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.

Click here to export results in Word format.

B489 - Effects of prenatal alcohol consumption and alcohol metabolising genes on child growth and neurodevelopment - 19/04/2007

B number: 
B489
Principal applicant name: 
Dr Ron Gray (Universityof Oxford, UK)
Co-applicants: 
Dr Elizabeth Draper (University of Leicester, UK), Dr Sarah J Lewis (University of Bristol, UK), Prof Jean Golding (University of Bristol, UK)
Title of project: 
Effects of prenatal alcohol consumption and alcohol metabolising genes on child growth and neurodevelopment
Proposal summary: 

(a) Aims of the project

To determine whether there is a causal association between:

  1. low-to-moderate prenatal alcohol exposure
  2. binge drinking during pregnancy
  3. polymorphisms of the main alcohol metabolizing genes in mother and child

and birth weight, length at birth, head circumference at 8 months; growth at 7/8 years; and neurodevelopmental outcome through to age 11?

Date proposal received: 
Thursday, 19 April, 2007
Date proposal approved: 
Thursday, 19 April, 2007
Keywords: 
Primary keyword: 

B483 - CONTAMED Contaminant mixtures and human reproductive health - novel strategies for human health impact and risk assessment of endocrine disrupters - 16/04/2007

B number: 
B483
Principal applicant name: 
Prof Andreas Kortencamp (Brunel University of London, uk)
Co-applicants: 
Title of project: 
CONTAMED Contaminant mixtures and human reproductive health - novel strategies for human health impact and risk assessment of endocrine disrupters
Proposal summary: 

CONTAMED has the following main objectives:

* To prepare the ground for epidemiological studies able to capture cumulative EDC exposure by developing and evaluating biomarkers for total effective internal EDC load. This will rely on in vitro bioassays representative of various EDC actions ("mode-of-action screens") and will utilize tissue specimens from three existing European mother-child cohorts.

* To substantiate observations from human studies in extended developmental toxicity rat studies by investigating the possible role of mixtures of estrogens, anti-androgens and other classes of EDC in producing long-lasting delayed adverse reproductive effects at environmentally relevant levels.

* To bring together human epidemiology and predictive toxicological risk assessment by comparing internal EDC exposures in humans with those resulting from controlled exposures producing clear effects in laboratory animal experiments. This will enhance the usefulness of animal data in making extrapolations to the human.

* To search for previously unrecognised EDCs in human tissues by combining analytical chemistry with in vitro EDC mode-of-action screens in

3

CONTAMED - Contaminant mixtures and human reproductive health

bioassay-directed fractionations ("toxicity identification and evaluation", TIE) and by using metabolomic profiling to identify xenobiotic as well as endogenous biomarker metabolites.

* To strengthen the European Environment and Health Action Plan and the Endocrine Disrupter Strategy by reflecting on the implications of project results for practical policy measures and human b

Date proposal received: 
Monday, 16 April, 2007
Date proposal approved: 
Monday, 16 April, 2007
Keywords: 
Primary keyword: 

B488 - A genome-wide study of copy number variation gene expression and quantitative traits in the ALSPAC population cohort - 12/04/2007

B number: 
B488
Principal applicant name: 
Dr Nigel Carter (Wellcome Trust Sanger Institute, London, UK)
Co-applicants: 
Dr Panos Deloukas (Wellcome Trust Sanger Institute, London, UK), Prof Emmanouil Manolis Dermitzakis (University of Crete, Greece, Europe), dR Matthew Hurles (Wellcome Trust Sanger Institute, London, UK)
Title of project: 
A genome-wide study of copy number variation, gene expression and quantitative traits in the ALSPAC population cohort
Proposal summary: 

No outline received

Date proposal received: 
Thursday, 12 April, 2007
Date proposal approved: 
Thursday, 12 April, 2007
Keywords: 
Primary keyword: 

B478 - Somatic and cognitive/neurodevelopmental trajectory in childhood See B355 - 22/03/2007

B number: 
B478
Principal applicant name: 
Dr Carolyn Salafia (Not used 0, Not used 0)
Co-applicants: 
Title of project: 
Somatic and cognitive/neurodevelopmental trajectory in childhood (See B355)
Proposal summary: 

No outline received

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

B477 - Stability of overweight and progression to obesity in the ALSPAC cohort - 21/03/2007

B number: 
B477
Principal applicant name: 
Prof John Reilly (University of Glasgow, UK)
Co-applicants: 
Dr Andrea Sherriff (University of Glasgow, UK)
Title of project: 
Stability of overweight and progression to obesity in the ALSPAC cohort
Proposal summary: 

Assessments of the stability of overweight and obesity require longitudinal data on changes in BMI over time. Published assessments to date have been severely limited by three factors: small sample size; older samples (stability lower in older cohorts living in less obesogenic environments); generalisability to the UK unclear. All three weaknesses would be addressed in an analysis of data already collected in ALSPAC and available to us as part of an existing BHF funded project.

