Proposal summaries
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.
B345 - Neurodevelopmental Disorders - DNA Access- Netherlands - 13/04/2006
(No outline received).
B344 - Environment and Injury Outcomes - 13/04/2006
(No outline received).
B333 - Vitamin D Pilot Study - 10/04/2006
(No outline received).
B352 - Vitamin D and CYP72B1 - 07/04/2006
(No outline received).
B359 - Pilot Record Linkage Study Investigating Feasibility of Linking ALSPAC with Avon General Practice Registration System Exeter System and Retrieving Information from General Practice - 01/04/2006
Ongoing ALSPAC clinic based data collection is impractical and not cost-effective. Alternative methods of ensuring and extending follow-up are required. Efficient and effective follow-up of the health status (and some other factors) of ALSPAC can be achieved through record linkage. 90% of health service contacts occur in primary care and primary care information systems record all significant clinical diagnoses and events throughout the life course such as hospital visits and admissions and data quality is improving. Projects based on "e health" supported by MRC and NIH are being developed in order to facilitate recruitment and follow-up of patients through primary care information systems (see http://www.pcpoh.bham.ac.uk/ primarycare/mdm/e-health.htm).
Information systems also are being developed regionally to enable Primary Care Trusts and Strategic Health Authorities to communicate and retrieve data from general practice information systems. Avon Information Management and Technology (Avon IMT), based in Bristol (http://nww.avon.nhs.uk/imtconsortium/Information_Services), administers the Exeter system which records details on all patients registered with GPs in Avon, has linked the Exeter system with Hospital Episode Statistics, and is commissioning a new information system to allow remote data retrieval from GP systems. The flagging and record linkage between ALSPAC and Avon Exeter systems is achievable - time and permission allowing. Confidentiality and data security are critical to the development of these new information systems linking and extracting data from primary care. Informed consent is required to allow access to the systems, and to allow ALSPAC to periodically update and follow-up health status of its cohort.
B341 - Preapplication for NIH Interdisciplinary Consortium Grant Toward a Developmental Science of Health Neurons to Neighbourhoods - 29/03/2006
(No outline received).
B332 - Impact of Size at Birth and Early Childhood Growth Patterns on the Microvasculature the Avon Longitudinal Study of Parents and Children ALSPAC - 29/03/2006
It is clear that early life events influence subsequent risk of cardiovascular disease, but the mechanisms involved remain obscure. This proposal will investigate the impact of low birth weight and postnatal growth patterns on the microvasculature of the retina in a birth cohort of children followed over the first 12 years of life. Measurements of retinal microvascular abnormalities will be made using digitally acquired retinal images analysed by an extensively validated semi-automated analysis system. The results of this study will provide novel insights into possible mechanisms linking early life events with future risk of hypertension, cardiovascular disease and diabetes and may contribute to development of appropriate early treatment and intervention
B330 - Dietary Patterns and Risk of Adverse Pregnancy Outcome - 24/03/2006
(No outline received).
B331 - Road Traffic Accident Analyses - 23/03/2006
Accidents in the road environment are the commonest cause of death and serious injury in adolescence. Use of transport to and from school and during leisure activities is an important measure of road accident risk, and also provides useful data for assessing the amount of exercise taken by young people. ALSPAC has collected data on accidental injury throughout childhood, and specifically road use and travel to school questions were asked at 13 yrs. We propose to repeat these road use questions at 16 yrs, and add relevant questions about pre- driver attitudes.
B335 - Nesstar Data Sharing Support Project - 20/03/2006
(No outline received).
B329 - Skin Barrier/Keratin Gene Atopy - 20/03/2006
Atopic diseases (including atopic dermatitis/eczema, and asthma) have increased in frequency in the last several decades (1) and now affect up to 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable (2). To date most genetic studies have focused on immunological mechanisms behind regulation of IgE and atopy, however, a primary genetic epithelial barrier defect has been anticipated (3). Recently we identified two functional genetic variants in the filaggrin gene (FLG) affecting epithelial barrier formation (Smith FJD et al., Nature Genetics, in press, preprint attached). In a second study, we have shown that these filaggrin variants show clear predisposition to this group of common conditions. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Two independent variants in this gene carried by ~9% of Caucasians, result in haploinsufficiency. We have shown that these null alleles are responsible for a substantial genetic predisposition to asthma, and atopic dermatitis (Palmer C et al, under review, Nature Genetics).
