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.

B702 - Follow-up analysis of signals associated with language comprehension ALSPAC GWAS within the complete ALSPAC sample - 05/11/2008

B number: 
B702
Principal applicant name: 
Dr Beate St. Pourcain (University of Bristol, UK)
Co-applicants: 
Dr Dave Evans (University of Bristol, UK), Dr Nic Timpson (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
Follow-up analysis of signals associated with language comprehension (ALSPAC GWAS) within the complete ALSPAC sample.
Proposal summary: 

The aim of this proposal is to perform follow-up genotyping of the top associated, listening language comprehension related SNPs within the remaining ALSPAC sample in order to replicate findings from the original ALSPAC genome-wide analysis. The signal at the candidate locus will be represented through common SNPs (r2 less than 0.6; N <= 5) identified from the original ALSPAC genomewide association testing in conjunction with bioinformatics analysis. The selected SNPs will also be subjected to further analysis in another large birth cohort.

No other GWAS on listening language comprehension has been published yet. The recognition and analysis of reliable genetic associates of listening language comprehension in the ALSPAC cohort marks therefore a crucial step towards the identification of biological correlates underlying complex neurocognitive processes such as the understanding of the human language.

Date proposal received: 
Wednesday, 5 November, 2008
Date proposal approved: 
Wednesday, 5 November, 2008
Keywords: 
Speech & Language
Primary keyword: 

B732 - Follow-up analysis of signals associated with early developmental traits ALSPAC GWAS within the complete ALSPAC cohort - 05/11/2008

B number: 
B732
Principal applicant name: 
Dr Beate St. Pourcain (University of Bristol, UK)
Co-applicants: 
Dr Dave Evans (University of Bristol, UK), Dr Nic Timpson (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
Follow-up analysis of signals associated with early developmental traits (ALSPAC GWAS) within the complete ALSPAC cohort.
Proposal summary: 

The aim of this proposal is to perform follow-up genotyping of the top associated signals associated with early developmental traits within the remaining ALSPAC sample in order to replicate findings from the original ALSPAC genome-wide analysis. The signal at each respective locus will be represented through 1-2 common SNPs identified from the original ALSPAC genomewide association testing in conjunction with bioinformatics analysis. The selected SNPs will also be subjected to further analysis in other large birth cohorts.

Date proposal received: 
Wednesday, 5 November, 2008
Date proposal approved: 
Wednesday, 5 November, 2008
Keywords: 
Development, GWAS
Primary keyword: 

B731 - Modelling Obesity Through Simulation MOTS - 05/11/2008

B number: 
B731
Principal applicant name: 
Dr David Shoham (University of Chicago, USA)
Co-applicants: 
Prof George Davey Smith (University of Bristol, UK), Prof Andy Ness (University of Bristol, UK)
Title of project: 
Modelling Obesity Through Simulation (MOTS).
Proposal summary: 

Childhood overweight and obesity has emerged as an epidemic. In 2003-2004, over 33% of US children and adolescents were overweight or obese, and over 17% were obese. As the cohort born since 1980 moves into adulthood and middle age, we will see increasing incidence of diabetes, heart disease, kidney failure, and related metabolic disorders. Considerable research effort has been expended to identify the causes of childhood obesity, a necessary first step in suggesting potential prevention strategies to mitigate or reverse this growing problem. However, to date only particular subsets of the problem have been addressed.

Some of the identified factors related to obesity are clearly nested within others. For example, characteristics of the built environment vary by race-ethnicity, and obesigenic factors are more prevalent in disadvantaged communities; this may increase the risk of obesity and low physical activity levels in children. Likewise, metabolic processes are nested within individuals, who are further located within neighborhoods; as a result, insulin resistance may also follow proximity to healthy neighborhoods and their amenities.

Disentangling the web of causation of childhood obesity is a formidable task, and both available data and standard epidemiologic analyses may be inadequate to capture multiple and interacting levels of causation. Furthermore, the presence of feedback loops precludes standard approaches to causality, which are based on acyclicity and SUTVA assumptions. For example, obese children are more likely to be socially isolated, spending more time watching television, and less time engaged in sports and clubs than non-obese children. Causality is difficult to assess in this situation: obese children may be shunned by peers, making them more likely to spend isolated recreation time watching television, and less likely to participate in sports and clubs. Alternatively, participation in clubs and sports may prevent obesity by giving children opportunities for social interaction and physical activity.

In response to RFA-HD-08-023 (Innovative Computational and Statistical Methodologies for the Design and Analysis of Multilevel Studies on Childhood Obesity), we propose a novel multilevel study design and analysis plan to address this problem. In particular, we propose a three-stage strategy based on simulation, confirmation, and manipulation.

We propose the following specific aims:

1. Generate a series of simulated datasets based on knowledge obtained from the literature.

The simulations will be created using both a statistical simulation approache and an agent-based modeling approach, whereby social interactions follow explicit rules. The characteristics [heterogeneity] of individuals and environments will be specified using existing literature. We will focus on the following levels:

(1) Proximal determinants of obesity, which are in feedback and through which other determinants operate.

* Energy expenditure, which is a weakly correlated, negative, and linear determinant of adiposity

* Energy intake, which is a strongly correlated, positive, and nonlinear determinant of adiposity

* Energy expenditure and intake jointly determine BMI through complex feedback

(2) Distal demographic determinants of energy intake and expenditure:

* Household income, parental education level, gender, and race-ethnicity

(3) Family/household behavioral and biologic characteristics of energy intake and expenditure.

