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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B645 - The impact of adiposity on risk profiles and the emerging arterial phenotype in the young - 30/04/2008

B number: 
B645
Principal applicant name: 
Prof John Deanfield (Great Ormond Street Children's Hospital, UK)
Co-applicants: 
Kate Madden-Raja (Not used 0, Not used 0), Prof George Davey Smith (University of Bristol, UK), Mrs Alicja Rapala (University of Bristol, UK)
Title of project: 
The impact of adiposity on risk profiles and the emerging arterial phenotype in the young
Proposal summary: 

No outline received

Date proposal received: 
Wednesday, 30 April, 2008
Date proposal approved: 
Wednesday, 30 April, 2008
Keywords: 
Cardiovascular
Primary keyword: 

B650 - Genome-wide association studies of ankylosing spondylitis - 28/04/2008

B number: 
B650
Principal applicant name: 
Dr Dave Evans (University of Bristol, UK)
Co-applicants: 
Prof Matt Brown (Not used 0, Not used 0), Prof John Reveille (Not used 0, Not used 0)
Title of project: 
Genome-wide association studies of ankylosing spondylitis
Proposal summary: 

The Australo-Anglo-American Ankylosing Spondylitis Consortium (TASC) has been funded by the NIH and other bodies to perform a genome-wide association study of a large Ankylosing Spondylitis cohort on the Illumina 317K SNP chip. The genotyping for this project has already been completed, and statistical analyses are being finalized. Preliminary analyses have identified several new variants underlying disease risk.

ALSPAC is currently awaiting the imminent arrival of genotype data for 2000 individuals who have been genotyped on the Illumina 317K chip. Inclusion of unselected control individuals can increase power to detect association. I am therefore asking that the committee consider allowing me to pool the ALSPAC genome-wide data with TASC in order to maximize power to detect association in the TASC study. As I will soon be leading the analysis of the genome-wide data in ALSPAC, such a pooling would be trivial to impliment. Additionally, since no phenotype data is required in this proposal, there would be no need for data linkage.

Date proposal received: 
Monday, 28 April, 2008
Date proposal approved: 
Monday, 28 April, 2008
Keywords: 
Genetics
Primary keyword: 

B644 - Prenatal paracetamol exposure asthma and DNA methylation - 21/04/2008

B number: 
B644
Principal applicant name: 
Prof Seif Shaheen (University of Bristol, UK)
Co-applicants: 
Prof John Henderson (University of Bristol, UK), Prof John Holloway (University of Southampton, UK), Dr Susan Ring (University of Bristol, UK), Prof Marcus Pembrey (University of Bristol, UK)
Title of project: 
Prenatal paracetamol exposure, asthma and DNA methylation
Proposal summary: 

Epigenetic mechanisms are thought to underlie the fetal programming of disease. A number of prenatal risk factors have been implicated in childhood asthma, and the possibility that prenatal epigenetic effects might be important in asthma has been mooted before(1). However, whilst there are indirect clues in support of this hypothesis, such as evidence for maternal line inheritance of asthma suggestive of imprinting, and data indicating transgenerational effects of grand-maternal smoking in pregnancy on asthma risk(2), direct evidence is currently lacking. We have found a positive association between prenatal paracetamol exposure and risk of asthma in ALSPAC and proposed that the underlying mechanism involves glutathione (GSH) depletion(3). This effect has become stronger for asthma at 91 months (odds ratio per category increase in paracetamol exposure 1.33 (95% CI: 1.15 to 1.54), P=0.000092), and the effect was modified by glutathione S-transferase (GST) M1 genotype in the mother and child (odds ratio 3.63 (1.48 to 8.92), P=0.005 if mother homozygous wild (HW) for GSTM1; OR 5.01 (2.13 to 11.74), P=0.00021 if child HW). Given that GSH depletion is thought to impair DNA methylation(4), and epigenetic mechanisms are thought to underlie fetal programming, we speculate that DNA hypomethylation may underlie the effect of prenatal paracetamol on asthma risk observed in ALSPAC.

Hypotheses

1) Prenatal paracetamol exposure leads to DNA hypo-methylation

2) Children with asthma have less DNA methylation than those without asthma

Date proposal received: 
Monday, 21 April, 2008
Date proposal approved: 
Monday, 21 April, 2008
Keywords: 
Allergies, Genetics, Respiratory, Atopy
Primary keyword: 

B646 - Early Sign of Autism - 18/04/2008

B number: 
B646
Principal applicant name: 
Zuzana Masopustov? (Institute for Research on Children, Youth and Family,IVDMR, Czech Republic , Europe)
Co-applicants: 
Ond?ej Bou?a (Institute for Research on Children, Youth and Family,IVDMR, Czech Republic , Europe), Stanislav Je?ek (Institute for Research on Children, Youth and Family,IVDMR, Czech Republic , Europe), Lenka Lacinov? (Institute for Research on Children, Youth and Family,IVDMR, Czech Republic , Europe)
Title of project: 
Early Sign of Autism
Proposal summary: 

The purpose of the proposed study is to describe a typical early development of children with childhood autism.

I specialize in the early signs of autism. As a member of Institute for Research on Children, Youth and Family I participate in the ELSPAC study in the Czech Republic.

The number of children with autism in the Czech ELSPAC study is too low and their data lead to inconclusive findings. Thus, we would like to analyse ALSPAC data, if possible. We would like to analyze the ALSPAC parental reports and compare the data from parents of children with autism with the data from parents of children with typical development or with other developmental disorders. We would like to create a typical autistic developmental chart with the symptoms that are the most specific and significant for the future diagnosis of childhood autism. The long term goal is to develop an early screening tool based on these signs.

Early signs of autism are difficult to identify. Even though the parents of children with autism usually start to suspect that there might be a problem in their child's development quite early, the diagnosis of autism is on average not set until three years of age (Filipek et al., 1999). Children with no other associated serious disease or developmental disorder are typically not in contact with a professional other than a pediatrician until they start to attend a kindergarten or school to be compared with their peers. That is why there is a strong need to help pediatricians to identify first signs of this developmental disorder in early infancy (age 0-3) to make possible earlier intervention (such as early speech therapy, motivation to eye-contact etc.).

The ALSPAC study offers an exceptional opportunity to analyze large-sample data about child's development from parental perspective before the time the diagnosis of autism was set and compare them with the same data on the development of typical child. Such data are methodologically and ethically superior to data from retrospective questionnaires because retrospective data are usually less complete and suffer from various memory distortions. Also retrospective questioning of parents of children with autism can have retraumatizing effect.

We assume the early development is culturally independent enough for us to be able to test our hypothesis about the early development of autism on the ALSPAC and ELSPAC samples and compare our findings from these two studies.

Journals like Autism or Journal of Autism and Developmental Disorders will probably be interested in an article on this topic. Institute for Research on Children, Youth and Family supports this research.

