Proposal summaries
B4097 - Investigating the impact of variation in BMI on the metabolome using multiple study designs - 29/06/2022
Obesity is known to have effects on cellular metabolism, which is reflected in a person’s circulating metabolome. Metabolomics, defined as the measurement and study of circulating small molecules that are the substrates and products of cellular metabolism, is increasingly used by epidemiologists to provide a functional read-out of bulk cellular activity and a proxy to individual current health. This approach also provides insight into biological pathways linking exposures and disease.
Measuring the metabolome of people with measured body mass index (BMI) allows us to look for ways in which BMI affects the metabolome. Metabolites found to be associated with BMI can then be further investigated and linked to cellular pathways – knowledge which will help us to understand the pathology of obesity. We have already begun to look at how bariatric surgery (within the By-Band-Sleeve trial (BBS), https://bristoltrialscentre.blogs.bristol.ac.uk/details-of-studies/by-ba...) and non-surgical weight loss interventions (within the DiRECT trial, https://www.directclinicaltrial.org.uk/) affect the metabolome, and we want to use the recall-by-genotype (RbG) Metabolon data in ALSPAC (https://onlinelibrary.wiley.com/doi/full/10.1002/oby.23441) to compare our results to population-level data. Bringing together data from these different study designs enables to unpick the metabolomic effects that are associated with BMI and their relevance to disease.
B4096 - Center for Causal Data Science for Child Maltreatment Prevention - 27/06/2022
Maltreatment by caregivers is associated with devastating consequences; include poor school performance, mental disorders, substance abuse, violence and suicide, and chronic health problems. Despite decades of research to acquire the scientific knowledge to prevent maltreatment exposures (ME’s) and maltreatment-related outcomes (MRO’s); only a small proportion of those children at risk have benefited. Complex etiology entails several requirements for scientific knowledge to achieve preventative results for a large proportion of children at risk: (1) etiology must be accurately determined (at the approximate level of its’ complexity), because intervention targeting non-etiological/non-causal factors cannot result in reduced risk, (2) valid models of complex etiology must be used to enable unbiased estimates of quantitative causal effect, (3) intervention targets must be identified from those factors with largest causal effect, and (4) personalized and precise intervention strategies must be determined from those intervention targets. We propose to address these considerable barriers to progress, by establishing the Center on Causal Data Science for Child and Adolescent Maltreatment Prevention (The CHAMP Center), to (1) discover the scientific knowledge on the complex etiology of the ME’s and MRO’s, by applying state-of-the -art methods of Causal Data Science to several large, and highly relevant existing data sets; (2) translate this knowledge into specific Decision Support Tools for those practitioners, whose decisions – when supported by these tools – can result in large-scale prevention, and (3) validate this knowledge in the field, in trials using the developed Decision Support Tools, with those practitioners, and the children and families whom they serve.
B4095 - Understanding predictors of study participation amongst individuals with mental health difficulties in established cohorts - 18/07/2022
This project aims to understand better the factors which affect participation in research, both academic and NHS service evaluation. This will involve a mix of quantitative bias analyses using electronic health records from the NHS Mental Health Partnership for Avon and Wiltshire Partnership, as well as a qualitative component aiming to understand better the reasons why continued participants (ALSPAC) and non-participants (recruited through AWP) perceive that individuals might participate or not participate in health research.
B4081 - Identifying master regulators of gene expression in human immune cells - 16/06/2022
Common genetic variants that differ between individuals in a population lead to millions of ‘natural experiments’ that can be used to gain insight into the principles of how our immune system works. However, most published studies relying on this information have been too small take full advantage of these natural experiments. In this project, we plan to assemble genetic variation and gene expression data from up 10-15 individual studies that have all profiled multiple cell types of our immune system. We expect that joint analysis of these data will help us to identify master regulators gene expression - genes that control the activity patterns of other genes - and help us understand how these genes contribute to complex immune-mediated disorders.
B4093 - Measuring steroid hormones in ALSPAC hair samples - pilot study - 11/07/2022
In response to a stressful situation, whether psychological or physical, the human body activates processes that aim to increase chance of survival. This “fight-flight-freeze” response could include making you feel more alert, giving the body energy and making you feel less pain. One key hormone involved in this response is cortisol.
Although the release of cortisol in response to stress is initially beneficial, it is thought that experiencing severe or ongoing stressful events can lead to a maladaptive stress response which can result in harmful effects on the body[1]. As such, the stress response system has been implicated in a range of adverse outcomes including obesity, cancer, heart disease, susceptibility to infection, and psychiatric disorder[2].
Commonly, cortisol is measured from saliva samples two or three times daily. However, as cortisol is secreted in a pulsatile fashion throughout the day, these measures are difficult to interpret and compare as it is uncertain whether samples are taken at the same time point along a pulse. Furthermore, saliva measures provide limited information about long-term cortisol secretion.
