Proposal summaries

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

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B473 - Investigating the role of SNPs associated with stature in type 2 diabetes patients and controls in the ALSPAC study - 06/03/2007

B number: 
B473
Principal applicant name: 
Prof Tim Frayling (Peninsula College of Medicine, University of Plymouth, UK)
Co-applicants: 
Dr Rachel Freathy (Peninsula Medical School, University of Plymouth, UK), Prof Mark McCarthy (University of Oxford, UK), Prof George Davey Smith (University of Bristol, UK), Prof Andrew Hattersley (Peninsula Medical School, University of Plymouth, UK), Nick Timpson (University of Bristol, UK), Dr Cecilia Lindgren (University of Oxford, UK), Dr Michael N Weedon (Peninsula Medical School, University of Plymouth, UK), Dr Ele Zeggini (Sanger Institute, UK)
Title of project: 
Investigating the role of SNPs associated with stature in type 2 diabetes patients and controls in the ALSPAC study.
Proposal summary: 

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.

Date proposal received: 
Tuesday, 6 March, 2007
Date proposal approved: 
Tuesday, 6 March, 2007
Keywords: 
Primary keyword: 

B496 - People of Britain transformations - 01/03/2007

B number: 
B496
Principal applicant name: 
Sir Walter Bodmer (Not used 0, Not used 0)
Co-applicants: 
Title of project: 
People of Britain transformations
Proposal summary: 

No outline received

Date proposal received: 
Thursday, 1 March, 2007
Date proposal approved: 
Thursday, 1 March, 2007
Keywords: 
Genetics
Primary keyword: 

B492 - Pregnancy related weight gain and factors associated with the development of obesity after pregnancy - 01/03/2007

B number: 
B492
Principal applicant name: 
Dr Ruth Bell (Universityof Newcastle, UK)
Co-applicants: 
Title of project: 
Pregnancy related weight gain and factors associated with the development of obesity after pregnancy
Proposal summary: 

No outline received

Date proposal received: 
Thursday, 1 March, 2007
Date proposal approved: 
Thursday, 1 March, 2007
Keywords: 
Primary keyword: 

B468 - The longitudinal course of depressive symptoms from late childhoood to early adolescence - 22/02/2007

B number: 
B468
Principal applicant name: 
Dr Carol Joinson (University of Bristol, UK)
Co-applicants: 
Title of project: 
The longitudinal course of depressive symptoms from late childhoood to early adolescence.
Proposal summary: 

Project outline: The longitudinal course of depressive symptoms from late childhood to early adolescence

The proposed 24-month project will investigate the developmental changes in depressive symptoms from late childhood (9 years) to adolescence (13 years) in the Avon Longitudinal Study of Parents and Children (ALSPAC). The research will exploit recent innovations in statistical modelling of longitudinal data that now make it possible to empirically test whether there are meaningful subgroups of individuals in the ALSPAC cohort that follow distinct developmental trajectories of depressive symptoms.

Using the statistical package Mplus (Muthen and Muthen 1998), the study will employ a range of approaches (both parametric, semi-parametric and non-parametric) to describe both the within-child and between child heterogeneity observed in a set of repeated measures of depressive symptoms. Techniques such as these will permit us to examine whether distinct developmental trajectories of depressive symptoms can be empirically identified in the ALSPAC cohort, and furthermore, allow us to test whether individuals cluster into distinct subgroups, each with a different trajectory profile of depressive symptoms. It is expected that there will be at least four distinct trajectory groupings relating to a) little or no depressive symptoms from childhood to adolescence (persistent low level); b) increasing levels of depressive symptoms from childhood into adolescence (increasing); c) onset of depressive symptoms in childhood with consistently high levels of depressed mood (chronic high); and d) moderate levels of depressed symptoms throughout the assessment period (moderate). Gender differences in the trajectory groupings will also be examined using two approaches: Firstly, by modelling the sample as a whole, it will be possible to examine the gender ratio observed within each trajectory group. Secondly, by fitting gender-specific models, we will be able to examine differences in trajectory shape. It is predicted that girls will show higher mean levels and sharper increases in depressive symptoms from childhood to adolescence than boys.

The second aim of the proposed study is to link distinctive trajectories with risk factors that might account for individual differences in the development of depressive symptoms.

