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.

Click here to export results in Word format.

B3323 - Longitudinal genome-wide association study of bone accrual in ALSPAC - 03/06/2019

B number: 
B3323
Principal applicant name: 
Ahmed Elhakeem | MRC Integrative Epidemiology Unit at University of Bristol
Co-applicants: 
Diana Cousminer
Title of project: 
Longitudinal genome-wide association study of bone accrual in ALSPAC
Proposal summary: 

While many genetic loci are known to be associated with adult areal bone mineral density (aBMD), less is known about genetic determinants of bone accrual. Our aims is to replicate in ALSPAC novel genome-wide associations with bone accrual in the Bone Mineral Density in Childhood Study.

Impact of research: 
High value publication
Date proposal received: 
Monday, 3 June, 2019
Date proposal approved: 
Monday, 3 June, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), GWAS, Statistical methods, Growth, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3322 - Assessing trajectories of e-cigarette use and smoking and their risk factors - 06/06/2019

B number: 
B3322
Principal applicant name: 
Katherine East | Addictions Department, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London (United Kingdom)
Co-applicants: 
Dr Sara Hitchman, Professor Ann McNeill, Dr Ioannis Bakolis, Jasmine Khouja, Amy Taylor, Dr Olivia Maynard, Professor Marcus Munafò
Title of project: 
Assessing trajectories of e-cigarette use and smoking and their risk factors
Proposal summary: 

Smoking is the world’s leading preventable cause of morbidity and mortality, killing over seven million people annually. Cigarettes contain nicotine, which is highly addictive. E-cigarettes are less harmful than smoking, can successfully deliver nicotine, and can help some smokers quit. However, their long-term health effects are unknown, and there are concerns about e-cigarette use among non-smokers. Longitudinal surveys show that non-smoking youth who use e-cigarettes are more likely to go on to try smoking. However, it is not clear whether (1) e-cigarette use can lead to nicotine addiction, sustained e-cigarette use, or regular smoking, (2) the association between e-cigarette use and smoking exists due to common risk factors.

This project therefore aims to assess the trajectories of e-cigarette use and smoking, and whether there are common risk factors for these trajectories.

Measures assessing e-cigarette use and smoking will be designed and included in the next questionnaire (2020-2021). Data from these will be combined with previous ALSPAC data on e-cigarette use and smoking to assess trajectories of product use. Previous ALSPAC data assessing individual, family, peer, school, and community-level factors will also be accessed and used to predict the different trajectories of use.

Impact of research: 
This project has the potential to impact e-cigarette and smoking policy and research. Findings may help: 1. Identify whether non-smoking young adults are becoming regular users of e-cigarettes, dependent on nicotine, and/or transitioning to smoking. 2. Identify groups at-risk for regular e-cigarette use, nicotine dependence, and smoking, to target prevention efforts. 3. Identify which risk factors for e-cigarette use and smoking are important to consider in future research.
Date proposal received: 
Wednesday, 29 May, 2019
Date proposal approved: 
Thursday, 30 May, 2019
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc.

B3313 - Biosocial Birth Cohort Research A cross-disciplinary network - 30/05/2019

B number: 
B3313
Principal applicant name: 
Sahra Gibbon | University College London
Co-applicants: 
Title of project: 
Biosocial Birth Cohort Research: A cross-disciplinary network
Proposal summary: 

This project will establish a network in which social scientists, geneticists and epidemiologists work together to better understand, and benefit from, longitudinal birth cohort studies, which follow participants throughout their lives, often including multiple generations. These studies are becoming more important in disease research, to understand how environmental factors affect our health. So far, social scientists have not played a prominent role in the design or implementation of this type of study. The input of social scientists is important to better understand the relationship between biology and society emerging from birth cohort studies. This project will fill this gap by creating a network of scientists from all disciplines, including the social sciences. The project will include longitudinal birth cohort studies in the Global North and also in the Global South, where little research has been carried out on how these studies work, how they are maintained and used.

