Proposal summaries

These are research proposals that have been approved by the ALSPAC exec. The titles include a B number which identifies the proposal and the date on which the proposals received ALSPAC exec approval.

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B3073 - Development of Caetanos discontinuity endogeneity test and application to the effect of vegetarianism on health - 06/03/2018

B number: 
B3073
Principal applicant name: 
David Carslake | MRC Integrative Epidemiology Unit (UK)
Co-applicants: 
Prof Kate Tilling, Dr Kate Northstone, Mr Wes Spiller, Prof George Davey Smith
Title of project: 
Development of Caetano's discontinuity endogeneity test and application to the effect of vegetarianism on health
Proposal summary: 

Observing that an exposure (e.g. higher meat intake) is associated with an outcome (e.g. higher BMI) does not necessarily mean that the exposure caused the outcome. Other factors may "confound" the association by causing both the exposure and the outcome. Such confounding can be difficult to detect if the factors responsible have not been measured. A recent study proposed a method to detect confounding by unmeasured variables if they cause discontinuous variation in the exposure. We intend to develop this method further and apply it to the question of whether eating meat affects a person's BMI. The method should tell us whether simple observation of people's meat intake and BMI reveals the causal effect or is confounded.

Impact of research: 
Our promotion and development of this method will make it available for a variety of epidemiological applications. The results will also inform our knowledge of the effects of dietary meat on adiposity and iron metabolism
Date proposal received: 
Wednesday, 21 February, 2018
Keywords: 
Statistics/methodology, Obesity, Computer simulations/modelling/algorithms, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., BMI, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Nutrition - breast feeding, diet, Statistical methods

B3109 - Predictive genomic classifiers for the risk assessment of common learning disabilities in children - 29/05/2018

B number: 
B3109
Principal applicant name: 
Emmanuel Labourier | Cognitive Genetics (USA)
Co-applicants: 
Dr. Dennis Wylie
Title of project: 
Predictive genomic classifiers for the risk assessment of common learning disabilities in children
Proposal summary: 

Learning disabilities are common disorders characterized by unexpected difficulty with a specific mode of learning in the context of adequate intelligence and academic opportunity. The high prevalence of these disorders in the general population represents a costly burden to the educational system and affected individual are often at risk for long-term adverse psychological and socioeconomic outcomes. Intervention programs work, but are more effective when tailored to individuals and administered earlier in life. The pre-symptomatic detection of individual who are at risk of developing learning disabilities, and who are more likely to benefit from early intervention, is therefore an important diagnostic opportunity with major economic and societal implications. The objective of this project is to evaluate the diagnostic performance and predictive value of genetic variants associated with learning disabilities in the ALSPAC cohort.

Impact of research: 
This research has the potential to improve the pre-symptomatic diagnosis of children at risk of developing learning disabilities and who may benefit from early intervention strategies
Date proposal received: 
Friday, 4 May, 2018
Keywords: 
Clinical research/clinical practice, Cognitive impairment, Learning difficulty, Speech/language problem, Computer simulations/modelling/algorithms, Cognition - cognitive function, Communication (including non-verbal), Genomics, Speech and language

B3091 - Solids and formula feeding as risk factors for morbidity in infancy - 29/03/2018

B number: 
B3091
Principal applicant name: 
Charlotte Wright | University of Glasgow (United Kingdom)
Co-applicants: 
Dr Pauline Emmett, Dr Ada Garcia, Angelina Lessa
Title of project: 
Solids and formula feeding as risk factors for morbidity in infancy
Proposal summary: 

A recent large scale evidence review has demonstrated the importance of exclusive breastfeeding to 6 months with partial breastfeeding continued though the first year of life, but few studies have considered whether starting solids earlier than 5-6 months, but with continued breastfeeding, increases the risk to health or causes earlier cessation of breastfeeding.
The review also found new evidence from the developing world that giving extra iron in children who are not short of iron may cause increased infections and slower growth. Formula milks which have higher iron content than either breast milk or doorstep milk are currently recommended from 6 months to 12 months where an infant is not breastfeeding to prevent iron deficiency anaemia and iron fortified follow on formulas are widely advertised. However the potential risks of iron supplemented formula milks have never been examined.

