Proposal summaries
B615 - Meta-analysis of genome-wide association studies on pulmonary function measured by forced expiratory volume in Caucasian - 18/02/2008
We and others previously reported that pulmonary function measured by the ratio of measured to predicted forced expiratory volume in one second (FEV1) - percent predicted FEV1(ppFEV1), which is used to diagnose chronic obstructive pulmonary disease (COPD) and asthma, is highly heritable. To identify specific genetic factors influencing on ppFEV1, we conducted a prospective meta-analysis on the results of four independent genome-wide association studies in healthy Caucasian non-smoker population. We identified two chromosomal regions - 2p25.3 and 8q12.3 are interesting and may play a role in pulmonary function. we therefore selected two SNPs (rs4971396 which is located in SNTG2 on chr2 and rs7017559 which is located on chr8) within these two regions which were associated with ppFEV1 and would like to replicate the association in the ALSPAC.
Method and subjects: all the participants who are non-smokers from the ALSPAC will be inlcuded. the data of their spirometer measurementsas well as their age, height, and weight will be retrived from the existing data. predicted FEV1 will be calculated using the prediction equation derived from the US sample and the percent predicted FEV1 will then be calculated and used in the analysis. the DNA samples will be retrived and sent to the in-house laboratory to genotype for the above two SNPs.
B612 - Hearing in the Alspac Study participants at age 17-18 years - 03/02/2008
A. SPECIFIC AIMS
INTRODUCTION
The principal focus of this application is to obtain resources to collect detailed audiometric data on the
adolescents enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC was
specifically designed to determine ways in which the individual's genotype combines with environmental
exposures and experiences to influence health and development (Golding 2001). Its strengths include use of a
total population sample unselected by disease status, and comprehensive data on children's physical, mental
and behavioral health, family and social circumstances and environmental features. In addition, a DNA bank
has been established on over 10,000 mothers and children with consent for undisclosed genetic analysis
(Pembrey 2004). ALSPAC is, therefore, uniquely positioned to explore genetic and environmental determinants
of common diseases and impairments.
Hearing loss is the commonest sensory deficit in developed countries(Davis 1989, Smith, Bale & White 2005.)
The cumulative prevalence of hearing loss in any population rises through the lifespan (Russ 2001). Hearing
loss and hearing function have been most closely studied at the extremes of life- in the neonatal period and in
old age. However, there have been very few population studies of hearing function in adolescence and even
fewer opportunities to examine the relationship between environmental factors such as otitis media, early life
risks and noise exposure and later hearing function. Similarly, very few studies have attempted genotypephenotype
correlations with respect to hearing function on a large population-based cohort, especially in
adolescence. To our knowledge, the detailed data we propose to collect on hearing in the ALSPAC 17-18 year
cohort would be the first opportunity to link detailed hearing phenotype data with genotype data on a
representative population-based sample of adolescents.
There is growing interest in the hearing function and abilities of adolescents. Widespread use of personal
listening devices such as iPods and MP3 players has heightened awareness of the potential vulnerability of
this population to the extremes of noise exposure from modern devices using current compression algorithms
(Fligor and Cox 2004). (reference - Output levels of commercially available portable compact disc players and
the potential risk to hearing.Fligor BJ, Cox LC Ear Hear. 2004 Dec;25(6):513-27)... Earler survey-based U.S.
data suggest that up to 3.4% 18-34 years olds self-report hearing problems ( NHIS 1990), while the US
National Health and Nutritional Examination Survey (NHANES) III documented 14.9% 6-19 year olds with
unilateral or bilateral losses greater than 16dBHL at low or high frequencies. (Niskar et al.1998). Consequently, we are
moving from a conceptualization of adolescence as a time when hearing is essentially intact, to one in which
considerable variations in hearing ability begin to emerge in the population. Hearing ability at any age will be
sensitive to the effects of multiple risk and protective factors, both genetic and environmental.
B614 - Early life determinants of blood pressure patterns in young adults - 01/02/2008
Early life determinants of blood pressure patterns in young adults
1. Background
1.1 The importance of blood pressure
Globally, elevated blood pressure is one of the most important risk factors for cardiovascular disease, accounting for two thirds of all stroke and a half of all coronary heart disease (CHD)1 . Blood pressure tracks throughout the lifecourse: hypertensive adults are likely to have higher than average blood pressure in youth, with the strongest tracking correlation being observed with the period of late adolescence2. Evidence that adult blood pressure is determined by factors operating in early life is strong3. These include maternal influences, such as smoking, blood pressure and breast feeding, and factors operating in childhood including salt intake and growth trajectories from birth. This latter appears to be a particularly strong determinant of subsequent adiposity, blood pressure and cardiovascular disease (CVD) risk4-10.
1.2 Early growth patterns and blood pressure
Developmentally, three critical post-natal periods have been identified: 1) the perinatal period, 2) the period of adiposity rebound and 3) puberty/adolescence. These represent periods when homeostatic set-points may be determined and when transient environmental exposures can exert long lasting effects11. The consequences of weight gain during development are complex. For example, weight gain during infancy appears to be beneficial in terms of adult risk of diabetes and CHD12-14. In contrast, adiposity rebound in childhood, particularly in low birthweight babies14 (so called accelerated growth or centile crossing) leads to an elevated risk of adult obesity, type 2 diabetes and elevated blood pressure5;10;13-18. Further, there is evidence that the earlier in childhood that this 'rebound' occurs, the greater the risk of subsequent CVD14;18. One mechanistic explanation for these observations is that rapid weight gain in childhood may result in persistently greater fat to lean mass ratio and central adiposity in adulthood19. This suggestion is of particular importance in view of the burgeoning epidemic of obesity and obesity-related disease in children in the developed world.
1.3 Limitations of brachial blood pressure
While there have been a number of longitudinal and cross sectional studies of blood pressure (BP) in childhood and adolescence20-22; all of these studies have been based on measurements of brachial blood pressure at rest. Although brachial blood pressure clearly predicts CVD in adults23, it is an imperfect measure, and has limitations as a measure of the BP experienced by the heart and cerebral circulation24 for a number of reasons. These are discussed below.
1.3.1 Brachial versus central blood pressure
Central (aortic) pressure appears to be a better predictor of CHD than brachial pressure25-27. On average BP measured in the brachial artery exceeds aortic or 'central' blood pressure by ~10mmHg 28, however the magnitude of difference between brachial and central BP is highly variable and is actually greater in young, fit individuals29-31. Sometimes this difference in brachial and central BP is so extreme that it results in a spurious diagnosis of hypertension in youth31-33. These observations suggest that brachial measurement of BP in young people may significantly underestimate relationships between early life events and central BP as a result of confounding by spurious augmentation of brachial BP. Consistent with this, one study of children aged 7-18 years attending paediatric outpatients34 reported that low birth weight was associated with increased central blood pressure and increased central augmentation index (AIx; a indicator of wave reflection). Increased AIx was associated with low birth weight independently of age, gender, diastolic BP, heart rate and current height, but the influence of current weight was not examined and relationships to measures of growth trajectory were not assessed.