Impact of research: 
Through virtual and face to face workshops and exchanges the project will have significant impact on the cross-disciplinary research activities of the leading experts involved in the network engaged in birth cohort research. The establishment of a visible web presence and public key note event in year two will allow the activities of the network to be disseminated to a broader audience, helping to develop wider cross-disciplinary capacity. We will publish in open access format; a. executive reports from the two workshop events b. a journal special issue including cross-disciplinary articles c. a position paper/commentary showcasing methodological innovation
Date proposal received: 
Wednesday, 15 May, 2019
Date proposal approved: 
Thursday, 30 May, 2019
Keywords: 
This project brings together cross disciplinary researchers from the social sciences and medical/life sciences., There is no specific disease condition that is the focus of this study., We are aiming to bring together expertise from the social sciences and biosciences (including social and genetic epidemiology)

B3312 - Neurocognition in Children with Atopic Dermatitis - 03/06/2019

B number: 
B3312
Principal applicant name: 
Joy Wan | University of Pennsylvania (United States)
Co-applicants: 
Title of project: 
Neurocognition in Children with Atopic Dermatitis
Proposal summary: 

Atopic dermatitis (AD), also known as eczema, is a chronic, itchy skin disorder that affects up to 20% of children. It has been associated with neuropsychiatric disorders such as depression, anxiety, and attention deficit hyperactivity disorder. Previous studies have shown higher rates of sleep disruption, inattention, and forgetfulness in children with AD compared to those without AD; these suggest that neurocognition, which encompasses functions such as language, memory, attention, and executive functions, may be impacted by AD. However, there are few studies of cognition in children with AD. Previous studies have also been limited by small sample size and have shown mixed findings. Thus, the purpose of this study is to compare neurocognitive function between children with and without AD using the large ALSPAC cohort. We will comprehensively assess multiple domains of cognition (e.g. attention, executive function, memory, IQ) using validated and standardized measurements. We will examine the overall impact of AD on these cognitive outcomes, accounting for demographic and socioeconomic factors and other comorbidities. In addition, we will examine whether cognitive function differs with respect to AD disease activity.

Impact of research: 
The proposed study addresses critical gaps in our knowledge about the cognitive impact of AD in the pediatric population. We expect that the findings will inform future prospective studies and mechanistic research on neuropsychiatric comorbidities of AD and also direct the development and implementation of interventions aimed at preventing and/or minimizing the cognitive impact of AD. The insight gained from our proposed aims has the potential to improve overall mental health care and clinical outcomes for children with AD.
Date proposal received: 
Wednesday, 15 May, 2019
Date proposal approved: 
Thursday, 30 May, 2019
Keywords: 
Epidemiology, Cognitive impairment, Eczema, Statistical methods, Cognition - cognitive function, Dermatology

B3319 - Clinical and cognitive profiles of adults with psychotic experiences with and without preceding PTSD - 28/05/2019

B number: 
B3319
Principal applicant name: 
Tjasa Velikonja | Icahn School of Medicine at Mount Sinai (USA)
Co-applicants: 
Eva Velthorst
Title of project: 
Clinical and cognitive profiles of adults with psychotic experiences, with and without preceding PTSD
Proposal summary: 

There is substantial evidence demonstrating that in addition to the well-established link between exposure to childhood trauma and Posttraumatic Stress Disorder, PTSD has been associated with an increased risk for other severe psychiatric disorders such as psychosis. Individuals with psychosis have been found to have higher comorbid rates of PSTD compared to the general population (30%-50% vs 7%-9%). Importantly, the link between psychosis and PTSD is complex and multifactorial. There is very little knowledge on what could explain the high comorbidity between PTSD and psychosis, and more specifically the mechanisms/pathways that may explain why trauma may lead to psychotic symptoms, PTSD or to a combination of both. To date, the literature has focused on two main hypotheses: a) PTSD stands as a mediator of the relationship between childhood trauma and psychotic symptom severity. A model of continuity has also been suggested, implying that psychotic symptoms would be an exacerbation of the PTSD symptoms and b) PTSD and psychosis are both part of a broader spectrum of reactions to trauma with similar explanatory mechanisms at the level of cognitive schemas (e.g. beliefs about self and others), attributional styles and dissociative processes. There is a paucity of empirical evidence evaluating either of these hypotheses. Examining clinical and cognitive profiles of adults with psychotic experiences, with and without preceding PTSD (after childhood trauma) would be the first step towards disentangling complex relationship between the two disorders.