Impact of research: 
Could change national recommendations on the age of first solid feeding and the use of formula milks; might lead to changes to the formulation of milks in future
Date proposal received: 
Thursday, 29 March, 2018
Keywords: 
Epidemiology, Growth, Statistical methods, Nutrition - breast feeding, diet

B3099 - Lung function growth and residential greenness in the ALSPAC cohort - 19/04/2018

B number: 
B3099
Principal applicant name: 
Elaine Fuertes | Imperial College London (United Kingdom)
Co-applicants: 
Dr. Debbie Jarvis, Dr. John Henderson, Dr. Osama Mahmoud
Title of project: 
Lung function growth and residential greenness in the ALSPAC cohort
Proposal summary: 

There is increasing evidence that residential greenspaces (proximity to and amount of green spaces and vegetation around a person's home) may be associated with various health outcomes, including increased physical activity levels and respiratory health outcomes, such as asthma. As lung function is associated with both physical activity and asthma, it could thus also be associated with greenspaces. However, to date, no study has examined whether an association between residential greenspaces and lung function exists in children, and what potential pathways may be playing an important role. Using the ALSPAC data, this study aims to fill this research gap.

Impact of research: 
Assuming that our hypothesis is true, this study will be the first to report positive associations between higher residential greenspace and lung function growth in children. This work thus has the potential to contribute to the growing body of evidence suggesting that surrounding greenspaces positively affect health. Of particular interest will be whether we can identify potential mechanisms that may be driving any observed link between greenspaces and lung function growth (either via physical activity, asthma, or air pollution).
Date proposal received: 
Monday, 16 April, 2018
Keywords: 
Epidemiology, Respiratory - asthma, Statistical methods, Development, Environment - enviromental exposure, pollution, Physical - activity, fitness, function, Sex differences

B3110 - Computational Models for the Prediction and Prevention of Child Traumatic Stress - 29/05/2018

B number: 
B3110
Principal applicant name: 
Glenn Saxe | NYU Langone (USA)
Co-applicants: 
Constantin Aliferis, MD, PhD, FACMI
Title of project: 
Computational Models for the Prediction and Prevention of Child Traumatic Stress
Proposal summary: 

More than 20% of children will experience a traumatic event before they are 16 years old. Of those who experienced a trauma, a sizable minority will develop Posttraumatic Stress Disorder (PTSD), and other deleterious developmental, health, and psychiatric consequences (herein called Child Traumatic Stress). To diminish the considerable burden of traumatic stress on children and their families, the capacity to predict a child’s risk and to intervene to diminish this risk is extremely important. The literature on prediction of child traumatic stress from risk factors has yielded only modest results and - of those risk factors found to be predictive – it is difficult to determine which represent processes would lead to a diminution of risk, if effective intervention were applied. Almost certainly, traumatic stress results from a complex set of interacting bio-behavioral and social environmental processes, unfolding in specific ways over the course of development, and related to specific aspects of the traumatic exposure. Our project aims to apply state-of-the-art Machine Learning predictive modeling methods with a wide array of risk variables from the ALSPAC data set to generate reliable and accurate predictive models of PTSD and other child traumatic stress outcomes. We also aim to apply advanced non-experimental causal discovery algorithms to discover potentially remediable processes leading to traumatic stress outcomes that may reveal new opportunities for preventative intervention.

Impact of research: 
To create reliable, accurate and interpretable predictive models of child traumatic stress that can guide future research and clinical care. To discover remediable processes that influence traumatic stress and can inform the development of new and promising preventative interventions.
Date proposal received: 
Friday, 4 May, 2018
Keywords: 
Statistics/methodology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Computer simulations/modelling/algorithms, Statistical methods, Childhood - childcare, childhood adversity, Genetics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Psychology - personality

B3075 - Genetic vulnerability to schizophrenia and major depressive disorder and the risk of childhood adversities - 08/03/2018

B number: 
B3075
Principal applicant name: 
Henning Tiemeier | Erasmus Medical Center, Rotterdam (The Netherlands)
Co-applicants: 
Title of project: 
Genetic vulnerability to schizophrenia and major depressive disorder and the risk of childhood adversities
Proposal summary: 

Since the recent publication of large genetic studies to identify genetic risk factors for debilitating psychiatric disorders such as schizophrenia and depression, it has been possible to use this genetic information to study to what extent genetic risk to, for example, schizophrenia or depression predict risk for psychiatric problems prior to the development of clinical disorders. Particularly interesting is to investigate how a child's genetics make him or her more vulnerable to the exposure of stressful life events. Moreover, it is still unclear to what extent this relationship mediates the association between genetic risk and childhood psychiatric problems.

Impact of research: 
Date proposal received: 
Monday, 26 February, 2018
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, GWAS, Childhood - childcare, childhood adversity, Genetic epidemiology

B3093 - Traits phenotypes and prognosis of childhood asthma - 29/03/2018

B number: 
B3093
Principal applicant name: 
John Henderson | PHS, Bristol Medical School (UK)
Co-applicants: 
Prof Claudia Kuehni, Ben Spycher
Title of project: 
Traits, phenotypes and prognosis of childhood asthma
Proposal summary: 

The proposal is to continue the collaborative work we have been doing with this Swiss group over the past few years. Ben Spycher was a Marie Curie Fellow who worked with ALSPAC data previously. Prof Kuehni leads eth Leicester Asthma Cohorts and has established the Swiss Paediatric Airway Cohort (SPAC). OUr joint objective is to discover influences that determine the onset and progression of asthma in children, how asthma varies between individuals in type and severity and whether we can predict the outcome of asthma using individuals' information. The data in eth Leicester adn Swiss cohorts is complementary to data held in ALSPAC and we have had joint publications where ALSPAC is able to replicate findings in the other cohorts run by the Swiss group.