* Preparing meals at home; eating meals together; parental adiposity; genetic factors (e.g., FTO)

(4) Social network characteristics as they relate to energy intake and expenditure

* Homophily: on race, gender, parental education, adiposity; centrality, prestige

* Network formation: p* models for obesity as an explanation of friendship; sport/club affiliation

(5) Characteristics of neighborhood

* SES, school funding, and the built environment (supermarkets, fast food, and recreation outlets)

Characteristics 3 through 5 will further incorporate rules of social interaction between heterogeneous agents with each other and with the social and build environments. Institutions may themselves be agents. In order to be realistic, the construction of these simulated datasets will require a thorough understanding of the mechanisms and processes by which obesity and obesegenic environments are produced, not merely an ability to predict the shape of the obesity outcome.

2. Test the agreement between the simulated models and actual (observed) patterns of obesity.

Tests will be against available data, based on the characteristics cited in Aim 1, as well as overall U.S. and regional overweight and obesity rates. Data will come from the literature as well as representative datasets (NHANES, Add Health, ALSPAC). Tests must be limited to what data are available; ALSPAC will be used primarily to understand the longitudinal dynamics of obesity, while Add Health will focus on the role of social networks. Agreement between the regression-based and agent-based models may indicate that agent-based models are unnecessary.

3. Perform pseudo-experiments using the simulated data that manipulate individual characteristics and/or rules of agent interaction.

The true significance of simulated data comes not only from demonstrating how properly specified properties and rules create realistic patterns of obesity, but in the ability to artificially manipulate these properties and rules to provide counterfactual contrasts. We may then ask questions that are impossible to answer (or would yield implausible results) using the traditional multilevel approach, e.g.: what would be the effect on childhood eating habits of adding a supermarket to a "food desert", or eliminating the stigmatizing effects of overweight on friendship formation and club participation?

A related approach involves the application of structural equation models to the simulated and longitudinal datasets (ALSPAC, Add Health). [Palloni's Monte Carlo method for SEM]

We note that only existing ALSPAC data will be used for the proposed work; there is no need for further data collection.

Date proposal received: 
Wednesday, 5 November, 2008
Date proposal approved: 
Wednesday, 5 November, 2008
Keywords: 
Obesity
Primary keyword: 

B729 - Genetic risk factors for pre-eclampsia gestational hypertension and non-pregnancy hypertension in women - 03/11/2008

B number: 
B729
Principal applicant name: 
Prof Debbie A Lawlor (University of Bristol, UK)
Co-applicants: 
Dr Nic Timpson (University of Bristol, UK), Dr Abigail Fraser (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
Genetic risk factors for pre-eclampsia, gestational hypertension and non-pregnancy hypertension in women.
Proposal summary: 

Background

Hypertensive disorders of pregnancy (Hypertension identified at least twice after the 20th week of gestation with proteinuria present at least twice after the 20th week of gestation (pre-eclampsia) or without proteinuria (gestational hypertension)) are by far the commonest complication of pregnancy and are associated with increased risk of maternal and perinatal mortality, small for gestational age and preterm birth in the short time and with increased risk of cardiovascular disease in mother and offspring in the long term. Hypertensive disorders of pregnancy (HDP) affect 10-20% of pregnancies in developed countries.

Despite the common occurrence of HDP, their important impact on maternal and child health in the short and long-term and the many decades of research into this condition, two recent reviews noted that the pathophysiology of these disorders, how to predict women who are at high risk and how to prevent HDP remained unclear. They note that in part this reflects the failure to appreciated the complex nature of the syndrome which is likely to be affected by a number of pathophysiological pathways; the limited ability in studies to date to explore possible differences in pathophysiology and consequences for potentially different sub-types and the lack of large studies with adequate maternal and fetal/offspring data. With respect to exploring pathophysiology and genetic pathways it has been noted that too few studies have examined maternal and fetal genotype together when taking a candidate gene approach and that no studies to date have examined within one study population a wide array of variants that relate to all of the plausible pathophysiolgogical pathways that are likely to be involved in these conditions. It was noted that studies that restrict samples to first pregnancies are problematic, because although pre-eclampsia is more common in nulliparous women, different subtypes may be more common in women who have experienced previous pregnancies and it is important to try to understand the whole spectrum of this condition.

Classical twin studies have reported heritabilities of around 20% for HDP and have lead some to conclude that the genetic contribution to HDP was smaller than hitherto believed. However, examining levels of association in twin mothers fails to recognise the potential importance of paternal genes expressed in the fetus. Two large studies using record linkage between Norwegian population registers and containing over 1 million participants examined a wide range of familial relationships and concluded that heritability was 30% with fetal paternal genotype. The plausible pathophysiological mechanisms for HDP, including maternal-fetal immunological maladaptation, maternal endothelial dysfunction, oxidative stress, inflammatory response and glucose-insulin metabolism mechanisms, have high heritabilities (greater than 50%).

A number of genome wide association studies (GWAS) of pre-eclampsia or HDP are currently underway. Only a minority of these include genetic information on fetus/offspring as well as mother. Other studies with genome wide data are potentially able to complete GWAS for pre-eclampsia with some having fetal genome wide data only and others maternal data only.

The 50K Cardiochip has densely typed loci for all pathways that are plausibly linked to HDP and cardiovascular disease and therefore provides an efficient way of establishing the many genetic variants that are likely to be associated with HDP. This includes loci that have to date been identified as relating to HDP. Brendan Keating (co-applicant) produced this chip and is responsible for updates/revisions to later versions.

Our aim is to submit a grant proposal to BHF in March 2009 that will have the following objectives:

1. Identify and collate all GWAS of HDP and also potential additional studies with genome wide data and the possibility to define cases of HDP. To combine data from all such studies in order to identify key loci in mothers and fetus associated with HDP.

2. Add any new loci from (1) to an update version of the cardiochip

3. Use the newly updated cardiochip on all ALSPAC mothers and offspring in order to determine the association of genetic variants (in mothers or fetus) associated with HDP, cardiovascular disease and plausible mechanisms for HDP, with patterns of change in blood pressure during pregnancy in ALSPAC mothers and with later blood pressure in ALSPAC offspring ages 7-17 and mothers at the 17 year postnatal clinic.

