Proposal summaries
B2980 - Asthma and BMI aetiology of lean mass versus fat mass - 13/11/2017
Asthma is a chronic and complex condition that can be difficult to diagnose. The annual prevalence of asthma in the UK is estimated to be 6.0 million people. Although there is evidence to suggest that the prevalence of asthma has plateaued in the UK since the 1990s, the NHS still spends around £1.1 billion on treating individuals with asthma. Observational studies have provided evidence of a positive association between adiposity (measured as body mass index (BMI)) and risk of asthma in both children and adults. Since the prevalence of asthma remains high, identifying modifiable risk factors, such as body composition, should be a priority. Since observational studies can suffer from confounding, we would like to apply Mendelian randomization analyses to the ALSPAC dataset to determine whether body composition has a causal effect on the risk of asthma.
B2982 - Lifecourse aetiology of dementia and cognitive decline Improving causal inference - 13/11/2017
Dementia describes a set of symptoms including memory loss and difficulties with thinking, problem-solving or language. The term 'dementia' encompasses several different types of disease, with Alzheimer's dementia being the most common. Dementia is now the second leading cause of death in England and Wales, thus, finding ways to prevent dementia is a public health priority. Dementia is not only a great burden on our economy and health care system, but also on the families and friends of those suffering with the disease. Furthermore, medications that are currently available are unable to delay the onset of, or cure, dementia. It is therefore essential that we identify factors that increase a person's risk of getting dementia, especially things that we are able to change (such as smoking or diet), so that we can intervene and try to prevent it occurring in the first place.
Findings from existing studies that have tried to identify risk factors for dementia are conflicting. The only risk factors for which we have good, consistent evidence so far are age (the older a person is, the greater their risk of dementia), sex (being female), low education, head trauma and some cardiovascular risk factors such as diabetes. Evidence for other risk factors such as smoking, alcohol consumption, diet and physical activity, is less clear in that they have reported positive (i.e. increasing risk), negative (i.e. decreasing risk) and no effects on dementia. One key problem is that there are many complications when studying causes of dementia. It is a complex disease that can begin up to 20 years before people start presenting with symptoms, making it difficult to assess whether the risk factors being studied are a cause or a consequence of dementia. For example, it is still unclear whether depression in adulthood is a risk factor for dementia, or whether the early brain changes in dementia cases result in depressive symptoms. Moreover, people with dementia who are still actively participating in studies are often the more 'healthy' than those who leave the study due to illness or death, which can bias study results (i.e. give us the wrong answer).
My project aims to characterise if and how people at increased genetic risk of dementia differ in terms of their cognitive capability across the whole life course. For example, do people with increased genetic risk of dementia achieve lower grades at school and achieve a lower cognitive peak in early life? Do they start to decline cognitively at an earlier age, or at a faster rate than people who are not at increased genetic risk of dementia? My project also aims to identify causal risk factors for dementia by employing state of the art analytical approaches and by studying many different groups of people (cohorts). Consistent research findings across multiple cohorts of people will not only provide confidence in my findings and yield important insights into true, causal risk factors for dementia, but it will also help to inform dementia prevention strategies.
In summary, the proposed research will help to bring clarity to some of the conflicting literature on dementia risk factors, which in turn will improve translation into public health policies for interventions, with the overriding aim of preventing dementia.
B2992 - Early life adversity and educational attainment - 16/11/2017
Early life adversity (e.g. abuse, neglect, parental illness, parental death, parental separation) is associated with a range of poor outcomes in later life, including both social and health outcomes. This project will investigate the association between early life adversity and educational attainment.
B2979 - Genome wide association study for dental anxiety - 09/11/2017
Dental fear is common and acts as a barrier to receiving routine oral healthcare. As well as the psychological impact of dental fear, the inability to access dental care may have impact on oral health status or even systemic health. Dental fear can result from negative experiences, but different individuals also have differing genetic susceptibility to dental fear and the condition is around 30% heritable. Despite this, there is limited understanding of the genetics of dental fear, probably because few large studies have measured dental fear using a validated index. Within ALSPAC dental fear was measured using the Corah anxiety scale at age 17.5 years.