Date proposal received: 
Friday, 18 April, 2008
Date proposal approved: 
Friday, 18 April, 2008
Keywords: 
ADHD, Antisocial Behaviour, Autism, Behavioural Problems, Childhood Adversity
Primary keyword: 

B647 - Blood vessels and patterns of brain function in twins - 17/04/2008

B number: 
B647
Principal applicant name: 
Atul Singhal (Institute of Child Health, University College London, UK)
Co-applicants: 
Prof John Deanfield (Not used -1, Not used -1)
Title of project: 
Blood vessels and patterns of brain function in twins
Proposal summary: 

Vascular function and cardiovascular risk factors in twins

The twin study was conducted in collaboration with the Multiple birth foundation and, for measures of vascular function, with Professor John Deanfield. We have recruited 210 pairs but require a further 20 pairs (particularly DZ twins). As we have exhausted the available twins from the multiple birth foundation we require additional data from twins collected as part of Professor John Deanfield's collaboration with ALSPAC. These cross-sectional data are already available in Professor's Deanfield's database of the ALSPAC cohort (eg measures of vascular function, demographic and anthropometric data, and conventional cardiovascular risk factors). We require only the identification of twins from this existing database and the method by which the zygosity was determined. We do not require any personal data. This will allow us to include the small number of twins (previously estimated as less than 25 pairs) collected as part of Professor Deanfield's collaboration with ALSPAC to be included in our study and hence achieve our sample size. All vascular measures in both studies have been made using identical techniques.

The twin study was funded by the MRC to test the following 2 hypothesis:

1. In twins discordant for birth weight we tested the hypothesis that low birth-weight is associated with endothelial dysfunction independent of maternal factors and the family environment (including socio-economic status). A twin study in children as opposed to adults allowed us to investigate early stages of atherosclerosis before the onset of lifestyle cardiovascular risk factors common in adulthood. This study has now been completed.

2. That the childhood environment strongly affects development of early atherosclerosis and its risk factors. Justification: Our own and other's data, suggest the atherosclerotic process may begin even in the first decade. But, the relative contributions of genetic and environmental factors to early atherosclerosis (as opposed to clinical CVD) are unknown. A classical twin model in children allow us to define the relative impact of additive genetic factors, and both shared and non-shared environmental factors on early atherosclerosis. The Framingham study (with a less robust family-based rather than twin study design) suggests that inherited genetic factors make a small contribution to early atherosclerosis. Similarly, our preliminary twin data suggest that shared environmental factors (including family environment and nutritional habits) have a major impact on arterial distensibility, while additive genetic factors make little contribution. Outcomes: In same-sex twin pairs aged 6-18years we have determined measures of vascular health such as flow mediated dilation, arterial distensibility and conventional CVD risk factors such as cholesterol concentration, insulin resistance, C-reactive protein concentration and leptin resistance. The relative contribution of additive genetic versus environmental factors to these outcomes will be assessed using published approaches. We require a further DZ twin pairs to complete this study.

Date proposal received: 
Thursday, 17 April, 2008
Date proposal approved: 
Thursday, 17 April, 2008
Keywords: 
Primary keyword: 

B641 - MRC training fellowship for A Fraser Obstetric lifestyle genetic determinants of vascular and metablic traits - 15/04/2008

B number: 
B641
Principal applicant name: 
Dr Abigail Fraser (University of Bristol, UK)
Co-applicants: 
Title of project: 
MRC training fellowship for A Fraser: Obstetric, lifestyle & genetic determinants of vascular and metablic traits
Proposal summary: 

Aim

To identify the obstetric, lifestyle, and genetic determinants, of variations in vascular and metabolic traits in women in their mid-40s, an age at which few will have died or been on treatment for cardiovascular disease (CVD).

Objectives

1. To determine the association of obstetric factors (BMI and blood pressure at the start of pregnancy, different patterns of changes in weight, blood pressure and glycosuria throughout the antenatal period, gestational diabetes and pregnancy induced hypertension) with variations in vascular and metabolic traits (fat mass, fat distribution, fasting insulin, glucose and lipids, and blood pressure), in women in their mid-40s, and to use this information to determine whether routinely collected antenatal data can usefully predict variations in metabolic and vascular traits in women in their mid-40s.

2. To use genetic variants with established associations with adiposity as instrumental variables to estimate the magnitude of the causal association of variations in average fat mass over the life course with metabolic and vascular traits in women.

3. To determine the different ways in which obstetric, lifestyle (different patterns of cigarette smoking, physical activity, and dietary intake including alcohol consumption) and genetic factors relate to each other to affect variations in vascular and metabolic traits in women in their 40s.

4. Contribute to determining the association of novel genetic variants (that will be identified by bioinformatics and genome wide association studies) with fat mass, fasting insulin, glucose and lipids, blood pressure and smoking, physical activity and alcohol patterns, and replicate these findings in independent studies; and to examine whether there are genetic variants that are related specifically to adverse metabolic profile in pregnancy.

Design & methodology

Study participants are mothers from the Avon Longitudinal Study of Parents And Children. For these women there is an established DNA bank, immortalised cell-lines, and data on obstetric, socio-demographic and lifestyle factors collected repeatedly, since their index pregnancy in the early 1990s. Fat mass, fat distribution and blood pressure measurements (N=5000), and fasting glucose, insulin and lipids (N=2000) will be collected for women attending their offspring's 15 year follow-up clinic (mean age: 44). Relevant statistical methods - generalised linear regression models, multilevel models, instrumental variables analysis - will be used on these data as appropriate.

Medical opportunities

Results from this study will provide the necessary evidence base for developing programmes aimed at preventing CVD in women. Identifying women at risk of future adverse metabolic and vascular risk profiles during their pregnancy is likely to be advantageous as over 85% of women experience a pregnancy and antenatal care, and they may be particularly receptive to preventive interventions at this stage in their life course.

Date proposal received: 
Tuesday, 15 April, 2008
Date proposal approved: 
Tuesday, 15 April, 2008
Keywords: 
Primary keyword: 

B638 - Anthropometric measures at 17 - 10/04/2008

B number: 
B638
Principal applicant name: 
Prof George Davey Smith (University of Bristol, UK)
Co-applicants: 
Ms Lynn Molloy (University of Bristol, UK), Prof John Henderson (University of Bristol, UK), Dr Susan Ring (University of Bristol, UK), Prof Andy Ness (University of Bristol, UK)
Title of project: 
Anthropometric measures at 17+
Proposal summary: 

Link with diet, bone density, weight in early teens

Predictive of life time risk of obesity and CVD etc

Linking to genetics????

Methodology

(Lifted and adapted from core renewal doc):

The measures below have been made at 15+ and at previous clinics, allowing us to examine not only associations between exposures and these measures at 17+ but also to examine the association between exposures and change in these outcomes.