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

B476 - ADAM 33 polymorphisms asthma lung function and bronchial responsiveness in children - 20/03/2007

B number: 
B476
Principal applicant name: 
Prof John Henderson (University of Bristol, UK)
Co-applicants: 
Prof John Holloway (University of Southampton, UK), Prof Seif Shaheen (Queen Mary, University of London, UK), Prof Jonathan Sterne (University of Bristol, UK), Dr Sarah J Lewis (University of Bristol, UK)
Title of project: 
ADAM 33 polymorphisms, asthma, lung function and bronchial responsiveness in children
Proposal summary: 

This project builds on the work of our group on the genetic aetiology of asthma in children and utilises previously collected data on objective outcome measures. There remains uncertainty about therole of ADAM33 in the context of asthma risk and this study gives the opportuntity to investigate several different (but related) respiratory oucomes in a population-based sample.

Date proposal received: 
Tuesday, 20 March, 2007
Date proposal approved: 
Tuesday, 20 March, 2007
Keywords: 
Primary keyword: 

B475 - Prenatal exposure to alcohol and the development of conduct problems in childhood and adolescence - 15/03/2007

B number: 
B475
Principal applicant name: 
Dr Marianne van den Bree (University of Cardiff, UK)
Co-applicants: 
Dr P Buckland (Not used 0, Not used 0), Prof Marcus Munafo (University of Bristol, UK), Prof Michael O'Donovan (University of Cardiff, UK), Prof Michael Owen (University of Cardiff, UK), Prof Peter Holmans (University of Cardiff, UK)
Title of project: 
Prenatal exposure to alcohol and the development of conduct problems in childhood and adolescence
Proposal summary: 

We would like to conduct a study into the longer-term behavioural outcomes of prenatal exposure to alcohol and the potential modifying influences of maternal and child metabolising genes. Although this is a topic of considerable public health importance, only a handful of studies, conducted in small convenience samples, have been conducted to date and many questions remain unanswered (please see scientific outline). ALSPAC is ultimately suited for such a study because it is large, population-based, a wealth of data already exists on pregnancy as well as offspring development throughout childhood and adolescence, while DNA has already been obtained as well.

Date proposal received: 
Thursday, 15 March, 2007
Date proposal approved: 
Thursday, 15 March, 2007
Keywords: 
Primary keyword: 

B474 - Effect of diet on the mental performance of children Nutrimenthe - 09/03/2007

B number: 
B474
Principal applicant name: 
Prof Christina Campoy (University of Granada, Spain, Europe)
Co-applicants: 
Dr Pauline Emmett (University of Bristol, UK), Miguel P?rez-Garcia (Not used -1, Not used -1), Mr Colin Steer (Not used 0, Not used 0)
Title of project: 
Effect of diet on the mental performance of children (Nutrimenthe)
Proposal summary: 

Aims

1. To re-analyze how the mother's diet during pregnancy and blood levels of DHA influence the WISC-III data from the ALSPAC study, considering the four indexes [verbal comprehension (VC), perceptual reasoning (PR), freedom from distractivility (FD) and processing speed (PS)]. The influence of FADS1, FADS2 and COMT polymorphisms as exposure variables, as well as other confounder factors will be also taken into consideration.

2. To study the potential long-lasting associations between mother's dietary intake of fish during pregnancy and the evolution of cognitive development. To achieve that, we will try to predict the cognitive score from 18 months to 8 years of age by comparing the scores from the Denver indexes with the WISC-III ones. After that, we will study the role of mother's blood DHA levels in the above hypotethized relationship.

Hypothesis

1. Maternal dietary intake of fish during pregnancy is correlated with the freedom from distractivility factor (FD) in WISC-III. FD is a factor which includes the subtests relating to working memory. In fact, FD is called working memory (WM) in the WISC-IV.

2. Children who show a high score in the Denver Scales at 18 months have also a high score in the WISC-III at 8 years old.

3. These relationships will be modulated by the influence of FADS1, FADS2 and COMT polymorphisms.

Statistical Procedure

1. To conduct an exploratory factorial analysis with the WISC-III subtests to obtain the factors/ indexes. Previous factor structure of the WISC-III was obtained in 2,200 children within a wide range of age from 6 to 16 years old (Weschler, 2003). However, it will be interesting to obtain a factorial structure for 8-9 year olds from ALSPAC, because some neuropsychological domains such us Working Memory have a critical period between 7 and 9 years of age.

2. For the second objective, regression analysis will be conducted using the WISC-III factors/indexes as dependent variables and the Denver indexes as predictors.

3. Once the factors are obtained, each factor will be related to the nutritional and genetic information.

Exposure variables

Mother's and children dietary intakes of fish

Mother's and child's blood levels of LC-PUFA (DHA & AA)

Genetic polymorphisms: FADS1, FADS2, FADS3, COMT

Outcome variables

WISC-III scores

Denver Developmental Screening Test

Confunder variables (all confounders considered in the ALSPAC Lancet paper in 2007).