Impact of research: 
The course of the illness, prognosis and treatment for psychosis (i.e. schizophrenia) and PTSD are very different, therefore, advancing knowledge on this complex relationship between psychosis and PTSD after childhood trauma is crucial in guiding targeted clinical interventions.
Date proposal received: 
Friday, 24 May, 2019
Date proposal approved: 
Tuesday, 28 May, 2019
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, PTSD, psychosis, cognition

B3316 - Genetics susceptibility to high BMI and its relationship to food intake in children - 23/05/2019

B number: 
B3316
Principal applicant name: 
Laura Johnson | Centre for Exercise, Nutrition and Health Sciences, School for Policy Studies, University of Bristol (United Kingdom)
Co-applicants: 
Franscisca Ibacache
Title of project: 
Genetics susceptibility to high BMI and its relationship to food intake in children.
Proposal summary: 
Impact of research: 
Understand the extent of genetics influence in relation to the development of obesity in children, and consequently, leading to stratified approaches to prevention and treatment, which is crucial for dealing with the current obesity epidemic that is known to have a multi-factorial aetiology.
Date proposal received: 
Monday, 20 May, 2019
Date proposal approved: 
Thursday, 23 May, 2019
Keywords: 
Genetics, Obesity, Statistical methods, Genetics

B3318 - Genetics of Child Growth Trajectories - 23/05/2019

B number: 
B3318
Principal applicant name: 
Kateryna D. Makova | Penn State University Department of Biology (United States)
Co-applicants: 
Sarah JC Craig, PhD, Francesca Chiaromonte, PhD, Matthew L. Reimherr, PhD, Ana Kenney
Title of project: 
Genetics of Child Growth Trajectories
Proposal summary: 

Our team is interested in variables that influence the weight gain patterns of young children. In this study we aim at identifying genetic variants (differences in the DNA between individuals) that could be used to predict which children are most at risk at developing childhood obesity. With this information we could identify children who would benefit most from early life obesity interventions.

Impact of research: 
Childhood obesity is a growing epidemic. With early life interventions, this growth could be prevented or even reversed. However, these interventions can often be expensive and labor intensive, which precludes their widespread implementation. If a test (such as a PRS) could be performed that identifies children who are most at risk of developing childhood obesity, intervention efforts could be focused on that sub-population. This would decrease the burden of intensive intervention programs.
Date proposal received: 
Tuesday, 21 May, 2019
Date proposal approved: 
Thursday, 23 May, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Obesity, GWAS, Statistical methods, Birth outcomes, BMI, Childhood - childcare, childhood adversity, Genetic epidemiology, Genetics, Genomics, Growth, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods

B3314 - The metabolomic profiling of cigarette smoking - 20/05/2019

B number: 
B3314
Principal applicant name: 
Osama Mahmoud | School of Psychological Science and Integrative Epidemiology Unit (IEU), University of Bristol (United Kingdom)
Co-applicants: 
Prof. Marcus Munafo , Professor George Davey Smith
Title of project: 
The metabolomic profiling of cigarette smoking
Proposal summary: 

It is hypothesized that exposure to cigarette smoking could influence the risk of cardiovascular diseases through direct modification of the lipoprotein profile, lipotoxicity and change in chronic oxidative stress. However, the metabolic profiling of cigarette smoking have not been precisely investigated.
Using the ALSPAC data, this study aims to provide insights into the molecular effect of smoking both in terms of the composition and the concentration of the molecular species affected.

Impact of research: 
Assuming that our hypothesis is true, this study will provide novel insights into the metabolic profiling of cigarette smoking in early adulthood. This work thus has the potential to contribute to the growing body of evidence suggesting association of smoking with cardiovascular disease through modification of metabolomics. Of particular interest will be whether we can identify potential mechanisms that are linking smoking exposure to cardiovascular disease.
Date proposal received: 
Thursday, 16 May, 2019
Date proposal approved: 
Monday, 20 May, 2019
Keywords: 
Epidemiology, coronary heart disease and cardiovascular disease., Metabolomics, NMR, Statistical methods, Cardiovascular, Metabolic - metabolism, cigarette smoking

B3315 - Intergeneration transmission of sexual abuse and violence - 20/05/2019

B number: 
B3315
Principal applicant name: 
Kate Walker | Coventry University, Coventry University (UK)
Co-applicants: 
Prof Sarah Brown
Title of project: 
Intergeneration transmission of sexual abuse and violence
Proposal summary: 

Children, particularly daughters, of mothers who have been victims of sexual violence and abuse have a higher risk of becoming victims of sexual violence and abuse, compared to children of mothers who have no such victimisation histories. The majority of studies examining this intergeneration 'transmission' of sexual abuse and violence have been conducted using samples from populations in which there are a high number of victims and outside the UK. Furthermore, studies have tended to focus on the sexual abuse histories of the mother and not the father. This study, using a general population sample (i.e., of people not specifically identified on the basis of being victims of sexual abuse) will enable us to identify the extent to which mothers' sexual abuse experiences increase the risk of similar victimisation in their children. We will also examine the impact of the sexual histories of fathers and what other factors (e.g., other types of abuse experienced by the mother and/or father, parents' mental health, children's early development and conduct disorders) exacerbate or reduce the risk of intergeneration transmission.