ALSPAC has been invited to join a new consortium investigating the genetics of dental fear, which may shed new light on the biology of dental fear or novel ways to identify individuals at risk.
This project aims to undertake analysis in ALSPAC as part of this consortium, allowing ALSPAC to contribute to this novel, exploratory research.
B2975 - Linking Antibiotic Use and Allergies - 31/10/2017
I were keen to explore ALSPAC for the data that would allow us to test the following hypotheses:
Hypothesis 1: Those who have more antibiotic exposure report a higher incidence of allergies/food intolerances
If there is data to support Hypothesis1, then we can explore more detailed hypotheses:
Hypothesis 2: Early childhood exposure to antibiotics is most important for predicting whether someone will acquire allergies/food intolerances (and which ones)?
Hypothesis 3: Those who have pets (particularly dogs) in the household are less likely to acquire allergies/food intolerances, regardless of antibiotic use.
B2976 - HDHL-Biomarkers Early life programming of childhood health a nutritional and epigenetic investigation ALPHABET - 31/10/2017
The rising prevalence of obesity, cardiometabolic disease, asthma, osteoporosis and neurodevelopmental disorders over recent decades cannot be fully explained by genetic or adult lifestyle factors. Increasing evidence suggests that early life exposures influence health throughout life. Maternal diet during pregnancy is a critical yet modifiable exposure, however the specific dietary requirements for optimal fetal growth and development are unknown. Furthermore studies of maternal diet tend, for the sake of simplicity, to focus on single nutrients. Nutrients, however, are not consumed in isolation so conclusions from these studies are limited. A continuing mystery is how early life exposures are able to affect health years later in spite of dramatic lifestyle changes in adulthood.
This project aims to advance the state-of-the-art by examining the combined health effects of multiple dietary components reflecting the whole diet and evaluating the potential of DNA methylation as a means by which the influence of early dietary exposures are maintained into old age. Utilising biological samples and data from existing European longitudinal birth cohorts such as ALSPAC, we will investigate the complex relationships between maternal diet (defined by dietary quality and a novel index of dietary inflammatory potential), offspring health outcomes (including adiposity, bone, cardiometabolic, respiratory and neurodevelopmental health) and DNA methylation patterns from birth to adulthood. We hope that these investigations will identify opportunities to refine dietary recommendations and to aid development of more effective evidence-based public health strategies to reduce obesity, improve health and attenuate development of a range of adverse health outcomes in future generations.
B2977 - Causal relationship between circulating low density lipoprotein C LDL-C and the IGF pathway A Recall by Genotype study in ALS - 09/01/2018
Population-based studies examining the relationship between IGF-I and IGFBP-3 with lipids have yielded conflicting results [1-3]. However, most of the studies are limited by their cross-sectional design and suffer from problems such as reverse causality and confounding. Several epidemiological studies have shown that statin use is associated with decreased levels of circulating IGF-I and IGFBP-3 [4-6]. These findings suggest that changes in the IGF pathway can be affected by metabolic changes. Further studies are needed to elucidate the direction of the causal relationship between lipids and the IGF pathway. One approach to investigate causality is Mendelian randomization (MR) which uses genetic variants as proxies for an observational exposure to assess and quantify the causal relationship between exposures of interest and outcomes or intermediate phenotypes [7]. Using summary level Genome Wide Association Studies (GWAS) results from two large-scale GWAS for IGF pathway (IGF-I and IGFBP-3) [8] and lipids traits (low density lipoprotein C (LDL-C), high density lipoprotein C (HDL-C) and triglycerides (TG)) [9], our recent MR analysis found evidence that increased LDL-C levels was associated with increased IGFBP-3 levels (unpublished results). To replicate these findings and to investigate the causal relationship between circulating LDL-C levels and members of the IGF pathway (IGF-I, IGF-II, IGFBP-2 and IGFBP-3), we are proposing to carry out a sample-based Recall by Genotype (RbG) study using a rare genetic variant in PCSK9 (rs11591147) that is associated with circulating LDL-C levels [10].
References
1. Friedrich, N., et al., Cross-sectional and longitudinal associations between insulin-like growth factor I and metabolic syndrome: a general population study in German adults. Diabetes Metab Res Rev, 2013. 29(6): p. 452-62.
