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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B4199 - The impact of command hallucinations and delusions of thought interference on suicidal behaviours - 21/11/2022

B number: 
B4199
Principal applicant name: 
Clara Humpston | University of York (United Kingdom)
Co-applicants: 
Title of project: 
The impact of command hallucinations and delusions of thought interference on suicidal behaviours
Proposal summary: 

Auditory verbal hallucinations are conceptualised as hearing voices or a sense of being communicated to without any external speaker present. Historically viewed as hallmarks of psychosis and other serious mental illnesses, we now know that nonclinical voices can occur with varying intensities and frequencies in the general population too. However, clinical voices such as those of a commanding nature often contribute to severe levels of distress and dysfunction, especially when the voices command the voice-hearer to carry out harmful actions against their will. Related phenomena, called delusions of (thought) interference, include thought insertion and delusion of control, defined as the feeling that someone external is sending or forcing thoughts into a person's mind and being under the influence of an external power, respectively. Command hallucinations, delusion of control and thought insertion breach if not erase the boundary between one's self and other, thus leading to a confusion between internal and external events which can make the commands exceedingly difficult to resist. Sometimes both the distress caused by and the coercive nature of such experiences can lead to suicidal feelings and behaviours including acts of self-harm. This project aims to investigate the relationships between such command hallucinations, inserted thoughts and suicidal behaviours by studying their trajectories, how they develop and change over time, as well as clarifying the impact of these experiences on individuals' mental wellbeing versus diagnoses of mental illness.

Impact of research: 
Better understanding of command hallucinations and thought insertion and their effects on suicidal behaviours in psychoses and related disorders - clinicians need to actively enquire about self-harm in psychotic disorders and any related thought interference symptoms rather than assuming the behaviours are due to a personality disorder when presented with self-harm for example.
Date proposal received: 
Monday, 14 November, 2022
Date proposal approved: 
Monday, 21 November, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Statistical methods, Cognition - cognitive function

B4198 - Revisiting the associations between asthma and psychotic experiences - 21/11/2022

B number: 
B4198
Principal applicant name: 
Golam Khandaker | Head, Immunopsychiatry Programme, MRC IEU, Bristol Medical School (United Kingdom)
Co-applicants: 
Dr Christina Dardani
Title of project: 
Revisiting the associations between asthma and psychotic experiences
Proposal summary: 

Asthma is a chronic condition influencing breathing and characterised by breathlessness, coughing and chest tightness. Asthma can be triggered by exposure to several allergens (e.g., pollen) or infections and is considered predominantly an inflammatory condition. There is increasing evidence suggesting that asthma in childhood may be linked to a number of adverse mental health outcomes including psychotic disorders such as schizophrenia and bipolar disorder. Specifically, previous studies using the ALSPAC resource have found evidence of associations between asthma at age 10 and psychotic experiences at age 13. Furthermore, studies using large nationwide data from Sweden, found that asthma in parents was associated with bipolar disorder in their children. The reasons underlying these associations are largely unknown and several explanations have been hypothesised. For example, it has been proposed that inflammatory mechanisms involved in asthma might be causal for psychotic disorders. Gaining a better understanding on the relationship between asthma and psychotic disorders can have important implications towards uncovering drug targets for these chronic mental health conditions.

Impact of research: 
Date proposal received: 
Monday, 14 November, 2022
Date proposal approved: 
Monday, 21 November, 2022
Keywords: 
Epidemiology, Respiratory - asthma, Statistical methods, Mendelian randomisation

B4200 - Plant-based diets iodine and neurodevelopmental outcomes - 21/11/2022

B number: 
B4200
Principal applicant name: 
Sarah Bath | University of Surrey
Co-applicants: 
Dr Kathryn Hart
Title of project: 
Plant-based diets, iodine, and neurodevelopmental outcomes.
Proposal summary: 

Iodine deficiency during pregnancy can result in impaired thyroid function and lead to altered brain structure. We have shown that even mild-to-moderate ID in UK pregnant women is associated with lower child IQ and reading scores at age 8-9 years.

Recent dietary recommendations promote plant-based diets for environmental sustainability and such diets are increasingly popular, particularly among young women. Since plant foods have low iodine content and animal foods are the main contributors to iodine intake, plant-based diets may increase the risk of iodine deficiency. Such diets, with high vegetable intake, may also be high in goitrogens (foods that may reduce the absorption and use of iodine in the body). A diet high in goitrogens but low in iodine may increase the risk of ID and its effects on child neurodevelopment, but there is a lack of data in this area.

In this project we plan to investigate whether a dietary risk score that considers both iodine intake and iodine inhibitors can predict mother's iodine status and thyroid function in pregnancy, and also child cognitive outcomes (e.g. IQ).

Impact of research: 
Further evidence of the role of iodine in pregnancy in areas of mild-to-moderate deficiency, building on our previous work with ALSPAC data.
Date proposal received: 
Monday, 21 November, 2022
Date proposal approved: 
Monday, 21 November, 2022
Keywords: 
Nutrition, Statistical methods, Nutrition - breast feeding, diet

B4189 - Methods to Detect and Adjust for Selection Bias - 14/11/2022

B number: 
B4189
Principal applicant name: 
Apostolos Gkatzionis | MRC Integrative Epidemiology Unit, University of Bristol (United Kingdom)
Co-applicants: 
Professor Kate Tilling
Title of project: 
Methods to Detect and Adjust for Selection Bias
Proposal summary: 

Biomedical research is often hindered by the presence of missing data. For example, missing data can occur due to study participants' unwillingness to disclose sensitive information about themselves (e.g. refusing to answer questions related to their mental health, smoking habits, alcohol consumption or drug use). In our research, we will develop novel statistical methodologies to assess the impact of missing data in epidemiologic studies, understand under which conditions the presence of missing data will bias an applied analysis, and overcome this form of bias.