Impact of research: 
This research is important to understand in a general UK population study whether the child of parents who have been sexually abuse are at a greater risk of being victims of sexual abuse than children whose parents have not been abused. It will also highlight whether it is the sexual victimisation specifically or other factors that co-occur that increase the risk. This will have important implications for the prevention of sexual abuse, particularly in respect of identifying areas that can be the focus of intervention and support for parents who have experienced sexual abuse, in order that the risk to their children is minimised. If the findings show that the children of sexually abused parents are not at increased risk (i.e., due to the nature of the sample in this study compared to the specific sexual abuse population samples in most other studies), then the findings have significant impact for theory/policy developed on the belief of intergenerational transmission.
Date proposal received: 
Saturday, 18 May, 2019
Date proposal approved: 
Monday, 20 May, 2019
Keywords: 
Social Science, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Statistical methods, Child sexual abuse Inter-generation transmission Sexual violence and abuse

B3311 - Prediction of cardio-metabolic risk from circulating metabolites A longitudinal study from childhood to early adulthood - 28/05/2019

B number: 
B3311
Principal applicant name: 
Dimitris Vlachopoulos | Children's Health and Exercise Research Centre, Sport and Health Sciences, University of Exeter (United Kingdom)
Co-applicants: 
Prof Sulin Cheng, Dr Petri Wiklund, Dr Alan R. Barker, Dr Xu Leiting
Title of project: 
Prediction of cardio-metabolic risk from circulating metabolites: A longitudinal study from childhood to early adulthood.
Proposal summary: 
Impact of research: 
The results of this project will reveal early metabolic deviations and circulating biomarkers that predict cardio-metabolic risk in adulthood. These results may be used for the identification of high-risk children and adolescents in clinical practice.
Date proposal received: 
Monday, 20 May, 2019
Date proposal approved: 
Monday, 20 May, 2019
Keywords: 
Epidemiology, Bone disorders - arthritis, osteoporosis, Hypertension, Obesity, Medical imaging, Metabolomics, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cardiovascular, Childhood - childcare, childhood adversity, Growth, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Nutrition - breast feeding, diet, Physical - activity, fitness, function

B3310 - Puberty timing and cardiovascular structure and function at age 25 years - 13/05/2019

B number: 
B3310
Principal applicant name: 
Linda O'Keeffe | MRC Integrative Epidemiology Unit, University of Bristol (UK)
Co-applicants: 
Lisa Ryan
Title of project: 
Puberty timing and cardiovascular structure and function at age 25 years
Proposal summary: 

Puberty timing has been decreasing for several decades. Earlier puberty is thought to be associated with greater cardiovascular disease risk. The aim of this project is to examine the association between puberty timing and cardiac measures at age 25 years.

Impact of research: 
This work will help to clarify the evidence around puberty timing and its health effects in a contemporary birth cohort with rich data. Impacts may include implications for initiatives to prevent early puberty due to its downstream cardiovascular impacts.
Date proposal received: 
Thursday, 9 May, 2019
Date proposal approved: 
Monday, 13 May, 2019
Keywords: 
Epidemiology, Puberty timing; cardiovascular disease, Statistical methods, Offspring

B3309 - Understanding the mechanisms linking the urban environment to psychotic experiences across the lifespan - 21/05/2019

B number: 
B3309
Principal applicant name: 
Joanne Newbury | King's College London and University of Bristol (United Kingdom)
Co-applicants: 
Title of project: 
Understanding the mechanisms linking the urban environment to psychotic experiences across the lifespan
Proposal summary: 

Individuals who are raised in urban (versus rural) settings are around twice as likely to develop a psychotic disorder in adulthood. This association has now been replicated for subclinical psychotic experiences during childhood and adulthood (e.g., hearing voices, extreme paranoia). These symptoms lie on a continuum with clinical psychosis and therefore provide a useful marker to explore the urbanicity-psychosis association in the general population. Given that 70% of the world’s population will live in urban areas by 2050, it is essential that we uncover the pathways linking cities and psychosis so that we can inform intervention efforts.

Research supports a role of neighbourhood social factors correlated with urbanicity in the aetiology of psychotic experiences, such as neighbourhood disorder and social fragmentation (i.e., weak connections between individuals in a community). In addition, emerging research suggests that urban residents have a higher genetic risk for schizophrenia, meaning that the urbanicity-psychosis association could be partly confounded by genes.