We will measure standing and sitting height to the nearest millimetre with shoes and socks removed using a Holtain stadiometer. Participants will be asked to pass urine (if they have not done so recently) before the impedance is measured. They will then be asked to undress to their underclothes. We will measure weight and leg-to-leg impedance using a Tanita THF300GS body fat analyser and weighing scales. We will measure total and regional fat, lean and bone mass using a Lunar Prodigy dual x-ray emission absorptiometry (DXA) scanner. The Lunar Prodigy uses a narrow-angle fan beam that results in very short acquisition times. Software options enable precise assessments of fat mass, lean mass and bone mass both overall and for the trunk, arms and legs. The scans will be visually inspected and realigned where necessary. We will measure grip strength using the Jamar Hydraulic Adjustable Hand Dynamometer NC70150, which measures isometric strength in kilograms. We will measure resting brachial systolic and diastolic blood pressure oscillometrically using a Dinamap BP pro. Arm circumference will be measured and an appropriate cuff size selected. Two measures of blood pressure and pulse rate will then be made at least one minute apart.

Date proposal received: 
Thursday, 10 April, 2008
Date proposal approved: 
Thursday, 10 April, 2008
Keywords: 
Endocrine Disruptors, Obesity, Weight
Primary keyword: 

B639 - Replication of genomewide associates for gestational age from the Northern Finnish Birth Cohort 66 in ALSPAC - 09/04/2008

B number: 
B639
Principal applicant name: 
Prof Mark McCarthy (University of Oxford, UK)
Co-applicants: 
Dr Nic Timpson (University of Bristol, UK)
Title of project: 
Replication of genomewide associates for gestational age from the Northern Finnish Birth Cohort ('66) in ALSPAC
Proposal summary: 

Recently, a genomewide association study was undertaken within the Northern Finnish Birth Cohort ('66). This study was designed around the analysis of ~4-5000 individuals for both early phenotypes and those at a later recorded age (31 yrs). Within the cohort, there are extensive phenotypes available and as such there have been a sereis of analyses undertaken in light of the availability of genomewide data a feature only available in the last few weeks. One area of considerable interest has been with respect to the early phenotypes available for this cohort and as such, analyses on birth weight, birth length, ponderal index and gestational age have been undertaken. Of these, that concerning gestational age has yielded preliminary results of great interest (see appendix) and such that warrant immediate replication before undertaking very large-scale follow-up analyses.

The forthcoming availability of genomewide data for the a selection of the ALSPAC cohort (data which may be interrgated on an in silico basis for the initial stage of this project) majes it possible to seek initial and immediate replication of this signal. We propose initally to take the top signals for gestational age and to recover genotypes for these from the genomewide data (currently being finalised at the Sanger Institute, Cambridge). As suggested by one of the key organisers of this project (Panos Deloukas), this is a plausible exercise and the expediated delivery os select genotypes may allow for the checking of initial findings in this ALSPAC sub set.

Following this, we propose (on the basis of inference made from both the Norther Finnish data and that of the ALSPAC sub set) to take promising signals forward to replication in a sample comprised of (within ALSPAC as one of the sample bases) in both all the children and mothers. We feel that this will allow us then to formulate a roubust argument as to the possible contribution of these data to the literature surrounding the genetic predisposition to pre-term delivery (an field ALSPAC already recognises as important and contributes to directly through alternative collaborations).

This second stage of analysis would be dependent on the initial, rapid, exploration of the Finnish signal and would be derived from funding form the Oxford group.

Overall we wish to (i) seek an initial insight into the top Finnish associated signals in an expediated set of ALSPAC genomewide data (such that can be analyse immediately by Dr N Timpson) and (ii) seek permission to genotye promising signals from this stage (of which there appear naively to be 4-5) withiin the whole ALSPAC cohort.

Date proposal received: 
Wednesday, 9 April, 2008
Date proposal approved: 
Wednesday, 9 April, 2008
Keywords: 
Genetics, Obstetrics, Pregnancy
Primary keyword: 

B635 - Childhood obesity child height and educational outcomes - 02/04/2008

B number: 
B635
Principal applicant name: 
Miss Stephanie von Hinke Kessler Scholder (University of Bristol, UK)
Co-applicants: 
Prof Carol Propper (Imperial College London, UK), Prof Frank Windmeijer (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK), Prof Debbie A Lawlor (University of Bristol, UK)
Title of project: 
Childhood obesity, child height and educational outcomes
Proposal summary: 

The study is part of the ALSPAC large grant (ESRC), project code B273.

In this study, we aim to examine the effects of childhood obesity and child height on children's educational outcomes. As the relationships between child weight or height and educational attainment are likely to be subject to confounding in observational studies, we wish to test the feasibility of using associated genotypes as instruments in Mendelian randomisation experiments. Within the ALSPAC cohort, data have already been collected on a series of single nucleotide polymorphisms, which are robustly associated with both height and body mass index (BMI), as has been confirmed by large independent studies. As such, we wish to use these (and other available data relating to these intermediate traits of interest) in instrumental variable analyses, allowing us to reappraise the observational relationships between these anthropometric measures and education.

We are conscious of the potential limitations of power within this setting, given that the genetic effects on the intermediate trait are relatively small and the variation in these traits required to shift educational attainment relatively large. However, it will be possible to assess the plausibility of studies such as this with data already collected in the ALSPAC cohort. At this stage, we only seek access to already available data.

As we already have access to the ALSPAC data on child and family background characteristics, we only wish to obtain the genetic markers related to children's obesity and height. We understand we cannot use the individual case identifiers we already have. So if needed, we are happy to provide you with the raw data we are using, so that you can merge in the genotypes and provide us with a new child ID for this study.

Date proposal received: 
Wednesday, 2 April, 2008
Date proposal approved: 
Wednesday, 2 April, 2008
Keywords: 
Obesity, Weight
Primary keyword: 

B637 - The relation between maternal nutrition and hypospadias - a case control study from the United Kingdom - 31/03/2008

B number: 
B637
Principal applicant name: 
Christianne de Kort (Centre for Research in Environmental Epidemiology (CREAL), Europe)
Co-applicants: 
M Mendez (Centre for Research in Environmental Epidemiology (CREAL), Europe), Prof Mark Nieuwenhuijsen (Centre for Research in Environmental Epidemiology (CREAL), Europe)
Title of project: 
The relation between maternal nutrition and hypospadias - a case control study from the United Kingdom
Proposal summary: 

The goal of our project is to assess the relationship between maternal nutrition in pregnancy and hypospadias, including associations with key food sources of folic acid and phytoestrogens using data from a 2004 case control study among pregnant women in the UK. Other dietary factors, including the use of different vitamin/mineral supplements, and, as in the earlier ALSPAC study, the role of a vegetarian diet, will also be examined using these data. Since the study was designed for other purposes, the abbreviated food frequency questionnaire which was used consists mainly of food groups instead of specific food items (e.g. questions ask about intakes of fresh green vegetables, dairy products, soy foods). In order to estimate intakes of key nutrients such as dietary folate and selected phytoestogens from the items included in this brief questionnaire, we propose to use external information from the ALSPAC study, which was conducted in a similar population, with more detailed information on intakes of individual food items within these food groups. These data will allow us to identify and rank the food group items on the abbreviated questionnaire as sources of the nutrients of interest, at the population level. We will also use the more detailed external ALSPAC data to examine whether there appear to be meaningful differences in the contribution of food groups to nutrient intakes across different age, ethnic and/or education strata as a result of varying patterns of food item intakes within these food groups. Based on these data, we will determine whether it may be appropriate to develop estimates of nutrient intakes/rankings for particular population subgroups, rather than for the study sample as a whole. Finally, we will use these external ALSPAC data to estimate the proportion of dietary folate and phytoestrogens not covered by the food group items in our abbreviated questionnaire, which was not comprehensive, and to examine the variability in intakes of these omitted items.