Impact of research: 
Our research is of methodological nature and will not have a direct impact on medical practice. However, we hope that it will be helpful to applied researchers working with datasets that contain missing data, or are subject to selection bias. This may include other ALSPAC users.
Date proposal received: 
Wednesday, 2 November, 2022
Date proposal approved: 
Monday, 14 November, 2022
Keywords: 
Statistics/methodology, Diseases/conditions/variables for which data are requested: obesity (body mass index), alcohol consumption, smoking, depression, self-harm. Also pregnancy-related variables. (Listed under "other" as the list does not allow for selecting multiple diseases/conditions), Statistical methods, Birth outcomes

B4192 - Assessing the robustness of multiple imputation strategies in practice - 14/11/2022

B number: 
B4192
Principal applicant name: 
Elinor Curnow | University of Bristol (United Kingdom)
Co-applicants: 
Professor Kate Tilling, Dr Jon Heron, Dr Rosie Cornish
Title of project: 
Assessing the robustness of multiple imputation strategies in practice
Proposal summary: 

Around 14,000 children initially participated in ALSPAC. Over time, many children have been lost to follow-up (“drop-out”) or have participated at some time-points and not at others (“sporadic non-response”). Missing data due to non-response can lead to bias when estimating associations. Multiple imputation (MI) is an analysis strategy that can correct this bias, by recovering information about the missing values using observed variables (“predictors”). However, there are methodological challenges with the correct application of MI. The aim of this project is to assess their impact in practice, and develop an automated expert system to guide researchers through the multiple decisions required when using MI.

Impact of research: 
The likely output of this research will be at least one publication in a peer-reviewed epidemiology journal, the impact of which may be improved practice by researchers when performing analyses with missing data.
Date proposal received: 
Friday, 4 November, 2022
Date proposal approved: 
Monday, 14 November, 2022
Keywords: 
Statistics/methodology, Cognitive impairment, Obesity, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods

B4193 - Examining the aetiology of alcohol use in autistic adults - 14/11/2022

B number: 
B4193
Principal applicant name: 
Evie Stergiakouli | MRC IEU
Co-applicants: 
Miss Stephanie Page
Title of project: 
Examining the aetiology of alcohol use in autistic adults
Proposal summary: 

Alcohol use is a major issue for the UK healthcare system. Little is known about the link between autism and alcohol use, but preliminary research suggests that autistic adults who drink are twice as likely to become dependent as their neurotypical counterparts (1; 2). This does not seem to be the case for autistic adolescents (but existing studies are limited methodologically by small sample sizes and cross-sectional study designs) (3). Using longitudinal population-based studies to understand alcohol use in autistic adolescents going into young adulthood could address these issues. Doing this while controlling for potential confounders will help us understand what influences the development of this association over time.
Further, it is unclear whether genetics influence this association. Exposure-outcome associations are often estimated without accounting for genetic confounding in epidemiological studies, leading to potential inaccuracies (4). A genetic variant in the autism susceptibility candidate 2 gene (AUTS2) has been found to be associated with alcohol consumption (5), but it is unclear whether there are other genetic variants associated with autism that influence alcohol use. To assess this, we could calculate polygenic risk scores for autism and explore their association with alcohol use. This will help us ascertain whether genetic overlap plays a role in the aetiology of this association and potentially improve the accuracy of future causal estimates.
(1) Bowri, M., Hull, L., Allison, C., Smith, P., Baron-Cohen, S., Lai, M. C., & Mandy, W. (2021). Demographic and psychological predictors of alcohol use and misuse in autistic adults. Autism, 25(5), 1469–1480. https://doi.org/10.1177/1362361321992668

(2) Butwicka, A., Långström, N., Larsson, H., Lundström, S., Serlachius, E., Almqvist, C., Frisén, L., & Lichtenstein, P. (2017). Increased Risk for Substance Use-Related Problems in Autism Spectrum Disorders: A Population-Based Cohort Study. Journal of Autism and Developmental Disorders, 47(1), 80–89. https://doi.org/10.1007/s10803-016-2914-2

(3) Arnevik, E. A., & Helverschou, S. B. (2016). Autism spectrum disorder and co-occurring substance use disorder - A systematic review. In Substance Abuse: Research and Treatment (Vol. 10, pp. 69–75). Libertas Academica Ltd. https://doi.org/10.4137/SART.S39921

(4) Pingault, J. B., Rijsdijk, F., Schoeler, T., Choi, S. W., Selzam, S., Krapohl, E., O’Reilly, P. F., & Dudbridge, F. (2021). Genetic sensitivity analysis: Adjusting for genetic confounding in epidemiological associations. PLOS Genetics, 17(6), e1009590. https://doi.org/10.1371/JOURNAL.PGEN.1009590

(5) Schumann, G., Coin, L. J., Lourdusamy, A., Charoen, P., Berger, K. H., Stacey, D., Desrivières, S., Aliev, F. A., Khan, A. A., Amin, N., Aulchenko, Y. S., Bakalkin, G., Bakker, S. J., Balkau, B., Beulens, J. W., Bilbao, A., de Boer, R. A., Beury, D., Bots, M. L., … Elliott, P. (2011). Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proceedings of the National Academy of Sciences of the United States of America, 108(17), 7119–7124. https://doi.org/10.1073/PNAS.1017288108