By taking advantage of extensive longitudinal data from ALSPACon socio-demographic background, family adversity and parental psychopathology, the proposed study will compare the risk factors for depressive symptoms beginning in childhood (9-11 years) compared to adolescence (12-13 years). We will empirically test whether social disadvantage and family adversity are more strongly associated with childhood onset depressive symptoms (i.e. persistent depressive symptoms beginning in childhood) compared to those with depressive symptoms emerging in adolescence.

The study will use longitudinal data from the Mood and Feelings Questionnaire to measure depressive symptoms (MFQ, Angold et al. 1995; Sharp et al, 2006). The use of this instrument allows both a categorical view of likely depressive disorder, as well as a dimensional measure of total depressive symptoms with severity ranging from none to severe.

Date proposal received: 
Thursday, 22 February, 2007
Date proposal approved: 
Thursday, 22 February, 2007
Keywords: 
Primary keyword: 

B469 - Childhood Cancer Research Group - 21/02/2007

B number: 
B469
Principal applicant name: 
Maureen E Murphy (University of Pennsylvania, USA)
Co-applicants: 
Title of project: 
Childhood Cancer Research Group
Proposal summary: 

Basically the study is a pilot to demonstrate that it is (or is not) possible to use neonatal Guthrie blood spots both for genotyping and separately immunological measures of infection contact. The ultimate aim is to study the relevance of (host resistance) genetic variation in the child (I know of the work on mannose binding lectin (MBL) in ALSPAC) but also immunological evidence in the child of specific infection contact during pregnancy (largely acquired by passive transfer of antibody from the mother, thoughherinfection contact may not have been during the pregnancy necessarily) for the occurrence of childhood tumours, particularly leukaemias.

In the absence of any really large centralised childhood biobanks in the UK of tissues other than neonatal blood spots (which exist in many discrete centres back to the 1980s) that could be used unambiguously to assess infection contact prior to childhood cancer diagnosis, it seems worthwhile to see whether it is technically feasible to make immunological measures in old blood spots.We know already that old blood spots (and other tissue samples) can be used reliably with amplification if necessary, to obtain DNA in sufficient quantities and quality for genotyping polymorphisms of interest (e.g. MBL, HLA).There are several reports also that it is possible to measure immunoglobulin evidence of specific infection contact, but we need to establish thoroughly whether we can do it reliably and in a multiplex way for several infections simultaneously given the everyday conditions of storage and availability of NHS blood spots.We will also need to

check those measures separately in maternal pregnancy sera, cord blood and perhaps childhood sera to demonstrate we can do it well, and the ALSPAC sample availability means this is possible.If we can demonstrate feasibility of such measurement, Scotland (which has stored centrally in one place blood spots for all children screened since 1968, and amongst whose childhood population we can identify about 3-4,000 cases of cancer) would be the place to carry out the definitive study, I think.

I have spoken to Dr Helena Kemp, Consultant Chemical Pathologist at North Bristol NHS Trust, and established that she holds easily retrievable blood spots for the Avon population born since about 1986, so the ALSPAC children should be included.With suitable permissions (I am not sure what ALSPAC families consented to) we could record-link ALSPAC to the NRCT here to define all childhood cancers in your cohort.I don't think this is intrinsically hugely interesting because there should only be about 30 cases, but power not withstanding, we should be able to use that event determination for other purposes also e.g. to study birthweight, growth and growth factors and risk, at least in a pilot sense.The meagre numbers also mean that it is unlikely anybody else will be particularly interested in childhood cancer in the ALSPAC cohort, so consumption of tissue for these kids and a small number of controls is unlikely to queer anybody else's future pitch.