However, very little is currently known about the potential role of air pollution in the link between cities and psychosis. Air pollution is the world's biggest environmental health problem, and is particularly problematic in cities. Recent cross-sectional research has provided the first evidence linking air pollution to psychotic experiences among teenagers.

However, longitudinal research into the link between air pollution and psychotic experiences is needed to establish the temporal nature of associations. In addition, neighbourhood social exposures are highly correlated with air pollution (i.e., the most deprived neighbourhoods also tend to be the most polluted). The interplay between neighbourhood social conditions and air pollution (i.e., confounding versus interaction) in relation to psychotic experiences is not known. Furthermore, though influences on inflammatory and cognitive processes are the most commonly suggested mechanisms linking urban exposures to psychosis, very few studies have directly tested these mechanisms.

This project will examine 1) the longitudinal associations of air pollution exposure from birth to age 15 with psychotic experiences in childhood and adolescence, 2) the interplay between neighbourhood social characteristics (neighbourhood disorder and social fragmentation) and air pollution in the emergence of psychotic experiences, and 3) potential biopsychological mechanisms linking urban neighbourhood exposures with psychotic experiences, including inflammation and cognition.

Impact of research: 
This research will serve a range of stakeholders, including researchers, industry, policymakers, and the general public. Air pollution is a known cause of physical disease, but very little is known about the impact of air pollution on mental health problems. My research will contribute to the evidence base on air pollution and mental health, which is essential for policymakers to make the economic case for tightening air pollution restrictions. Though a major global challenge, urban expansion nevertheless provides a unique opportunity for promoting healthy urban design. My research will also be useful to industry and policymakers to provide evidence on targets in the urban environment that could be modified to improve mental health. By identifying modifiable targets in the urban environment, this research has the strong potential to improve the mental health of urban residents now and for years to come. My plan for maximising impact of the findings is as follows: 1) I expect that the research proposed will lead directly to at least four publications in highly regarded journals with a broad readership. 2) I will disseminate findings via oral presentations at six international psychiatry/epidemiology conferences that attract a wide audience such as MQ Mental Health Science Meeting. 3) I will liaise with press teams such as the Science Media Centre to maximise the impact of the findings through press releases and press briefings. 4) I will ensure that findings are clearly presented to the public by preparing blogs and podcasts, and by participating in interactive open workshops and talks. 5) I will share my findings with policymakers by holding a policy lab with support from Policy Bristol.
Date proposal received: 
Wednesday, 8 May, 2019
Date proposal approved: 
Thursday, 9 May, 2019
Keywords: 
Epidemiology, Mental health, Statistical methods, Environment - enviromental exposure, pollution

B3306 - Modelling techniques for accelerated longitudinal studies - 07/05/2019

B number: 
B3306
Principal applicant name: 
Gwen Fernandes | Population Health Sciences (United Kingdom)
Co-applicants: 
Dr Jon Heron, Dr Fanny Kilpi , Professor Kate Tilling, Professor Debbie Lawlor
Title of project: 
Modelling techniques for accelerated longitudinal studies
Proposal summary: 

I met with Dr Fanny Kilpi following her presentation on some of the maternal data with cognitive outcomes from ALSPAC. Dr Jon Heron noticed the similarity in terms of structure of her dataset and wondered whether we could use these data to trial a new method of handling data produced from another study that we are involved with called cVEDA.

The purpose of this exercise is to trial a method/s of dealing with data including missing data that is completely new to me and the cVEDA (Indian cohort) team. It is purely for learning purposes and to consider any assumptions and adjustments we may make to our models when our final dataset is officially released at the end of 2020 i.e. a practice dataset.

Despite a publishable manuscript not being our primary goal it would be useful to have some input into how best to use these data, and which exclusions to make (e.g. HRT etc). Also, we may discover the analytical approach to be useful to you and then a publication may result if all collaborators consider this a worthwhile exercise and outcome.

Impact of research: 
The most tangible impact of this work will be to help guide our analysis plans for the final cVEDA dataset. As this is exploratory, we do not envisage publishing any of our findings but we will share these with Dr Kilpi and her team at every stage to ensure that we have their statistical input but also, if it might help inform their results, the collaboration could be mutually helpful.
Date proposal received: 
Wednesday, 1 May, 2019
Date proposal approved: 
Tuesday, 7 May, 2019
Keywords: 
Epidemiology, Methodological development without focus on specific outcome however we will be using either grip strength (biomechanical outcome) or cognitive functioning (mental health outcome) , Computer simulations/modelling/algorithms, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3307 - A multi-cohort GWAS of income using ALSPAC - 07/05/2019

