Proposal summaries
B375 - Sleep Stress and Mental Health - 16/06/2006
(No outline received).
B393 - Dyslexia Genotypes - 16/06/2006
(No outline received).
B370 - Analysis of Homocysteine and B Vitamins in Relation to Several Outcomes in Mothers and Children - 15/06/2006
Observational studies have shown an association between moderately elevated levels of plasma total homocysteine (tHcy) and a number of common diseases, including cardiovascular disease, pregnancy complications, foetal abnormalities, cognitive impairment and dementia, depression, osteoporosis, and mortality (see Refsum(1, 2) for relevant literature).
There have been very few studies that specifically addressed the questions:
1. 'Are raised tHcy levels, or low-normal levels of B vitamins in the mother associated with an increased risk of diseases or syndromes in their children?
2. 'Are raised tHcy levels, or low-normal levels of B vitamins in early life associated with an increased risk of diseases or syndromes?
Aims
The ALSPAC cohorts of mothers and children offer a unique opportunity to address the above broad questions. The aim is to see if there is any relation of these markers to health and well-being in mother and child, making use of the many outcome measures in ALSPAC. Some specific questions include:
- Are maternal tHcy and B vitamins related to pregnancy outcomes, such as size of baby at birth? (see our studies in Norway(3) & India(4))
- Is maternal tHcy related to placental vasculopathology?
- Are maternal tHcy and B vitamins related to markers of behaviour, cognition and school performance in children?
- Are tHcy and B vitamins in children related to markers of behaviour, cognition, and school performance?
- Are tHcy and B vitamins in children related to other disease or functional outcomes?
- Is there evidence of interactions between common polymorphisms in genes such as MTHFR, levels of folate, B12, tHcy and any of the outcome measures?
B513 - Obesity prevention via physical activity promotion in school associations between habitual physical activity and executive function in the ALSPAC cohort - 11/06/2006
Aim :To test for associations between habitual physical activity and executive function at age 11- the ALSPAC cohort provides a unique opportunity to test this hypothesis due to its combination of large sample size, good measures of habitual physical activity (accelerometry) and executive function, and key confounders.
B368 - Preventing Type 2 Diabetes Through Interventions During Childhood - 09/06/2006
(No outline received).
B365 - Obstretic Events and Subsequent Gynaecological Consequences - Feasibility Study - 05/06/2006
Denervation of pelvic organs taking place at vaginal delivery results in subsequent reinnervation and wide-ranging gynaecological symptoms e.g. vulvodynia, dyspareunia, chronic pelvic pain, irritative bladder symptoms, rectal hypersensitivity, menorrhagia and dysmenorrhoea (1-12). All benign myometrial pathology e.g. endometriosis, adenomyosis, leiomyomata, etc. has specific neural abnormalities in the spectrum of denervation-reinnervation (4-7). Reinnervation, in several different patterns, has been described in every female pelvic organ often in association with a prior history of difficult vaginal delivery including premature, or prolonged, maternal voluntary efforts (8-12).
In nulliparous women, straining to achieve defaecation has been demonstrated to cause specific neurological lesions in different pelvic viscera (8, 9, 12), and this mechanism, operating at the endometrial-myometrial nerve plexus , has been proposed as a source of impaired placentation in nulliparous pre-eclampsia. intrauterine growth retardation, abruption, placenta accrete/percreta (13, 14).
The question arises: "Do nulliparous women with severe obstetric problems e.g. early-onset preeclampsia. IUGR, preterm delivery, abruption, etc. suffer subsequent gynaecological symptoms e.g. menorrhagia, dysmenorrhoea, chronic pelvic pain, that require specific medical and surgical interventions e.g. hysteroscopy, laparoscopy, hysterectomy, etc. within the subsequent 10 years".
B364 - Disordered eating in adolescence a longitudinal study of risk factors - 05/06/2006
The purpose of this study is to identify the risk factors related to the development of disordered eating and to determine risk factors for the persistence of disordered eating during adolescence. This will aid the development of early intervention and preventative strategies for disturbed eating in children and adolescents.