In contrast, hair cortisol concentration can provide a non-invasive, alternative assessment method capturing information about cortisol levels over the course of several months, thus overcoming the difficulties of single timepoint measures. Validation studies strongly support the assumption that hair cortisol concentration provides a valid index of long-term cortisol concentrations[3]. As such, given its advantage of providing information on the mean stress levels during a chosen extended period, hair cortisol analysis is increasingly being applied in many studies of physical and mental health[4-6].
We propose to conduct a pilot study in ALSPAC (n= 10-20 hair samples, collected at age 15years) to determine the feasibility of measuring steroid hormone concentrations from adolescent hair samples using liquid chromatography tandem mass spectrometry (LC-MS/MS)[7]. If successful, these results will be used in a funding proposal to extend measurement to a larger number of ALSPAC hair samples.
Within the funding proposal, we aim to use measures to investigate the associations between hair cortisol concentrations and subsequent mental health, and to perform a genome-wide association study (GWAS) of hair cortisol concentrations. GWAS results will be meta-analysed with 9 other cohorts within the CORtisol NETwork (CORNET) to provide the first GWAS to date of hair cortisol concentrations.
References
1. Charmandari, E., et al., Endocrinology of the stress response. Annual Review of Physiology, 2005. 67: p. 259-84.
2. Adam, E.K., et al., Diurnal cortisol slopes and mental and physical health outcomes: a systematic review and meta-analysis. Psychoneuroendocrinology, 2017. 83: p. 25-41.
3. Stalder, T., et al., Analysis of cortisol in hair--state of the art and future directions. Brain, Behavior, and Immunity, 2012. 26(7): p. 1019-29.
4. Iob, E., et al., Cardiovascular Disease and Hair Cortisol: a Novel Biomarker of Chronic Stress. Current Cardiology Reports, 2019. 21(10): p. 116.
5. Ling, J., et al., Body mass index, waist circumference and body fat are positively correlated with hair cortisol in children: A systematic review and meta-analysis. Obesity Reviews, 2020. 21(10): p. e13050.
6. Koumantarou Malisiova, E., et al., Hair cortisol concentrations in mental disorders: a systematic review. Physiology & Behavior, 2021. 229: p. 113244.
7. Gao, W., et al., Quantitative analysis of steroid hormones in human hair using a column-switching LC–APCI–MS/MS assay. Journal of Chromatography B, 2013. 928: p. 1-8.
B4047 - Assessing the association between a DNA methylation-based exposure score for maternal smoking during pregnancy and neurodevelopm - 14/06/2022
Maternal smoking during pregnancy has been related to lower child neurodevelopment and higher behavioural problems. However, there is a need to replicate such analyses in a consortium of several European cohorts, using machine learning-based DNA methylation smoking scores. The harmonization of mental health problems in several population-based birth cohorts will allow us to perform trajectory analyses with specific mental health domains.
B4090 - Early Psychedelic Use and Brain Structure in Young Adults - 13/06/2022
There has been a dramatic reemergence of research into the therapeutic effects of psychedelic substances over the past decades (Nutt & Carhart-Harris, 2021). For example, a recent randomized controlled trial investigated the effects of psilocybin on depressive symptoms among patients with moderate-to-severe major depressive disorder. The results showed that the psilocybin condition was at least as effective as a leading antidepressant (escilatopram) in reducing depressive symptoms (Carhart-Harris et al., 2021). Although previous research has found associations between long-term use of ayahuasca (20 ayahuasca users versus 20 matched controls) and brain structure (Bouso et al., 2015), relatively little is known about the potential effects of other psychedelics such as psilocybin (‘magic mushrooms’) and lysergic acid diethylamide (LSD) on brain structure, especially in adolescence. This research project therefore aims to investigate associations between early use of psychedelics (i.e., psilocybin, LSD) and brain structure.
References
Bouso, J. C., Palhano-Fontes, F., Rodríguez-Fornells, A., Ribeiro, S., Sanches, R., Crippa, J. A. S., ... & Riba, J. (2015). Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans. European Neuropsychopharmacology, 25(4), 483-492.
Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., ... & Nutt, D. J. (2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine, 384(15), 1402-1411.
Nutt, D., & Carhart-Harris, R. (2021). The current status of psychedelics in psychiatry. JAMA psychiatry, 78(2), 121-122.
B4089 - Genome-wide association study of suicidal thoughts and attempts - 08/06/2022
Genome-wide association studies (GWAS) have been instrumental in highlighting associations between genetic variants and 1000s of traits. A recent GWAS of suicide attempts by the psychiatric genetics consortium (PGC) Suicide Working Group identified 2 genome-wide significant loci (Mullins et al., 2021). The PGC are expanding their work to separate GWAS of suicidal ideation and attempts and are seeking additional cohorts. We plan to include ALSPAC data from the mothers and the children in the next round of analysis for suicide attempts and suicidal ideation PGC GWAS. We will prepare summary statistics from the GWAS to be shared with the PGC and perform subsequent in cohort analysis. This will be a big step towards incorporating ALSPAC data into psychiatric genetics. The summary statistics will contain no identifiable information.