B number: 
B3307
Principal applicant name: 
Tim Morris | University of Bristol (United Kingdom)
Co-applicants: 
Prof Nic Timpson, Dr Neil Davies, Mr Alex Kwong
Title of project: 
A multi-cohort GWAS of income using ALSPAC
Proposal summary: 
Impact of research: 
Academic
Date proposal received: 
Thursday, 2 May, 2019
Date proposal approved: 
Tuesday, 7 May, 2019
Keywords: 
Genetics, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., GWAS, Genetics, Genome wide association study, Social science

B3308 - The development of genetically-based pathways underlying problematic alcohol use - 07/05/2019

B number: 
B3308
Principal applicant name: 
Frances Wang | University of Pittsburgh (United States)
Co-applicants: 
Bernie Devlin
Title of project: 
The development of genetically-based pathways underlying problematic alcohol use
Proposal summary: 

Problematic alcohol use is a serious public health threat. Research suggests that there exist unique, biologically-based "types" of adolescents who are at high risk for problematic alcohol use. Discovering these types will help us identify personalized prevention targets for this condition. This proposal will examine patterns by which adolescent risk factors for problematic alcohol use (conduct problems, depressive symptoms, and personality traits) are inherited to identify new highly heritable traits. This proposal will also test sex differences in these new genetically-based traits and their relation to problematic alcohol use to shed light on whether differing treatments are needed for males and females.

Impact of research: 
This research could accelerate personalized prevention targets relevant to problematic alcohol use.
Date proposal received: 
Thursday, 2 May, 2019
Date proposal approved: 
Tuesday, 7 May, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, GWAS, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Development, Genetics, Psychology - personality, Sex differences

B3297 - Methods to identifying genetically regulated components using transcriptome data - 09/05/2019

B number: 
B3297
Principal applicant name: 
Jin Liu | Duke-NUS Medical School, National University of Singapore (Singapore)
Co-applicants: 
Title of project: 
Methods to identifying genetically regulated components using transcriptome data
Proposal summary: 

Although genome-wide association studies (GWAS) have been very successful in identification of genetic variants associated with complex traits, the mechanistic links between these variants and complex traits are still largely unknown. A scientific hypothesis is that genetic variants influence complex traits via affecting cellular traits, e.g., regulating gene expression and altering protein abundance. Yet, how to systematically examine this hypothesis remains an open problem.
Recently, large genomic consortia are generating a vast volume of genomic data towards comprehensively characterizing the regulatory role of genetic variants. For example, the Genotype-Tissue Expression Project (GTEx) has collected genomic profile of 449 individuals, comprised of measurements of gene expression from multiple tissues and about 12.5 million DNA bases, providing unprecedented opportunities to dissect genetic contributions to complex traits. Statistical methods that effectively harness multilayer data (genetic variants, cellular traits and organismal traits) for mechanistic interpretation are highly demanding. The phenomenon that genetic variants have individually weak effects on complex traits makes statistical modeling very challenging, because it requires that the developed models can efficiently exploit information in low signal-noise-ratio (SNR) regimes.
In the proposed research, we aim at developing statistical methods to advance mechanistic understanding of the role of associated variants in complex traits. The key idea is built upon the emerging scientific evidence that genetic effects at the cellular level are much stronger than those at the organismal level. In our pilot study, we proposed a statistical approach, AUDIS, to accounting for uncertainty in dissecting genetic contributions to complex traits by leveraging regulatory information. We also developed a parameter expanded expectation-maximization (PX-EM) algorithm to ensure that AUDIS can perform stably in low SNR regimes. Interestingly, two popular methods in this field, SKAT and PrediXcan can be connected via a stagewise view of AUDIS, as supported by results from comprehensive simulation studies. Then we applied stagewise AUDIS to analyze 20 complex traits in GERA by incorporating the transcriptome data in the Genetic European Variation in Health and Disease (GEUVADIS) Project. Real data analysis results show that AUDIS can identify more genetically regulated genes that are significantly associated with complex traits, without inflated type I errors. To continue in this promising direction, we propose generalized AUDIS models to allow detection of trait-associated expression quantitative trait loci (eQTLs), as well as integrative analysis of GWAS data with transcriptome data from multiple tissues. We also propose to investigate theoretical properties of our methods, e.g., why AUDIS can be immune to model mis-specification.
The novelty of this research is that a statistically efficient and computationally feasible framework is developed to dissect genetic contributions to complex traits. Specifically, the proposed methods (AUDIS and its generalizations) can effectively borrow regulatory information at the cellular level and then boost statistical power of identifying genetically-regulated and trait-associated genes, even though in low SNR regimes. The stagewise view of AUDIS not only offers a statistical connection between existing approaches, but also highlights the importance of statistically rigorous design. Unlike conventional engineering approaches that often only consider a point estimate or a maximum a posteriori probability estimate, the stagewise view of AUDIS implies that the posterior distribution obtained in former stage should be naturally incorporated as the prior in the later stage. This gives birth to a modularized design of the whole data analytics system, greatly helping biomedical researchers to gain new scientific insights. The statistical and computational skills developed here are also broadly useful to many other applications in the field of data science.