Impact of research: 
To our knowledge, this will be the first ever longitudinal study to look at alcohol use in autistic adolescents going into young adulthood. This will help us understand whether associations emerge at a certain age and the direction of any association. It will also help us understand whether any association is driven by confounders. Further, the second study will help us understand whether genetics influence the association between autism and alcohol use. This could help to improve future causal estimates and thus our understanding of this relationship.
Date proposal received: 
Monday, 7 November, 2022
Date proposal approved: 
Monday, 14 November, 2022
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Developmental disorders - autism, Statistical methods, Statistical methods

B4190 - Social behaviour and communication in context A multivariate genomic study of precursors and later-life outcomes - 21/11/2022

B number: 
B4190
Principal applicant name: 
Beate M St Pourcain | Max Planck Institute for Psycholinguistics (Netherlands)
Co-applicants: 
Professor Simon Fisher, Danielle Admiraal
Title of project: 
Social behaviour and communication in context: A multivariate genomic study of precursors and later-life outcomes
Proposal summary: 

Background
Mastering motor milestones and social personal skills may lead to a developmental transition that initiates a cascade of developmental changes, including social interaction and language learning(1). For example, the onset of walking(1,2) and sitting skills(3) but also social-personal skills can predict children's vocabulary size, which may potentially affect literacy-related abilities in later life. Similarly, early abilities to distinguish prosody and rhythm may affect children’s progress in learning language and (social) communication. For example, musical rhythmicity is strongly linked to cognition due to the synchronization of the partner's language expression in social communication(4).
Various studies have shown the genetic overlap between interpersonal milestone development and neurodevelopmental disorders. For example, individuals diagnosed with Autism Spectrum Disorder (ASD) show delayed development of cognitive and social functioning and, therefore, may reach early developmental milestones later (smiling, walking, spoon feeding themselves, crawling) or not at all(5).

This project will use data from ALSPAC and other large cohorts to investigate the genetic architecture of early social/communicative/language abilities as well as social /social communication abilities during the life course within large consortia (e.g. meta-Genome Wide Association Analyses (GWAS) within the EAGLE consortium) including in-depth structural models of genetic factors. The study will biologically annotate the genetic architecture of early social/communicative abilities as well as social abilities through genetic enrichment and variance partitioning analyses. Once social behaviour has been modelled genetically, we will derive genetic tools to identify genetic overlap with neuro-developmental disorders and other health-related, educational and (social) behavioural outcomes in later life, as well as brain-related encodings (e.g. brain structure and function). The project will finally assess evidence for correlation and causal mechanisms linking precursors of social/communicative abilities (e.g. musicality, motor behaviour and temperament) to social performance and, in turn, social behaviour and social communication skills to later-life outcomes (e.g. health, education, behaviour).

1. Walle, E. A. Infant Social Development across the Transition from Crawling to Walking. Front. Psychol. 7, (2016).
2. Walle, E. A. & Campos, J. J. Infant language development is related to the acquisition of walking. Dev. Psychol. 50, 336–348 (2014).
3. Libertus, K. & Violi, D. A. Sit to Talk: Relation between Motor Skills and Language Development in Infancy. Front. Psychol. 7, (2016).
4. Ravignani, A., Honing, H. & Kotz, S. A. Editorial: The Evolution of Rhythm Cognition: Timing in Music and Speech. Front. Hum. Neurosci. 11, 303 (2017).
5. Kuo, S. S. et al. Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis. JAMA Pediatr. 176, 915–923 (2022).

Impact of research: 
Date proposal received: 
Wednesday, 2 November, 2022
Date proposal approved: 
Monday, 14 November, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), GWAS, Statistical methods, Childhood - childcare, childhood adversity, Communication (including non-verbal), Genetic epidemiology, Genetics, Genomics, Genome wide association study, Speech and language

B4195 - What makes clocks tick Mapping determinants of epigenetic age acceleration in early life - 15/11/2022

B number: 
B4195
Principal applicant name: 
Charlotte Cecil | Erasmus University Medical Center (the Netherlands)
Co-applicants: 
Rosa Mulder, PhD, Dr Matthew Suderman
Title of project: 
What makes clocks tick? Mapping determinants of epigenetic age acceleration in early life
Proposal summary: 

DNA methylation, the binding of a methyl-group to the DNA structure, can affect gene transcription and is related to aging. So strongly, in fact, that DNA methylation at specific sites (i.e. ‘CpGs’) can be used to estimate a persons’ age through the use of so-called ‘epigenetic clocks’. Not only do the age estimates produced by epigenetic clocks relate highly to chronological age, but the extent to which they deviate from chronological age is an important predictor of health: in adults, epigenetic age acceleration (i.e. being epigenetically older than one’s age) relates to greater disease risk and mortality, whereas conversely, deceleration relates to better health and longevity.
Research from our group suggests that an individual’s epigenetic age acceleration might be determined early on. We brought together the world’s largest developmental datasets with repeated epigenetic assessments to map how DNA methylation patterns change over the first two decades of life. We found that sites that make up epigenetic clocks already show substantial differences between individuals in early life, sometimes even from birth. This raises the possibility that longevity differences apparent in old age may already be influenced by factors occurring at a young age, opening new opportunities for early detection and intervention.
Here, we aim to identify the early origins of epigenetic aging, by examining the contribution of genetic and environmental influences, beginning in pregnancy. To do so, we use individual-level DNA methylation patterns of change at clock CpGs, already created. In addition, we will study early outcomes of inter-individual variation in early epigenetic age acceleration at the molecular and system-level.