B4087 - UK LLC Examining the serological response to SARS-CoV-2 infection and vaccination across the National Core Studies - 03/06/2022
Information can be obtained from ALSPAC (B number folder) or the UK LLC on request
B4086 - UK LLC Methodological enhancement and documentary analysis of the UK LLC - 03/06/2022
Information can be obtained from ALSPAC (B number folder) or the UK LLC on request
B4088 - Inconsistencies in accounting for age in studies on epigenetic accelerated aging and recommendations for best practices - 01/06/2022
Individuals age at different rates depending a variety of factors such as their genetics, lifestyle and exposure history. Numerous studies have shown that DNA methylation measured in blood and saliva can provide aging estimates that are informative about future risk of death and disease. Through a review of this literature, we uncovered popular approaches that incorrectly evaluate correlations between DNA methylation aging estimates and aging-related disease and their risk factors. We would like to use ALSPAC data to determine the likely implications these incorrect evaluations have had on published findings. In particular, we propose to calculate correlations between aging estimates and disease risk factors in ALSPAC both correctly and incorrectly to determine how much they differ.
B4085 - The structure of HCL-32 in ALSPAC - 01/06/2022
Non-clinical individuals with subsyndromal hypomanic experiences have been shown to be at a heightened risk for developing BD and have been linked to similar severity and impairment experienced by people with BD. A better understanding of the characterisation of hypomania in young people may help improve accurate and timely diagnosis of BD. Despite its potential importance, limited research is available concerning the structure of hypomania among non-clinical young people, particularly in the UK. Therefore, the current study will explore the structure and characterisation of hypomania in a British nonclinical cohort. We propose to examine the distribution and underlying structure of components of hypomania in ALSPAC, along with measure of different psychological and psychopathological dimensions and investigate hypomania symptoms’ association with other psychopathological variables (e.g., substance abuse). Using confirmatory factor analysis and latent class analysis, this study may help explore the structure and characterisation of hypomania in young people. Better understanding of hypomania could provide opportunities for targeted intervention and prevention.
B4077 - Using metabolomic data statistics and machine learning to predict severe COVID-19 and long COVID - 30/05/2022
The central idea of the proposed research is to use metabolic biomarkers to predict the severity of COVID-19 and the likelihood of long COVID for individuals that have not necessarily been diagnosed with a pre-existing health condition. To this end, we will use pre-pandemic data from several cohort studies which, in addition to basic information on age, sex, ethnicity, etc, contain hundreds of metabolic biomarkers for thousands of individuals. To understand the link between these characteristics and the impact of COVID-19, we will use symptoms data for those individuals in the cohort studies that had COVID-19. The data will be analysed with statistical methods to identify associations between the characteristics of individuals before the pandemic and the severity of the disease. This analysis will be complemented with computer programs developed to predict if the infection of an individual will have serious effects based on his/her characteristics before the pandemic. Machine learning techniques will be used to train computer programs to automatically recognise metabolic features that represent a risk for severe COVID-19.
B4076 - The effects of childhood and adolescent physical activity for mental health across future life stages - 30/05/2022
It is well established that physical activity has positive associations with mental wellbeing, and can protect against ill-being and mental health disorders. Further evidence suggests that in general, the most active young people continue to be the most active during adulthood. This infers that more active young people might be at less risk of poor mental health across future life stages. Findings from our recent systematic review (in press) suggested that there was reasonably consistent evidence for a beneficial effect of activities performed between the ages of 5-17 for depression at least 12 months later. Findings relating to anxiety and wellbeing were equivocal and require further research. The current study aims to take an evidence-based approach using the conclusions of our systematic review to direct research methodology. Findings will have implications for public health policy by expanding our understanding of active living in youth and the potiential impact this has on self-reported mental health across future life stages.
B4080 - Does LCT predict milk consumption - 30/05/2022
A single genetic variant (rs4988235) found in the intron of a the gene MCM6 and located -13,910 base pairs from the gene LCT controls the expression of LCT and the production of lactase, an enzyme required to digest lactose sugar commonly found in fresh milk products. In the ancestral state once infants are weened from breast milk the expression of LCT stops, but in some global human populations, including Europeans, the expression of LCT persists into adulthood and throughout one's life leading to what is commonly referred to as lactase persistence. Here we wish to ask if the genetic variant rs4988235 perviously associated with lactase persistence influences milk consumption in ALSPAC mothers.