We would like to use the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in Bristol as the source material of choice in the pilot study. 14,541 pregnant women with a delivery date in 1991-92 were enrolled, and for many of those offspring in whom childhood leukaemia or other cancers were diagnosed, this will already be known to you, but we would propose to record link the cohort to the NRCT to determine fully the 30 or so malignancies (10 leukaemia, 20 other) the cohort of babies will have experienced by age 14. There is an abundance of other children to act as controls, and we propose concentrating on the 10 leukaemias, 20 other cases and 30 controls in this pilot study. For most women and children in the cohort there exists a maternal blood sample taken antenatally (gestation varies) and cord blood for the babies (and placenta/cord tissue sample). In addition though not directly relevant to us there is blood from each child who was followed at age 7 and blood on a 10% sample of the children for each of the first 5 years. The Guthrie blood spots for each child will have been obtained and stored separately by the Health Authority (Dr Kemp), rather than the ALSPAC team. Because the Guthrie spots might be a precious resource, undertaking the study in the ALSPAC cohort diminishes the force of the argument against consuming (part of) them in this way, because, unusually, similar tissue samples are known to exist for the same babies in the ALSPAC study if they were needed by others (and ALSPAC precious resources are unlikely to be wasted because few would want to focus particularly on the childhood cancer cases when the numbers in the cohort are so few, outside of a pilot study of the sort we propose). We would hope to obtain access in ALSPAC to the maternal antenatal blood, the baby's cord blood, and separately, (part of) the stored Guthrie samples. We would develop a method for immunological measurements in the blood spots (to be correlated with the maternal antenatal blood and foetal cord blood estimations) for one control infection (rubella) and one or two infections that might have occurred prenatally (or before the pregnancy) and be relevant to childhood leukaemia.

As prototype examples we would probably choose Influenza (many women will have been exposed in the 1989/90 epidemic, though 1991 and 1992 were relatively quiet flu years) and Epstein Barr virus, since significant frequency of recrudescence of this infection during pregnancy has now been linked twice to ALL risk and EBV is a plausible candidate infection for increasing risk.

The aim of the study is simply to demonstrate that for candidate infections of interest, markers of contact can be estimated in blood spots, which faithfully reflect other measures of contact by the mother before or during the pregnancy.If the ALSPAC team is happy to consider this request for a collaborative pilot study using your samples, I would be grateful if you could remind me of any costs that might need to be anticipated for use of data/samples on about one hundred children.

Date proposal received: 
Wednesday, 21 February, 2007
Date proposal approved: 
Wednesday, 21 February, 2007
Keywords: 
Primary keyword: 

B462 - Maternal folate in pregnancy and incidence of breast cancer and all cause mortality - 12/02/2007

B number: 
B462
Principal applicant name: 
Prof Andy Ness (University of Bristol, UK)
Co-applicants: 
Title of project: 
Maternal folate in pregnancy and incidence of breast cancer and all cause mortality
Proposal summary: 
Date proposal received: 
Monday, 12 February, 2007
Date proposal approved: 
Monday, 12 February, 2007
Keywords: 
Primary keyword: 

B464 - A GWA study of QTL in 4 UK pop cohorts - 05/02/2007

B number: 
B464
Principal applicant name: 
Dr Panos Deloukas (Sanger, UK)
Co-applicants: 
Title of project: 
A GWA study of QTL in 4 UK pop cohorts
Proposal summary: 

General Aims : Our objective in this project is to use individual genotyping and genome-wide association studies (GWAS) in two UK population cohorts , one a family-based adult cohort (twins) and the second a prospective study of children with parental information (ALSPAC). Both have overlapping multiple intermediate phenotypes useful to uncover novel susceptibility genes, explore gene-gene and gene-environment interactions and advance understanding about gene networks which influence disease susceptibility. The other wider aim is to provide a UK resource of several finely genotyped and complimentary population cohorts with overlapping phenotypes for replication.

Specific Aims: The specific project aim is to use existing DNA from a sub-cohort of heavily phenotyped 1,500 dizygous (DZ) twins and 1500 unrelated MZ twins to perform individual genotyping using 300k Illumina Bead Chip Array. We will then conduct a genome-wide association analysis of this data using both total association and family-based statistics to test for associations with extensive existing phenotype and environmental data (i.e. greater than 1000 phenotypes) we have collected over the past 15 years GWAS projects survey common genetic variation by testing a dense set of single nucleotide polymorphisms (SNP) across the genome and we expect this will be an efficient method to uncover novel genes, gene-gene interactions and gene-environment interactions that are relevant to common chronic diseases

Specific Aim 1: Genotype approximately 317,000 SNPs (Illumina Hap300 beadChip) in each of 1,000 female Caucasian twin individuals (500 pairs) and 1000 ALPAC children starting October 2006. Test for association with 20 primary phenotypes related to cardiovascular, metabolic, respiratory and bone and other common complex genetic diseases. Test for stratification and perform test for total and family-based association with the primary phenotypes (First phase).