Impact of research: 
We think we can identify early genetic and environmental determinants of epigenetic age acceleration and identify early health outcomes. This research would help us understand the mechanism of biological aging and identify potential targets of intervention, to help people age healthily.
Date proposal received: 
Wednesday, 9 November, 2022
Date proposal approved: 
Friday, 11 November, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Allergy, Epilepsy, Hypertension, Infection, Learning difficulty, Mental health, Obesity, Pain, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Respiratory - asthma, Speech/language problem, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cancer, Chronic fatigue, Cognitive impairment, Diabetes, Eating disorders - anorexia, bulimia, Eczema, GWAS, Metabolomics, Microarrays, RNA, Ageing, Biological samples -e.g. blood, cell lines, saliva, etc., Genomics, Genome wide association study, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Birth outcomes, Childhood - childcare, childhood adversity, Development, Environment - enviromental exposure, pollution, Epigenetics, Expression, Genetic epidemiology

B4187 - Inter-generational transmission of intimate partner violence and abuse IPVA influence of IPVA measures patterns and timing - 08/11/2022

B number: 
B4187
Principal applicant name: 
Alexa Yakubovich | Dalhousie University (Canada)
Co-applicants: 
Alexis Bragman, George Kephart
Title of project: 
Inter-generational transmission of intimate partner violence and abuse (IPVA): influence of IPVA measures, patterns, and timing
Proposal summary: 

Around one-quarter of young people in the UK report intimate partner violence and abuse (IPVA, that is, physical or sexual violence, or emotional abuse) among their parents by age 16. Research in US student samples suggests that for these young people, they are more likely to be victimised in their own intimate relationships as adolescents and young adults, this association my vary according to the timing of exposure to parental IPVA, and may be even higher for those with other adverse childhood experiences, such as maltreatment or parental mental illness. However, this has rarely been studied in a general population sample, or in the UK. Further, little is known about the burden
of continued IPVA over the life-course on later health, that is, witnessing IPVA among parents to then experiencing IPVA in one’s own relationship. However, IPVA among parents does not guarantee future IPVA, and many go on to not to experience this in their own intimate relationships. Understanding what factors (e.g. parent-child relationships, school, peers) help to break the cycle of intimate partner violence, can inform policies and interventions to prevent further violence and improve quality of life in these families.

Impact of research: 
Existing research on the intergenerational transmission of IPV is limited because studies tend to only ask participants about their exposure to IPV between their parents once they have already reached adulthood. This retrospective research may be biased because people experiencing IPV in adulthood may be more or less likely to classify their childhood experiences as violent compared to those who are not currently experiencing IPV. Our research will allow us to produce a more robust understanding of the measurement and occurrence of the intergenerational transmission of IPVA in the general population, and the UK population in particular. It will help determine to what extent parental IPVA drives offspring IPVA beyond other co-occurring childhood experiences and whether the timing or chronicity of exposure to parental IPVA is importance to this association. In addition, we will be able to examine the cumulative impacts of exposure to IPVA over the life course on health and wellbeing. Our findings will inform future directions for national and international research on IPVA and the potential effectiveness of intervention strategies focused on early childhood and family environments. This research will thus be of interest to public health practitioners and researchers in the fields of adverse childhood experiences, resilience, and domestic and dating violence.
Date proposal received: 
Tuesday, 1 November, 2022
Date proposal approved: 
Tuesday, 8 November, 2022
Keywords: 
Epidemiology, Intimate Partner Violence and Abuse, Statistical methods

B4194 - Genetic Determinants of Longitudinal Changes in Anthropometric Traits - 09/11/2022

B number: 
B4194
Principal applicant name: 
Loic Yengo | Institute for Molecular Bioscience - The University of Queensland (Australia)
Co-applicants: 
Dr Nicole Warrington, Mr Samuel McEwan, Dr Geng Wang , Dr Christopher Flatley , Professor Kate Tilling, Professor Deborah Lawlor
Title of project: 
Genetic Determinants of Longitudinal Changes in Anthropometric Traits
Proposal summary: 

This project aims to identify and characterize the contribution of genetic variation to growth-related traits. One part of this project will be conducted in collaboration with international consortia to identify genetic variants associated with height and body mass index (BMI) variation across childhood. The other part of the project will focus on genetic variants already associated with adult traits (height and BMI) and will characterise the critical time periods in childhood development when these variants start and stop to exert their effects.

Impact of research: 
Our research will expand knowledge of (i) the genetic determinants of healthy growth and their interplay with the environment and (ii) illuminate how maternal characteristics may impact children's future health.
Date proposal received: 
Tuesday, 8 November, 2022
Date proposal approved: 
Tuesday, 8 November, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Diabetes, Hypertension, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Gene mapping, GWAS, Statistical methods, Blood pressure, BMI, Mendelian randomisation, Mothers - maternal age, menopause, obstetrics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Puberty, Statistical methods, Cardiovascular, Development, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Growth, Hormones - cortisol, IGF, thyroid

B4188 - Parental Type 2 Diabetes and Cardiovascular disease polygenic risk scores by offspring birthweight and placental weight - 14/11/2022

B number: 
B4188
Principal applicant name: 
Charlie Hatcher | University of Bristol
Co-applicants: 
Professor Nicholas Timpson
Title of project: 
Parental Type 2 Diabetes and Cardiovascular disease polygenic risk scores by offspring birthweight and placental weight
Proposal summary: 

Birth weight (BW) and placental weight (PW) have been associated with adult health outcomes, and a genetic component for this relationship has been established. Similar associations between offspring BW and PW and parental health have been found in observational studies. We aim to investigate the association of parental diabetes and cardiovascular disease risk variants with offspring BW and PW.