1.3.2 Resting versus ambulatory blood pressure
Ambulatory blood pressure over a 24 hour period provides a more comprehensive assessment of blood pressure burden, and is generally a stronger predictor of cardiovascular outcomes than clinic measures, even in the general population35. Further, nocturnal blood pressure may be more informative in predicting risk, in part as loss or reversal of nocturnal blood pressure dipping is associated with an adverse CVD risk factor profile 36,37, and with increased arterial stiffness38. More recently, exaggerated blood pressure variability, particularly at night (assessed as the standard deviation of blood pressure), has also been shown to increase CVD risk, independently of absolute nighttime pressure39. Many of these phenomena have also been observed in youth; ambulatory blood pressure is superior to clinic measures in detecting disordered blood pressure patterns and associated measures of target organ damage 40,41. However, determinants of these altered 24 hour patterns have been less well studied and are conflicting. For example, whilst some studies shown an association between loss of nocturnal blood pressure dipping and obesity42, others do not43. Similarly, reports of associations between blood pressure variability and birthweight are inconsistent 44,45. As above, detailed assessment of growth trajectory, and other early life influences have not been comprehensively studied in association with blood pressure patterns in youth, but may account for the discrepancies observed.
1.3.3 Static versus dynamic blood pressure measurements
An exaggerated BP rise in response to exercise or dynamic pressor tests predicts the development of hypertension46-49, and stroke risk, independently of resting BP50. These independent associations may be due to impaired exercise induced vasodilation, as a consequence of arterial wall remodelling resulting in increased peripheral vascular resistance51;52 or endothelial dysfunction53, but early life determinants of dynamic blood pressure responses, and their associations with large artery structure and function, have not been studied.
1.4 The impact of blood pressure on the vasculature
Chronic elevated blood pressure is associated with increased pulse wave velocity (PWV; an indicator of arterial stiffness) and increased intima-media thickness (IMT) of large blood vessels, such as the carotid or femoral artery. These changes have been associated with subsequent cardiovascular risk, independent of other risk factors, including blood pressure itself, and have therefore acquired the status of surrogate CVD endpoints54-58. Obesity in youth and elevated blood pressure have been associated with increased thickness of the carotid artery wall in adolescence and early adulthood59-60. However associations between risk factors (e.g. maternal blood pressure and childhood growth) and arterial stiffness in youth have been inconsistent, with some studies showing the anticipated inverse relationship with, for example birthweight7 61, while others have shown no relation or counter-intuitive relationships with growth or maternal blood pressure 62, 6364. No study has explored the association between detailed early growth patterns, blood pressure and arterial wall thickness and stiffening, which may help to account for some of the inconsistent previous findings, and help to determine how these parameters influence structure and function of the large vessels.
In summary, elevated blood pressure in adolescence, tracks to adult blood pressure and subsequent CVD risk. Key determinants of blood pressure operate in early life, in particular growth trajectories, but the exact role of these determinants is unclear, and their relations with structural and functional aspects of the large vessels inconsistent. In part, previous studies may have been confounded by marked differences between brachial and central BP that are common in youth and failure to capture the full complexity of blood pressure patterns, including circadian patterns of BP, the inherent variability of BP and response to stressors. In addition, previous studies have not had a comprehensive assessment of maternal and early life influences in a sufficiently large study sample. We propose to measure such detailed aspects of BP, including central BP, wave reflection, arterial stiffness, ambulatory BP, ambulatory arterial stiffness index (AASI) 65 and dynamic BP responsiveness and relate these to key determinants such as early life influences, particularly post-natal growth trajectories and current obesity, and with surrogate CVD outcomes (i.e. carotid IMT, PWV) in the ALSPAC cohort.
B613 - FADS2 SNPs omega-3 fatty acids and childrens mental development - 01/02/2008
Aims and Objectives
*1. In the proposed study funded by the Waterloo Foundation we will (a) assay the maternal and infant DNA for the two SNPs that Caspi considered in regard to breast feeding and IQ (rs174575 and rs 1535). (b) take the statistical models used for the ALSPAC study which showed associations between maternal seafood intake and childhood cognitive and behavioural outcomes (see Lancet paper of 2007) and determine whether such relationships are conditional upon the maternal or infant genotypes; and (c) test the finding of Caspi et al in regard to a breast feeding effect on IQ only apparent if the child has a particular genotype.
B611 - Validation and Replication of Genetic Variants in Predicted microRNA Binding Sites and their Effect on mRNA Expression Levels - 31/01/2008
Scientific case for doing the genetic association study in ALSPAC (up to about three pages) :
Genetic variation is associated with mRNA expression levels in a heritable fashion and has been mapped in humans and model organisms as expression quantitative trait loci (eQTL). We have previously determined a number of associations between genetic variation in microRNA (miRNA) binding-sites and target mRNA expression levels.We have identified 18 genetic variants in miRNA binding-sites that are significantly associated with target gene expression levels after stringent permutations in the HapMap CEU samples and that replicate in other populations and on multiple platforms. For five miRNA binding-site variants, we are able to narrow the interval of association of which two are the most associated variants in the region. This is consistent with the hypothesis that this is the true regulatory variant. Furthermore, we find an over-representation of significant miRNA binding SNPs associated with target mRNA expression levels compared to most other annotation classes.
Given the initial evidence that SNPs within microRNA binding sites effect mRNA expression levels, we hope to further replicate these findings in other samples. The ALSPAC dataset serves as an excellence and unique resource for this endeavour.
B609 - 1958 cohort - application for continued funding for processing and distribution of DNA and cell lines - 29/01/2008
Introduction and rationale
The British 1958 birth cohort1 is based on all persons born in Britain during one week in March in 1958. Participants have been followed throughout their lives and biomedical information has been collected at various time points. Biological samples were collected from the cohort during medical examinations between Sept 2002 and March 2004. Funding for creation of a blood derived DNA bank was provided by the MRC (strategic project grant G0000934). Funding for creation of lymphoblastoid cell lines, cell line derived DNA extraction, banking and distribution was funded by the Wellcome Trust (grant no 068545).
DNA and cell line banks were created in the ALSPAC Laboratory. Blood derived DNA is available from 8018 individuals and has been used successfully in several genotyping studies.
Cell lines from 2288 individuals were created at ECCAC, Porton and a further 5239 in the ALSPAC laboratory. DNA has been extracted from all of these samples and has been organised into geographically representative subgroups of samples specifically for use as control samples in case control studies. Samples have been distributed to over 20 collaborators and were used as control samples by the Wellcome Trust Case Control Consortium2.
Further funding was obtained in 2006 and extended in 2007 for management of the cell line and DNA banks and distribution of samples (grant number GR079996). This funding will end on 31st May 2008 and we are therefore applying for additional funds to continue these functions.
The ALSPAC laboratory
The ALSPAC Genetic Epidemiology Laboratory is part of the Department of Social Medicine, University of Bristol. The department has a strong track record in genetic epidemiology. The department currently has custodianship of samples for the Avon Longitudinal Study of Parents and Children (ALSPAC), Caerphilly, Speedwell, Boyd Orr, Christs Hospital, Barry-Caerphilly studies.
The ALSPAC laboratory is equipped to create and manage biological sample, DNA and cell line banks and currently actively manages sample collections for ALSPAC and the 1958 birth cohort. The ALSPAC laboratory team works closely with the Bristol Genetics Epidemiology Laboratory (BGEL www.bgel.genes.org.uk) which was established by Professor Ian Day in 2004. The group also has a bioinformatics core led by Dr Tom Gaunt.
