conference, Ulster University, Northern Ireland.
Poster presentation: "Impact of folic acid supplementation during pregnancy on cognitive performance of children at age 11 years: preliminary results from the FASSTT Offspring study"
Year(s) Of Engagement Activity 2018
 
Description Press release and coverage for BPS talk 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release by the BPS on Prof. Cassidy's talk, covered by over 62 media articles, including notably the Daily Mail and even the Guardian blog from Nigeria, as well as a radio interview
Year(s) Of Engagement Activity 2017
URL https://www.google.co.uk/search?q=tony+cassidy+%2B+folic+acid&rlz=1C1GGRV_enGB748GB748&oq=tony+cassi...
 
Description Press release for EpiFASSTT 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Press release to highlight the folic acid intervention and follow-on work in psychology, epigenetics and brain imaging to be done under EpiFASSTT, Resulted in a radio interview and further questions and interest
Year(s) Of Engagement Activity 2015
 
Description Prof Helene McNulty - Radio interview on BBC Radio 4 Health special programme looking at 'Folic acid fortification' 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Radio interview by Helene McNulty on BBC Radio 4 Health special programme looking at 'Folic acid food fortification'.
BBC Radio 4 - Inside Health, The Nobel Prize for Medicine, new plans to add nutrients to foods
Year(s) Of Engagement Activity 2021
URL https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.bbc.co.uk%2Fprogrammes%2Fm0010...
 
Description Radio interview 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Radio interview on Q radio, who have a network of local radio stations across Northern Ireland. Prof. Helene McNulty represented the team since the interviewers were particularly interested in the folic acid angle.
Year(s) Of Engagement Activity 2015
 
Description Seminar at MRC Integrative Epidemiology Unit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Third sector organisations
Results and Impact Gave a seminar on the EpiFASSTT study and outcomes so far to the academics, PhD students and postdocs and NHS professional practitioners at the Bristol unit. This was the start of a collaborative project with the group there.
Year(s) Of Engagement Activity 2016
 
Description Soapbox Science Ireland (public engagement event - women in science) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact On 20th June 2015, eminent women scientists from UK and Ireland talked to the general public about their work and passion for Science, Technology, Engineering, Mathematics and Medicine (STEMM) on the Belfast streets. The event's mission was to help eliminate gender inequality in science by raising the profile, and challenging the public's view, of women and science. The event was well attended by renowned UK/Ireland women scientists, postgraduate and undergraduate students, who had a chance to disseminate their research to the public in an interactive and engaging manner. This sparked questions from the general public coming from men, women and children.
Year(s) Of Engagement Activity 2015
URL http://soapboxscience.org/soapbox-science-2015-ireland/
 
Description Statistical approaches for epigenetics: Challenges and potential solutions workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact The aim of this workshop was to bring together statisticians and epigeneticists to present and discuss statistical challenges faced in the field of epigenetic epidemiology. The focus was on current approaches, their strengths and limitations and the discussion of solutions to outstanding problems.
Year(s) Of Engagement Activity 2016
 
Description Symposium - Maternal folic acid during pregnancy and cognitive performance of children at 11 y: preliminary results from the FASSTT Offspring study and related epigenetic effects 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A symposium called International Association for Cellular Coenzymes (IACC) Symposium took place in 2018 at Kings College London, England. Presentation called: Maternal folic acid during pregnancy and cognitive performance of children at 11 y: preliminary results from the FASSTT Offspring study and related epigenetic effects. Audience interested in Cellular coenzymes in health and disease.
Year(s) Of Engagement Activity 2018
 
Description The Irish Society of Human Genetics Conference (Belfast City Hospital) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact The Irish Society of Human Genetics Meeting promoted research and education in human genetics from a wide spectrum of individuals professionally involved in human genetics and molecular medicine whether in research, education, clinical service or other professional activity. The purpose was to disseminate our research to this group of experts, to network and keep up to date with those in the field of genetics.
Year(s) Of Engagement Activity 2016
 
Description The Irish Society of Human Genetics Conference (Dublin) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact The Irish Society of Human Genetics Meeting promoted research and education in human genetics from a wide spectrum of individuals professionally involved in human genetics and molecular medicine whether in research, education, clinical service or other professional activity. The purpose was to disseminate our research to this group of experts, to network and keep up to date with those in the field of genetics.
Year(s) Of Engagement Activity 2015
 
Description Third Epigenetics Discovery Congress, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Third sector organisations
Results and Impact Reported our findings to an audience consisting of senior academics and participants from industry. Has led to subsequent collaborative discussions and ongoing interactions with colleagues who we met there, one of whom is now an invited speaker at our upcoming workshop.
Year(s) Of Engagement Activity 2017