Methods

PILOT

Before submitting the grant application we would like to complete a small pilot study in ALSPAC. This would involve using the current version of the cardiochip on 1000 ALSPAC samples (500 mothers and their 500 offspring). Debbie Lawlor is able to identify 500 mothers who have had obstetric data abstracted and for whom there is extracted DNA on both mother and offspring. From this 'eligible' sample she will identify 300 mothers-offspring pairs where mother had severe HDP (pre-eclampsia and/or systolic BPgreater than 200 on at least 2 occasions after 20 weeks gestation) and a random sample of 200 mother-offspring pairs where there is no evidence of HDP or existing hypertension in mother. We would like permission to ship DNA from these mother-offspring pairs (1000 samples in total: 500 mothers/500 offspring) to the University of Pennsylvania ASAP (DAL can provide IDs immediately) where Brendan Keating will provide genotyping with the cardiochip. The cardiochip will be provided for free for this pilot and MRC CAiTE will cover shiping costs. Analyses will be completed by DAL, Brendan Keating & Nic Timpson.

Brendan Keating requires 1ug total of DNA (50 or 100ng/ul) not from cell-lines for this work.

FULL GRANT PROPOSAL

The aims of the full grant proposal are detailed above.

With respect to ALSPAC we would request funds to complete genotyping using the cardiochip on all ALSPAC mothers and offspring with DNA. Our plan would be for this genotyping on the complete sample to be completed at University of Pennsylvania with a newly updated cardiochip. Funds would be requested for shipping samples; completion of the genotyping; merging of large amount of new genetic data with the existing ALSPAC data; a statistician to complete analyses under supervision of applicants. If funded for this complete project we would again require 1ug of DNA (50 or 100ng/ul) from whole blood samples and not cell lines for each sample from mothers and offspring.

This proposal has been discussed with Sue Ring who feels that is is feasible.

Date proposal received: 
Monday, 3 November, 2008
Date proposal approved: 
Monday, 3 November, 2008
Keywords: 
Genetics, Pregnancy, Pre-eclampsia, Risks
Primary keyword: 

B681 - Prenatal folate intake and subsequent childhood leukaemia - a multicentre study - 01/11/2008

B number: 
B681
Principal applicant name: 
Terence Dwyer (Murdoch Childrens' Research Institute (MRCI), ROW)
Co-applicants: 
Dr Gabriella Tikellis (Murdoch Childrens' Research Institute (MRCI), ROW), Dr Jessica Miller (Murdoch Childrens' Research Institute (MRCI), ROW)
Title of project: 
Prenatal folate intake and subsequent childhood leukaemia - a multicentre study.
Proposal summary: 

(No proposal form received).

Date proposal received: 
Saturday, 1 November, 2008
Date proposal approved: 
Saturday, 1 November, 2008
Keywords: 
Cancer, Pregnancy
Primary keyword: 

B721 - Associations between childhood temperament and obesity in the ALSPAC cohort - 30/10/2008

B number: 
B721
Principal applicant name: 
Dr Andrea Waylen (University of Bristol, UK)
Co-applicants: 
Title of project: 
Associations between childhood temperament and obesity in the ALSPAC cohort.
Proposal summary: 

(No outline received).

Date proposal received: 
Thursday, 30 October, 2008
Date proposal approved: 
Thursday, 30 October, 2008
Keywords: 
Behavioural Problems, Obesity
Primary keyword: 

B727 - An investigation into the determinants of scoliosis induction/progression and the impact of scoliosis on young adults - 29/10/2008

B number: 
B727
Principal applicant name: 
Dr Emma Margaret Clark (University of Bristol, UK)
Co-applicants: 
Prof Ashley Blom (University of Bristol, UK), Dr Jon Tobias (University of Bristol, UK)
Title of project: 
An investigation into the determinants of scoliosis induction/progression, and the impact of scoliosis on young adults.
Proposal summary: 

Scoliosis is defined as a lateral curvature of the spine greater than 10 degrees[1]. It most commonly starts between aged 10 years and skeletal maturity[2] (adolescent idiopathic socliosis, AIS), and has an incidence ranging between 1-3% depending on populations studied[3, 4], although this incidence does appear to be increasing[5]. There is an equal gender prevalence for minor scoliotic curves (10 degrees), but far more girls have curves greater than 30 degrees compared with boys[6]. For unknown reasons, 80-90 percent of thoracic and thoracolumbar curves are to the right[7] suggested to be linked with handedness[8], but 70% of single lumbar curves are to the left[7]. Again, for reasons that are not clearly understood, some scoliotic curves progress: estimates vary from 3.5%[9] to 15%[10], while others remain static.

Scoliosis is not always a benign structural abnormality, although the mortality rate for individuals with AIS is comparable to that of the general population[11]. There is a direct correlation between the magnitude of the thoracic scoliotic curve and pulmonary function[12]; back pain is a complaint in 80% of scoliotic patients in long-term follow-up studies[13]; and the psychological and social effects of scoliosis are real but variable and hard to quantify. Nevertheless, studies that have looked into this area consistently find mild social dysfunction such as an unwillingness to wear snug clothing or bathing suits[12], but also high rates of work disability[14,15] and reduced rate of marriage[15], although no studies that we could find assess the psychological and social effects in children and young adults.

Current knowledge about the causes of the initiation or induction of the scoliotic curve is scarce. Some work has been carried out on the determinants of the initiation or induction of the scoliotic curve, but very little using a longitudinal prospective study design. Some work has also been done on the determinants of curve progression, but contradictory results have been found for the association with bone density, anthropometry, and hypermobility, probably because of small sample sizes. No coherent picture on the genetic determinants of either induction or curve progression has been found, probably because scoliosis is due to a complex interplay between environmental and genetic influences. This also suggests that scoliosis may be a heterogeneous group: more accurate phenotyping according not only to curve structure, but associated clinical features, may therefore allow more accurate classification into subgroups with different prognosis and different genetic determinants.