Prof George Davey-Smith is director of ALSPAC and has recently been awarded an MRC centre CAiTE - Centre for Causal Analyses in Translational Epidemiology, which opened in September 2007. The centre has recruited 5 academics working in the genetic epidemiology field hence increasing the expertise in this area within the department.
The ALSPAC, BGEL and MRC Centre laboratories and sample stores will move to a new purposed designed facility in summer 2008.
The laboratory is equipped for high throughput cell line production and DNA processing. Two custom designed robotic cell maintenance systems are used for lymphoblastod cell line growth. Two DNA processing robots (Tecan Genesis Freedom 2000, and Beckman Biomek 2000) are used to quantitate DNA samples with picogreen, normalise the concentration, and prepare plates for distribution to genotyping centres. A Quadra 96SV is also available for production of 384 well plates.
The laboratory is licensed by the Human Tissue Authority for storage of human tissue for research purposes and has developed custom designed Laboratory Information Management System to log processes and track samples. Samples are stored in secure cryostores and freezer stores. These are alarmed and a member of staff is contactable automatically 24hrs a day in the event of a freezer failure to prevent loss of samples.
The laboratory is a member of the Public Population Project in Genomics (P3G) DNA quantification project that was set up in 2006 to establish internationally recognised standards in DNA quantification. DNA samples from the laboratory have been successfully genotyped in a number of different laboratories using a variety of methods including the Affymetrix 500K human mapping array and Illumina Human Hap550 genotyping Bead Chip high throughput systems.
Genotyping
The laboratory distributes DNA to collaborators for genotyping although for simple SNP genotyping for the ALSPAC study we have established links with K Biosciences (http://www.kbioscience.co.uk/). The company hold stocks of DNA from the ALSPAC cohort and collaborators are encouraged to use the company. This is cost effective in terms of DNA use and genotyping costs and has simplified quality control processes. We propose to set up a similar arrangement for investigators using 1958BC DNA.
Receipt and storage of genotyping data and quality control The Laboratory has experience of handling genetics data.All genotyping data generated from ALSPAC study samples is returned to the laboratory and incorporated into an Oracle database. Before inclusion various quality control checks are run on the data including ensuring data is in Hardy-Weinberg Equilibrium and comparisons of genotypes from duplicated samples specifically included in sample sets for quality control purposes. Where data do not appear to be of suitable quality the problems are discussed with the genotyping laboratory and appropriate steps taken to improve the results. Documentation regarding the genotyping method and outcome of quality control checks is stored with the data.
Proposal for 1958 Sample ManagementAdministrative duties for 1958BC Interim Oversight Committee
All proposals to use 1958BC DNA need to be approved by the 1958BC Interim Oversight Committee. Dr Ring represents the Bristol laboratory on the committee and Dr Wendy McArdle will continue to advise regarding the feasibility of providing samples to users and technical advice regarding proposals.
Completion of a Material Transfer Agreement (MTA) is necessary before samples can be released to users. We understand that Professor Paul Burton's group in Leicester will undertake the administration associated with MTAs but they will continue to be signed off by the University of Bristol.
Ethical Approval
An application to extend the current ethical approval to include generic approval for genetic analysis, similar to that in place for the ALSPAC study will be coordinated by the Bristol team in order to allow the transfer of genetics data to Bristol and distribution to collaborators as approved by the Interim Oversight Committee.
DNA Bank Management
DNA has been extracted from all blood samples and cell lines although the yield from some samples was lower than others. Our current funding has covered extraction of further cell line pellets from low yield samples but only from those cell lines originally prepared in Bristol. By June 2008 there will be at least 400mg of DNA available from all such cell line samples but stocks of some ECCAC prepared cell lines are significantly lower. The maximum amount of DNA distributed from any sample in the last 12 months is 20mg. Therefore no further extractions will be necessary from the samples established in Bristol in the next 2 years assuming requests continue at a similar rate. However further regrowth and extraction of some of the 2288 samples produced at ECCAC will be required. Stocks of these cell lines were transferred to Bristol recently to enable us to restock the DNA bank when necessary.
DNA Distribution
We will continue to distribute DNA to users who have been approved by the 1958 Interim Oversight Committee. Dr Wendy McArdle will continue to liaise with users regarding supply of samples and any technical issues.
DNA is supplied to collaborators either as standard issue plates (1micro-g per well at 50ng/ micro-l) or at bespoke concentrations and volumes for large genotyping projects. In the last 12 months we have supplied 21 standard issue plates and prepared 5 bespoke requests. We anticipate that the level of requests for DNA will increase in the next 24 month period as results from genome wide association studies become available. We will continue to maintain a stock of "standard issue" plates for immediate issue from stock to collaborators and where necessary prepare samples at bespoke concentrations and volumes for large genotyping projects. Receiving laboratories will continue to be asked to cover the cost of transport. Requests for "cherry picked" samples, ie provision of a subset of samples which need to be individually picked from stock plates rather than an aliquot of all samples in a given plate can be accommodated. However, we would need to ask the requestor to cover the costs of the additional staff time involved in sample preparation as we have done for such requests in the past.
In addition we will set up an arrangement for providing a single SNP genotyping service withK Biosciences (http://www.kbioscience.co.uk/) if required. A stock of 1958BC DNA will be sent to the company and orders for genotyping placed via the Bristol laboratory in order to ensure that all genotyping has been approved by the 1958BC Interim Oversight Committee. In order to test this set up and associated quality control monitoring we have asked for funds to run 5 SNP genotypes on all samples. Details of the SNPs selected will be submitted to the oversight committee for approval before genotyping.
Please note that for some requests we require information about previous genotyping or phenotypes in order to select specific samples or plates of samples. We do not have access to this information in Bristol and are currently advised which samples are required by Professor David Strachan. In order to continue to provide samples selected on the basis of phenotype or previous genotyping results we will need to be advised by someone who has in depth knowledge of all 1958 data. We understand that the Centre for Longitudinal Studies will provide this support since the Bristol team currently have no access to phenotypic data.
Receipt of Genetics Data
The Bristol group has considerable experience of handling genetics data. If required we would set up systems similar to those used for the ALSPAC study to handle genetics data for the 1958 cohort. Quality control checks will be carried out including comparison of results from control samples and verifying that results are in Hardy Weinberg Equilibrium. Any problems highlighted by the quality control checks will be discussed with the genotyping lab and genotyping repeated or excluded if necessary. Results will be stored on a genetics results database designed specifically for the 1958 cohort study but based on the design of systems currently used in the laboratory. Data would be released in agreed formats when necessary. If required summary data can be provided via a website. Several Bristol staff currently have the expertise to oversee the development of such quality control, database and web site management but such processes are time consuming therefore we would require funding for a full time researcher to develop and manage the system and a fulltime data preparation assistant to assist with data cleaning and distribution.
Cell Line Bank Management
The cell line bank is established and aliquots of all cell lines are stored in Bristol with backups stored at ECCAC, Porton Down. Samples will continue to be kept in a viable condition in secure cryovessals. Sample will be regrown to replenish DNA stocks as described above. No costs for regrowth and provision of cell lines for other purposes, eg expression studies, have been included in this proposal but such studies could be facilitated if extra funds were made available to cover the staff and consumable costs.