In this study the two null variants were genotyped in 1008 Scottish Caucasian schoolchildren with unknown disease status (population cohort) and in 604 Scottish Children with asthma. The frequency of carriers of mutation R501X was 5.8% and the mutation 2282del4 variant was present in 3.8% of the schoolchildren, giving a combined carrier frequency of 9.6%. Both filaggrin variants were over-represented in the asthmatic cohort (mutation R501X: 9.2%, mutation 2282del4: 7.5%, combined carrier frequency: 15.7%) with carriers of either allele demonstrating a dominant risk for asthma (mutation X dominant OR = 1.6, 95%CI = 1.1-2.3, p = 0.025, mutation del4 dominant OR = 2.1 95%CI= 1.3-3.2, p = 0.002, combined genotype dominant OR = 1.8 95%CI= 1.3-2.5, p = 0.0002).
AD is co-associated with asthma (3) and since this is a major epidermal protein, null alleles should be expected to be more strongly associated with the combined AD/asthma phenotype than with asthma alone. Consistent with this, 72% of all the children in the asthma cohort carrying a null allele had AD, in contrast to only 46% of those without these filaggrin variants. A co-dominant model comparing individuals with asthma and AD to the population controls provided the best fit and the most significant association (p = 4.8x10-11).
Over the past several years, the mechanisms by which allergen exposure through the skin could initiate systemic allergy and predispose to asthma have become clearer. Epicutaneous sensitization with a protein allergen has been shown to induce a Th2-type immune response with concomitant high IgE production in mice (4). In mice sensitized with ovalbumin, cutaneous exposure of this allergen induced a T cell and eosinophil-rich cellular infiltrate along with a cytokine response that closely mirrored those seen in AD. Significantly, in addition to generating allergen-specific IgE, these mice developed airway hyper-responsiveness on intravenous challenge with methacholine after a single inhalation challenge with ovalbumin (5). These observations imply that the presence of a heritable defect in the skin barrier, in a substantial proportion of the asthmatic patients in our dataset, who would have increased susceptibility to transepidermal allergen transfer, therefore amplifying the epidermal-driven Th2 response and provoking the onset of atopic disease.
AIMS AND OBJECTIVES OF THIS PROPOSAL
This proposal seeks to further develop the initial findings detailed above and to specifically study:
- To accurately delineate the longitudinal health risk of happloinsufficiency in this key epidermal protein with particular reference to phenotypic expression of atopic disease including atopic dermatitis, asthma, and allergic rhinitis and intermediate atopic traits such as skin prick test positivity to house dust mice and grasses and bronchial hyperesponsiveness.
- To study the frequency of these alleles in subsets within the study population identified as having atopic dermatitis, asthma or rhinitis and all combinations of these conditions. We expect to be able to accurately quantify the population-attributable risk of these functional polymorphisms for each of these atopic phenotypes.
- To examine possible genetic modifiers of the phenotype (gene:gene interactions) in the approximately 900 individuals we expect to identify as happolinsufficient for this key epidermal protein. Possible candidate genes for this phase of the study include genes involved in formation of the stratum corneum and in the inflammatory cascade. As this aspect of the study develops we will discuss each of these potential candidate genes individually with the committee prior to commencing any studies.
- To explore possible gene:environment interactions in this cohort of 900 individuals. Relevant environmental parameters would include urban versus rural living, smoking by parents, keeping pets, type of accommodation. This will not form part of the preliminary study and will be discussed in detail with the committee prior to work commencing.