Impact of research: 
Date proposal received: 
Tuesday, 1 November, 2022
Date proposal approved: 
Monday, 7 November, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Diabetes, Statistical methods, Genome wide association study

B4021 - longitudinal modeling of high-dimensional molecular measurements in birth cohort studies - 07/11/2022

B number: 
B4021
Principal applicant name: 
Dennis Wang | Singapore Institute for Clinical Sciences (Singapore)
Co-applicants: 
Dr Mauricio Alvarez, Ai Ling Teh, Dr Arthur Leroy, Dr Pan Hong, Dr Varsha Gupta, Michelle Kee, Dr Evelyn Lau
Title of project: 
longitudinal modeling of high-dimensional molecular measurements in birth cohort studies
Proposal summary: 

Our group at the Singapore Institute for Clinical Sciences and the University of Manchester have received funding from the Wellcome Trust to investigate the machine learning modelling techniques for high-dimensional measurements from population studies. Recently, high-throughput 'omics technologies have allowed us to collect large numbers of molecular measurements from a single sample. Analysing these large datasets poses a problem, because existing techniques do not allow us to analyse all measurements jointly as outcomes. We will develop a statistical technique for jointly analysing large numbers of molecular measurements, using recent advances in statistical inference, as well as applying prior knowledge to reduce the number of relationships between measurements that needs to be explored. Additionally, we will develop a method for designing longitudinal studies to gain optimal information about these high-dimensional outcomes. The benefits of our approach will be two-fold: First, in allowing us to gain additional information about the relationships between longitudinal measurements, and second in improving the design of future studies, which will lead to time and cost savings.

Impact of research: 
The benefits of our approach will be two-fold: First, in allowing us to gain additional information about the relationships between longitudinal measurements, and second in improving the design of future studies, which will lead to time and cost savings for future population studies.
Date proposal received: 
Monday, 31 October, 2022
Date proposal approved: 
Monday, 7 November, 2022
Keywords: 
Bioinformatics, This is only for methodology development, but we will test models of association between molecular factors and any disease outcome observed in >100 subjects., Computer simulations/modelling/algorithms, Epigenetics, Expression, Genome wide association study, Statistical methods

B4178 - Validation of selected candidate blood metabolites biomarkers for age at menopause - 07/11/2022

B number: 
B4178
Principal applicant name: 
Despoina Manousaki | CHU Sainte-Justine (Canada)
Co-applicants: 
Mojgan Yazdan Panah, Dr, Nahid Yazdan Panah, Dr
Title of project: 
Validation of selected candidate blood metabolites biomarkers for age at menopause
Proposal summary: 

Female reproductive longevity, controlled by the timing of menarche and menopause, can vary greatly depending on genetics, lifestyle, and environmental exposures. While variations in age at menarche (AAM) and age at natural menopause (ANM) have a complex multi-factorial aetiology, the biological mechanisms underlying these variations are still not fully understood. Identifying biomarkers allows for a better understanding of the pathophysiology underpinning variations in AAM and ANM and their interconnection, while the same molecules could represent potential targets to pharmacologically modify timing of these events. High-throughput metabolomics studies have led to the discovery of a number of candidate biomarkers for a variety of traits. However, simultaneous measurement of hundreds of circulating metabolites in case-control studies is cost prohibitive and subject to confounding and reverse causation. Large genome-wide association studies (GWAS) have become available for both metabolites and AAM and ANM, advancing our knowledge on the genetic determinants of these traits. Mendelian randomisation (MR) is an established method in genetic epidemiology that explores whether a modifiable exposure is causally linked to an outcome by using genetic variants for this exposure as instrumental variables. The MR design can avoid potential bias from confounding that are typical in conventional observational studies by taking advantage of the fact that inherent genetic variants are not susceptible to environmental risk factors and reverse causation. In a setting known as two-sample MR, GWAS data for an exposure and an outcome measured in independent populations can be used to test causality of risk factors on complex health outcomes.
By employing two-sample MR, we screened hundreds of previously measured circulating metabolites for causal association with AAM and ANM. Genetic variants associated with each metabolite were extracted from four large metabolomic GWAS and effects of these variants on AAM and ANM were retrieved from the largest GWAS conducted for AAM (N = 329,345), and ANM (N = 200,000). We discovered 12 blood metabolites with evidence of a causal relationship with the AAM and 114 metabolites associated with ANM. Using multivariable MR, we found that the majority of these metabolites affect the timing of AAM or ANM regardless of body mass index (BMI). These molecules cluster in specific pathways, such as that of amino acid synthesis and glycerophosphocholine synthesis. We identified two of the candidate metabolites for AAM as significantly associated with ANM in ALSPAC participants (data requested as part of a separate project [B3667], aiming to predict AAM using a combination of genetic and non-genetic risk factors). Specifically we found an association between higher phosphatidylcholine levels and a later onset of AAM, and a link between lower isoleucine levels and an earlier onset of AAM, and the magnitude of the effects were comparable with those of the MR study. In this proposal, we request data on metabolites levels and AAM of ALSPAC mothers, in order to seek validation for a portion of the 114 candidate metabolites for ANM prioritized by our MR study, which have been measured in ALSPAC. This validation will provide further support to our MR findings, suggesting a causal role of the above metabolites in ANM.

Impact of research: 
We were able to identify circulating metabolites potentially influencing reproductive longevity using MR and follow-up pathway analyses. Notably, choline-containing phospholipids appear to influence both early puberty and menopause timing. The validation in ALSPAC of two metabolites for AAM is promising. Here, we week validation of additional candidate metabolites for ANM in ALSPAC. The results of this analysis can potentially provide an additional line of evidence to our MR findings and further support the idea that differences in the metabolic profiles of women with different pubertal or menopausal timing, while also uncovering new biological pathways underlying female reproductive aging.
Date proposal received: 
Wednesday, 2 November, 2022
Date proposal approved: 
Monday, 7 November, 2022
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Computer simulations/modelling/algorithms, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc.