The costs of back up storage at ECCAC are covered until December 2010 from previous 1958 funding therefore no further contribution to cover ECCAC costs is required for the duration of this proposal.
Storage of Biosamples
If required the Bristol laboratories would be able to store and distribute other biological samples held by the 1958BC. Costs have been included to cover storage of samples; distribution costs would need to be assessed on a case by case basis.
B616 - Technology use privacy and teenagers - 25/01/2008
Aims and objectives
Identity and privacy have recently rarely been out of the headlines. Government has justified the need to identify
citizens and track behaviour or security reasons, and promoted data sharing with the promise of the benefits of
transformational government. Business argues that it needs to track customer behaviour both in the real world and the
Internet to deliver personalised services that offer more targeted information and identify new business opportunities.
The public is generally portrayed as unconcerned about privacy: based on opinion poll data, government argues that the
majority of citizens support identification and surveillance, and commercial companies argue that customers are happy
to volunteer detailed information about themselves in return for discounts or entry in a prize draw. In a recent report, the
UK Information Commissioner characterised the situation as Sleepwalking into a Surveillance Society.
Do citizens and customers really not care? Previous research has shown that in many situations, people opt for
immediate benefits (or promises thereof), and are less concerned about future possible risks (or not aware of them).
However, once people experience negative consequences, or discover risks they were unaware of, they tend to respond
strongly - often abandoning services and technologies involved altogether. For example, 11% of Icelandic citizens
opted out the country's DNA database after government attempts to sell access to commercial researchers (Anderson,
1998). Examples of data sharing and leakage have raised awareness how data can be used and abused. Increasingly,
people try to defend against the collection of sensitive or inappropriate data by refusing to register, or giving false
information (Dutton & Helsper, 2007). Such responses can cause significant economic damage, or - in case of large
numbers opting out or providing "fake" information - lead to a collection of data that has little or no value. Data
owners' approach has often to been collect "all the data we can get", because "you never know when it might be
useful." However, the resulting data quality is often low, and can lead businesses to make poor long-term decisions.
For instance, if a bank or phone company refuses a mortgage or phone contract to a solvent individual because of
incorrect or outdated information, this is business lost. If 50% of people interested in a service do not register because
they fear a telemarketing assault, this is a lost business opportunity. Increasing data quality and transparency on how it
is used would have significant business benefits, and an equitable, cooperative relationship between data owners and
data subjects creates the foundation for this. This is particularly important to the UK financial sector: about 10% of
adults are spending more than their monthly income, and as a result, individual insolvencies rose by 62% to 109,288 in
2006. The traditional approach of excluding anyone with a history of financial difficulty, or charging a hefty premium,
is not sustainable. Financial exclusion can lead to social exclusion because of impact in other areas of life - housing,
employment and personal relationships, so understandably, such individuals are particularly sensitive to privacy issues.
The cost and benefit of collecting and storing data about individuals has not been properly examined, and the value of
holding information about individuals for specific purposes is not understood. The project will help government and
business to understand the value of personal data, as well as the value and risks for other stakeholders. The Home
-4-
Office estimates that identity theft costs the UK £1.7bn each year, but without a proper cost-benefit analysis, it is
impossible for data-collectors to understand how, or indeed whether, to reduce the amount of data that they collect.
Research into privacy has both benefited and suffered from its multidisciplinary nature. The multitude of perspectives
and methods has led to many detailed findings, but there is still a lack of clarity of what privacy is and what it means to
different stakeholders in different contexts/scenarios of use. There has been no attempt to measure the cost and benefits
to the stakeholders involved in comparable units. Most studies are one-off surveys, 'feeling the temperature' to general
questions about privacy. There has been no study of how stakeholders' perception evolves over time, in response to
experiences of benefits and drawback of data held about them. There is a lack of quality, empirical data on these issues,
and how to collect it. The problem of collecting reliable data on people's perceptions surrounding sensitive data about
them is akin to Schrodinger's Cat - to discuss privacy, you have to reveal things you want to keep private. The goal of
the pvnets project is to develop new methodologies that enable us to break this paradox - and more specifically:
- To produce a strong empirical base for developing concepts of privacy across contexts and timeframes.
- To investigate ways in which to establish an equitable relationship between stakeholders in terms of the value
and costs inherent in the collection, processing and use of personal data.
- To develop and apply new, validated, ethical and privacy-sensitive methodologies for the study of privacy.
- To produce a toolkit to enable commerce and Government to understand the role of personal information in
business processes and enhance strategic decision-making and the value of that information to all parties.
- To support UK businesses to become world leaders in the area of trustworthy products, systems and services
B605 - The influence of social and family factors on the developmental effects of persistent otitis media with effusion - 24/01/2008
ALSPAC has prospective data relating to early otitis media with effusion (OME), developmental outcomes and family factors on a large, normal population of children. It is ideally placed to study the sequelae of early OME and any interaction with family factors.
B766 - Genetic causes of sex differences in ADHD and schizophrenia - 23/01/2008
Background
Many psychiatric disorders display distinct sex differences. Men are more likely to be affected by neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. ADHD is a childhood onset disorder characterised by inattention, overactivity and impulsiveness. The disorder affects males more than females at a ratio of 4:1. In schizophrenia, the age of onset in men is significantly earlier (21 years) than for women (25 years). The disorder is more severe in male patients and they generally have more negative symptoms (Preston et al, 2002).
The causes of sex differences in neurodevelopmental disorders could be due to endocrine, genetic, or environmental factors and their possible interactions. In terms of genetic factors men and women differ in their sex chromosome complement and therefore the Y chromosome is potentially an important influence on male susceptibility to neuropsychiatric disorders.
Animal studies where it has been possible to disaggregate gonadal sex and sex chromosome complement have found that the Y chromosome is associated with more aggressive and less parental behaviour (De Vries et al, 2002; Gatewood et al, 2006). Possession of two Y chromosomes as in the chromosomal abnormality XYY is associated with a higher risk of antisocial behaviour when compared to those with an XXY chromosomal anomaly (Rutter et al, 2003).
However, there are difficulties in studying the Y chromosome: there is no recombination, no widely accepted nomenclature and its distribution depends highly on geographic origin (Jobling and Tyler-Smith, 2003). These difficulties have led to the Y chromosome being largely excluded from genetic and genomic studies of neuropsychiatric disorders.
To overcome this lack of knowledge surrounding the Y chromosome in psychiatric disorders, we chose to study Y chromosome variants in a sample of 210 cases with ADHD, 310 cases with schizophrenia and 700 U.K. controls.
Our hypothesis is that:
* Y chromosome haplogroups increase male susceptibility to ADHD and SZ directly
* Y chromosome haplogroups increase male susceptibility to ADHD and SZ indirectly by interacting with autosomal genes expressed in brain or environmental factors
* Y chromosome haplogroups influence sexually dimorphic cognitive performance which has a modifying effect on the disorders
Y chromosome SNPs were selected after extensive research on markers used in previous Y chromosome studies, Y chromosome Consortium data, which contain information on all the Y chromosome haplogroups (groups of haplotypes), and personal communication with research experts on the Y chromosome. These SNPs were selected in order to capture the most frequent Y chromosome haplogroups in the U.K.