B4075 - Anxiety and depression in young people who do they affect who seeks treatment and who responds to treatment - 30/05/2022
Anxiety and depression are common mental health conditions, and represent a major cause of distress and disability in young people. We do not yet understand a) which factors predict vulnerability in young people, b) what predicts who seeks treatment, or c) what characterises young people who respond to treatments compared to those who do not. We need to understand risk factors to allow us to target preventative efforts more effectively. Furthermore, understanding what determines who seeks treatment might allow greater outreach and support to be given to underserved populations, and understanding the factors determining treatment response may allow future research into novel treatments to be targeted, and greater clinical monitoring of those at risk of non-response. Performing this research in young people specifically is important: not only are young people at a critical point in life where they are forming relationships and making decisions about education and careers, but successful treatment access and response might also determine their future mental health. We propose to analyse data from the ALSPAC study, among others, to understand the factors affecting all these parts of young people’s mental health pathways. We also aim to produce an online, interactive, browser-based application that a) researchers, educators, clinicians and policy-makers can use to understand who to target prevention efforts towards, and b) so that young people and their families can have access to the same knowledge as those involved in treating them.
B4083 - Social connection as an active ingredient to prevent depression and anxiety in youth - 30/05/2022
The different types of social connections that young people have when they grow up can affect their mental health. Yet we know very little about how these social factors interact with each other and how they impact the development of depression and anxiety in children and young people. We set out to study how, when and for whom social connections work as an active ingredient for the prevention of common mental health problems (depression and anxiety) in children and young people. We use data collected from ALSPAC to investigate how the development of depression and anxiety was impacted by different types of social connections at different stages of their life. We will use data collected about different types of social relationships experienced by the children and young people at different points in time (such as connections with their family, community, online, teachers and friends) to investigate how these affect development of depression and anxiety over time. We will also analyse data collected from respondents when they were children to see if there is evidence to suggest that social connections in early life affect the development of depression and anxiety at later time points.
B4084 - AvonCAP Hospital Study - 11/07/2022
AvonCAP is an ongoing surveillance study, which aims to record detailed information on every adult patient admitted to Bristol’s two large NHS Trusts with symptoms, signs and/or X-ray evidence of acute disease in the lungs. This includes patients with pneumonia, non-pneumonic respiratory infection, exacerbation of chronic respiratory disease (eg asthma, COPD, pulmonary fibrosis) and heart failure. Additionally, we include patients hospitalised with a positive SARS-CoV-2 test. The study is designed to provide comprehensive surveillance of all adults hospitalised with acute respiratory disease in a defined geographic area, thereby providing an accurate estimate of disease incidence. AvonCAP further aims to investigate how lung diseases may be changing during the COVID-19 pandemic, particularly those which may be preventable in the future by new vaccines. This will enable better implementation and design of public health measures, and may be used to determine national vaccination implementation policy.
Health related data is collected for study eligible adults hospitalised at NBT or UHBW NHS Trust, either via consent or under COPI regulations (the study holds CAG approval to use non-consented data). Some study patients also give their consent to provide samples e.g. saliva, nasopharyngeal swabs, etc.
This proposal will identify patients who are in both the AvonCAP and ALSPAC datasets, and allow sharing of specified data fields between the two studies for these patients. Due to the age range of AvonCAP participants, this is likely to include the parents of the Children of The 90s.
Only relevant ALSPAC data fields will be shared with the AvonCAP study team, and will include potential risk factors for lung disease (e.g. occupation and environment factors, pets), details of GP visits and COVID-19 test results. The AvonCAP study will in turn provide data fields of interest to the ALSPAC project.
This proposal allows data collected on participants in these two studies to have added value and greater contribution to the scientific aims of each project.
B4082 - Sex stratified acne GWAS meta-analysis - 27/05/2022
Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Family and twin studies indicate a substantial genetic contribution to acne susceptibility with heritability estimates of 78 and 81%. Genome-wide association studies (GWAS) have made a substantial contribution to the understanding of the genetic basis of several common cutaneous inflammatory disorders. Here we perform a genomewide association analysis, comparing severe cases of acne with controls in females and males separately to identify and replicate genetic determinants.
B4067 - Adverse Childhood Experiences and the onset of mental health symptom stages - 27/05/2022
Adverse childhood experiences (ACEs), such as abuse, threaten individuals’ life-long
well-being. A growing body of research has supported ACEs’ negative influence on long-term
mental health; however, many existing studies measured ACEs by retrospective self-report, that
is, by adults recalling their childhood experiences. However, there is a need to study
prospectively followed cohorts in order to minimise biases in participant selection and
measurement of ACEs. Examining the impact of ACEs on symptom outcomes conceptualised as
stages could help improve our understanding of the staging model in psychiatry. Therefore, this project proposes to explore the prospective impact of ACEs on the progressive stages of mental disorders in adulthood,