Impact of research: 
THere have been several attempts to produce an asthma risk score to address the question most parents of wheezy children ask of clinicians. Many of these have reasonable predictive ability but rely on variables that are not routinely measured in clinical practice. If a scoring tool can be developed that has utility in primary care, it will have a major impact on ability to detect children at high risk fo asthma and target them for early intervention.
Date proposal received: 
Thursday, 29 March, 2018
Keywords: 
Clinical research/clinical practice, Respiratory - asthma, Statistical methods, Statistical methods

B3104 - Impact of Breastfeeding on Cardiovascular and Metabolic Outcomes in Women with a History of Hypertensive Disorders of Pregnancy - 26/04/2018

B number: 
B3104
Principal applicant name: 
Abigail Fraser | MRC IEU, University of Bristol
Co-applicants: 
Dr. Jill Demirci, Dr. Janet Catov, Dr. Mandy Schmella
Title of project: 
Impact of Breastfeeding on Cardiovascular and Metabolic Outcomes in Women with a History of Hypertensive Disorders of Pregnancy
Proposal summary: 

Women who experience a hypertensive disorder of pregnancy are at greater risk for diseases of the heart and blood vessels. Breastfeeding may reduce this risk in women in general and particularly in those who have had a hypertensive disorder of pregnancy. This proposed study will examine if the duration/amount of breastfeeding has a beneficial effect on markers of heart health in later life in women who did and did not develop a hypertensive disorder of pregnancy.

Impact of research: 
Knowledge gained from this study will provide insight into whether or not breastfeeding is cardio-protective in women with hypertensive disorders of pregnancy. If we find that breastfeeding has a cardio-protective effect in this high risk population, this could inform intervention design, policy, and breastfeeding promotion efforts among women who develop or who are at risk of developing hypertensive disorders of pregnancy
Date proposal received: 
Thursday, 26 April, 2018
Keywords: 
Epidemiology, Hypertension, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Birth outcomes, Blood pressure, BMI, Breast feeding, Cardiovascular, Nutrition - breast feeding, diet

b1234 - TEST PROJECT PLEASE IGNORE

B number: 
b1234
Principal applicant name: 
TEST USER PLEASE IGNORE2 |
Co-applicants: 
Title of project: 
TEST PROJECT PLEASE IGNORE
Proposal summary: 
Date proposal received: 
Tuesday, 7 July, 2015
Keywords: 

B3078 - Single SNP Replication of rs71564871 - 08/03/2018

B number: 
B3078
Principal applicant name: 
Kaitlin Wade | Integrative Epidemiology Unit (United Kingdom)
Co-applicants: 
Title of project: 
Single SNP Replication of rs71564871
Proposal summary: 

A single mutation within the genome (called rs71564871 near a gene called BEND6) has been previously linked to fat distribution in the body, specifically the proportion of fat stored across the waist compared to the hips, in women of the ORCADES study and UK Biobank. Within this study, we want to assess whether this single mutation is similarly related to the same pattern of fat deposition in the Avon Longitudinal Study of Parents and Children.

Impact of research: 
Identifying the genetic contribution of fat distribution to further use in causal analyses to understand how specific regional fat deposition is related to adverse health outcomes.
Date proposal received: 
Thursday, 1 March, 2018
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Obesity, GWAS, BMI, Genetic epidemiology, Genetics, Statistical methods

B3088 - Metabolic profile of prediabetes using genetic susceptibility and repeat metabolomics to inform early detection - 29/03/2018

B number: 
B3088
Principal applicant name: 
Joshua Bell | IEU
Co-applicants: 
Dr Emma Vincent, Dr Caroline Bull, Prof Nicholas Timpson, Dr Marc Gunter
Title of project: 
Metabolic profile of prediabetes: using genetic susceptibility and repeat metabolomics to inform early detection
Proposal summary: 

Type 2 diabetes develops for many years before it is diagnosed. Using data from ALSPAC offspring, we aim in this study to harness genetic susceptibility to adult type 2 diabetes and detailed metabolic profiling to better understand the early stages of diabetes development that are detectable in blood. This will involve describing associations of a genetic risk score comprised of hundreds of genetic variants for adult type 2 diabetes with hundreds of metabolic traits from targeted metabolomics at four key stages of early life – childhood (age 8y), adolescence (age 15y), early adulthood (age 18y), and formal adulthood (age 25y) – to view subtle changes in metabolism over time which precede the onset of clinical diabetes. Recognizing the early signs of diabetes is vital for early detection and for preventing downstream cardiovascular diseases and cancers.