Statistical analysis of Y chromosome haplogroups revealed no significantly increased representation of any haplogroup in cases with ADHD (p=0.539) or schizophrenia (p=0.679) compared to controls.
B607 - Investigating the role of type 2 diabetes genetic loci in fetal growth childhood growth and T2D intermediate traits - 23/01/2008
We wish to use the ALSPAC cohort to investigate the effects of novel and previously-confirmed type 2 diabetes loci on fetal growth, growth in childhood and intermediate traits related to type 2 diabetes.
Following our analyses of the first UK type 2 diabetes genome-wide association (GWA) study, which identified 6 new type 2 diabetes genes (FTO, CDKAL1, CDKN2A/2B, HHEX, IGF2BP2, SLC30A8) [1, 2], we have performed a meta-analysis of GWA data, combining our UK study with the DGI [3] and FUSION [4] GWA scans (N=10,128 individuals and ~2.2 million SNPs, directly genotyped and imputed). We followed-up promising signals by performing replication studies of up to 63,532 independent samples [5]. Four loci showed robust evidence for association at Pless than 5x10-8. We are therefore confident that the results exceed the stringent levels of statistical support needed for genetic association studies.
The associated SNPs are as follows:
JAZF1 rs864745
CDC123/CAMK1D rs12779790
ADAMTS9 rs4607103
THADA rs7578597
The precise nature of the biological mechanism by which each of these genes predisposes to type 2 diabetes is largely unknown. We have used replication and robust statistical data, rather than biology, to identify these genes. Further analyses of their roles in intermediate traits, using ALSPAC, are likely to help to uncover further biological pathways.
In addition to the above, we would like to complete the list of currently-confirmed type 2 diabetes loci genotyped in ALSPAC by including the following:
WFS1 rs10010131
PPARG rs1801282
KCNJ11 rs5219
We therefore propose to analyse the polymorphisms in ALSPAC to test the following hypotheses:
1. Fetal genotype and maternal genotype alter fetal growth.
2. Fetal genotype and maternal genotype alter growth velocity in childhood
3. Genotype alters intermediate traits related to type 2 diabetes 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. In the event of associations with intermediate traits in mothers we will propose to test the role of maternal genotype on fetal and childhood growth and body composition and biochemistry. For example, if the SNP alters BMI the SNP can be used in a Mendelian randomisation framework to test the role of maternal BMI in fetal growth and body composition free from confounding factors such as socio-economic status.
Whether the results are negative or positive they will help in our understanding of how the novel genes function and, if positive, provide important insights into growth and other diabetes intermediate phenotypes.
* Specific ALSPAC phenotypes being considered:
To do this we would like to genotype (at Kbioscience) all ~20,000 ALSPAC samples. We will need the following phenotypes to test our hypotheses:
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.
In addition, we are keen to examine the KCNJ11 variant in relation to physical activity in the ALSPAC children. This is to follow up a nominal association observed in the RISC cohort (Mark Walker, personal communication).
Plans for replication:
ALSPAC will provide the largest 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), Plymouth Earlybird study (300 parent-5 yr old trios - T Wilkin) the North Cumbria community genetics project (3000 mother child pairs - C Relton), the Northern Finnish 1966 Birth Cohort (4600 individuals with own birth measures) and the 1958 cohort (7000 individuals with own birth measures). We hypothesize that real genetic associations will be consistent across all these studies - i.e. even if individually studies show only nominal significance, a meta-analysis of all studies will provide highly significant results.
B767 - GWAS analysis of cortical bone geometry - 22/01/2008
Background
Understanding of the genetic determinants of osteoporosis has recently been advanced by GWAS studies looking at associations with bone mineral density (BMD) in adults (1,2), an approach we have recently applied to ALSPAC (Timpson et al, submitted for publication). However, one of the limitations of these studies is that whereas BMD is related to the risk of osteoporotic fracture in later life, this parameter does not take account of other characteristics of the skeleton which also contribute to fracture risk, such as cortical geometry. In contrast to conventional DXA scanners, pQCT, which has been obtained in all available ALSPAC children at age 16 and is currently being repeated at age 18, can accurately measure cortical bone geometry.
Aims
We plan to conduct the first GWAS analysis of cortical bone geometry, based on pQCT data obtained in ALSPAC children.
Methods
1. GWAS analysis will be performed between results of illumina chip whole genome analysis and pQCT as measured at age 16, in all available ALSPAC children (expect around 800 with 317k chip and 800 with 610k chip). Summary statistics (beta coefficients and P values) will be derived for associations with tibial cortical BMD and periosteal circumference (50% site), adjusted for age, height, weight and gender.
2. GWAS analysis will be performed between results of 610k illumina chip and approximately 1000 18-20 year old men from the GOOD cohort (3). Summary statistics (beta coefficients and P values) will be derived for associations with tibial cortical BMD and periosteal circumference (25% site), adjusted for age, height and weight.
3. A meta-analysis will be performed based on results from ALSPAC and GOOD, following which the top 100 hits will be identified (where necessary, missing genotypes from the 317k platform will be imputed).
4. A proportion of these hits will be carried forward for selective genotyping in the following three cohorts, using a variety of selection strategies (e.g. screening markers for evidence of cis-regulation in human osteoblast cells in collaboration with T Pastinen, McGill University):-
a. Remaining ALSPAC children not included in GWAS analysis
b. MrOS Sweden (approximately 1500 elderly men with pQCT data and available DNA)
c. Hertfordshire cohort (approximately 650 subjects (men and women combined) mean age 65 approx with pQCT data and available DNA)
5. Further meta-analyses will be performed (i) combining ALSPAC GWAS, GOOD and ALSPAC replication cohorts, and (ii) combining all five cohorts
References
1. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD 2008 Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371(9623):1505-12.
2. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K 2008 Multiple Genetic Loci for Bone Mineral Density and Fractures. N Engl J Med.
3. Lorentzon M, Mellstrom D, Ohlsson C 2005 Association of Amount of Physical Activity With Cortical Bone Size and Trabecular Volumetric BMD in Young Adult Men:The GOOD Study. J Bone Miner res 20:1936-1943.
B765 - An investigation into the relationship between maternal and paternal depression over time using multilevel modelling - 22/01/2008
Aim
We aim to explore the relationship between maternal and paternal depression over time in order understand the direction of causality taking into account reciprocal effects. A further aim is to explore how this relationship alters according to child behaviour and life stresses and finally how this relationship impacts on future child emotion and behaviour.
Method
We propose analysing the ALSPAC data up to age 8 including repeated measure of maternal and paternal mood and measures of child emotional and behavioural problems. We will begin by exploring reciprocal causation between maternal and paternal depression and investigate how this varies as a function of life stress, child behaviour, marital relationship and family size. We will use multilevel models to investigate the random slopes for lags and crosslags this represents a novel method of investigating these questions with the advantage that this more flexible statistical model can model the more complex reciprocal relationships likely to arise within families.
Variables
Our main variables will be:
Maternal Mood EPDS pregnancy 18 weeks & 32 weeks antenatally 2, 8, 21 33 61 73 and 97 months postnatally
Paternal mood EPDS pregnancy 18 weeks antenatally 2, 8, 21 33 61 73 and 97 months postnatal
Child emotional and behavioural problems - Carey infant temperament 6 months and Carey toddler temperament 24 months EAS temperament 38, 57 and 69 months Rutter parent Scale for preschool chidldren 42, 57 & 69 months SDQ 47 81 97 months.