Impact of research: 
The impact of our research will lie on two sides. First, we will develop statistically rigorous methods to conduct integrative analysis of multi-platform genetic/genomic data. Second, the results from our analysis will help people better understand the mechanistic link that genetic variants influence complex traits via affecting cellular traits.
Date proposal received: 
Tuesday, 16 April, 2019
Date proposal approved: 
Tuesday, 30 April, 2019
Keywords: 
Bioinformatics, Bone disorders - arthritis, osteoporosis, Developmental disorders - autism, Cancer, Diabetes, Eating disorders - anorexia, bulimia, Eczema, Hypertension, Mental health, Obesity, Computer simulations/modelling/algorithms, GWAS, Medical imaging, Statistical methods, Statistical methods

B3299 - Clinical and Genetic Predictors of Polycystic Ovary Syndrome - 30/04/2019

B number: 
B3299
Principal applicant name: 
Laura Torchen | Northwestern University Feinberg School of Medicine (USA)
Co-applicants: 
Laura Rasmussen-Torvik, Margrit Urbanek
Title of project: 
Clinical and Genetic Predictors of Polycystic Ovary Syndrome
Proposal summary: 

Polycystic ovary syndrome (PCOS) is a common disorder affecting women associated with major adverse health outcomes including subfertility and increased risk for type 2 diabetes. PCOS is a complex genetic trait which arises from a combination of genetic risk and environmental such as obesity. Currently, a conclusive diagnosis of PCOS cannot be made until sexual maturation is complete and the patient develops the characteristic diagnostic features of hyperandrogenism, oligomenorrhea, and/or polycystic ovarian morphology. However, studies in girls with increased risk for PCOS, including daughters of affected women and girls with obesity, have identified early reproductive and metabolic features of the syndrome even prior to the onset of puberty. Investigations into the early origins of PCOS have been limited by small sample size and lack of longitudinal data. The ALSPAC cohort includes critical data needed to investigate PCOS, including maternal reproductive histories, hormone levels, and offspring pubertal development, reproductive hormone levels, and menstrual histories. These proposal seeks to identify early clinical and genetic predictors of PCOS. Data collected in this project will be used for preliminary data in planned future innovative investigations of the early origins of PCOS. This study will propose using a translational approach integrating whole genome sequencing, epigenetic, and metabolomics data available in this cohort with clinical predictors of PCOS. This proposed research will have a sustained and lasting impact on the field as it will inform future efforts toward development of targeted prevention and early treatment approaches in at-risk girls.

Impact of research: 
The proposed research will generate critical preliminary data required for a planned future extramural application aiming to employ this rich data source for innovative investigations of the early origins of PCOS. This study will propose using a translational approach integrating whole genome sequencing, epigenetic, and metabolomics data available in this cohort with clinical predictors of PCOS. This proposed research will have a sustained and lasting impact on the field as it will inform future efforts toward development of targeted prevention and early treatment approaches in at-risk girls.
Date proposal received: 
Wednesday, 17 April, 2019
Date proposal approved: 
Tuesday, 30 April, 2019
Keywords: 
Endocrinology, Polycystic ovary syndrome, GWAS, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Puberty, BMI, Development, Genetics, Genome wide association study, Hormones - cortisol, IGF, thyroid, Mothers - maternal age, menopause, obstetrics, Metabolic - metabolism, Offspring

B3305 - EFSA systematic review of Sugars 30-04-2019 - 120653 - 30/04/2019

B number: 
B3305
Principal applicant name: 
Pauline Emmett | CACH, University of Bristol (United Kingdom)
Co-applicants: 
Title of project: 
EFSA systematic review of Sugars (30-04-2019 - 12:06:53)
Proposal summary: 

Review of the literature relating dietary intake of sugars to adverse health outcomes is being undertaken by EFSA. Five ALSPAC papers have been selected for the review and need extra details added on precise intakes of sugars in order to improve their usefulness to the review