Concept: Maternal dietary intakes (food items) during pregnancy

Specific measures: intakes of food items including items from the following food groups:

- Dairy products and eggs

- Soy food

- Beans and peas

- Fruit and vegetables

- Poultry and meat

- Fish and seafood

- Chocolate

- Bread and cereals

- Oil

- Nuts and seeds

Person: Mother

Source: Questionnaire

Time Point: Pregnancy

Other variables:

- Maternal age

- Maternal ethnicity (white, nonwhite)

- Household annual income

- Highest level of maternal education

- Maternal vegetarianism during pregnancy (no, never / yes, in the past / yes, I am now)

- Maternal consumption of organic foods (frequency)

- Maternal Body Mass Index

Date proposal received: 
Monday, 31 March, 2008
Date proposal approved: 
Monday, 31 March, 2008
Keywords: 
Diet, Eating disorders
Primary keyword: 

B636 - Decision Making and gambling behaviour in adolescence a prospective population study - 31/03/2008

B number: 
B636
Principal applicant name: 
Prof Alan Emond (University of Bristol, UK)
Co-applicants: 
Title of project: 
Decision Making and gambling behaviour in adolescence, a prospective population study
Proposal summary: 

Study Aims

The overall aims are to investigate the distributions and correlates of problem gambling in young people, and to describe the developmental trajectories from early childhood of adolescents with problem gambling

Specific objectives:

1. To describe the prevalence of gambling behaviours at 17 years, and their relation to parental gambling patterns.

2. To describe the associations of problem gambling with other risk taking behaviours, alcohol and drug use in adolescence and with debt.

3. To elucidate the interactions between gambling behaviour, developmental conditions such as ADHD and affective states such as depression

4. To investigate the relationship between problem gambling behaviour in adolescents and impulsivity and altered decision-making.

5. To describe developmental trajectories from early childhood of adolescents with problem gambling.

6. In those with a parent who gambles, to investigate the resilience factors which are associated with the young person not developing problem gambling behaviours.

Study design

The Avon Longitudinal Study of Parents and Children is a population-based cohort from the South West of England. Allbirths to women resident in the former Avon Health Authority area, with an expected date of delivery between 1st April 1991 and 31st December 1992 were eligible for enrolment in the ALSPAC study, resulting in a total cohort of 14,062 live births. Active contact is maintained with over 10,000 participants and their parents. At the age of 17 years, the young people and each of their parents will be sent a postal questionnaire (with an option to complete questionnaire online) and the young person will be invited to a research clinic. We will assess the children's and their parents' gambling behaviour and associated cognition in the 17-year questionnaire, and assess the young person's decision-making using a computerised test in the 17-year clinic.

a) gambling behaviour

We propose to use questions from theCanadian Problem Gambling Inventory (CPGI) The CPGI consists of 31 questions: including 'core' items to give a prevalence rate for problem gambling, and other items which are indicators of gambling involvement and correlates of problem gambling to develop a profile of different types of gamblers. Using the CPGI, respondents are classified into five groups: Non-Gamblers, Non-Problem Gamblers, Low Risk Gamblers, Moderate Gamblers and Problem Gamblers. Although ALSPAC previously used the South Oaks Gambling Screen (SOGS) with the parents, the CPGI is preferred because it gives a better spread of categories of gambler.

Problem gambling will be defined using theProblem Gambling Severity Index (PGSI), a 9-item scale derived from the 31 items larger screen. The PGSI is a well validated test which was used in the 2007 BGPS (Wardle, 2007), and in other international prevalence studies (e.g., inAustralia). A validation study (Wenzel, 2004), comparing the performance of the SOGS, the PGSI and the Victorian Gambling Screen (VGS) found that the PGSI outperformed the other two screens. The PGSI items each have four response options. For each item, 'sometimes' is given a score of one, 'most of the time' scores two, and 'almost always' scores three. A score of between zero and 27 is therefore possible, and a threshold of 8 is used to identify problem gamblers., and a score of 3-7 defines 'moderate risk' of PG. Questions from the CPGI, including the PGSI, will be included in the 17-year questionnaires, to be sent to all young people still in the cohort and to both their parents, between January 2009 and June 2010.

b) gambling cognition and decision-making

We propose to use theGambling Related Cognitions Scale(GRCS; Raylu & Oei, 2004) to assess cognition in gambling. The GRCS is a five-factor 23-item questionnaire, which includes questions which cover the wide range of gambling-related cognitive errors that have been reported in the gambling literature. The GRCS asks participants to use a 7-point Likert scale to indicate the extent to which they agreed with the value expressed in each statement. Scoring consisted of totalling the values such that the higher the score the higher the number of GRC displayed. The GRCSwill be included in the 17-year questionnaires, to be sent to all young people and to their parents.

As well as collecting behavioural data to identify types of gamblers (PGSI), and attitudinal data to assess gamblers' cognitive style (GRCS), we believe it is also important to directly test the young people to objectively measure their decision making under gambling conditions. We propose to use a computerised version of The Iowa Gambling Task (IGT), a measure of decision taking under ambiguity. The IGT is based on the Somatic Marker hypothesis (Bechara et al, 1994), and gives information about the development/impairment of orbitofrontal/ventromedial prefrontal cortex. Low performances in IGT have been linked to pathological gambling, alcohol dependence, Parkinson's disease and ADHD (in both adults and children). The IGT can be done manually or computerised: it consists on four decks of cards, two of them bring big wins and big losses, and the other two bring small wins but small losses and in the long-term are advantageous. Participants have different levels of awareness though the test, most participants know and can explain which decks are "advantageous" at card 80 (100 cards possible). Every participant will perform one "round" of the computerized adult version of the IGT (100 cards). Estimated time 10-15 minutes. The computerised IGT will be applied to all ALSPAC participants in the 17-year+ clinic (expected n=6000) between October 2008 and September 2010.