Other variables:
Age mother
Age father
Number of children in home
Primip vs multip
Nature of delivery
SES (highest educational level mother)
Quality of Marital relationship - Intimate bond measure 21 and 33 months
Life events 18 weeks 32 weeks antenatally, 2, 8, 21 33 47, 61, 73 months.
B599 - Association of validated breast cancer susceptibility single nucleotide polymorphisms and modifiable childhood traits - 09/01/2008
No outline received
B598 - Gene x gene and gene x enviroment interactions underlying speech language and reading development - 04/01/2008
e propose to conduct a gene x gene and gene x environment analysis of candidate factors that have been shown to increase susceptibility for dyslexia and SLI in previous research or that have been chosen on the basis of their biological function. We will genotype all the available ALSPAC children DNA samples (greater than 10,500) for susceptibility variants within candidate genes and conduct the analysis using cognitive outcomes and environmental exposures already assessed in the ALSPAC project.
The genotyping will be performed using the Sequenom i-plex technology in collaboration with the Genomics Core facility at WTCHG. We already have in our laboratory the sufficient quantity of ALSPAC DNA required by this project.
We will select for analysis measures of reading, language and speech abilities, including measures of single word reading, non-word reading, phoneme awareness, orthographical skills, spelling, short-term memory (including NWR), verbal expression, comprehension and IQ. Many of these measures are the same as those used in our current dyslexia and SLI linkage and association studies. We plan to include in the analysis measures of attention and hyperactivity behaviour since attention deficit hyperactivity disorder (ADHD) shows extensive co-morbidity with both dyslexia and SLI.
The environmental factors will include measures that have already been proposed as risk factors for SLI, for example otitis media with effusion (OME) and maternal education, or associated with dyslexia, for example the home literacy environment and Omega-3 fatty acid consumption. We will consider also the child's environment, more general aspects of parenting and parent-child interaction. Statistical analysis will be based on linear regression models extended to include one or more covariates. We will also interrogate for multilocus interactions and genetic effects specific to factors underlying the phenotypes using techniques such as principal component or cluster analysis. Analysis will be performed both for single SNPs and haplotypes.
A detailed list of genotypes, phenotypes and environmental measures is given in the appendix.
Strategy details
Aim 1: To investigate whether the effect of dyslexia and SLI susceptibility variants can be modulated by different genetic factors (gene x gene interactions). We will select the maximum number of SNPs that can be accommodated in three i-plex reactions. Most of the novel dyslexia candidate genes we are proposing for this project have been selected for showing a strong signal in the recent WGA analysis we conducted in 600 individuals with dyslexia collected in Germany and in the UK as part of the collaborative NeuroDys project (www.neurodys.com). Other genes have been selected for their (i) similarity to other established dyslexia candidates (KIAA0319-like), (ii) interaction with established dyslexia candidates (we have recently identified interaction between the AP2M1 and KIAA0319 proteins) or (iii) role in neuronal migration, a biological pathway to which most of the reported dyslexia candidates seem to contribute. We will also include candidate genes for ADHD since this disorder show an extensive co-morbidity with dyslexia and SLI. SNPs have been selected either for showing significant association in previous work or for tagging the most common haplotype across the genes of interest. Statistical analysis will be conducted at different levels. We will first test for association between single SNPs and quantitative measures of reading, language and speech in a linear regression framework. This analysis will enable us to prioritise further investigations on the basis of the strength of association found with each gene. Following these initial association analyses, we plan to test for gene x gene interactions between the genotyped loci for example by integrating an epistatic component into the regression model. In this second step of the analysis we will incorporate also genes for which we have already obtained ALSPAC approval*.
A specific question we aim to answer is whether any tested SNP or haplotype can modulate the effect of the KIAA0319 risk haplotype (which we have recently identified within the ALSPAC sample) and whether it is possible to detect any specific interactions between candidate genes involved in the same biological pathways, such as between genes involved in neuronal migration.
Aim 2: To investigate the role of environmental factors in modulating the effect of genes that contribute to measures of reading, speech and language (gene x environment interactions). This analysis will aim to test whether any environmental factors can modify the effect of an individual's genetic background in either a protective or adverse manner for reading and language ability. The SNPs, haplotypes and gene x gene interactions that show significant associations in Aim 1 will be tested for gene x environment interaction using the environmental measures described in the Appendix.
Aim 3: To test whether shared genetic or environmental factors can explain co-morbidity between dyslexia and SLI and whether it is possible to identify a correlation between genetic/environment background and specific sub-groups of phenotypes. The data generated in Aim 1 and Aim 2 will be used to assess whether it is possible to identify causative factors that either have a particular effect on specific phenotypes or affect different, broader areas of cognition. Factors that are found to have a pleiotropic effect across different phenotypes will be further explored to investigate a possible role in determining the observed co-morbidity between SLI, dyslexia and related disorders such as ADHD. Since both dyslexia and SLI could be hypothesised to be caused by an underlying phonological deficit it will be interesting to see if specific genes contribute to the variation of phonological outcomes. The identification of association between single factors and multiple phenotypes will lead to the question of whether it is possible to identify additional interacting factors that result in more distinctive phenotype. The ultimate aim of this analysis is to test whether it is possible to distinguish between well-defined cognitive deficits on the basis of determined genetic/environmental background.
B597 - Development of ear drum retractions - 21/12/2007
Background
Disorders of the tympanic membrane (ear-drum) such as perforation, scarring, thinning and retraction are commonly found on routine ear examination in both symptomatic and asymptomatic patients. In many cases these conditions will have no long-term detrimental effects and some will resolve spontaneously. However, in many cases of retraction, progression will occur resulting in deafness, discharge from the ear and in some cases meningitis, intracranial infection and even death. It is not currently possible to identify which patients with retractions may run into problems and which ones will be stable or improve in the longer term. This means that many patients are followed up in clinic unnecessarily, whilst those that may benefit from closer surveillance, allowing timely intervention if progression of disease is seen, or early intervention as prophylaxis against disease development, are often not identified until damage has been done to the ear and hearing. In the meantime these patients may suffer with infection, discharge and intermittent or progressive deafness, often having significant lifestyle impact on top of the long-term risk to hearing and health. The ability to identify those patients at risk of complications would, potentially, have significant long-term health and lifestyle benefits.
Methods
As part of the focus group, 8,000 children from ALSPAC have undergone regular assessment of their hearing. At a previous assessment, 7,250 children had digital photographs taken of their eardrums showing thepars flacida(top of eardrum) andpars tensa(main part of ear drum); these have subsequently been analysed for the presence of abnormalities as shown below:
Area
No retraction
Retraction
Moderate / Severe disease
Pars Flacida
13,704
558
271
Pars Tensa
13,918
444
113
In the first instance the group of children identified as having a moderate / severe retraction will be invited for a clinical review with repeat photographs of the eardrum taken. A cohort from the group previously identified as normal will be assessed in the same clinics.Ethical approval will be obtained from ALSPAC and from the local regional ethical committee. Appropriate information sheets will be provided with the initial invitation to attend and consent forms completed at the time of review.