B360 - Cigarette Smoking and Psychopathology Genetic and environmental effects on initiation and cessation among children and mothers in the ALSPAC cohort - 18/05/2006
Applications are invited from suitably qualified psychology graduates to join a team investigating the development of depressive symptoms. The PhD will be undertaken in the Department of Community Based Medicine and will focus on examining the nature of the relationship between depressive symptoms and smoking.
Previous studies have found evidence for an association between depression and smoking in adolescence, but the nature and direction of the relationship is unclear. Some studies have found evidence that depressive symptoms precede the onset of smoking; others have found that smoking precedes depression, and some studies report a bi-directional relationship. The PhD student will have the opportunity to develop skills in statistical modelling of longitudinal data to model the developmental heterogeneity of depression and smoking from late childhood into adolescence and examine potential covariates including gender, behaviour and conduct problems, social adversities, stressful life events, and parent-child relationships.
The project will take advantage of the unique and extensive longitudinal data collected by ALSPAC, an ongoing longitudinal population-based study investigating a wide range of environmental and other influences on the health and development of children. Detailed information on the ALSPAC study is available on the web site: http://www.alspac.bris.ac.uk.
Data required:
Depression- Mood and feelings questionnaire (child and parent report) from 9-15 years.
Smoking- (child and parent report) from 8-15 years.
(we are aware that data from the 15/16 year questionnaire/clinic is not yet available)
Other possible data requirements: Behaviour and emotional problems- DAWBA, SDQ, antisocial behaviour questionnaire.
Social adversities and stressful life events.
Questions on parent-child relationships.
B384 - Research Study on Potential Link between Infant Feeding and Autism - 16/05/2006
(No outline received).
B361 - Androgen Receptor and Behavioural Pubertal Outcomes - 16/05/2006
(No outline received).
B357 - Infancy Data from Children in Focus Study for WHO Chart Comparison - 15/05/2006
(No outline received).
B355 - Second Methods Grant Role of placental size and shape in predicting childhood growth - 09/05/2006
We propose a pilot analysis using the placental data already collected from the Chidlren in Focus subset (CIF, N=1050), and BMI, waist & fat & lean mass (DXA) at age 9. These pilot analyses will provide strong support for our (generally well received) October submission, and we are optimistic about receiving funding based on our July resubmission. Jon Heron and Jeremy Miles will work together on data analysis, which will be incorporated into the July grant that will include Dr Lawlor, Dr Davey-Smoth and potentially Dr David Barker in the research team.
Previously submitted and approved protocol (our ref B355)
We propose to develop an R01 application utilizing placental data to be submitted as a supplement to the NIH funded R01 "Maternal overnutrition and offspring fat mass, metabolic and vascular function" (Principal Investigator: Dr. Debbie Lawlor, University of Bristol). We outline below the specific aims for such a supplement and provide a model illustrating the integration of these aims with the aims of the currently funded study. While Dr. Lawlor's grant aims refer to "offspring" generally, we have explicitly separated out the neonatal (birth outcomes) within our aims given the focus on the placenta.
SPECIFIC AIMS
Specific Aim 1: To investigate the influence of maternal BMI, weight gain, and diet during pregnancy on placental anthropometric measures. Specifically, we will assess and study the following placental parameters: placental weight, thickness, diameters; umbilical cord length; shape; symmetry measures; chorionic vascular branching pattern). The following null hypotheses will be tested:
1A. Maternal BMI does not explain variation in placental size and shape.
1B. Maternal weight gain does not explain variation in placental size and shape.
1C. Maternal diet does not explain variation in placental size and shape.
Specific Aim 2: To determine whether and how placental size and shape influences birth size. The following null hypotheses will be tested:
2A. Placental size and shape are not associated with birth size (e.g. weight, birth weight ratio, length, ponderal index).
2B. Associations between maternal factors and birth size are mediated by variation in placental size and shape.
Specific Aim 3: To determine whether and how placental size and shape influence offspring growth. Offspring growth was measured at multiple time points beginning at age 1 year up to 15 years of age and includes measures of adiposity (DXA assessed fat mass and fat distribution), vascular function (blood pressure, pulse pressure and endothelial function), and metabolic function (fasting glucose, insulin and lipids). The following null hypotheses will be tested:
3A. Placental size and shape are not associated with offspring childhood adiposity.