B4174 - Better understanding the inter-generational transmission of intimate partner violence and abuse - 07/11/2022

B number: 
B4174
Principal applicant name: 
Alexa Yakubovich | Dalhousie University (Canada)
Co-applicants: 
Dr. Annie Herbert, UoB, Dr. Jon Heron, UoB, Gene Feder, Alexis Bragman, Bridget Steele, George Kephart, Jennifer Silcox
Title of project: 
Better understanding the inter-generational transmission of intimate partner violence and abuse
Proposal summary: 

Around one-quarter of young people in the UK report intimate partner violence and abuse (IPVA, that is, physical or sexual violence, or emotional abuse) among their parents by age 16. Research in US student samples suggests that for these young people, they are more likely to be victimised in their own intimate relationships as adolescents and young adults, this association my vary according to the timing of exposure to parental IPVA, and may be even higher for those with other adverse childhood experiences, such as maltreatment or parental mental illness. However, this has rarely been studied in a general population sample, or in the UK. Further, little is known about the burden of continued IPVA over the life-course on later health, that is, witnessing IPVA among parents to then experiencing IPVA in one’s own relationship. However, IPVA among parents does not guarantee future IPVA, and many go on to not to experience this in their own intimate relationships. Understanding what factors (e.g. parent-child relationships, school, peers) help to break the cycle of intimate partner violence, can inform policies and interventions to prevent further violence and improve quality of life in these families.

Impact of research: 
Existing research on the intergenerational transmission of IPV is limited because studies tend to only ask participants about their exposure to IPV between their parents once they have already reached adulthood. This retrospective research may be biased because people experiencing IPV in adulthood may be more or less likely to classify their childhood experiences as violent compared to those who are not currently experiencing IPV. Our research will allow us to produce a more robust understanding of the measurement and occurrence of the intergenerational transmission of IPVA in the general population, and the UK population in particular. It will help determine to what extent parental IPVA drives offspring IPVA beyond other co-occurring childhood experiences and whether the timing or chronicity of exposure to parental IPVA is importance to this association. In addition, we will be able to examine the cumulative impacts of exposure to IPVA over the life course on health and wellbeing. Our findings will inform future directions for national and international research on IPVA and the potential effectiveness of intervention strategies focused on early childhood and family environments. This research will thus be of interest to public health practitioners and researchers in the fields of adverse childhood experiences, resilience, and domestic and dating violence.
Date proposal received: 
Tuesday, 1 November, 2022
Date proposal approved: 
Monday, 7 November, 2022
Keywords: 
Epidemiology, Violence and Abuse, Statistical methods, Childhood - childcare, childhood adversity, Fathers, Mothers - maternal age, menopause, obstetrics, Offspring, Parenting, Sex differences

B4182 - Neurodevelopmental characteristics of children with genetic risk for epilepsy - 31/10/2022

B number: 
B4182
Principal applicant name: 
Doretta Caramaschi | University of Exeter (United Kingdom)
Co-applicants: 
Dr James Hodge, Dr Gemma Sharp, Rosie Walker, Mr Alexandros Primikiris
Title of project: 
Neurodevelopmental characteristics of children with genetic risk for epilepsy
Proposal summary: 

Epilepsy is the most common primary neurological disorder worldwide, with 10% of people experiencing a seizure during their life. Seizures often occur in combination with other neurological or behavioural traits indicating altered brain development. Seizures might also themselves negatively impact the neurocognitive development in early life. Understanding the links between epilepsy and other neurodevelopmental and neurological conditions is key to understanding the mechanism and impact of the disease. Large genome-wide association studies of epilepsy have found specific genes that are linked to brain function and might therefore explain the vulnerability of specific brain circuits in people experiencing seizures. It is not clear though how these genetic predispositions to epilepsy would affect other brain properties, for instance neurocognitive development. Therefore, we propose to investigate the molecular, neurodevelopmental and cognitive outcomes of having a genetic predisposition for epilepsy in the ALSPAC children.

Impact of research: 
This work will generate preliminary data to inform later projects aimed at understanding epilepsy and its co-occurring conditions.
Date proposal received: 
Wednesday, 26 October, 2022
Date proposal approved: 
Monday, 31 October, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Epilepsy, Statistical methods, Development, Epigenetics, Genetic epidemiology, Genomics, Intelligence - memory, Neurology, Speech and language, Statistical methods

B4185 - To investigate pathways relating to environmental risk factors immune markers and mental health outcomes in early adulthood - 31/10/2022

B number: 
B4185
Principal applicant name: 
David Cotter | Royal College of Surgeons in Ireland (Ireland)
Co-applicants: 
Jennifer Murphy
Title of project: 
To investigate pathways relating to environmental risk factors, immune markers and mental health outcomes in early adulthood
Proposal summary: 

We and others have identified numerous factors that influence mental health in young adults and early adulthood. These include obstetric complications, adversity, cannabis use, population density, immigrant status (PMID: 29352556, 12091183, 31563981) and most recently exposure to COVID (PMID: 35987197). Additionally, in the ALSPAC cohort, we recently identified that suicidal ideation at age 17 is associated with 7-fold increased odds of psychotic disorder, and with depressive disorder and generalised anxiety disorder at age 24. Indeed, over 40% of those with psychotic disorder in early adulthood had experienced this symptom in late adolescence (Mongan et al, 2022, unpublished).