B328 - Socio-economic Deprivation and Respiratory Health - 20/03/2006
This project will address the question of health inequalities, by addressing the relationships between measures of socio-economic deprivation and respiratory health, particularly wheezing illnesses, asthma and lung function. The first part of the study will focus on the detailed information on respiratory health and socio-economic factors in the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine the association of socio-economic deprivation and respiratory outcomes during childhood. We will further investigate these associations by attempting to identify explanatory variables, including lifestyle (smoking, diet) and environmental exposures. Observed associations will then be examined using a lifecourse epidemiological approach to investigate whether associations that we observe in a contemporary population of children (ALSPAC) are reproducible across previous generations in the United Kingdom and whether deprivation in childhood is associated with adult respiratory outcomes, independently of adult socio-economic status. In turn, this will allow us to explore the possible effects of social mobility on adult respiratory health. The project brings together expertise on the analysis of inequalities in health from an economics perspective, with a focus on measures of access to resources, and the exploitation of dynamics in data and the use of GIS tools to map local features to individuals (in the Department of Economics), childhood respiratory epidemiology, including assessment of asthma and lung function in a longitudinal birth cohort sample (Department of Community-based Medicine) and the multidisciplinary specialty of lifecourse epidemiology, including access to archived information on other existing cohorts (Department of Social Medicine). Therefore, this is a unique opportunity to build a global, comprehensive picture of the factors associated with socio-economic deprivation in the U.K. and their potential effects on an important aspect of public health.
B327 - Lesbian mothers and their children A community study - 16/03/2006
(No outline received).
B463 - Analysis of Triangle Test Skuse IQ and cognition Y13b data - 13/03/2006
We wish to use the ALSPAC study to investigate the effects of type 2 diabetes susceptibility variants at the KCNQ1 locus on fetal growth, growth in childhood and intermediate traits related to type 2 diabetes.
Recently, two genome-wide association (GWA) studies of East Asian subjects simultaneously reported a strong association between variants in the KCNQ1 gene and the odds of type 2 diabetes [1, 2]. The effect size estimates were large (OR 1.3-1.4) and the associations were robust, exceeding stringent criteria for statistical significance appropriate to GWA studies (Pless than 5x10-8).
This association had not been identified previously in European GWA studies due to the lower allele frequency (5% vs 40%) and consequently reduced power [3]. However associations were observed in European samples following the East Asian GWA studies, and the effect size estimates were consistent [1-3]. The index SNP, rs2237895, has also shown detectable effects on beta cell function in Europeans [4].
The associations with type 2 diabetes and beta cell function make the KCNQ1 locus an excellent candidate for influencing early growth. A variant that predisposes to reduced insulin secretion and diabetes in adulthood may also influence insulin secretion/action in utero, and thereby reduce birth weight [5]. Our preliminary data on the CDKAL1 and HHEX loci support this (PLoS Med, under review). Maternal diabetes genes may additionally influence birth weight through their effects on the intrauterine environment [6]. We have observed that the maternal risk alleles for fasting glucose and type 2 diabetes at GCK and TCF7L2, respectively, are associated with higher offspring birth weight [7, 8].
The KCNQ1 locus is of additional interest in relation to early growth because the locus is imprinted and may harbour elements that influence the imprinting of neighbouring genes [9, 10]. The region is implicated in Beckwith-Wiedemann syndrome and Silver-Russell syndrome, rare neonatal disorders of fetal overgrowth and growth restriction, respectively.
We therefore propose to analyse the polymorphisms in ALSPAC to test the following hypotheses:
1. Fetal genotype and maternal genotype are associated with fetal growth.
2. Fetal genotype and maternal genotype are associated with growth phenotypes (height, BMI, growth velocity) in childhood
3. Offspring genotype is associated with diabetes-related traits in childhood including fasting insulin, fasting glucose and insulin secretion (in the subset of offspring with OGTT data), triglycerides, HDL, LDL and total cholesterol, anthropometric measures including BMI, lean/fat body mass, WHR, waist circumference, skin folds where available.
4. Due to imprinting, association between the risk allele in the offspring and early growth is dependent upon the parent of origin (we will be able to assess this using informative mother-offspring pairs).