3B. Placental size and shape are not associated with offspring childhood vascular function.
3C. Placental size and shape are not associated with offspring childhood metabolic function.
3D. Associations between placental size and shape with offspring outcomes are mediated by effects of the placenta on birth size.
Specific Aim 4: To investigate the role of genetic variation on placental size and shape. DNA was extracted from mothers and offspring in the parent study. The following null hypotheses will be tested:
4A. Genetic variation does not explain variation in placental size and shape.
4B. Interactions between genes and the selected maternal factors (BMI, weight gain, diet) do not explain additional variations in placental size or shape.
Specific Aim 5: To develop and validate a placental index to identify offspring at risk for adverse outcomes with regard to adiposity, vascular function, and metabolic function.
B372 - TwinsUk Cohort - Proposal for GWAS of 500 Female Non-identical Adult Twin Pairs - 05/05/2006
Using the twin resource - our scientific program is directed at identifying quantitative trait loci (QTLs) for important biomedical traits relevant to common complex disease including cardiovascular, respiratory and bone diseases. We have been working towards this goal for the past 15 years with substantial success [Spector, 2006 #2; Wilson, 2006 #5; Reneland, 2005 #14; Valdes, 2006 #1; Hammond, 2004 #19]. However, with the completion of the human genome sequence and technological advances in the genotyping, we are now seeking to accelerate this scientific discovery process and shorten timelines for productivity. Our objective in this project is to use individual genotyping and genome-wide association studies (GWAS) in a family-based cohort (twins) with multiple intermediate phenotypes to uncover novel susceptibility genes, explore gene-gene and gene-environment interactions and advance understanding about gene networks which influence disease susceptibility. The current plan will use unique data from the twins in conjunction with other adult population cohorts, which are being genotyped by Sanger (1958BC and Ely Epic study) to provide replication datasets with overlapping phenotypes. We will also compare results with overlapping phenotypes in children to explore age-gene interactions in a study which may be run in parallel (Alspac study).
The specific project aim is to use existing DNA from a sub-cohort of heavily phenotyped 1,000 dizygous (DZ) twins to perform individual genotyping using 250k Illunina Bead Chip Array. We will then conduct a genome-wide association analysis of this data using both total association and family-based statistics to test for associations with extensive existing phenotype and environmental data (i.e. greater than 1000 phenotypes) we have collected over the past 15 years GWAS projects survey common genetic variation by testing a dense set of single nucleotide polymorphisms (SNP) across the genome and we expect this will be an efficient method to uncover novel genes, gene-gene interactions and gene-environment interactions that are relevant to common chronic diseases.
B353 - To determine the factors including weaning practices that influence the development of clinical allergy or tolerance to food proteins in infants - 04/05/2006
(No outline received).
B362 - Autism and Cysteine Dioxygenase Gene - 03/05/2006
(No outline received).
B367 - Hyperactivity and ADHD in ALSPAC - 01/05/2006
(No outline received).
B354 - Determining factors including weaning practices that influence the development of clinical allergy or intolerance to food proteins in infants - 28/04/2006
(No outline received).
B348 - The Economics of Social Networks their Evolution Economic Function and Dynamic Implications - 24/04/2006
Social networks are pervasive. Diverse examples range from friendship groups, neighbourhoods, and the decisions of companies over whom they conduct business with, to more formal networks such as workplaces, political groupings, local voluntary organisations, and international trade organisations. Analysing the formation and evolution of networks is complex and important.
* It is complex because there are two inter-related processes taking place. On one hand, the value any one individual or company gets from belonging to the network, their commitment to it, and the ethos and effectiveness of the network depend crucially on other members of the network. But, at the same time, these factors also influence how the membership changes over time. This complex relationship and feedback provides a rich diversity of potential outcomes and dynamics, not all of which are economically or socially beneficial.