We and others have also identified evidence for inflammatory marker dysregulation both preceding and in association with psychiatric disorders including psychosis, depression and recently, long COVID (PMID: 36085284 , 35472304). Dysregulation of acute inflammatory markers [such as Interleukin (IL)-6 and C-Reactive Protein] and complement proteins has been reported prior to and in association with these outcomes (PMID: 25133871, PMID: 32857162). Using ALSPAC data we identified for the first time the cross-sectional association of suPAR (soluble urokinase plasminogen activator receptor- an established marker of chronic inflammation) and IL-6 (an established marker of primarily acute inflammation) with psychotic disorder in young adults (Mongan et al 2022, under review). We previously found an inverse association between the antiinflammatory marker n-3 fatty acid docosahexaenoic acid (DHA) at age 17 and psychotic disorder at age 24 in the ALSPAC cohort (PMID 34059620). Using ALSPAC data we have also shown for the first time that elevated suPAR is associated cross-sectionally with cannabis exposure, itself a marker for mental illhealth (Power et al 2022 (under review)). We now seek to expand our knowledge to mental health outcomes in early adulthood (at age 24 and also at age 30 (when available)). We wish to examine not only associations between risk factors and inflammation in relation to clinical thresholds of psychiatric disorders, but also in relation to specific symptoms and symptom severity.

We hypothesise that exposure to environmental risk factors and early-life adversity is associated with chronic inflammatory dysregulation, in line with recent evidence (PMID: 31682707, 26033244, 34990745). We also hypothesise that inflammatory dysregulation will be more common in those who go on to report mental disorders in adulthood (PMID: 25133871, PMID: 32857162). Crucially, we hypothesise that inflammatory dysregulation mediates the relationship between environmental exposures and adult mental disorders, which could provide evidence for a biological mechanism by which environmental exposures influences the risk of adult mental disorder. Alternatively, environmental exposures and biological risk factors may operate independently, but have a cumulative effect on the risk of mental disorders.

We propose to investigate this using a combination of existing ALSPAC data, and new data derived from assays undertaken by us which assessed levels of the robust marker of chronic inflammation, suPAR, in age 24 plasma samples donated by ALSPAC participants.

Only data from B4168 will be used.

Impact of research: 
This research will allow us to further elucidate the relationship between risk factors for mental disorders, biological markers of inflammation, and psychiatric and functional outcomes
Date proposal received: 
Friday, 28 October, 2022
Date proposal approved: 
Monday, 31 October, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc.

B4186 - Investigating pathways relating to environmental risk factors immune markers and mental health outcomes in early adulthood - 31/10/2022

B number: 
B4186
Principal applicant name: 
David Cotter | Royal College of Surgeons in Ireland (Ireland)
Co-applicants: 
Jonah Byrne
Title of project: 
Investigating pathways relating to environmental risk factors, immune markers and mental health outcomes in early adulthood
Proposal summary: 

We and others have identified numerous factors that influence mental health in young adults and early adulthood. These include obstetric complications, adversity, cannabis use, population density, immigrant status (PMID: 29352556, 12091183, 31563981) and most recently exposure to COVID (PMID: 35987197). Additionally, in the ALSPAC cohort, we recently identified that suicidal ideation at age 17 is associated with 7-fold increased odds of psychotic disorder, and with depressive disorder and generalised anxiety disorder at age 24. Indeed, over 40% of those with psychotic disorder in early adulthood had experienced this symptom in late adolescence (Mongan et al, 2022, unpublished).

We and others have also identified evidence for inflammatory marker
dysregulation both preceding and in association with psychiatric disorders
including psychosis, depression and recently, long COVID (PMID: 36085284 ,
35472304). Dysregulation of acute inflammatory markers [such as Interleukin
(IL)-6 and C-Reactive Protein] and complement proteins has been reported prior to
and in association with these outcomes (PMID: 25133871, PMID: 32857162).

Using ALSPAC data we identified for the first time the cross-sectional association of suPAR (soluble urokinase plasminogen activator receptor- an established marker of chronic inflammation) and IL-6 (an established marker of primarily acute inflammation) with psychotic disorder in young adults (Mongan et al 2022, under review). We previously found an inverse association between the anti-inflammatory marker n-3 fatty acid docosahexaenoic acid (DHA) at age 17 and psychotic disorder at age 24 in the ALSPAC cohort (PMID 34059620). Using ALSPAC data we have also shown for the first time that elevated suPAR is associated cross-sectionally with cannabis exposure, itself a marker for mental illhealth (Power et al 2022 (under review)).

We now seek to expand our knowledge to mental health outcomes in early adulthood (at age 24 and also at age 30 (when available)). We wish to examine not only associations between risk factors and inflammation in relation to clinical thresholds of psychiatric disorders, but also in relation to specific symptoms and symptom severity.

We hypothesise that exposure to environmental risk factors and early-life adversity is associated with chronic inflammatory dysregulation, in line with recent evidence (PMID: 31682707, 26033244, 34990745). We also hypothesise that inflammatory dysregulation will be more common in those who go on to report mental disorders in adulthood (PMID: 25133871, PMID: 32857162). Crucially, we hypothesise that inflammatory dysregulation mediates the relationship between environmental exposures and adult mental disorders, which could provide evidence for a
biological mechanism by which environmental exposures influences the risk of adult mental disorder. Alternatively, environmental exposures and biological risk factors may operate independently, but have a cumulative effect on the risk of mental disorders.

We propose to investigate this using a combination of existing ALSPAC data, and new data derived from assays undertaken by us which assessed levels of the robust marker of chronic inflammation, suPAR, in age 24 plasma samples donated by ALSPAC participants.