Therefore the aims of this project are

1. to quantify the incidence of scoliosis in the UK population from aged 7 to 17 years, and to describe the percentage progression and regression (i.e. natural history), using a large population based birth cohort.

2. to assess the association between the standard Adams forward bending test with Cobb angle measured by DXA analysis in children

3. to assess the impact of scoliosis induction and progression in children (in terms of time off school, pain, sleep, physical activity, fractures)

4. to accurately phenotype and therefore classify into relevant subgroups, children with scoliosis in terms of curve structure and associated clinical features such as hypermobility, bone density, muscle function, family history

5. to prospectively investigate the risk factors for scoliotic curve induction or initiation, focussing on early life events, bone and muscle quality and growth

6. to prospectively investigate the risk factors for scoliotic curve progression or regression, focussing on growth, anthropometry, puberty, bone density and hypermobility

7. to investigate the genetic determinants of scoliosis using a large population based birth cohort to carry out genome wide association studies, with replication and further study to be carried out in a secondary care disease cohort

Methods

The Adams forward bending test was performed at research clinics when the offspring were aged 7, 9, 10, 11 and 13 by trained research assistants. We are requesting funding for this measure to be repeated at aged 17. The results of the Adams forward bending test will be used as the main outcome of interest, with children being categorised into having or not having scoliosis on the basis of an ATI greater or less than 7 degrees. Analyses will be repeated using the ATI as a continuous outcome to assess trends. In addition, total body DXA scans have been performed with full spinal DXA results. Cobb angles (traditional method of assessing scoliosis on plain X-rays) will be measured on these scans.

Exposures of interest

(1) demographics and early life events, (2) growth, (3) bone and muscle parameters, (4) genetics

Concept: Specific measure: Person: Source: Time point:

demographics gender child Q birth

ethnicity child Q birth

SES mother Q preg, birth, aged 4

early life event gestational age child Q birth

birth weight and length child assessment birth

growth anthropometry child assessment 7, 9,10,11,13,15,17

puberty child Q 9, 11, 13, 15

R/L handedness child Q

arachnodactyly child assessment 12

bone and muscle parameters total body DXA child assessment 9,12,15

grip strength child assessment 13

hypermobility child assessment 13,17

genetics GWAS data child biological

Impact of scoliosis

(1) chronic pain, (2) sleep, (3) physical activity, (4) time off school, (5) psychological, (6) lung function (7) fractures

Concept: Specific measure: Person: Source: Time point:

chronic pain chronic pain child Q 17

sleep disrupted/poor sleep child Q 13,14,16

physical activity reported child Q 9

accelerometer child assessment 12, 17

time off school time off school child Q 14,16

psychological DAWBA child Q 7,9,10,11,13,15

CIS-R child Q 7,9,10,11,13,15

lung function methacholine challenge child assessment 8

spirometry child assessment 9

NO, salbutamol challenge child assessment 15

fractures fractures child Q 12, 15

[1] Kane W (1997) Clin Orthop 126:43-46

[2] Dobbs MB et al (1999) Orthop Clin N Am 30:331-341

[3] Wang Y et al (1996) Chinese J Epi 17:160-162

[4] Grivas et al (2002) Studies Health Tech Info 91:76-80

[5] Wong HK et al (2005) Spine 30:1188-1196

[6] Roach JW (1999) Orthop Clin N Am 30:353-365

[7] Rinsky LA et al (1988) West J Med 148:182-191

[8] Burwell RG (2003) Develop Neurorehab 6:137-170

[9] Robitaille YVON et al (1984) Int J Epi 13:319-323

[10] Dickson RA et al (1980) BMJ 281:165-167

[11] Weinstein SL et al (1983) J Bone Joint Surg Am 65:447

[12] Aaro S et al (1984) Spine 9:220

[13] Weinstein SL et al (1981) J Bone Joint Surg Am 63:702

[14] Fowles JV et al (1978) Clin Orthop 134:212-217

[15] Nachemson A (1968) Acta orthop Scand 39:466-476

Date proposal received: 
Wednesday, 29 October, 2008
Date proposal approved: 
Wednesday, 29 October, 2008
Keywords: 
Bones
Primary keyword: 

B726 - The Association of Maternal Physical Activity and Maternal Weight with Incident Asthma among Offpsring The ALSPAC study - 29/10/2008

B number: 
B726
Principal applicant name: 
Dr Lisa Loehr (National Institute of Environmental Health Sciences, USA)
Co-applicants: 
Prof John Henderson (University of Bristol, UK), Dr Raquel Granell (University of Bristol, UK), Prof Andy Ness (University of Bristol, UK), Dr Andrea Sherriff (University of Glasgow, UK)
Title of project: 
The Association of Maternal Physical Activity and Maternal Weight with Incident Asthma among Offpsring: The ALSPAC study.
Proposal summary: 

Obesity and overweight have been found as risk factors for asthma and asthma severity, although it is difficult to isolate exposure to obesity per se from sedentary activity and dietary factors associated with obesity(Beuther and Sutherland 2007). Furthermore, sedentary lifestyle and possibly even dietary indiscretion are thought to be mediators of this association. Unfortunately, both asthma and obesity have been increasing in prevalence(Chinn and Rona 2001). Little information exists about the potential effects of maternal obesity on the risk of asthma in their offspring. The lung branch of the National Health Lung and Blood Institute (NHLBI) has suggested studies explore in utero exposure to obesity as a possible causative factor in childhood asthma(Weiss and Shore 2004). Biologic plausibility exists for this association; obesity and asthma are both conditions with an increase in certain inflammatory markers. It has been hypothesized that obesity during pregnancy may cause immunologic changes (increase in TNF alpha, IL 4 and IL5) that can be transferred to the fetus resulting in increasing risk of atopy among offspring(L.-G. Hersoug 2007). Leptin levels known to be increased in obesity also exist in fetal lung and are associated with fetal lung maturation(Torday, Sun et al. 2002).