Impact of research: 
To enhance the contribution of ALSPAC to a systematic review
Date proposal received: 
Tuesday, 30 April, 2019
Date proposal approved: 
Tuesday, 30 April, 2019
Keywords: 
Epidemiology, Diabetes, BMI

B3304 - HDR Data Discovery Preparation for ATLAS - 02/05/2019

B number: 
B3304
Principal applicant name: 
Philip Quinlan | University of Nottingham (UK)
Co-applicants: 
Matt Styles, Tom Giles
Title of project: 
HDR Data Discovery: Preparation for ATLAS
Proposal summary: 

Medical research in the UK is still hindered by a perceived lack of suitable data and sample resources that can be used by the research community. This perception contrasts starkly with the knowledge that there are hundreds of potential resources that can supply data and samples. The work of the Tissue Directory and Coordination Centre and backed by the Medicines Discovery Catapult has shown that the actual problem experienced by both academic and commercial researchers is the inability to find suitable resources. The consequence is that researchers tend to utilise the resources that are close by proximity (because they can go and talk to the resource directly) rather than close to their research goals. This approach is driven because there is no easy mechanism in which to discover other potential national resources.
The Tissue Directory and Coordination Centre (TDCC) is the UKs national centre that is tasked with coordinating biobanks (samples and data) to ensure that researchers re-use existing resources before seeking to collect new samples or datasets. TDCC is a joint endeavour between the University of Nottingham and University College London. TDCC has created a Tissue Directory to allow a high-level search on aggregated meta data that works well for clinical and disease orientated biobanks. In part the Tissue Directory has begun to solve the issue of findability but the challenge has evolved. Researchers can search on very high-level classification of disease, gender and age and resources matching those criteria are displayed. This Directory acts as a first filter but does not allow researchers to ask detailed feasibility questions. Although candidate resources are listed the confidence that the data or samples required do actually exist remain low once sub-typing is considered. Assuming the identified resources have a search portal (many do not), the researcher would have to create accounts in each in order to perform a more detailed search. This effort can often go unrewarded as the ultimate answer is often that once more detailed criteria are added, the resource does not have the data or samples required.

It is clear that in order to support and utilise existing UK investment in health care resources we must have a more efficient mechanism in which a researcher can ask a relatively detailed question and understand whether resources exist that could support them. It is especially important that researchers find out quickly if something is not feasible (rather than investing time and finding it is not) and equally that referrals to the resources (such as ALSPAC) from the search system does not create irrelevant traffic. By bringing together key academic, technology and research infrastructure stakeholders we are seeking to change this to make the necessary change.

Impact of research: 
Date proposal received: 
Monday, 29 April, 2019
Date proposal approved: 
Tuesday, 30 April, 2019
Keywords: 
Data Discovery at scale

B3302 - Road traffic injuries and risk behaviours in children and young people with special educational needs - 29/04/2019

B number: 
B3302
Principal applicant name: 
Julie Mytton | University of the West of England, Bristol
Co-applicants: 
Dr Nicola Christie, Sarah O'Toole, Dr Elizabeth Orton, Prof Alan Emond
Title of project: 
Road traffic injuries and risk behaviours in children and young people with special educational needs
Proposal summary: 

Road traffic injuries are known to affect the vulnerable in our society. Children travelling to and from school, and young people especially young road drivers, are known to be at risk of being involved in a road traffic crash. We wish to explore whether children and young people with special educational needs (including physical or behavioural disabilities or learning difficulties) are at an increased risk of being injured in a road traffic crash. By better understanding how children with special educational needs are involved in road traffic crash events we can develop and test targeted interventions to prevent these injuries and deaths, and support the parents and carers of children and young people with special educational needs.

Impact of research: 
The identification of vulnerable road users and associated risk factors for injury may inform policy and prevention / intervention efforts to reduce road traffic injuries. Understanding how the risk of road traffic injury compares in children with SEND to those in typically developing young people may inform efforts to support these young people to keep safe on the roads. The parents and carers of young people with SEND may be more involved in providing support to their children beyond the time period of young people without such needs. The outputs from this research may therefore inform parents and carers of any additional risk their child may face and lead to improved resources for parents and carers. We intend to distribute outputs from this research to networks of organisations working with young people with SEND. Outputs will also include peer reviewed publications and conference presentations.
Date proposal received: 
Saturday, 20 April, 2019
Date proposal approved: 
Monday, 29 April, 2019
Keywords: 
Epidemiology, Injury, Statistical methods, Injury (including accidents)

Pages