* It is important because networks have important effects on educational outcomes, on employment levels, on social unrest, on how industries grow and decline, etc., and ultimately, through these effects, on the strength of the economy and society. Social networks have been widely studied in a sociological context, but it is only in recent years that the study of such networks has started to affect the way that we think of economic behaviour and the dynamic processes in society and economies. Both theoretical and empirical work in this area is difficult but recent developments in theory and newly available datasets make this possible. This is a new and exciting research agenda, which can provide insights into the importance of collective behaviour and collective norms for economic outcomes, and therefore on the growth of the economy. CMPO has already contributed to this agenda through its work in two distinct areas - corporate culture and neighbourhoods - and, building on this work, we are in a position to make a major contribution to this new field. It is clear from our work and our reading of the other research in this area that this emerging field of study could be pushed forward by a two pronged approach that undertakes (a) theoretical analysis that recognises that the existing
apparently diverse research is really one big issue, and (b) empirical analysis of the development, dynamics and consequences of critical social networks.
Our aim is to undertake a major study with two core, linked, components:
* Theoretical analysis of economic and social networks and communities, and of how different networks interact. The objective is to provide a global analysis that can be used to give deeper insight into specific types of networks. This will build on existing work that is currently based on three distinct but interrelated themes: (i) individual actions based on complementarities, (ii) group formation to achieve group objectives, and (iii) research that focuses on linkages between members.
* A series of econometric studies on large datasets and case studies to test the theories in specific contexts. The topics include (i) the long run implications of patent commons (open-sourced communities where firms share patents), (ii) the transition at retirement from work-based networks to social-based networks, (iii) how workplace networks affect career concerns and career paths, (iv) what is the impact of neighbourhood and peer groups in school on educational outcomes, (v) what is the impact of networks and neighbourhood on productivity and employment, (vi) when and with whom do lasting friendships form among teenagers and how these friendship networks influence educational attainment and criminal or anti-social behaviour.These projects will build on our experience of developing theory alongside empirical analysis, and exploit the skills and the large datasets we have built up over the past 7 years.
B346 - Depression and Anxiety in Men During and After Pregnancy - 21/04/2006
The study of depression in women in the perinatal period has led to increased understanding about the course, causes and potential points of intervention and screening. The importance of, for example, post-natal depression in women is now well recognised, both in terms of its effect on maternal health and on children's development. There is growing evidence that the perinatal period is also a point of increased risk for men, and constitutes a public health concern. For example, research to date suggests that men are also affected by the birth of their child, and previous work by this team has shown that depression in men is associated with an increased risk of behavioural and emotional problems in their children. A novel feature of this research is that it examines an under-appreciated health concern in men, depression and anxiety, in a transition period of increased strain. There is ample evidence, for instance, that the transition to parenthood is associated with a marked decrease in marital quality, but little of that work incorporates the findings from perinatal psychiatry. An improved understanding of mood and anxiety changes in men in the perinatal period is important in its own right and will increase our understanding of the dynamics of mental disorder between partners in a period of increased normative stress. This will enable us to improve our prediction and assessment targeting of families at risk for individual, couple, and family disturbance.
B350 - Mini-Satellite Mutations in Parents of Children with Cancer Follow-on from A85 - 20/04/2006
We previously received DNA samples from 110 ALSPAC family trios to determine the frequency of germline minisatellite mutations. These were screened for mutations in the CEB1 minisatellite locus and genotypes obtained from 60 families. Following modification of the genotyping method the family trios were re-screened, and genotypes were obtained from 52 families. In a significant number of cases (n=50), no amplification from at least 1 family member prevented us from obtaining a genotype. We belive that this was due to an insufficient amount of DNA. We now wish to assemble a set of genotypes from 200 ALSPAC families. Although DNA from blood samples would be preferable, DNA from LCL might suffice as long as we can establish that a "germline" mutation is not in fact a somatic mutation caused by the establishment of the cell line. We are thus requesting DNA from 148 families, which could include material from the 50 families that originally failed to amplify. In addition, we would like to test samples derived from LCL made from 20 of the 52 genotyped families, so that we can check that the genotypes are the same. In all therefore, we are requesting DNA from 168 family trios, either from LCL or native DNA.