Specific Aim 2: Compare results of overlapping phenotypes with other genotyped cohorts (EPIC and 1958BC) to obtain replications and between adult and child populations to examine age-gene interactions for the same phenotype. Note these other cohorts will initially have been genotyped with 500,000 Affymetrix SNPs. In addition, the 1958BC will have also been typed with the Illumina 550K chip and the EPIC with the 317K chip. Thus all samples will have data on the 317K SNP set but some comparisons will be region rather than SNP specific.

Specific Aim 3: Use the data from the second wave of genotyping in TwinsUK and ALSPAC for further confirmatory association studies. The added power will allow detection of gene effects of more modest influence and again replicated in the other cohorts. In any gene shown to have compelling association from first and second phase, resequence the promoter (+2kb up stream), 5'UTR exons and 3'UTR (+2kb down stream), in 50 individuals selected from opposite ends of the associated trait distribution. This will fully characterise genetic variation in any genes showing compelling association and confirm the pattern of linkage disequilibrium and the HT-SNPs.

Specific Aim 4: Share the data with other investigators - as the amount of data generated in this multiple phenotype approach will be immense, it will be impossible for any single group to analyse. The nature of the cohorts makes it ideal to be used as a control group for female Caucasian case series and children.

Specific Aim 5: Use the results after phase 1 and 2 to assess value of extending the genotyping to the whole twin and ALSPAC sample..

Date proposal received: 
Monday, 5 February, 2007
Date proposal approved: 
Monday, 5 February, 2007
Keywords: 
Primary keyword: 

B458 - Acqisition and analysis of MR data in the ALSPAC cohort - 01/02/2007

B number: 
B458
Principal applicant name: 
Tomas Paus (University of Toronto, Canada)
Co-applicants: 
Penny Gowland (University of Nottingham, UK), Alain Pitiot (University of Nottingham, UK), Prof George Davey Smith (University of Bristol, UK), Dr Carol Joinson (University of Bristol, UK), Prof Debbie A Lawlor (University of Bristol, UK), Prof Glyn Lewis (University of Bristol, UK), Dr Margaret May (University of Bristol, UK), Dr Kate Northstone (University of Bristol, UK)
Title of project: 
Acqisition and analysis of MR data in the ALSPAC cohort
Proposal summary: 

This application seeks support for the acquisition and analysis of magnetic resonance images (MRI) in 1,000 adolescents from a population-based birth cohort established in England in early 1990's, namely the Avon Longitudinal Study of Parents and Children (ALSPAC). Our long-term objective is to discover trajectories, from conception through childhood, that give rise to healthy vs. abnormal brain in adolescence. This objective will be achieved by combining a multimodal assessment of brain structure in adolescence with the existing prenatal and post-natal datasets acquired over the past 15 years in this cohort. The normative component of our study will be strengthened by our participation in three other MR-based developmental studies, namely the Saguenay Youth Study (SYS), the NIH-funded MR Pediatric Atlas and the EU-funded IMAGEN study (see Section B2).

Acquiring MRI data in the ALSPAC cohort, when the adolescents are between 16 and 17 years of age, will allow us to answer a number of questions within each of the following four specific aims:

Specific Aim 1: Nutrition

We will evaluate the role of nutrition during infancy and childhood on brain structure in adolescence.

Specific Aim 2: Physical Growth

We will evaluate the predictive value of pre-natal and post-natal physical growth (thriving) vis-a-vis cognitive development during childhood and brain maturity in adolescence.

Specific Aim 3: Addiction

We will examine the impact of prenatal (e.g. substance use during pregnancy) and postnatal (e.g. early menarche) factors on the offsppring addictive behaviour and its neural substrate in adolescence.

Specific Aim 4: Psychosocial Adversity

We will evaluate factors determining vulnerabilty vs. resilience to psychosocial adversity vis-a-vis psychopathology and brain structure in adolescence.