Other measures

The ALSPAC study has extensive epidemiological data regarding parental socioeconomic status, co-morbidity and gambling history measured with the SOGS scale (measured when children were 7 years). The children's behavioural and psychological profile has been measured since infancy, with some measures such as the Strengths and Difficulties Questionnaire (SDQ) repeated at several time points during childhood and adolescence. Psychometric assessments, including measures of cognition, attention and depression in children have been collected at various time points. (see appendix for table of measures already collected).

At 15-16 yrs, the participants have been assessed in the 15+ clinic, with direct measures of IQ (WASI), impulsivity (Stop Signal) and psychopathology (Development and Well Being Assessment- DAWBA). Over 6000 participants were tested in the 15+ clinic.GCSE results on the whole cohort at 16 yrs will be made available by DCSF.

At the 17 year+ clinic, which starts in autumn 2008, young people will complete computerised assessments of mood, funded by a grant from the Wellcome Trust (PI Lewis).We will assess depression and anxiety disorders using the revised clinical interview schedule (CIS-R), that has been widely used in the Psychiatric Morbidity Surveys in the UK, and assess psychological factors, including depressogenic cognitive styles, that are associated with depression and appear to reflect underlying vulnerability. Negotiations are advanced with government departments to fund computerised questions on debt and attitudes to financial risk taking in the 17+ clinic.

Date proposal received: 
Monday, 31 March, 2008
Date proposal approved: 
Monday, 31 March, 2008
Keywords: 
Alcohol, Drugs, Smoking
Primary keyword: 

B634 - Genetic variants associated with obesity in childhood and early adulthood - 31/03/2008

B number: 
B634
Principal applicant name: 
Sonja I Berndt (Division of Cancer Epidemiology & Genetics, National Cancer Institute, USA)
Co-applicants: 
Richard Hayes (Division of Cancer Epidemiology & Genetics, National Cancer Institute, USA)
Title of project: 
Genetic variants associated with obesity in childhood and early adulthood
Proposal summary: 

ABSTRACT

Obesity is major health problem in many developing countries. In the United States, approximately 17% of children and adolescents are overweight and one-third of adults are estimated to be obese (1). Body mass index (BMI) is thought to have a substantial genetic component with heritability estimates of 40 to 70% (2). However, genetic variants related to obesity have proved difficult to find and replicate. With the advent of genome-wide scans, new efforts to comprehensively search the genome have begun to identify common variants associated with susceptibility to obesity, such as the recently discovered common SNP in FTO (3). As part of the Genomic Investigation of Anthropometric Traits (GIANT) consortium, we have pooled the results from genome-wide scans in three cohorts to identify genetic variants associated with BMI in early adulthood (N~5,500). We have identified over 80 promising loci associated with BMI at age 20 with a p-value of 10-5 or smaller and are currently replicating 45 of the top SNPs in an additional 10,000 subjects from other cohorts. We propose to follow-up the loci that are replicated in the ALSPAC cohort to determine if the SNPs are also associated with BMI in childhood.

BACKGROUND

Although inherited factors are thought to contribute to obesity, results from candidate gene and genetic linkage studies of obesity have been largely inconsistent [reviewed in (4,5)]. However, recently, as the result of large genome-wide association studies, common variants in the FTO gene were found to be associated with susceptibility to obesity (3) and obesity-related traits (6). The finding of FTO has spurred renewed interested in discovering additional loci associated with obesity and obesity-related traits and spawned large collaborative efforts, such as the Genomic Investigation of Anthropometric Traits (GIANT) consortium, which is an effort to pool genome-wide scan results from multiple cohorts and identify loci associated with height and obesity.

PRELIMINARY DATA

As part of the GIANT consortium, we have pooled the results from three genome-wide scans (encompassing 2.5 million single nucleotide polymorphisms that were either directly genotyped or imputed) with information on BMI at age 18 or 20 to identify genetic variants associated with BMI in early adulthood (N~5,500). We have identified approximately 87 independent loci with a p-value of 10-5 or smaller for BMI in early adulthood. Some of these loci are located near or in potentially promising genes, and we are currently genotyping 45 of the top loci in an additional 10,000 subjects from other cohorts with information on BMI in early adulthood.

PROPOSED PROJECT

Assuming that some of the loci identified in our initial meta-analysis are replicated in the follow-up cohorts, we propose to genotype those same SNPs in the ALSPAC cohort to determine whether the loci are also associated with BMI in childhood. We estimate that only a few loci will be convincingly replicated in our follow-up cohorts; however, it is conceivable that up to 10 SNPs may warrant further study. We plan to genotype these SNPs in the same children (N~7,500) that were genotyped in the recently submitted manuscript by Loos et al. (7). Similar to the study by Loos et al., we plan to evaluate the association with BMI at ages 7-11 as well as fat and lean body mass as measured by whole-body dual energy X-ray absorptiometry (DEXA) scan at age 9.

DATA REQUESTED

Biological Samples: DNA (~10 ng of DNA per genotype) for children. We plan to genotype up to 10 SNPs depending on the results of our replication study.

Clinical measurements: Height, weight, and BMI at ages 7-11 years for children. Fat, lean body, and bone mass as measured by a whole-body dual energy X-ray absorptiometry (DEXA) scan in children at age 9.

Date proposal received: 
Monday, 31 March, 2008
Date proposal approved: 
Monday, 31 March, 2008
Keywords: 
Genetics, Obesity, Weight
Primary keyword: 

B633 - GSTM1 and cognitive functioning - 31/03/2008

B number: 
B633
Principal applicant name: 
Prof George Davey Smith (University of Bristol, UK)
Co-applicants: 
Dr Beate Glaser (University of Bristol, UK)
Title of project: 
GSTM1 and cognitive functioning
Proposal summary: 

Concept Specific measure Person Source Time point(s)

GSTM1 Del Child DataBase -

GSTM1 Del Mother DataBase -

Cognitive and neurodevelopmental phenotypes in children, measured on the scales of general cognitive, verbal, perceptual-performance, quantitative, memory and motor development, include the MacArtur Communicative Development Inventory (15 mns), the Denver Developmental Screening test (18 mns), the Wechsler Objective Reading Dimension test (WORD, 91 mns), the Wechsler intelligence Scale for Children (WISC, 8.7years), the Wechsler Objective Language Dimension (WOLD test 8.5 years) and the Counting span test (10 years). In addition, child pervasive developmental (DAWBA, Development and Well-Being Assessment, 91 mns) and autism spectrum disorders will be investigated. Genotypic effects of GSTM1 on cognitive and neurodevelopmental outcomes in children will be studied conditional on maternal smoking before, during and after pregnancy, partner smoking, maternal alcohol consumption during pregnancy and type/duration of breastfeeding. Analysis of cognitive functioning in children will be controlled for by birth weight, gestational age at birth, social communications problems (Social Communications Disorder Checklist) and height. Environmental and demographic factors including socio-economic status and maternal factors will be also included in the analyses as covariates.