A study from the Fragile Families and Child Wellbeing study found an association between maternal pre-pregnancy weight and self-reported physician-diagnosed incident asthma in offspring up to age 3 years old(Reichman and Nepomnyaschy 2007). We propose to study the association of maternal weight (and weight gain during pregnancy) with incident asthma (and atopy) among offspring up to age 7 1/2 years old in the Avon Longitudinal Study of Parents and Children (ALSPAC). This analysis differs from the one study in this area, in that maternal weight at 18 weeks will be the exposure rather than pre-pregnancy weight, and the outcome of incident asthma will extend to 7 1/2 years rather than just 3 years. One advantage of ALSPAC is the phenotype of asthma is further validated in a subgroup of children through bronchial hyperresponsiveness testing with methocholine challenge. A disadvantage is that maternal weight was self-reported. Since we are relating asthma to in utero exposures, it is unlikely that follow-up beyond age 7 1/2 will be useful at this point, especially if there is no association in this age group.

Table 1 (see attached) shows the variables requested for this analysis. The main exposure will be self-reported weight and height at the week 18 pregnancy visit, maternal weight change during pregnancy, and self-reported physical activity level during pregnancy. The outcome of incident asthma will be defined in 3 separate ways and then also as a composite of these measures. First, asthma up to 3 years of age will be based on maternal responses about wheeze in their child up to that time. Second, asthma at age 7 1/2 years will be based on questions about symptoms of wheeze, treatment for asthma and a history of a physician diagnosis of asthma. Third, asthma will be defined by bronchial hyperresponsiveness (BHR) as tested with methacholine challenge. BHR testing was performed in those with a baseline FEV1 of at least 70%. A positive test indicative of BHR will be defined as a greater than 20 % reduction in FEV1 from the postsaline value prior to delivery of the maximum dose of methacholine (6.1 micro-mol). Atopy will be defined as a separate outcome based on positive responses to the pin prick skin testing. Atopic responses will be defined as those with a 2 mm or greater wheal reaction to selected common antigens and a negative reaction to the control.

Potential confounders for these analyses include maternal physical activity (hours per week participated in 11 specific exercise activities), maternal nutrition information, maternal age, maternal smoking, maternal history of asthma, maternal history of allergy/atopy, maternal housing inadequacy, maternal financial difficulties, maternal education, maternal psychopathology, and maternal social support, complications during pregnancy, pre-eclampsia, gestational diabetes, types of delivery (ie, vaginal, c-section), child's birth weight, child's gestational age at birth, child's gender, child length of time breastfed, BMI of child, child's sedentary behavior and TV viewing, child's exposure to pets, and child's exposure to environmental tobacco smoke.

References

Beuther, D. A. and E. R. Sutherland (2007). Overweight, Obesity, and Incident Asthma: A Meta-analysis of Prospective Epidemiologic Studies. 175: 661-666.

Chinn, S. and R. J. Rona (2001). Can the increase in body mass index explain the rising trend in asthma in children? 56: 845-850.

L.-G. Hersoug, A. L. (2007). "The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance?" Allergy 62(10): 1205-1213.

Reichman, N. E. and L. Nepomnyaschy (2007). "Maternal Pre-Pregnancy Obesity and Diagnosis of Asthma in Offspring at Age 3 Years." Matern Child Health J.

Torday, J. S., H. Sun, et al. (2002). "Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation." Am J Physiol Lung Cell Mol Physiol 282(3): L405-10.

Weiss, S. T. and S. Shore (2004). Obesity and Asthma: Directions for Research. 169: 963-968.

Date proposal received: 
Wednesday, 29 October, 2008
Date proposal approved: 
Wednesday, 29 October, 2008
Keywords: 
Physical Activity, Weight, Asthma
Primary keyword: 

B718 - Analysis of genome-wide allelic and genotypic birth frequencies - 29/10/2008

B number: 
B718
Principal applicant name: 
Prof Ian Day (University of Bristol, UK)
Co-applicants: 
Dr Tom Gaunt (University of Bristol, UK), Santiago Rodriguez (University of Bristol, UK)
Title of project: 
Analysis of genome-wide allelic and genotypic birth frequencies.
Proposal summary: 

We have recently demonstrated that genotype-specific loss of subjects may introduce bias into Mendelian Randomization studies (Rodriguez et al, American Journal of Epidemiology, in press). A lifecourse analysis of alleles and genotypes would enable us to rigorously (and comparatively with other UK cohorts) determine precise and accurate estimates of allelic and genotypic birth frequencies on which "intention to randomize" analysis could be based in Mendelian Randomization studies. We request all available primary genome-wide genotyping data (i.e. raw fluorescence data) for ALSPAC subjects to enable highly controlled (precise and accurate beyond the level of the standard automatic software) estimates to be made of genotype and allele frequencies. We also wish to analyse the raw (primary) data to determine specific technical reasons for selective loss of genotypes in individual markers. We do not intend to directly analyse genotype against phenotype data for this project; instead we will generate a data resource which will facilitate more robust genetic epidemiological analyses.