Date proposal received: 
Thursday, 1 February, 2007
Date proposal approved: 
Thursday, 1 February, 2007
Keywords: 
Primary keyword: 

B456 - Maternal Stress Theory - 26/01/2007

B number: 
B456
Principal applicant name: 
C Houston (Not used 0, Not used 0)
Co-applicants: 
Title of project: 
Maternal Stress Theory
Proposal summary: 

No outline received

Date proposal received: 
Friday, 26 January, 2007
Date proposal approved: 
Friday, 26 January, 2007
Keywords: 
Primary keyword: 

B454 - Analysis of physical activity and low birth weight - 26/01/2007

B number: 
B454
Principal applicant name: 
Dr H Wildschut (University Hospital Dijkzigt, Erasmus University, Rotterdam, The Netherlands, Europe)
Co-applicants: 
Title of project: 
Analysis of physical activity and low birth weight
Proposal summary: 

I would be very interested to examine the association between physical activity and birth weight (continuous variable, low birth weight (less than 2500 grammes), SGA (less than the 10the percentile [the question is which standards tot use), gestational age (continuous variable), preterm birth (less than 37 weeks). Firstly, I would like to analyse the univariate association between the abovementioned factors and the aforementioned outcome measures. Secondly I would like tot do a multivariate analysis looking at physical activity and the aforementioned outcome measures, thereby adjusting for variables that emerged forom the univariate analysis as statistically significantly associated the outcome.

Date proposal received: 
Friday, 26 January, 2007
Date proposal approved: 
Friday, 26 January, 2007
Keywords: 
Primary keyword: 

B455 - The apgar score as a predictor of physiological measures - 25/01/2007

B number: 
B455
Principal applicant name: 
Dr David Odd (University of Bristol, UK)
Co-applicants: 
Title of project: 
The apgar score as a predictor of physiological measures
Proposal summary: 

The aim of the project is to investigate the relationship between the composite Apgar score and its individual components.

Date proposal received: 
Thursday, 25 January, 2007
Date proposal approved: 
Thursday, 25 January, 2007
Keywords: 
Primary keyword: 

B453 - Evaluating Childhood Obesity Interventions - 25/01/2007

B number: 
B453
Principal applicant name: 
Dr Leo Trasande (NYU Langone Medical Centre, USA)
Co-applicants: 
Title of project: 
Evaluating Childhood Obesity Interventions
Proposal summary: 

Obesity among American children has reached epidemic proportions. 34.8% of children in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) sample were at risk for overweight (greater than 85%ile Body Mass Index, or BMI) or overweight (greater than 95%ile BMI) (37). Childhood obesity is an extremely strong predictor of adult obesity, poor cardiovascular health and a number of significant and lifelong health problems that manifest during childhood (38). Childhood obesity is thus extremely costly to society, reducing quality of life and burdening our health care system.

Though the epidemic of childhood obesity is widely recognized, the future consequences of overweight and at risk of overweight for the current generation of American children are not known. Preventing adult obesity by preventing or reversing childhood obesity may represent a major cost-effective strategy to improve present and future health in America, but no study has predicted future prevalence of obesity (and associated increases in cardiovascular and other morbidities) if additional efforts are not devoted to its prevention or reversal.

Aim 1 of this research proposal is therefore to apply data from longitudinal cohort studies on the tracking of obesity, the existing literature on the comorbidities associated with childhood obesity, and extant federal databases (NHANES, National Longitudinal Survey of Youth, Medical Expenditure Panel Survey and the National Hospital Discharge Survey) to predict the health and economic consequences of obesity in present and future cohorts of American children. Markov processes will be developed to describe each of the transitional probabilities of obesity over the lifespan, and multi-variable sensitivity analysis using Monte Carlo simulation will also be employed to develop a range that most accurately describes the possible consequences of childhood obesity.

Childhood obesity at its most basic level represents an imbalance between dietary intake and physical activity. Poor diet and physical inactivity are the leading etiologic factors of childhood obesity in America. In its report Preventing Childhood Obesity: Health in the Balance, the Institute of Medicine has identified a variety of promising approaches in childhood and adolescence to reducing morbidity of childhood obesity (39). Resources to combat childhood obesity are limited, and thus the most cost-effective interventions should be applied in order to reduce morbidity from childhood obesity, yet no study has systematically evaluated the relative cost-effectiveness of strategies to reduce morbidity from childhood obesity.

In Aim 2 of this research proposal, I will use data from the Iowa Bone Development Study to quantify the potential impact of various changes in diet and physical activity on future risk of obesity. I will then apply a decision-analytic model that compares the scenario in which no intervention is applied with the scenario in which an intervention that reduces children's television viewing, increases physical activity or improves diet is applied across the appropriate age cohort(s). The goal will be to assess the potential cost-effectiveness and cost-benefit profile of effective interventions identified by the Cochrane Group (40) that could reduce morbidity from childhood obesity by reducing children's television viewing, increasing physical activity or improving diet.