The letters would be sent by ALSPAC, replies would collected by ALSPAC, and only those that confirm their desire to participate will have their details supplied to the research team. The research team would then use NHS resources to book appointments.
Transport costs will be paid and a voucher offered as an incentive to attend. Review will be undertaken in the ENT department at St Michael's Hospital by one if the investigating team, either in a regular ENT clinic or a specific research clinic; if it is more convenient for those invited, clinics will be undertaken at a peripheral site, e.g. Weston General Hospital, assuming local approval. If possible we would like to identify some children of interest who are part of the ALSPAC cohort and are already due for ENT assessment or review to act as a pilot study. We would aim to do this by obtaining consent from patients seen in the clinic, who may be part of the relevant focus group, to contact ALSPAC to see if data is held on them. Since the children would have already been reviewed and appropriate clinical information obtained, costs would be kept to a minimum. If this approach is unsuccessful, we would seek ethical approval to obtain the NHS Numbers from ALSPAC of the young people identified previously, and attempt to match those with young people already booked for ENT examination in one of the main hospitals. A pilot study would allow us to fine-tune our study and subsequently apply for substantial funding for the review of the remaining children
If significant disease is identified at review, the child's GP will be contacted to arrange further assessment.
AnalysisDigital photographs will be analysed and classified in the same way as the original images. Comparison will be made between individuals with regard to whether the previously documented retraction has progressed, stayed the same or improved. ALSPAC data will be analysed to identify potential risk factors for disease progression.
This study will eventually describe changes in retraction pockets in a cohort of approximately four hundred patients over a six-year period. It will identify three possible outcomes: improved, stable or progressed. Identifying changes in these patients will allow appropriate clinical follow up if not already arranged and will identify a cohort of patients suitable for further analysis of a variety of potential risk factors, including environmental and genetic
B596 - ANTECEDENTS OF OPPOSITIONALITY IN YOUTH - 21/12/2007
Oppositional defiant disorder (ODD) is the single most prevalent psychiatric illness in children and adolescent in the UK(1) and is a very strong predictor of psychiatric disorders in adulthood (2). The strongest associations of ODD are with conduct disorder, antisociality, and ADHD (1, 3-5); however, ODD is also strongly correlated with emotional disorders both cross-sectionally and longitudinally (4-6). This wide range of associations and predictions suggests that ODD plays a pivotal role in the development of psychiatric illnesses (4). Despite intense research interest in ODD, it remains unclear what the underlying causes for this breadth of associations may be. A better understanding of ODD could potentially help explain issues of particular importance to child psychiatry. Firstly, it would shed light on the puzzling rates of comorbidity in children and adolescents (5, 7), and, secondly, it could help understand developmental trajectories from early life into adulthood.
We have recently been able to demonstrate in a large national sample (the Office for National Statistics Child and Adolescent Mental Health Studies from 1999 and 2004), that ODD may comprise of three dimensions that carry relatively distinct associations with other childhood psychiatric disorders (Stringaris & Goodman, submitted). We have provisionally termed these three dimensions Irritable, Headstrong, and Hurtful, conforming to their respective predictions. The Irritable dimension, composed of items indexing temper outbursts and anger, has strong associations with emotional disorders, whilst the other two dimensions predict more strongly to conduct disorders. In addition, the Headstrong dimension appears to be most strongly associated with ADHD and the Hurtful dimension to be a strong predictor of pre-meditated aggressive offending. As a result of these findings, which preliminary evidence suggests are replicated in longitudinal analyses, we are proposing a new model for ODD. Thereby, the three dimensions we have identified represent relatively distinct contributions to ODD that we hypothesize will arise from different sets of predisposing factors.
To study these questions will require a longitudinal study with measures of ODD symptomatology in middle/late childhood, and hypothesized predictors earlier in development. ALSPAC is the only study in the United Kingdom and one of the few in the world that would allow us to address these issues.
AIMS
The aim of the present study is to identify underlying factors for oppositionality in children and adolescents. Based on our findings so far, our main hypothesis is that the three dimensions we have identified as contributing to ODD are predicated on distinct predisposing factors. We expect the distinct correlates to lie in the domains of child temperament, family mental illness, parent child relationship, and academic attainment. Our hypotheses are as follows:
Temperament: we predict the Headstrong and Hurtful dimensions to be best predicted by "difficult" temperament. In contrast, we hypothesize that the temperament underlying the Irritable dimension will be mixed, encompassing both "inhibited" and "difficult" temperaments.
Family Mental Illness: we expect that all three dimensions will be predicted by a family history of antisociality. However, we predict that a family history of emotional disorders, such as depression and anxiety, will be differentially associated with the Irritable dimension.
Family Relationships: our prediction is that family relationships are important for both the Headstrong and the Irritable dimension. In contrast, we predict that such environmental effects will be of limited influence for the Hurtful dimension. This is due to evidence we have gathered so far showing that this dimension may be linked to callous and unemotional traits; these have been shown to be mostly due to additive genetic effects.
Cognitive Attainment: similar to our predictions about other environmental effects, we expect that frustration due to low academic achievement will be most relevant for the development of the Irritable and Headstrong dimension and significantly less so for the Hurtful dimension.
ANALYTIC DESIGN
This will be a developmental follow-back study, that is, we will establish symptom dimensions at the ages of 8 and 10 years and will then seek to establish their antecedents as detailed above. The study could thus be completed entirely on the basis of existing ALSPAC data. The instrument we will use to construct the dimensions will be parent-reported ODD (awkward and troublesome) symptoms collected as part of the DAWBA assessments completed at XX and YY months (this we have also used in the ONS study).
IMPLICATIONS
We expect our findings to help better understand the development of mental illness in childhood and adolescence. In particular, we expect our results to be particularly relevant for the central question of comorbidity between mental disorders in childhood. Furthermore, if childhood oppositionality encompasses more than one dimension this could mean that differential interventions might be indicated.
B595 - Neighbourhood variations in child physical activity The role of area definition - 11/12/2007
Although "neighbourhood effects" on health have been recognised in many studies1 very little is known about the underlying mechanisms and very little experimentation has been done to find out what kind of neighbourhoods might have the greatest influence on health. While researchers have been challenged to consider the geographical scales at which processes might operate and to compare alternative neighbourhood sets, few studies so far have done this. By analyzing health variations within a single set of neighbourhoods, almost all published studies have been blind to whether alternative definitions of neighbourhoods might produce different results. The question is important for two reasons. Firstly, knowledge of the characteristics of the set of neighbourhoods that produce the strongest relationship with health might help to identify any processes involved. Secondly, policy-makers advocating interventions that focus on disadvantaged areas to improve individual health need to be better informed about how to identify the areas most amenable to treatment.
We (Jones and colleagues) have recently examined the importance of alternative neighbourhood definitions on the strength of area effects on accident rates to preschool children in the ALSPAC cohort2. Alternative sets of subjective and automated zone design neighbourhoods which incorporated different boundaries and different scales were used.Neighbourhoods based on different criteria produced similar area effect sizes as did neighbourhoods at different scales, but slightly stronger effects were observed in areas with populations less than 4,000.Most of the characteristics of children and mothers associated with accident risk were themselves associated with neighbourhoods, and particularly with the neighbourhoods of smallest size.