Multiple regression models, with appropriate adjustment for covariates will be constructed. In addition to categorical coding (2 df test), genotypic effects will be analysed under recessive, dominant and additive disease model assumptions. Recessive coding corresponds to a GSTM1 present vs GSTM1 null analysis. For categorically coded outcomes also deletion-specific analysis will be preformed. For all nominally significant associations empirical p-values will be derived using permutations to account for increased type I error due to multiple testing.

Date proposal received: 
Monday, 31 March, 2008
Date proposal approved: 
Monday, 31 March, 2008
Keywords: 
Genetics
Primary keyword: 

B632 - n-3 fatty acids and cognition in children - 31/03/2008

B number: 
B632
Principal applicant name: 
Miss Alice Wilson (University of Bristol, UK)
Co-applicants: 
Prof Peter Rogers (Not used 0, Not used 0), Prof Bruce Hood (Not used 0, Not used 0), Prof Jean Golding (University of Bristol, UK), Mr Colin Steer (University of Bristol, UK), Dr Pauline Emmett (Not used 0, Not used 0)
Title of project: 
n-3 fatty acids and cognition in children
Proposal summary: 

Several studies published recently have suggested that intake of n-3 fatty acids may influence certain cognitive outcomes in certain populations. This was demonstrated in a group of children with develoment coordination disorder by Richardson & Montgomery (2005). However, whether or not these effects can be found in typically developing children remains an interesting hypothesis.

We propose undertaking a statistical analysis of Food Frequency Questionnaire (FFQ) data gathered from children at 7yrs of age and cognitive measures gathered at around the same age (or slightly older). The aim of this analysis is to investigate potential relationships between reported intake of fish (and therefore n-3 fatty acids) and performance on specific cognitive tasks. The specific cognitive measures we are interested in are listed in the table below.

We will also need data from previous parent questionnaires in order to control for 28 confounding variables identified in a previous study examining mother's intake of fish during pregnancy and childhood neurodevelopmental outcomes (Hibbeln, Davis, Steer, Emmett, Rogers, Williams & Golding, 2007).

We further propose to investigate the relationship between reported dietary intake of n-3 fatty acids and the fatty acid profile of the children's blood samples and whether or not the fatty acid profile of the blood samples correlates with performance on the cognitive measures. This will be subject to availability of the data within the time scale. We understand that the sample analysis is being undertaken in the labs of Dr Joseph Hibbeln at NIH in Washington DC and that the work has commenced and will be available during 2008. Therefore this work will be subject to availablity of the results within the timescale of this project.

Date proposal received: 
Monday, 31 March, 2008
Date proposal approved: 
Monday, 31 March, 2008
Keywords: 
Diet, Eating Disorder, Neurology
Primary keyword: 

B630 - Effect of prenatal smoking exposure on symptoms related to PTSD - 31/03/2008

B number: 
B630
Principal applicant name: 
Dr Marina Picciotto (Yale University, USA)
Co-applicants: 
Aesoon Park (Not used 0, Not used 0), Stephanie O'Malley (Not used 0, Not used 0), Prof Marcus Munafo (Not used 0, Not used 0)
Title of project: 
Effect of prenatal smoking exposure on symptoms related to PTSD
Proposal summary: 
Date proposal received: 
Monday, 31 March, 2008
Date proposal approved: 
Monday, 31 March, 2008
Keywords: 
ADHD, Antisocial Behaviour, Environmental Exposure
Primary keyword: 

B662 - Investigating the role of a common nicotine addiction SNP in smoking behaviour in pregnancy and offspring phenotypes - 17/03/2008

B number: 
B662
Principal applicant name: 
Prof Tim Frayling (Peninsula Medical School, University of Plymouth, UK)
Co-applicants: 
Dr Rachel Freathy (Peninsula Medical School, University of Plymouth, UK), Dr Caroline Relton-DO-NOT-USE (University of Bristol, UK), Prof Andrew Hattersley (Peninsula Medical School, University of Plymouth, UK), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
Investigating the role of a common nicotine addiction SNP in smoking behaviour in pregnancy and offspring phenotypes.
Proposal summary: 

In this study we propose to test the hypothesis that a SNP influencing smoking addiction will reduce the likelihood of giving up smoking just before or in pregnancy, and in turn affect fetal growth and gestational age. We would also like to test whether maternal genotype has longer term effects on childhood metabolic and growth outcomes, through "programming" to an adverse intra-uterine environment. Finally if, available , the effects of maternal genotype on paternal smoking behaviour and paternal genotype on paternal smoking will also be interesting to test.

Decode Genetics reported at a Keystone Meeting (Santa Fe, Genetics of complex traits) in March 2008 that a SNP, rs1051730, in the CHRNA3 (cholinergic receptor, nicotinic, alpha) gene is associated with the number of cigarettes smoked per day within smokers. The nimor allele frequency varies from 0.30 in light smokers (1-10 cigarettes per day) to 0.40 in people who smoke greater than 31 cigarettes per day. The odds ratio for being a heavy smoker compared to a light smoker (1.41) is greater than that for being a smoker at all (1.17) indicating the association is about addiction to nicotine rather than taking up smoking in the first place. The SNP is associated with lung cancer and peripheral artery disease in the direction expected, although with stronger effects than predicted from the simple SNP vs smoking quantity and smoking quantity vs disease associations.

Specific hypotheses:

1. Genotype predicts smoking behavior before during and after pregnancy.

2. Maternal genotype influences offspring fetal growth and gestational age.

3. Maternal genotype infleunces offspring growth and metabolism in childhood.

4. Offspring genotype influences fetal growth and gestational age (independently of maternal genotype - fetal genotype may alter in utero sensitivity to the toxic effects of nicotine).

5. If paternal DNA becomes available during the course of the project we would be keen to test fathers as well to test the hypothesis that the SNP alters expectant fathers' ability to give up smoking when their partners are pregnant. (Indeed without paternal DNA we could still test whether maternal genotype influenced paternal behaviour - although without paternal genotype this test will be less powerful)

* 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. Full details of maternal smoking details before, during and after pregnancy,

2. Birth weight, length and head circumference. Gestational age as offspring primary outcomes

3. Growth measures in childhood (height, weight and BMI aged 7-11)

4. Covariates of birth weight to check if genotype is acting through them: maternal age, maternal BMI, smoking , parity, twin status to exclude non-singletons, ethnicity as genotype frequency may alter with ethnic origin and confound analyses.

Genotyping of one SNP will only use 5-10ng of DNA per sample based on the current Kbioscience techniques.