Traditional pediatric disease prevention has focused on identification of individual risk factor-disease relationships, and development of effective interventions to reduce risk. By executing the proposed research plan, I will become expert in the application of mathematical modeling and economic analysis to the design and evaluation of evidence-based interventions against obesity and other chronic childhood diseases and in the effective translation of science into evidence-based prevention.

Date proposal received: 
Thursday, 25 January, 2007
Date proposal approved: 
Thursday, 25 January, 2007
Keywords: 
Primary keyword: 

B452 - Cerebral visual function in ALSPAC children - development and abnormalities - 25/01/2007

B number: 
B452
Principal applicant name: 
Miss Cathy E M Williams (University of Bristol, UK)
Co-applicants: 
Prof Andrew Whitelaw (University of Bristol, UK), Dr Eileen Birch (Retina Foundation of the Southwest, USA), Prof Alan Emond (University of Bristol, UK), Mr Richard Harrad (University of Bristol, UK), Prof Ian Gilchrist (University of Bristol, UK)
Title of project: 
Cerebral visual function in ALSPAC children - development and abnormalities
Proposal summary: 

AIMS

The development of simple visual acuity is most rapid in the first 1 - 3 years of life. However, the maturation of the neural pathways that refine this information and that relate visually acquired information to other systems on the brain (eg, cognitive processing, visuomotor skills including eye movements, systems of attention), in other words help one understand and react to what one sees, occurs in over a longer period and important changes are thought to occur in late childhood and teenage years.

Cerebral visual impairment (CVI) is now the commonest cause of severe sight restriction or blindness in children in the UK1and other developed countries. Less severe manifestations of CVI are increasingly described in the literature, often correlating well with lesions seen on MRI2,3 and are recognised clinically as having a major impact on child's ability to achieve their potential and extensive resources may be needed to support affected children in school and at play4-6.

Several patient groups have been described as being likely to have abnormal cerebral visual function (for example individuals born prematurely with periventricular leucomalacia4, individuals with with cerebral palsy7, hydrocephalus8, autism9 , ADHD10,11, schizophrenia12,13) but little is known about the variability in cerebral visual functions in children without identifiable pathologies, or about the pathways that lead to cerebral visual abnormalities. We have collected some data relating to development of cerebral visual functions in the ALSPAC cohort. These data include:

* Accommodation (F7, TF3)

* Stereopsis (CiF, F7, F11, TF1, TF3)

* Eye Preference (CiF, F7, F11, TF3)

* Saccadic and pursuit eye movements (CiF, F7)

* Contour detection (F7 - in a subset, F11, TF1, TF3) 14,15

* Circular contour deformation (F11, TF1, TF3) 16

* Structured history items in questionnaire sent when cohort were aged 13 years. (Questionnaire TA at 13 yr) 17

The questions asked from the "structured history" covered topics such as difficulties finding objects on a crowded background, getting lost or losing things, problems judging doorways and steps and problems seeing objects pointed out in the distance. Many relate to part of the brain known as the "dorsal stream" which comprises neurones relaying information about "where" things or the individual, are. Difficulties with these tasks can be very disabling and have been observed in children with a variety of developmental or educational problems.

Date proposal received: 
Thursday, 25 January, 2007
Date proposal approved: 
Thursday, 25 January, 2007
Keywords: 
Cognitive Function, Vision
Primary keyword: 

B450 - Asthma and Swimming - 18/01/2007

B number: 
B450
Principal applicant name: 
Prof Jean Golding (University of Bristol, UK)
Co-applicants: 
Prof John Henderson (University of Bristol, UK)
Title of project: 
Asthma and Swimming
Proposal summary: 

There is currently much discussion as to whether exposure to the chemicals used in swimming pools early in a child's life is responsible for the initiation of symptoms of asthma in susceptible children. The main evidence for this comes from Belgium, and there have not been studies in Britain to our knowledge. There is some anxiety at DfES concerning the validity of these results, particularly since it is government policy that all primary school children learn to swim as part of the current curriculum.

ALSPAC did not ask about swimming directly in early parental questionnaires, but did ask about activities with the child undertaken with the mother and with the father at various time points. Reports of swimming would occur as text.