Maternal age, mother's education, mother's BMI, smoking, breast-feeding, cultural level, Apgar score,..

This work would be a reanalysis of the data already used by Colin Steer for the Nutrimenthe work but looking at the neuropschological variables in more depth - the data can be compiled by Colin Steer so minimal support would be required from ALSPAC.

Date proposal received: 
Friday, 9 March, 2007
Date proposal approved: 
Friday, 9 March, 2007
Keywords: 
Primary keyword: 

B470 - Diagnostic accuracy of waist circumference vs BMI percentile for high fat mass in children - 09/03/2007

B number: 
B470
Principal applicant name: 
Prof John Reilly (University of Glasgow, UK)
Co-applicants: 
Title of project: 
Diagnostic accuracy of waist circumference vs. BMI percentile for high fat mass in children
Proposal summary: 

Background and Aims

The paediatric obesity epidemic has led to renewed interest in the development and validation of relatively simple methods for defining or diagnosing obesity which are suitable for clinical and epidemiological purposes (Reilly Int J Obes 2006;30: 595-597). Systematic reviews-which reviewed data up to the end of 2001(e.g. SIGN 69, www.sign.ac.uk)-concluded that the evidence base from diagnostic studies (including a previous collaboration between the applicant and ALSPAC, Reilly et al Int J Obes 2000; 24: 1623-1627) supports the use of a high BMI percentile or SD score as a means of diagnosing or defining obesity in children and adolescents. Defining obesity as a high BMI for age has high specificity and moderate sensitivity when a high fat mass is used as the reference definition of obesity. In addition, children with high fat mass are at significantly increased risk of a number of morbid conditions, so the definition is not just arbitrary but has biological/clinical meaning.

More recently, there has been increasing evidence that a high waist circumference for age may be a promising alternative definition of obesity for paediatric use (Reilly Int J Obes 2006; 30: 595-597) . At present however the diagnostic accuracy of a high waist circumference in children and adolescents is unclear- the optimal cut-off point in the waist circumference distribution is unknown , ie the cut-off which best defines children with high fat mass and those children at greatest risk of co-morbid conditions. We also lack evidence from paediatric studies which have made direct comparisons of the diagnostic accuracy of the BMI and waist circumference as all studies published to date have reported on one or the other index but not both in the same sample.

The aims of the present study are therefore to

a. Estimate the diagnostic accuracy (e.g. sensitivity, specificity, predictive values) of a high waist circumference for a high fat mass index (fat mass measured by DEXA adjusted for height; Wells & Cole 2002 Int J Obes 26: 947-952).

b. Use ROC analysis to identify the optimum cut-off point in the waist circumference SD distribution which best identifies children with high fat mass index.

c Make a direct comparison between the diagnostic accuracy of BMI and waist by estimating sensitivity, specificity and predictive values for the currently recommended definitions based on BMI (such as BMI above the 91st and 95th percentiles) and the optimum definition derived from the present study, aim b above.

Methods

Date proposal received: 
Friday, 9 March, 2007
Date proposal approved: 
Friday, 9 March, 2007
Keywords: 
Primary keyword: 

B471 - Balance problems and dizziness in childhood - 08/03/2007

B number: 
B471
Principal applicant name: 
Rachel Humphriss (University Hospitals (St Michaels) Bristol, UK)
Co-applicants: 
Dr Amanda J Hall (University of Bristol, UK)
Title of project: 
Balance problems and dizziness in childhood
Proposal summary: 

Aims of the project

The broad aim of this study is to look the prevalence and predictors of balance problems and dizziness in children at age 7 and age 10.

The specific aims are:

  1. To determine the prevalence of poor balance function and dizziness in 10 year old children
  2. To examine any associations between balance function at age 7 and balance function and dizziness at age 10.
  3. To describe the nature of symptoms of dizziness and imbalance, determining diagnoses where possible
  4. To explore some of the early predictors of poor balance function and dizziness in 10 year old children, specifically:
    1. To examine the associations with maternal factors

Factors such as smoking, drinking alcohol, illness and taking medication during pregnancy will be examined

    1. To examine the association between childhood anxiety and balance dysfunction

Anxiety disordered children have been shown to have excessive sensitivity to balance-challenging situations and it has been suggested that there may be a sub-clinical balance disorder in childhood anxiety (Erez et al, 2004)

    1. To examine the association between weight gain during childhood and balance

Balance in adulthood has been found to be associated with weight during childhood (Kuh et al, 2006).

    1. To examine the association with educational difficulties

Dyslexia, Attention Deficit Disorder and learning disabilities have been linked to cerebellar-vestibular dysfunction (Levinson, 1990); anti-motion sickness medications (Levinson, 1991) and vestibular exercises (Reynolds et al, 2003) have even been suggested as possible treatments.

A systematic review of evidence around these research questions will be incorporated.

Date proposal received: 
Thursday, 8 March, 2007
Date proposal approved: 
Thursday, 8 March, 2007
Keywords: 
Primary keyword: 

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: 

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: 

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: 

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: 

Pages