2. Lam, C.S., et al., Circulating insulin-like growth factor-1 and its binding protein-3: metabolic and genetic correlates in the community. Arterioscler Thromb Vasc Biol, 2010. 30(7): p. 1479-84.
3. Eggert, M.L., et al., Cross-sectional and longitudinal relation of IGF1 and IGF-binding protein 3 with lipid metabolism. Eur J Endocrinol, 2014. 171(1): p. 9-19.
4. Bergen, K., K. Brismar, and S. Tehrani, High-dose atorvastatin is associated with lower IGF-1 levels in patients with type 1 diabetes. Growth Horm IGF Res, 2016. 29: p. 78-82.
5. Narayanan, R.P., et al., Atorvastatin administration is associated with dose-related changes in IGF bioavailability. Eur J Endocrinol, 2013. 168(4): p. 543-8.
6. Szkodzinski, J., et al., Effect of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors on the concentration of insulin-like growth factor-1 (IGF-1) in hypercholesterolemic patients. Pharmacol Rep, 2009. 61(4): p. 654-64.
7. Davey Smith, G. and G. Hemani, Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 2014. 23(R1): p. R89-98.
8. Teumer, A., et al., Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. Aging Cell, 2016. 15(5): p. 811-24.
9. Global Lipids Genetics, C., et al., Discovery and refinement of loci associated with lipid levels. Nat Genet, 2013. 45(11): p. 1274-83.
10. Consortium, U.K., et al., The UK10K project identifies rare variants in health and disease. Nature, 2015. 526(7571): p. 82-90.
B2970 - Prediction of occurrence of postnatal depression a study based on linked cohort data - 28/10/2017
The aim of this study is to develop a predictive model for risk of depression in mothers after birth. The Avon Longitudinal Study of Parents and Children will be utilised to answer the research question âhow much percentage of postnatal depression can be predicted?â. The findings from this study will help health care professionals or policy makers develop and implement evidence-based preventive interventions. This project will benefit woman and her family by providing a greater understanding of the prevention of postpartum depression.
B2971 - Tracking the epigenetic clock across the life-course - 28/10/2017
It is possible obtain accurate estimates of age from DNA methylation profiles derived from human tissues. When estimates over-estimate chronological age, we say that the corresponding individuals have accelerated DNA methylation age. Recent publications have shown that these individuals tend to have poor health compared to others. What we do not know is how stable age acceleration is throughout life. We would like to use the longitudinal DNA methylation profiles in ALSPAC to determine how often individuals with accelerated age at one time point are also accelerated at other time points.
B2972 - Identification of genetic variants that influence human viability - 28/10/2017
Our understanding of adaptation in humans is currently limited to indirect methods that search for footprints of ancient selection that has acted for over thousands to millions of years in the genomes of present-day humans. We aim to take advantage of the availability of large data sets, such as ALSPAC, to identify genetic variants that impact survival in humans today. With large enough data sets, we should expect to detect small changes in the frequencies of genetic variants that happen within a few generations, i.e., directly observe natural selection in action.
B2973 - The long term effects of prenatal exposure to violence on psychosocial health - 30/01/2018
B2974 - ATLAS - Automated Transcription Language Analysis Software - 28/10/2017
ATLAS will be an app that speech and language therapists can use to screen children for developmental
language disorders. It is very important that developmental language disorders are detected because providing
the right help from speech and language therapists as early as possible is shown to make a signficant impact in
that child's potential to succeed at school and later life. We know that the benefit of providing enhanced speech
and language therapy for all children aged 6 to 10 who currently have a developmental language disorder
exceeds the cost of therapy by £741.8million.
The challenge at the moment is that speech and language therapists do not have sufficient time to complete the
screening (30 minutes) and then the transcription and analysis (90 minutes) that is needed to decide on the best
therapy plan. Our app will use automated audio and language analysis tools built into the app, along with
machine learning frameworks. Our project will look at which of these, or which combination of these tools, is
best to detect a developmental language disorder.
ATLAS will be built and trained using a very large dataset of recordings taken from the Avon Longitudinal Study
of Parents and Children so that we can compare whether the technology used is comparable to the analysis
completed on those recordings previously by speech and language therapists.