Date proposal received: 
Wednesday, 29 October, 2008
Date proposal approved: 
Wednesday, 29 October, 2008
Keywords: 
Genes
Primary keyword: 

B725 - Measurement and modelling of functional trajectories including blood pressure across the life course - 28/10/2008

B number: 
B725
Principal applicant name: 
Prof Debbie A Lawlor (University of Bristol, UK)
Co-applicants: 
Title of project: 
Measurement and modelling of functional trajectories, including blood pressure, across the life course.
Proposal summary: 

Life course epidemiology is concerned with understanding how risk factors occurring during development and degenerative periods combine to affect disease risk.(1) Central to this approach is an understanding that many physiological processes reach a peak level (their highest functional level) early in life, remain relatively stable through mid-life, and then decline during older age. For example, there is evidence that greatest lung volume is usually attained in late adolescence / early adulthood in humans, that it then remains constant into the 6th/7th decade of life in healthy non-smokers and then begins to decline.(2) Similarly, peak bone mass, though achieved somewhat earlier in females compared to males, is achieved by the end of the second decade in both genders, remains constant through middle-age, before declining, particularly post-menopause in women.(3) Peak vascular and metabolic health appears to be reached by late adolescence and begins to decline in healthy individuals during their 60s/70s.(4, 5) Disease risk, related to sub-optimal levels of physiological function, may result from attaining lower than average peak levels of function (most likely due to risk factors early in life during developmental periods), earlier decline from the peak level or more rapid decline in older age.(2) The importance of the developmental period in determining the level of the peak function has been emphasised in relation to bone health by describing the actual value of peak bone mass achieved by late 20s as the "bone bank for the remainder of life".(3)

This underlying theory suggests that ideal life course studies will have repeat measurements of key physiological functions across life in large cohorts of individuals and will be able to examine the relative importance of level of peak function, age at decline and speed of decline in relation to future health risk as well as key risk factors for these different aspects of functional trajectories. To our knowledge, no existing study has such repeat life course measurements from early age into late adulthood and it will be some decades before existing birth cohorts that do have repeat infant and childhood measurements reach older age. One potential alternative to examining life course trajectories in markers of physiological function in a single cohort study is to use multiple cohorts that cover different life course stages. The aim of this study is to examine the extent to which this might be possible.

We have chosen blood pressure as our measurement of an important marker of physiological function since it is an important risk factor for cardiovascular disease and is likely to have been measured in most cohort studies. Textbook descriptions of age related changes in blood pressure are based on series of cross-sectional studies of different age groups.(6) These show marked increases in systolic blood pressure from birth to age 1 (from on average 70mmHg to 95mmHg), followed by steady increases of 1-2mmHg per year to late 20s after which the rise is more marked to age 80 when it begins to level off, but never appears to decline with increasing age.(6) A very different pattern is observed for diastolic blood pressure, which appears to have a more gentle increase in early life, rising by just 2mmHg in the first year of life and then 0.5-1mmHg per year to age 40, where they remain relatively stable until the 6th decade and then show a very gradual decline.(6) On top of these average age-related changes are gender differences with little evidence of a gender difference until adolescence, at which time increases in both systolic and diastolic blood pressure become more gentle in females compared to males, so that mean blood pressure is greater in males than females by age 18.(6) On average systolic blood pressure is 10mmHg in males than females at age 18.6 However, in middle-age the increase in systolic blood pressure is greater in females than males so that by age 70 year systolic blood pressure is on average 10mmHg higher in females than males.(6) Whether these age-related differences in blood pressure from cross-sectional studies are found in prospective studies of the same individuals with repeat measurements is unclear.

The specific objectives of this study are:

1. To develop statistical methods to model the average population age related trajectory of blood pressure by combining information from cohorts of different ages with repeat measures of blood pressure.

2. To apply these models to MRC funded cohorts in order to investigate the sociodemographic differences in such trajectories.

3. To apply latent class analysis to individual cohort to identify groups of individuals with different trajectories and to investigate the risk factors for such groups.

Methods

Cohort selection

Cohorts are selected on the basis of (i) receiving core funds from the UK Medical Research Council (the first objective of our grant was to identify such cohorts and because funding is from MRC public health network the focus is primarily on MRC funded cohorts (though we hope to extend this if possible in the future); (ii) general population cohort studies; (iii) have at least three examinations on study participants where blood pressure was assessed.

To date 5 cohorts fulfiling these criteria have been identified of which ALSPAC is one

Statistical methods

Analyses will be undertaken within each individual cohort using Bayesian models and latent class analyses as appropriate.

Variables required from ALSPAC

Gender

Month & Year of birth

Whether singleton/twin/triplet

Mothers education

Fathers education

Head of household social class

Age at each clinic measurement 7, 8, 9, 10, 11, 13, 15

Systolic blood pressure at each clinic measurement 7, 8, 9, 10, 11, 13, 15

Diastolic blood pressure at each clinic measurement 7, 8, 9, 10, 11, 13, 15

History of blood pressure medication

Height and weight at age clinic measurement 7, 8, 9, 10, 11, 13, 15

Birth weight

Gestational age

References

(1) Kuh D, Ben-Shlomo Y, Lynch J, Hallqvist J, Power C. Life course epidemiology. J Epidemiol Community Health 2003 October;57(10):778-83.

(2) Strachan DP, Sheikh A. A life course approach to respiratory and allergic diseases. In: Kuh D, Ben-Shlomo Y, editors. A life course approach to chronic disease epidemiology. 2nd Edition. 2 ed. Oxford: Oxford University Press; 2004. p. 240-59.

(3) Mora S, Gilsanz V. Establishment of peak bone mass. Endocrinol Metab Clin North Am 2003 March;32(1):39-63.

(4) McGill HC, Jr., McMahan CA, Herderick EE, Malcom GT, Tracy RE, Strong JP. Origin of atherosclerosis in childhood and adolescence. Am J Clin Nutr 2000 November;72(5 Suppl):1370S-15S.

(5) Lawlor DA, Chaturvedi N. Treatment and prevention of obesity--are there critical periods for intervention? Int J Epidemiol 2006 January 5;35:3-9.

(6) Bazzano LA, He J, Whelton PK. Blood pressure in westernized and isolated populations. In: Lip GYH, Hall JE, editors. Comprehensive Hypertension.Philadelphia: Mosby, Elsevier; 2007. p. 21-30.