Impact of research: 
The likely output of this research will be at least one publication in a general medical or epidemiology journal, the impact of which may be theoretical advancement in active research fields of metabolism and diabetes, and recommendations for clinical practice.
Date proposal received: 
Thursday, 22 March, 2018
Keywords: 
Epidemiology, Diabetes, Metabolomics, Metabolic - metabolism

B3122 - Genome-wide analysis of selection and methylation - 06/06/2018

B number: 
B3122
Principal applicant name: 
Tom Gaunt | University of Bristol (United Kingdom)
Co-applicants: 
Ms Charlie Hatcher, Dr Santi Rodgriguez
Title of project: 
Genome-wide analysis of selection and methylation.
Proposal summary: 

Human evolution has been associated with drastic changes in environment and lifestyle over time, with each of these changes resulting in selective pressures (Voight et al., 2006). Natural selection is the differential reproductive success of genetically distinct individuals or genotypes within a population. Strongly deleterious mutations will rapidly be eliminated from populations, whereas strongly positive mutations will quickly rise to fixation leading to changes in allele frequency over time. This process leaves signatures on the genome which can then be detected (Sabeti et al., 2006).

Epigenetics refers to heritable changes outside of the DNA sequence itself and provides a potential mechanism by which environmental and lifestyle exposures can impact gene expression over the course of a lifetime. Epigenetic mechanisms can include DNA methylation and histone modifications. DNA methylation is the most widely studied epigenetic change and involves the addition of methyl groups to nucleotide bases (Vocht et al., 2018).

Natural selection is a long term, multigenerational response to environmental factors that can influence the role of genes in human traits (Bamshed and Wooding, 2003) whereas epigenetic inheritance allows stable changes in DNA methylation to be passed from one generation to the next (Feil and Fraga, 2012). Both selection and methylation act in response to environmental exposures but over different timescales. This project will aim to unravel the interplay between selection and methylation to assess whether DNA methylation offers a mechanism to respond to exposures in the short term which may eventually lead to changes in allele frequency.

References
1. Bamshad, M. & Wooding, S.P. Signatures of natural selection in the human genome. Nature Reviews Genetics 4, 99-111A (2003).
2. de Vocht, F. et al. DNA methylation from birth to late adolescence and development of multiple-risk behaviours. Journal of Affective Disorders227, 588-594 (2018).
3. Feil, R. & Fraga, M.F. Epigenetics and the environment: emerging patterns and implications. Nature Reviews Genetics 13, 97-109 (2012).
4. Sabeti, P.C. et al. Positive natural selection in the human lineage. Science 312, 1614-1620 (2006).
5. Stearns, S.C., Byars, S.G., Govindaraju, D.R. & Ewbank, D. Measuring selection in contemporary human populations (vol 11, pg 611, 2010). Nature Reviews Genetics 12, 1 (2011).
6. Voight, B.F., Kudaravalli, S., Wen, X.Q. & Pritchard, J.K. A map of recent positive selection in the human genome (vol 4, pg 154, 2006). Plos Biology 4, 659-659 (2006).

Impact of research: 
Generally, selection and methylation are assessed separately. We hope that analysing both concurrently will provide insight into the relationship between these two mechanisms and help us to better understand the impact of environmental exposures genome-wide.
Date proposal received: 
Tuesday, 29 May, 2018
Keywords: 
Genetics, Gene mapping, Statistical methods, Epigenetics, Genetic epidemiology, Genetics, Genomics, Statistical methods

B3554 - Asthma and COVID-19 - 08/06/2020

B number: 
B3554
Principal applicant name: 
Raquel Granell | MRC Integrative Epidemiology Unit (IEU) Population Health Sciences (United Kingdom)
Co-applicants: 
Dr James Dodd
Title of project: 
Asthma and COVID-19
Proposal summary: 

Asthma affects the lives of 5.4 million people across the UK. COVID-19 attacks the lungs and can trigger asthma symptoms like wheezing, chest tightness and difficulty breathing, which is very distressing for patients and can cause feelings of anxiety. We want to know if participants with asthma at 23-24 years were more likely to report respiratory symptoms, mental health issues, shielding during the COVID-19 lock-down.

We'll also be interested to explore differences between people with asthma and COVID-19 related symptoms and people with asthma and non-related COVID-19 symptoms, e.g. economical status, asthma severity....

Impact of research: 
Date proposal received: 
Friday, 5 June, 2020
Keywords: 
Epidemiology

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