Date proposal received: 
Monday, 17 March, 2008
Date proposal approved: 
Monday, 17 March, 2008
Keywords: 
Pregnancy, Smoking
Primary keyword: 

B629 - Validation of a Non-Invasive Method for Estimating Biological Maturation in British Youth - 17/03/2008

B number: 
B629
Principal applicant name: 
Dr Sean Cumming (University of Bath, UK)
Co-applicants: 
Title of project: 
Validation of a Non-Invasive Method for Estimating Biological Maturation in British Youth
Proposal summary: 
Date proposal received: 
Monday, 17 March, 2008
Date proposal approved: 
Monday, 17 March, 2008
Keywords: 
Primary keyword: 

B628 - Patterns of Physical Activity and Sedentary Behaviours in Children of Different Physical Activity Levels - 12/03/2008

B number: 
B628
Principal applicant name: 
Harriet Koorts (University of Bath, UK)
Co-applicants: 
Prof Chris Riddoch (University of Bath, UK), Kevin Deere (Not used 0, Not used 0), Prof Andy Ness (Not used 0, Not used 0), Mr Calum Mattocks (University of Bristol, UK)
Title of project: 
Patterns of Physical Activity and Sedentary Behaviours in Children of Different Physical Activity Levels
Proposal summary: 

Background & Study Rationale

Although a physically active lifestyle has established health benefits, a large proportion of children and adolescents fail to meet the health related guidelines for physical activity recommendations (Corbin & Pangrazi, 2004; Riddoch, Mattocks, Deere et al, 2007). This public health guideline advises children and adolescents to achieve one hour of moderate intensity physical activity per day, continuous or intermittent throughout the day (Riddoch, Mattocks, Deere et al, 2007). Longitudinal studies of physical activity levels and health amongst children have shown that although physical activity levels steadily increase during childhood (5-11 yrs), there is a steep decline during adolescence, 12 yrs and onwards (Janz et al, 2000; Kimm et al 2000; Sallis, 2000), shown to track into adulthood (Deflandre et al, 2001). Childhood obesity is now recognized as a global epidemic (Tremblay & Willms, 2000), and the development of interventions to promote physical activity amongst children and adolescents has as a result, become critical (Rowe et al, 2007; van der Horst et al, 2006).

There are important environmental and situational factors that relate to children's physical activity (Harwood, 2002). There is however less evidence detailing the strength of association between these factors. Gaining a better understanding of what combined impact the type of physical activity, time of day it is performed (before, during and after school), and context (school or non school day) have upon physical activity levels of children, is critical.

Aim and research questions

The main aim of this study is to assess how active and inactive children (identified using accelerometer data) differ in the types of physical activities they participate in, and the time of day they do this, on both school days and non school days (as reported in the PDPAR questionnaire).

RQ1a. Do the physical activity patterns of children who are active differ to those who are inactive, on school and non school days?

RQ1b.How is this related to the type of activity, and time of day it is performed?

RQ2. Are there differences in the times of day that active and inactive children are physically active, and how do the patterns of physical activity compare?

RQ3. Are the gender, SES and weight of active and inactive children associated with the differing level of physical activity, and does this relate to the types of activities they do, and when they do them?

To address these questions, a secondary analysis will be conducted using data from the ALSPAC study, of children aged 13 years.

Methods

The data for physical activity levels will be taken from the ActiGraph accelerometer, worn over a 7-day period. Data for the time of physical activity participation and type if activity will be taken from the Previous Day Physical Activity Recall Questionnaire (PDPAR).

Questionnaire Data

Data will represent both school and non school days. Six separate times of day will be considered for a school day and four separate times for a non-school day (see below). There will be seven different categories of physical activity behaviour for both a school and non-school day (see below).

The specific times of the day that the type of physical activity was recorded, include;

School Day-

1. Getting up - Start of School

2. Starting School - Lunch

3. Lunch Break

4. Lunch - End of School

5. End of School - Teatime/Dinner

6. Teatime/Dinner - Going to Bed

Non-School Day-

1. Getting up - Breakfast

2. Breakfast - Lunch

3. Lunch - Tea/Dinner

4. Tea/Dinner - Going to Bed

The types of activity measured are;

1. Watching TV/playing computer game/reading/homework.

2. Work around the house

3. Play a game outside

4. Do any sport/games/PE

5. Do a job/activity

6. Travel to and from school

7. Walk/cycle anywhere

Two main physical activity variables will be used to define active/inactive children;

1. Total physical activity - total average accelerometer counts/mins over the full period of valid recording. The recommended total time spent in MVPA is greater than 60 mins per day.

2. Time spent in MVPA - the average minutes of moderate and vigorous physical activity per valid day. The lower threshold of moderate intensity activity considered as 3600 counts/min.

Date proposal received: 
Wednesday, 12 March, 2008
Date proposal approved: 
Wednesday, 12 March, 2008
Keywords: 
Physical Activity, Physical Fitness
Primary keyword: 

B627 - An investigation of common genes influencing depression and cardiovascular disease in early life - 11/03/2008

B number: 
B627
Principal applicant name: 
Dr Pamela McCaskie (University of Western Australia, Australia)
Co-applicants: 
Prof Lawrence Bailin (Not used 0, Not used 0), Dr Eugen Mattes (Not used 0, Not used 0), Anke van Eekelen (Not used 0, Not used 0), Prof Craig Pennell (University of Bristol, UK), Prof George Davey Smith (Univeristy of Bristol, UK)
Title of project: 
An investigation of common genes influencing depression and cardiovascular disease in early life
Proposal summary: 

1536 SNPs are planned for genotyping in Raine in early 2008 including tagged genes on both cardiovascular and depression pathways. A further literature review will be performed once the project has commenced to ensure, during this rapid discovery and replication phase of genetic research, that all additional validated, common CVD and depression susceptibility SNPs are included. With an anticipated 5% of all genotyped SNPs in Raine being significantly associated with our primary outcomes of interest, approx 80 SNPs will be genotyped in ALSPAC. The Illumina Golden Gate assay requires a minimum of 5micro-l of DNA normalized to 50ng/micro-l in TE.

The phenotypic data required for the research in this proposal include:

  • Data have on maternal and paternal social background, lifestyle and habits (including diet and physical activity), and medical history by self-completion.
  • Details of the mother's medical condition and medical history, the medical history of her partner, socioeconomic and lifestyle characteristics of both parents and the clinical course of the mother's index pregnancy.
  • Blood pressure.
  • Carotid IMT measured in the far wall of the left common carotid artery.
  • Cholesterol measures
  • Measures of cognition, attention, emotions and psychotic-like symptoms
  • Measures of socioeconomic position and other potential covariates including smoking, alcohol and drug use
Date proposal received: 
Tuesday, 11 March, 2008
Date proposal approved: 
Tuesday, 11 March, 2008
Keywords: 
Genetics
Primary keyword: 

B626 - Obesity and Lower Extremity Pain in Adolescents - 07/03/2008

B number: 
B626
Principal applicant name: 
Dr Sharon Bout-Tabaku (Children's Hospital of Philadelphia, USA)
Co-applicants: 
Dr Nicolas Stettler (Not used 0, Not used 0), Dr Renee Moore (Not used 0, Not used 0)
Title of project: 
Obesity and Lower Extremity Pain in Adolescents
Proposal summary: 

Pediatric obesity has increased at an alarming rate in the last 30 years. As a result pediatric cardiovascular, endocrine and pulmonary obesity related morbidities have also risen. However, other pediatric complications of obesity important to public health and quality of life, such as bone, joint and muscle pains, are understudied and their prevalence, incidence and etiology remain unclear. In adults there is abundant evidence that obesity is a risk factor in the occurrence and progression of knee pain and knee osteoarthritis (KOA). In children, despite anecdotal and clinical impression there is sparse evidence on the link between obesity and musculoskeletal pain. Once this is understood the association between childhood obesity and its consequences for osteoarthritis can be investigated.