Date proposal received: 
Tuesday, 28 October, 2008
Date proposal approved: 
Tuesday, 28 October, 2008
Keywords: 
Blood Pressure
Primary keyword: 

B719 - Is childhood obesity associated with pet ownership - 27/10/2008

B number: 
B719
Principal applicant name: 
Dr Carri Westgarth (University of Liverpool, UK)
Co-applicants: 
Title of project: 
Is childhood obesity associated with pet ownership?
Proposal summary: 

Childhood obesity is a major and increasing public health concern, with prevalence in the UK rising rapidly in children as young as 3 years (Buchan et al., 2007; Bundred et al., 2001). Some risk factors associated with childhood obesity include parental obesity, maternal smoking, increasing birth weight, and a positive mismatch between energy intake and energy expenditure (Prentice & Jebb, 1995; Reilly et al., 2005). Similarly, the incidence of obesity in companion pets is also thought to be increasing (German, 2006), and is known to have detrimental effects on pet health and longevity (Kealy et al., 2002; Lund et al., 2006). Furthermore, there is emerging evidence of a possible link between human and companion animal obesity, since overweight owners are more likely to own overweight dogs (Holmes et al, 2007). Given that the prevalence of childhood obesity is greater in families where mothers are heavier (Hawkins & Law 2006), there may be close associations between the causes of obesity in both children and companion animals. This is, perhaps, not surprising since the owner-pet relationship is similar to that between parent and child (Berryman et al., 1985). Given such associations, it is likely a major cause of human and companion animal obesity is the fact that all family members (including pets) are exposed to common environmental factors, namely the 'family food environment' (Campbell & Crawford 2001), which may predispose to obesity.

Half of UK households own a pet of some type, with one in four owning a dog( Anon, 2004; Westgarth et al., 2007). In a community-based study of 1278 households, we have identified a number of factors that are associated with households that choose to own dogs, including families with school age children being more likely to own a dog (Westgarth et al., 2007a). The beneficial impact of companion animal ownership on the physical, social and psychological health of people has been well documented (Friedmann, 1995; Headey, 2003; Katcher, 1981; Katcher & Friedmann, 1982; McNicholas et al., 2005). However, although there is some evidence of a link between obesity in dogs and their owners, there has been no specific research into a possible association between pet ownership and childhood obesity.

In the light of the increasing childhood obesity epidemic across western societies, and failure of measures taken so far to control this, new intervention means are urgently required. Intervention may also have implication for the pet population; given the suggested links between obesity in humans and companion animals, interventions can be adopted which tackle both problems concurrently. Indeed it is possible that pet ownership, and in particular dogs, may reduce the risk of childhood obesity. This may be through exercise and lifestyle factors, or some other measure associated with the types of families that choose to own dogs/pets. In fact, a previous study has demonstrated the effectiveness of a combined weight loss programme, for owners and pets, and suggested that social support for human weight loss in family members should be extended to include pets (Kushner et al., 2006).

The null hypothesis to be tested using ALSPAC data is that pet ownership has no association with childhood obesity. In order to investigate this a number of strategies will be used, including investigation of ALSPAC data of children of 7yrs. On discussion with the ALSPAC group and subject to there being appropriate data, the investigation may also be conducted in a longitudinal manner, using pet ownership and BMI at different ages of the child. This may provide additional insight into direction of causality.

Variables requested will be similar to this paper

Reilly, J. J., Armstrong, J., Dorosty, A. R., Emmett, P. M., Ness, A., Rogers, I., Steer, C. & Sherriff, A. (2005). Early life risk factors for obesity in childhood: cohort study. Bmj 330, 1357.

As this paper only includes risk factors before 3yrs (but an outcome of obesity at 7yrs), other useful variables may be identified up to the age 7yrs, on discussion with the ALSPAC group.

Pet ownership variables are also requested, including during pregnancy and each year, in addition to contact with animals, those years that these questions were asked. All data was collected using questionnaires unless otherwise stated. Pet ownership and contact with animals will be investigated as a whole and for individual species types.

BMI, child, 7yrs (and possibly yearly).

Pet ownership, mother/principal carer, pregnancy to 7 years.

Contact with animals (at least once a week at home or elsewhere), for child, 15, 24, 38 and 54 months.

Maternal social class (SES), mother, 32 weeks gestation.

Maternal education, mother, 32 weeks gestation.

Ethnicity, child, birth.

Energy Intake of Child, child, food frequency questionnaire at 30 months.

Birth weight, child, birth, delivery room.

Sex, child, medical records.

Maternal parity, mother, questionnaire 18 weeks gestation.

Maternal smoking during pregnancy, mother, 32 weeks gestation.

Season of birth, child, medical records.

Gestational age, child.

Number of foetuses, child, medical record.

Breast feeding, child, 6 months questionnaire.

Age at introduction of complementary feeding, child, 6 months questionnaire.

Parents body mass index, mother, prepregnancy.

Parents body mass index, father, prepregnancy.

Number of siblings, child, 18 months.

Ethnicity of child, child, 32 weeks gestation.

Age of mother at delivery, mother, birth, clinical records.

Time spent watching tv per week, child, 38 months.

Time in car on weekdays per day, child, 38 months.

Time in car on weekend days per day, child, 38 months.

Duration of nighttime sleep, child, 38 months.

Dietary patterns (food frequency questionnaire), child, 38 months.

A range of studies have now demonstrated human health benefits from pets. However, the vast majority of this work has used samples of Caucasian origin. Where non-Caucasian owners have been included, they have been in numbers too low to draw conclusions about differences in pet ownership across ethnic groups. It is important to look at patterns of pet ownership across ethnic groups to understand differences in attitudes and behaviour toward pets. Significance of the relationship with pets, levels of attachment and patterns of activity with pets may all vary so that ethnic groups may differ in potential benefits from pet ownership. The ALSPAC data may provide us with some insights to ethnic differences in pet ownership within the UK.