In order to assess the feasibility of undertaking a study of swimming in ALSPAC we therefore propose coding the activities undertaken with the child over time. This would allow us then to undertake power calculations to ascertain the appropriateness of carrying out a detailed analysis of the ALSPAC asthma data in this regard.

To this end we have managed to obtain a promise of £3500 - which I anticipate will cover the costs of JG coding all the activities over the pre-school and possibly the primary school period, and the computing team adding the data to the SPSS built files. The funders are the Amateur Swimming Association and the Pool Water Treatment Group, with some help possibly from DfES.'

Date proposal received: 
Thursday, 18 January, 2007
Date proposal approved: 
Thursday, 18 January, 2007
Keywords: 
Primary keyword: 

B451 - Are sedentary behaviuors related to adiposity in 10 year old children - 16/01/2007

B number: 
B451
Principal applicant name: 
Angie Page (University of Bristol, UK)
Co-applicants: 
Title of project: 
Are sedentary behaviuors related to adiposity in 10 year old children?
Proposal summary: 

no outline received

Date proposal received: 
Tuesday, 16 January, 2007
Date proposal approved: 
Tuesday, 16 January, 2007
Keywords: 
Primary keyword: 

B444 - Genetic and environmental risk-factors for myopia in the ALSPAC study cohortLinked to B1169 - 09/01/2007

B number: 
B444
Principal applicant name: 
Dr Jez Guggenheim (University of Cardiff, UK)
Co-applicants: 
Miss Cathy E M Williams (University of Bristol, UK)
Title of project: 
Genetic and environmental risk-factors for myopia in the ALSPAC study cohort.(Linked to B1169)
Proposal summary: 

In Western countries, there are no cohorts of childhood refraction data large enough to provide the statistical power to detect subtle genetic effects (e.g. QTL controlling less than 5% of the variation in the trait phenotype). This study will provide complementary information to a moderately sized study (1400 children) in Asia, in which refraction data has been collected, and selected SNP genotyping is planned. This work will also provide preliminary data to inform a future genomewide association studies for refractive error in this cohort.

Date proposal received: 
Tuesday, 9 January, 2007
Date proposal approved: 
Tuesday, 9 January, 2007
Keywords: 
Primary keyword: 

B564 - The influence of prenatal alcohol exposure on childhood behaviour and learning - 08/01/2007

B number: 
B564
Principal applicant name: 
Dr Kapil Sayal (University of Nottingham, UK)
Co-applicants: 
Dr Jon Heron (University of Bristol, UK), Prof Alan Emond (University of Bristol, UK), Prof Jean Golding (University of Bristol, UK)
Title of project: 
The influence of prenatal alcohol exposure on childhood behaviour and learning
Proposal summary: 

Research Questions:

1. Is there an independent effect of maternal consumption of alcohol during pregnancy on childhood behavioural, mental health and learning outcomes?

2. Is there a dose-response relationship?

3. Do the patterns and timing of alcohol consumption during pregnancy influence outcomes?

4. What are the causal and mediating relationships in influencing these outcomes?

Background

There is robust evidence of an aetiological relationship between high levels of alcohol consumption during pregnancy and adverse physical and neuropsychological childhood outcomes. When specific criteria are met, these have been best characterized at the extreme end as Fetal Alcohol Syndrome (Sokol et al, 2003). However, this raises the question of whether there is a safe level of drinking during pregnancy or if lower levels of exposure are also independently associated with adverse outcomes. There are conflicting accounts as to whether there is a small independent effect from lower levels of exposure (Linnet et al, 2003; Sood et al, 2001). Policy recommendations have become more cautious in recent years, suggesting abstinence from alcohol throughout pregnancy. However, the extent to which these recommendations are based on evidence remains uncertain.

Previous studies addressing these questions have had methodological limitations such as the use of high-risk samples which do not readily generalise to the wider population, short periods of follow-up, limited measures of antecedent confounders (such as maternal mental health), and retrospectively collected data that risks recall bias relating to the exposure (Linnet et al, 2003). In contrast, the ALSPAC dataset is very well placed to overcome these methodological issues in a large representative epidemiological sample.