Whether the results are negative or positive they will help our understanding of how the KCNQ1 variants function and, if positive, provide important insights into growth and other diabetes-related phenotypes.
To do this we would like to genotype (at Kbiosciences) all ~20,000 ALSPAC samples. We will need the following phenotypes to test our hypotheses (a detailed list is in the next section):
1. Birth weight, length and head circumference
2. Growth measures in childhood (height, weight and BMI aged 7-11)
3. Covariates of birth weight to check if genotype is acting through them: gestational age, maternal age, maternal BMI, smoking , parity, twin status to exclude non-singletons, ethnicity as genotype frequency may alter with ethnic origin and confound analyses.
4. Type 2 diabetes-related intermediate traits including fasting insulin, fasting glucose and insulin secretion (in the subset of offspring with OGTT data), triglycerides, HDL, LDL and total cholesterol, anthropometric measures including BMI, lean/fat body mass, WHR, waist circumference, skin folds where available.
Plans for meta-analysis:
ALSPAC will provide the largest European-ethnicity dataset for association studies with fetal growth. However, we have access, through our own studies and extensive collaborations to samples from the Exeter family study (950 population based parent-newborn trios), the Northern Finland 1966 Birth Cohort (4600 individuals with own birth measures) and the Hyperglycemia and Adverse Pregnancy Outcomes study (4000 European mother-offspring pairs; 2000 Thai/Chinese mother-offspring pairs; 1250 African-Caribbean mother-offspring pairs; 2500 other ethnicity). We hypothesize that real genetic associations will be consistent across all of these studies - i.e. even if individually studies show only nominal significance, a meta-analysis of all studies will provide highly significant results.
B373 - Anthropometry in ALSPAC - 13/03/2006
(No outline received).
B324 - Sleep Disordered Breathing and Growth Failure in Young Children - 06/03/2006
Infant malnutrition is a major problem on the South Asian subcontinent. Rates of malnutrition and stunting are very high in South Asian societies. Interestingly, some evidence suggests that this phenomenon may be influenced by cultural factors. These include infant feeding practices such as a use of the supine position, feeding while sleeping, the prolonged use of the bottle, delay of protein and adult food. Other cultural factors that may influence this phenomenon have to do with the low status of women in South Asian societies. Maternal depression has been strongly linked to infant malnutrition; furthermore, female infants and children are far more likely than males to experience malnutrition and related diseases and problems, and to die before reaching the age of five. The problem of childhood malnutrition, while grave in itself, may also increase vulnerability in the South Asian population to the later development of obesity and metabolic-related problems such as diabetes.
There has been very little study of this phenomenon in communities of the South Asian diaspora, including immigrants from India, Pakistan, and Bangladesh. Such research is important. Comparative research is especially crucial in this regard, since it could permit the identification of culture-specific practices and behaviors that might be amenable to modification. Our research team has considerable experience working in the New York City South Asian community (and, mention your stuff). We would like to develop a research intervention to assist South Asian families in this regard. However, to develop and fund pilot work, we would like to present preliminary data indicating the features, correlates, and prevalence, of infant and child malnutrition in South Asians. Comparative research which shows that some practices and behaviors are especially common or uncommon among South Asian families, will be particularly helpful in this regard.
We propose to conduct a secondary analysis of ALSPAC data. The 82 families of South Asian origin will be compared to 82 families of white-European background. We will select a comparison group matched on factors such as: housing status, parity, maternal and paternal education, gestational age at birth, and birth length.
We will compare the South Asian and control groups with regard to the primary outcome variables related to growth, e.g.,: BMI, height- Z scores, and head circumference Z scores. Secondary outcomes will include the longitudinal parent-reported feeding measures of: difficulty feeding, being choosy with food, not intaking a sufficient amount of food. Co-variates will include measures of; matenral depression, sociodemogrphics, child gender, parenting scores (i.e. HOME), etc.
Note, no new data are requested. We will conduct analyses with the dataset we already have, and will not require ALSPAC assistance.
B323 - PhD studentship - Development of an Automated Diagnostic Video Otoscope - 06/03/2006
(No outline received).