Another health related outcome where it is of interest to investigate the possible existence of neighbourhood effects is that of physical activity. In his report At least five a week, the Chief Medical Officer notes that the scientific evidence for the health benefits of physical activity are compelling. Nevertheless, the majority of adults and children fail to meet government guidelines for activity. Reviews of the evidence of the effects of individual level interventions indicate that while positive changes in physical activity can be achieved, the effects are small and short term3. In children and adolescents there is no evidence for the effect of individual-based educational interventions4. Larger, more sustainable changes in physical activity are more likely to be achieved by a multi-level strategy combining environmental and individual level interventions4. In recent years the research focus has moved from individuals to the environment. It is hypothesised that the environment is strongly associated with physical activity yet its actual relationship with physical activity in adults and children is relatively unknown within a UK context5.
One of the unanswered research questions concerns the role which the neighbourhood might play in determining the activity levels of the children living within it. It could be, for example, that certain neighbourhoods are more conducive to activity than others. Such effects could be ascribed to their physical characteristics, or may be associated with shared norms and behaviours amongst residents. Understanding how activity levels vary between different types of neighbourhoods will guide further studies of the more detailed environmental determinants of physical activity in children. The aim of this preliminary study is to compare the strength of neighbourhood effects on physical activity levels in children aged 11 years in the ALSPAC cohort, using alternative, contrasting sets of neighbourhoods.
Methods:
Based on our previous research we will divide the ALSPAC study area into thirteen different sets of neighbourhoods. One set are enumeration districts, the smallest units in the 1991 population census. The other twelve sets all use enumeration districts as building blocks and group them into larger units at three spatial scales. Some of these neighbourhoods are based on "communities" defined by planners in Bristol whilst others have been generated by the automated zone design program "A2Z". A more detailed description and maps showing examples of the zones within Bristol are given elsewhere.6
B594 - Investigation of associations between diet and blood pressure in CIF at 5 and 7 years - 11/12/2007
Aim
The aim of this project is to investigate the associations between diet and blood pressure, measured at 5 years and 7 years in the CIF sample.
Background
Cardiovascular disease is the leading cause of death in industrialised countries, and raised blood pressure is a major risk factor(1). Geographical variations in childhood blood pressure in the UK coincide with geographical variations in adult cardiovascular mortality, and are likely to be related to childhood environment(2). Blood pressure level in childhood has also been shown to track through to adulthood(3). Diet has been shown to relate to blood pressure(4) in childhood and there is evidence that dietary changes in very early life may have persistent effects on blood pressure(5). This suggests that dietary interventions aiming to lower blood pressure in childhood could have an impact on adult cardiovascular mortality. However, data on the associations between diet and blood pressure in childhood are limited. The aim of this study is to investigate the cross-sectional and longitudinal associations between dietary intakes and blood pressure levels measured in the CIF sample at ages 5 and 7 years, taking account of potential confounding variables. Key dietary variables considered will include intakes of sodium, potassium
, magnesium, calcium, fat, protein, wholegrains, fish, fruit and vegetables. These results will be of use in formulating dietary recommendations for children.
References
1. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic and cardiovascular risk factors: US population data. Archives of Internal Medicine. 1993;153:598-615.
2. Whincup PH, Cook DG, Adshead F, Taylor S, Papacosta O, Walker M, Wilson V. Cardiovascular risk factors in British children from towns with widely differing adult cardiovascular mortality. BMJ 1996;313:79-84.
3. Kivimaki M et al. Early socioeconomic position and blood pressure in childhood and adulthood: the Cardiovascular Risk in Young Finns Study. Hypertension 2006;47:39-44.
4. Simons-Morton DG et al. Nutrient intake and blood pressure in the Dietary Intervention Study in Children. Hypertension 1997;29:930-936.
5. Geleijnse JM, Hofman A, Witteman JCM et al., Long-term effects of neonatal sodium retention on blood pressure, Hypertension 1996; 29, pp. 913-917.
Data requested
1. Food and nutrient intakes assessed by dietary diary at 5 years and 7 years in the CIF sample
2. Blood pressure measured in the Focus@7 clinic in the CIF sample
3. Blood pressure measured at 5 year clinic in the CIF sample
4. Birthweight, measured or abstracted from medical records
5. Gestational age abstracted from medical records
6. Height and weight and waist circumference at 5 years measured in the CIF clinic
7. Height and weight and waist circumference measured in the Focus@7 clinic in the CIF sample
7. Physical fitness measured at 5 year clinic in the CIF sample
8. Measures of maternal educational level and paternal occupational class by questionnaire
9. Maternal smoking in pregnancy measured by questionnaire
10. Duration of breast-feeding assessed by questionnaire
11. Age of introduction of solids assessed by questionnaire
B593 - The assessment of gene loci confirmed to alter adult height in longitudinal growth in children - 11/12/2007
The assessment of gene loci confirmed to alter adult height in longitudinal growth in children.
In summary we plan to use genome wide data from 43,000 to 50,000 individuals from at least 12 different studies to identify in the region of 50 new loci that alter adult height. We will not know the exact number of loci until we have followed up ~200 SNPs in 55,000 samples from the HUNT study but our QQ plots and False discovery rate calculations suggest this is a realistic number. These will be in addition to the current 20 loci we have identified and typed in the ALSPAC children recently (results pending).
We propose to genotype, using Kbiosciences, the 50 SNPs representing these loci, in the 10,000+ ALSPAC children. This will enable us to test the hypothesis that common gene variants known to alter adult height alter birth length, and childhood growth at different ages. We will colloborate with Bruna Galobardes who has expertise in using the ALSPAC growth longitudinal data.
Statistics
We will use within study and within sex Z scores and the same genetic model (additive, dominant, recessive) that fits the adult data. We will initially perform cross sectional analysis at each age point from birth to the maximum age available. We will then collaborate with Bruna to model the longitudinal data.
Table of data needed (form does not allow tables!):
Children
Birth - length, weightChildhood, ages 2 months to 15 years, all measures of length/height, sex, puberty data
Mothers
Adult height, age
B588 - Alspac maths data - 30/11/2007
We want to us ALSPAC maths data as we feel that information on maths and maths teachers is particularly strong. Young people's attitudes to maths have been examined at different stages in their lives, and their ability has been tested through independent tests in years 4, 6 and 8 (covering specific domains of maths). In addition, there have been surveys of maths teachers' experience and attitudes in the main ALSPAC schools (in KS3) which could be linked to individual pupil data. None of this data has yet been analysed. Our understanding is that the data for assessments at Year 4 and Year 6 are now available, but Year 8 needs additional funding to clean and release the data, as does the data from the maths teacher questionnaires in 2002/3 and 2004/5, and the linking of questionnaires from teachers to children.
Once this data is available we intend to commission a separate analysis project. This will be competively tendered. The successful tenderer will require access to the data.
There are three possible areas for analysis:
* Young people's experience - using the questionnaires and independent assessments to examine how the young people have developed capability and confidence in maths, either looking at evidence throughout their lives (up to 14 or 16) or just at change between Y4-Y8.
* Teachers' experience - using the teachers' questionnaires to look at teacher attitudes and relating these to their school circumstances, stress and confidence
* Linking teacher and child experience - how teacher experience and attitudes link to child enjoyment, engagement and ability.
Funding may be available this financial year to make this data available. Please advise on timetable and costs.