Our preliminary analyses focussed on the effects of occasional drinking during pregnancy (Sayal et al, 2007). This is the largest published study (n=9086) that investigates the effects of prenatal alcohol use on child mental health outcomes and the methodology and findings are of international relevance. After controlling for a range of prenatal and postnatal factors, we found that the consumption of less than one drink of alcohol per week during the first trimester was independently associated with clinically significant mental health problems in girls (assessed at three time points between the ages of 4-9 years using ratings from 2 different informants). We have also found that the consumption of four or more drinks in a day in the second or third trimesters was independently associated with higher total levels of mental health problems (especially hyperactivity and conduct problems) in girls at the age of 47 months and in both genders at 81 months (paper in preparation). The consumption of four or more drinks continued to carry risk for these outcomes in the absence of daily drinking. Based on these preliminary findings, we wish to investigate whether these associations and outcomes persist over time (till age 13) and generalise to other outcomes (such as child temperament, development, learning, and mood).

Key Measures

Exposure: Maternal (and paternal) use of alcohol during pregnancy.

Outcomes:

Pre-school: Temperament measures (using the Carey & EAS scales); SDQ at 47 months; development (using the Denver Developmental Screening Test - done at 18, 21, 30 months).

School age: child mental health (externalising and internalising problems as measured by the SDQ at later time points, parent and teacher DAWBAs, & Mood & Feelings Questionnaires); cognition and learning (IQ measures and school SEN information); and neuropsychological/attentional outcomes (such as the TEACH).

Confounder variables: The analyses will control for a range of pre-, ante-, and post- natal factors such as maternal and paternal pre- and post- pregnancy alcohol consumption; maternal smoking and drug use in pregnancy; gestational age; birth weight for gestational age; birth complications; child gender; family structure and maternal and paternal age, mental health, education, and socio-economic status;.

Analytical Approach: Following initial bivariable analyses, multivariable logistic regression analyses will assess the effect of prenatal alcohol use on child outcomes. As sample attrition may be related to both the exposure and outcome, response status at follow-up will be related to baseline variables. As there are repeated measures of outcomes, latent constructs will be developed approaches such as structural equation modelling will be used to explore overlapping predictor factors for dependent variables and to test for causal and mediating relationships. This will also quantify the role of other key risk factors, especially smoking during pregnancy.

Date proposal received: 
Monday, 8 January, 2007
Date proposal approved: 
Monday, 8 January, 2007
Keywords: 
ADHD, Antisocial Behaviour
Primary keyword: 

B448 - International growth reference for school-age children and adolescents - 08/01/2007

B number: 
B448
Principal applicant name: 
Prof Jorg Siekmann (German Research Centre for AI, Europe)
Co-applicants: 
Title of project: 
International growth reference for school-age children and adolescents
Proposal summary: 

No outline received

Date proposal received: 
Monday, 8 January, 2007
Date proposal approved: 
Monday, 8 January, 2007
Keywords: 
Primary keyword: 

B447 - Markers of prenatal sex hormone exposure and their relations with atopy and asthma - 08/01/2007

B number: 
B447
Principal applicant name: 
Prof Seif Shaheen (University of Bristol, UK)
Co-applicants: 
Title of project: 
Markers of prenatal sex hormone exposure and their relations with atopy and asthma
Proposal summary: 

We will link the above variables to the data on atopic outcomes and confounders (and PSAI score) which we already have, and carry out appropriate multivariate analyses in boys and girls separately. We will examine relations of digit ratio to the other variables above, and to testosterone levels in pregnancy in the subset with these data. We will stratify by maternal atopic disease and parity (especially number of older brothers which has been linked to digit ratio and to atopy), and stratify the handedness analyses by family history of atypical handedness. We could also relate maternal handedness to atopic disease in the mothers. If we confirm novel associations with digit ratio we will write these results up first.

Date proposal received: 
Monday, 8 January, 2007
Date proposal approved: 
Monday, 8 January, 2007
Keywords: 
Primary keyword: 

B369 - Risk Evaluation of Commercial Seafood with a Focus on the Risk of Methal Mercury - 30/12/2006

B number: 
B369
Principal applicant name: 
M Bolger (Not used 0, Not used 0)
Co-applicants: 
Title of project: 
Risk Evaluation of Commercial Seafood with a Focus on the Risk of Methal Mercury.
Proposal summary: 

(No outline received).

Date proposal received: 
Saturday, 30 December, 2006
Date proposal approved: 
Saturday, 30 December, 2006
Keywords: 
Diet, Eating disorders, Mercury
Primary keyword: 

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