Therapy Box has an established customer base for the app. It is the market leader in speech and language
therapy apps; having had 197,500 apps downloaded from the iTunes AppStore across its own brand apps since
2011.
The team includes the technical and commercial experts at Therapy Box - who bring clinical, technical and
commercial know how to delivering this project. The team is lead by Rebecca Bright MBE who is a speech and
language therapist and since 2011 has worked to deliver specialist apps to for unmet communication needs.
Her co-founder Swapnil Gadgil has a technical and commercial focus and oversees the research and
development of the latest technologies for the company's app range and for apps for clients such as the United
Nations and universities around the world. Dr Yvonne Wren is Director of Research at Bristol Speech and
Language Therapy Research Unit. Her research has focused on speech development and disorder in children
and has included the development and trialing of software for use in speech and language therapy
intervention and extensive use of the ALSPAC dataset. Professor Steve Renals and Dr. Korin Richmond from the University of Edinburgh have a wealth of experience in applying machine learning methods to speech data
B2968 - Educational attainment affect socioeconomic outcomes and family formation in young adulthood - 22/03/2018
In this project, we will use new surveys and linked administrative data to investigate the factors that influence family formation in the ALSPAC cohort. Education is strongly associated with fertility, and after Mills et al fertility GWAS it's becoming increasingly apparent that this is likely to be causal. We only have limited evidence about why there are fertility differences by education. E.g. it could just be preferences, i.e. more education leads people to want fewer children, it could be because those with more education typically have less time after they complete education to start a family, or it could be because education makes people likely to find a partner. On the latter point, there is some evidence that men are reluctant to choose a partner who is more educated than they are. This may make it harder for educated women to find a partner. These questions would be relatively straight forwards to address using a survey of the ALSPAC young people, and theyâre coming up to the age of peak fertility so it seems a natural time to survey them about it.
B2969 - The genetics of fear learning and extinction - 18/10/2017
Anxiety is a common, costly and growing problem in our society. Despite considerable heritability and being a primary cause of lifelong disability, little is known about the molecular basis of anxiety. However, experimental psychology has developed exceptionally robust paradigms that model in both animals and humans how anxiety (fear) is developed (or learned) and how it is treated (or extinguished). No study has attempted to apply to combine modern genetic approaches with the use of these experimental paradigms at scale, with sufficient power to allow transformative science. We propose to conduct the largest systematic genetic study of an experimental psychology paradigm - fear learning and extinction - in order to significantly advance our understanding of mechanisms underlying the development and treatment of anxiety.We will also develop genetic tools for use in predicting treatment outcome, paving the way for personalised treatment decisions for anxiety disorders.
B2967 - Educational outcomes for children with combined visual and hearing loss - 12/10/2017
This project will investigate the impact of combined mild hearing and visual loss in childhood on educational attainment in later years.
Background
Problems with vision and hearing are extremely common in childhood. In most cases, the impairment is mild and often transient; severe visual or hearing impairments are relatively rare in the UK.
It is well established that severe visual and hearing impairments have a detrimental effect on childhood development, behaviour and educational attainment. The impact of mild visual or hearing impairment is less well characterized, but appears to be more variable, dependent on additional factors such as underlying cause, duration and socioeconomic factors.
The research question is: what is the effect of combined mild hearing and visual impairment on development during childhood and educational attainment?.
Project Description
Using data from the ALSPAC study, this project aims to address this question, focusing specifically on the educational attainment of children with combined mild visual and hearing impairments. The ALSPAC birth cohort study has gathered data on over 14,000 individuals, providing us with a unique opportunity to investigate this question.
We will use data collected from the ALSPAC research clinic when participants were 7 years of age to identify all children with both mild visual and hearing impairments.Their subsequent Keystage 2 and GCSE results will be compared with those of children with normal vision and hearing at age 7, and those with a single hearing or visual impairment.
When comparing these results, we will take into account factors that may be independently associated with both hearing and vision in childhood and educational performance. For example, low socioeconomic status is risk factor for problems with vision and hearing, and also associated with lower educational attainment. Other factors we will be adjusting for include gender, birth weight, maternal education and ethnicity.