We will characterize the relationship of obesity to lower extremity (LE) pain in adolescents with the following aims:

A. Specific Aims

Specific Aim 1: To estimate the prevalence of LE pain cross-sectionally in all children aged 11-13 and specifically, compare the prevalence of obese adolescents to non -obese adolescents aged 11-13 years.

Hypothesis: Obese adolescents will have LE pain that is double that of their non-obese counterparts in an adjusted analysis.

Specific Aim 2: To estimate, using a cohort study design (in a subgroup with no pain at baseline), the incidence of LE pain among obese compared to non-obese adolescents over a period of 2 years (11 to 13 years).

Hypothesis: In looking at the subgroup with no pain at baseline, the incidence of LE pain will be 2 fold greater in the obese adolescents compared to the non-obese adolescents over these two years.

Secondary Aims:

Our secondary aims will examine other important relationships within the cohort.

To estimate the correlation and trend in the incidence of knee pain among adolescents at increasing levels of obesity.

To explore the effect of lean mass and fat mass in obese adolescents who develop knee pain at year 2.

To understand the effect of activity levels on the association between BMI and LE pain in all subjects at year 2.

To assess the impact of knee pain and obesity on functionality and quality of life.

B. Background and Significance

Childhood Obesity and the Musculoskeletal System

The prevalence of childhood obesity, defined as body mass index (BMI: weight/height2) at or above the 95th percentile of a reference population, has more than tripled in the United States since the 1970's to over 15%. Obesity leads to morbidities in children and is a risk factor for adult morbidity and mortality. Medical problems range from compromised cardiovascular, endocrine and pulmonary health. However, other pediatric complications of obesity important to public health or quality of life, such as bone, joint and muscle pains, are understudied and their prevalence, nature, and consequences unclear.

Certain musculoskeletal disorders such as Slipped Capital Femoral Epiphyses and Blount's disease are clearly linked to excessive weight but the association of obesity on non-specific lower extremity pain is unknown. Pediatric musculoskeletal (MSK) pain constitutes the third leading category for office visits among adolescents and prevalence estimates range from 6-33%, with the leading cause being trauma, followed by mechanical / overuse syndromes. In healthy Spanish children 10% of adolescents presented to doctors offices with MSK pain.In all children knee pain, soft tissue pain and other joint pains represented 65% of all complaints with adolescents localizing pain to the lower limb and lower back. [deInnocencio 2004]

The literature in obese children is sparse however two recent studies found the lower extremities to be the most common site of MSK pain in overweight adolescents compared to controls. A small Brazilian non-population based study demonstrated that obese adolescents had a two fold increase in pain compared to the normal weight counterparts. (sa Pinto 2006)

As the key structural elements for joint health rapidly evolve in healthy adolescents it may be adversely affected by obesity, through unsustainable levels of mechanical loading, which in the short term, may lead to pain and functional disability and in the long term, may irreversibly alter the lower extremity joint milieu.

C. RESEARCH DESIGN AND METHODS

C.1. Choice of Study Design

Until now, existing prevalence data on musculoskeletal pain has a wide range, has not been examined in a large population and has not looked at the impact of obesity. Thus our cross-sectional study design will estimate the prevalence of lower extremity pain in adolescents. Additionally, a longitudinal design using prospective data to estimate incidence has the advantage of assessing directionality and establish causality in the association of obesity on lower extremity pain at baseline (11 yrs) and at follow up (13 years).

C.2. Data source and study subjects

We propose to study subjects from the Avon Longitudinal Study of Parents and Children (ALSPAC) which is a large prospective birth cohort study investigating the health and development of children.

This cohort study is ongoing and starting at the age of 7 had annual assessments performed. Currently 6000 still attend clinic visits and data is being collected on the following variables of interest: age, gender, race, socioeconomic status, parental reports of pain, function and quality of life, height/weight, DXA, medical history and activity.

Inclusion criteria:

The entire ALSPAC cohort of ages 11-13 years will be included for study.

Exclusion criteria:

Subjects with underlying orthopedic conditions, surgery related to the lower extremities, juvenile idiopathic arthritis, other inflammatory lower extremity disorders and those with congenital abnormalities of the lower extremities will be excluded.

C.3. Data to be used:

We propose to use the existing data from the ALSPAC study in all children with visits at age 11 and 13 that include the following variables of interest:

Lower extremity pain is assessed by 2 questions on a validated questionnaire answered by the child and caregiver, as "yes" or "no" format with a followup one speculating on the cause.

Functionality and quality of life(QOL) will be assessed by questionnaire and QOL measures.

Anthropometric data from annual clinic visits include height and weight data. From that the BMI (body mass index) will be calculated using the formula weight/height2 as well as age- and gender-specific standard deviation scores (z scores) for weight, height, and body mass index , using the International Obesity Task Force (IOTF) definitions.

With DXA data we will assess lean and fat mass. Actigraph data will quantify activity levels. Socio-demographic data on socioeconomic status, age, gender and race will be analyzed. Finally, underlying medical history data from the clinic chart will be used to identify subjects for exclusion

D. HUMAN SUBJECTS RESEARCH

D.1. Protection of Human Subjects

a. Risks to the subjects: This protocol incurs minimal risk to the subjects as it uses an existing database with completed data. There will be no interaction with the subjects and no additional data is to be collected on behalf of this protocol.

b. Sources of materials: The data have already been obtained and are being requested to be shared with this investigator under the ALSPAC collaboration agreement. All the variables of interest will be shared as de-identified data.

c. Potential risks and benefits: There are no risks or benefits to the subjects under study. The results of the study will not be shared with the subjects and will not benefit them individually, although results will benefit public health policy initiatives.

D.2. Importance of the knowledge to be gained: The results of this study will provide prevalence and incidence of pain of lower extremties in obese children and reveal the short and long term impact of obesity on the musculoskeletal system with ramifications for further studies.

Date proposal received: 
Friday, 7 March, 2008
Date proposal approved: 
Friday, 7 March, 2008
Keywords: 
Endocrine, Obesity, Weight
Primary keyword: 

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