Only data from B4168 will be used

Impact of research: 
This research will allow us to further elucidate the relationship between risk factors for mental disorders, biological markers of inflammation, and psychiatric and functional outcomes
Date proposal received: 
Friday, 28 October, 2022
Date proposal approved: 
Monday, 31 October, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc.

B4180 - Exploring the social transmissibility of smoking between parents and offspring - 27/10/2022

B number: 
B4180
Principal applicant name: 
Hannah Sallis | Population Health Sciences
Co-applicants: 
Mr Benjamin Woolf, Professor Marcus Munafo, Dr Neil Davies
Title of project: 
Exploring the social transmissibility of smoking between parents and offspring
Proposal summary: 

We aim to explore if parental smoking causes offspring to smoke more. Estimating the effect of social transmissibility of traits is methodologically difficult because people relatives generally share similar genetics and environmental exposures. This can make issues around confounding difficult to control for.
Children inherit a random half of each parent’s genetic liability. Mendelian randomisation (MR) is a study design in epidemiology which leverages this to analogise with a randomised controlled trial (RCT). In an RCT some people are randomised to an exposure, and then followed up over a period of time. In an MR study people are randomised to a genetic variant which increases their liability to an exposure at conception, and then recruited into a study some time after birth.
Although understanding the effects of second-hand smoking has important public health implications, it would be unethical to randomise someone to exposure to second hand smoking because of the definite harm on the individual who would have to smoke, and the probable harm on the person exposure to second-hand smoking.
Here we aim to explore an extension of MR to explore the social transmissibility of traits, and specifically whether parental smoking influences their children to smoke. Although we only inherit half of each of our parent’s genetic variants, the other half can still influence us via our parents. For example, if a parent has a variant which causes them to smoke, this variant in effect exposes their child to second-hand smoking. Thus, randomly not inheriting a smoking variant, is analogous to being randomised to second-hand smoking. Our research here will build on theoretical and simulation research already conducted to demonstrating the theoretical utility of this approach.

Impact of research: 
We expect two effects: firstly, the analysis will demonstrate the application of MR to study social and intergenerational transmission of health exposures. Secondly, there is currently a dearth of quantitative evidence demonstrating the social transmissibility of smoking. Our research could therefore provide important evidence for informing public health interventions.
Date proposal received: 
Tuesday, 25 October, 2022
Date proposal approved: 
Thursday, 27 October, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Statistical methods, Genetic epidemiology, Mendelian randomisation

B4179 - Allomaternal care and cooperation - 31/10/2022

B number: 
B4179
Principal applicant name: 
Pauline Grosjean | UNSW (Australia)
Co-applicants: 
Dr Sarah Walker , Professor Alessandra Cassar, Dr Matthew Olckers, Alice Calder
Title of project: 
Allomaternal care and cooperation
Proposal summary: 

A large literature has explored the implications of allomaternal care (care of children by people other than their mother) on child human capital development. This project will describe parental network of help in a developed country setting, and how help received with childcare from different caregivers influence child outcomes. We will also explore how such networks predict mother return to work decisions and wellbeing. Our findings will have implications to understand how social support networks influence child and maternal outcomes.

Impact of research: 
The government of Australia is implementing a series of reforms on parental leave and of the early childcare sector in the aim of boosting female labor force participation. The findings from the ALSPAC analysis will help us understand how child care networks (beyond formal childcare) influence maternal working decisions.
Date proposal received: 
Tuesday, 25 October, 2022
Date proposal approved: 
Thursday, 27 October, 2022
Keywords: 
Health Economics, Mental health, Statistical methods, Social science

B4183 - Separating adiposity from hormonal changes at menopause and investigating their causal relationship with cancer - 31/10/2022

B number: 
B4183
Principal applicant name: 
Joshua Bell | MRC IEU, University of Bristol (United Kingdom)
Co-applicants: 
Luke Mahoney, Prof Sarah Lewis, Prof Anna Murray, Dr Kate Ruth, Dr Rebecca Richmond
Title of project: 
Separating adiposity from hormonal changes at menopause and investigating their causal relationship with cancer
Proposal summary: 

Cancer is a leading cause of death, responsible for one in six deaths worldwide. Of these, breast is most common cancer and the 5th leading cause of death among all cancers. Breast cancer can be categorised as a hormone-sensitive cancer, along with prostate, endometrial and ovarian cancer, meaning the development of these cancers is driven by hormones. Menopause marks the end of a woman’s reproductive life and is characterised by changes in a woman’s biology including in the levels of sex hormones circulating their body. The levels of these hormones have been implicated in the risk of these hormone-sensitive cancers. The amount and distribution of fat (adiposity) are also known to change across the menopausal transition and in addition are known major risk factors for cancer. What is not currently known is how the changes in hormones and fat, specifically due to the menopause, affect the risk of cancer. Both hormone levels and fat quantity and distribution are known to be regulated, to some extent, by genetics. This project aims to use genetics of changes in hormone levels and fat quantity and distribution to determine their causal role in cancer risk, both independently and through their interaction. This research will help to identify the causal role of risk factors for cancer at a specific time-point which could then be targeted to prevent cancer.

Impact of research: 
This research aims to identify potentially modifiable risk factors at a time in a woman’s life that is of increasing importance in research. This will be used to inform targets for prevention of hormone-specific cancers.
Date proposal received: 
Thursday, 27 October, 2022
Date proposal approved: 
Thursday, 27 October, 2022
Keywords: 
Epidemiology, Cancer, GWAS, Genetic epidemiology

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