If our initial results do indicate that combined mild visual and hearing impairments have a negative impact on educational attainment, we will attempt to understand why this is. We will thus look at factors such as working memory, reading skills and co-occuring developmental disorders (Dyslexia, Autism & Dyspraxia) to see if children with combined hearing and visual impairments are more likely to perform worse on these measures, or display particular behavioral traits which may explain differences in educational attainment at age 16.
Finally, the results of this study may have implications for the way children with combined mild visual and hearing impairments are identified and supported through their education.
B2965 - Evaluating the causal effect of gene expression on cardiovascular function - 04/10/2017
Genome-wide association studies (GWAS) have uncovered hundreds of genetic variants across the human genome which influence cardiovascular disease risk. However, the underlying mechanisms which may explain these effects have yet to be explored in detail. This project aims to develop our understanding of these mechanisms by assessing changes in gene expression levels.
B2966 - Patterns prevalence and disease trajectories of food allergy in adults - 11/10/2017
The project aims to use a combination of existing and new epidemiological data and data from adults attending allergy clinics in the UK to determine the prevalence of food allergy in adults, to describe the phenotypes of food allergy (adult-onset, persisting childhood-onset, threshold dose of allergen, type of food allergens) adn to describe the different trajectories of the development and natural history of food allergy across the lifecourse.
B2964 - UNICORN Unified Cohorts Research Network Disaggregating asthma and allergic diseases - 05/10/2017
Asthma and allergic diseases (food allergies, rhinitis, eczema) are the most common chronic diseases in childhood and adolescence. They usually start before school-age and are responsible for a heavy burden of ill health, including premature death. In response, we propose an innovative scientific research program which embraces a truly trans-disciplinary team science approach, and is of fundamental relevance both to biomedical research and to evidence-based health science more broadly. UNICORN builds directly on the substantive prior investments in both the science and infrastructure underpinning research in this domain. The project will assist UK to leverage its cohort studies with a focus on asthma and allergy more productively, and to develop a sustainable, scalable scientific infrastructure to facilitate future work in this and other biomedical domains.
B2963 - The strucuture of the placental chorionic plate vessels and its relationship to childhood retinal microvascular structure - 02/10/2017
Placental size and dimensions are linked to later disease susceptibility especially cardiovascular disease. We have recently identified that an in utero insult is associated with altered vascular structure in the eye. We want to determine if there is a link between the placental vascular development and the development of the vascular system in the eye. It may be possible to predict cardiovascular risk in later life by examining the vascular structure of the placenta
B2962 - Joint patterns of multi-genetic/epigenetic factors via non-parametric clustering and their association with allergic diseases - 27/09/2017
Eczema is a chronic skin inflammatory disease infecting 10-30% of children and 2-10% of adults and increasing. Researchers have struggled to understand the genetic and environmental factors that appear to play a role in eczema's increasing prevalence. The majority of current studies focus on one or two specific types of Genome-wide data in association with eczema such as SNPS, DNA methylation levels, or gene expression levels. Current statistical methods have forced this limitation as none exist, to our knowledge that allow clustering of subjects across multi-dimensional and multi-faceted variables. Therefore, in this project we aim to introduce a novel clustering approach that will cluster subjects across genes which contain SNP information, DNA methylation levels, and gene expression levels. Summarized clusters will then tested for associated risk of eczema or any allergic disease. Genetic patterns associated with eczema will then be further explored to better identify the behavior genetic data and itâs uniqueness. The method will be built in R Gui as a free downloadable package making it accessible and easy to use. We will apply the proposed method to the third generation Isle of Wight cohort data. The third generation cohort data consist of children born (2010-current time) from the original cohort of children born between 1989 and 1990 on the Isle of Wight in the UK and contains Genome-wide datasets, disease and exposure status, and allergy information across multiple follow-ups. The implications of this study not only impact the statistical field with a new clustering approach but the eczema and allergy field as well as no other studies have been able to analyze three Genome-wide datasets in concert associated with the risk of allergic diseases. Currently, we are looking for a second but similar dataset in which we hope to replicate our eczema findings.