The University of Liverpool is an appropriate institution to be conducting this study, due to its international reputation, in both medical and veterinary fields, for obesity research and track record of collaboration. Comparative obesity research is actively encouraged and co-ordinated through the Liverpool Obesity research Network (LORN), which arranges regular meetings and discussion on all aspects of obesity research. Previous collaborations between the Faculties of Veterinary Science and Medicine have been highly successful, for instance, leading to the foundation of Europe's' first weight management referral clinic for companion animals (www.pet-slimmers.com), funded by WALTHAM. Dr Peter Bundred is an acknowledged expert in the field of childhood obesity epidemiology, and has published widely in this area. Therefore, he is accustomed to the procedures necessary for undertaking such research. Dr Alex German is an RCVS-recognised specialist in internal medicine whose main research focuses is in companion animal obesity biology, and who already collaborates with WALTHAM in this area. Dr Carri Westgarth is experienced in investigating factors associated with pet ownership and the characteristics of human-dog interactions.

The science is novel and of high priority, given that it targets the most important medical disease in humans and companion animals and given current estimates on obesity prevalence. The information gained will significantly increase the understanding of beneficial or other associations between pet ownership and childhood obesity, and be the first step towards developing effective strategies to improve obesity management.

Anon (2004). Pet ownership trends. Pet Food Manufacturers Association

Available at http://wwwpfmacom/public/petownershiphtm.

Berryman, J.C., Howells, K., Lloyd-Evans, M. (1985) Pet owner attitudes to pets and people: a psychological study. Veterinary Record, Vol 117, Issue 25-26, 659-661

Buchan, I. E., Bundred, P. E., Kitchiner, D. J. & Cole, T. J. (2007). Body mass index has risen more steeply in tall than in short 3-year olds: serial cross-sectional surveys 1988-2003. Int J Obes (Lond) 31, 23-29.

Bundred, P., Kitchiner, D. & Buchan, I. (2001). Prevalence of overweight and obese children between 1989 and 1998: population based series of cross sectional studies. Bmj 322, 326-328.

Campbell K & Crawford D (2001). Family food environments as determinants of pre-school aged children's eating behaviours: implications for obesity prevention strategies. Australian Journal of Nutrition and Dietetics 58, 19-25.

Friedmann, E. (1995). The role of pets in enhancing human well-being: physiological effects. In The Waltham Book of Human-Animal Interaction: Benefits and Responsibilities of Pet Ownership, pp. 33-53. Edited by I. Robinson. Oxford: Elsevier Science Ltd.

German, A. J. (2006). The growing problem of obesity in dogs and cats. J Nutr 136, 1940S-1946S.

Hawkins, SS & Law, C (2006). A review of risk factors for overweight in preschool children: a policy perspective. Int J Pediatr Obes 1(4), 195-209.

Headey, B. (2003). Pet ownership: good for health? Medical Journal Of Australia 179, 460-461.

Holmes, K.L., Morris, P.J., Abdulla, Z., Hackett, R. & Rawlings, J.M. (2006) Risk factors associated with excess body weight in dogs in the UK. Journal of Animal Physiology and Animal Nutrition 91, 166-167.

Katcher, A. H. (1981). Interactions between people and their pets: form and function. In Interrelations between people and pets, pp. 41-67. Edited by B. Fogle. Springfield: Charles C. Thomas.

Katcher, A. H. & Friedmann, E. (1982). Potential health value of pet ownership. California Veterinarian 36, 9-13.

Kealy, R. D., Lawler, D. F., Ballam, J. M. & other authors (2002). Effects of diet restriction on life span and age-related changes in dogs. Journal of the American Veterinary Medical Association 220, 1315-1320.

Kushner, R.F, Jackson Blatner, D., Jewell, D.E., Dudloff, K. (2006) The PPET Study: People and Pets Exercising Together. Obesity 14:1762-1770

Lund, E. M., Armstrong, P. A., Kirk, G. A. & Klausner, J. S. (2006). Prevalence and risk factors for obesity in adult dogs from private US veterinary practices. International Journal of Applied Research in Veterinary Medicine, 177-186.

McNicholas, J., Gilbey, A., Rennie, A., Ahmedzai, S., Dono, J.-A. & Ormerod, E. (2005). Pet ownership and human health: a brief review of evidence and issues. BMJ 331, 1252-1254.

Prentice, A. M. & Jebb, S. A. (1995). Obesity in Britain: gluttony or sloth? Bmj 311, 437-439.

Reilly, J. J., Armstrong, J., Dorosty, A. R., Emmett, P. M., Ness, A., Rogers, I., Steer, C. & Sherriff, A. (2005). Early life risk factors for obesity in childhood: cohort study. Bmj 330, 1357.

Westgarth, C., Pinchbeck, G. L., Bradshaw, J. W., Dawson, S., Gaskell, R. M. & Christley, R. M. (2007). Factors associated with dog ownership and contact with dogs in a UK community. BMC Vet Res 3, 5.

Date proposal received: 
Monday, 27 October, 2008
Date proposal approved: 
Monday, 27 October, 2008
Keywords: 
Obesity, Pets
Primary keyword: 

B720 - Comparing the magnitudes of different measurements of adiposity with metabolic and vascular outcomes - 22/10/2008

B number: 
B720
Principal applicant name: 
Prof Debbie A Lawlor (University of Bristol, UK)
Co-applicants: 
Miss Amy Taylor (University of Bristol, UK), Prof Naveed Sattar (University of Glasgow, UK)
Title of project: 
Comparing the magnitudes of different measurements of adiposity with metabolic and vascular outcomes.
Proposal summary: 

It is widely claimed that body mass index (BMI) is a poor measure of adiposity since it does not directly measure fat mass and does not give an indication of fat distribution. Measurements of central adiposity such as waist circumference or waist:hip circumference are said to be better predictors of adverse metabolic outcomes and more direct measurements of total or regional fat mass (such as obtained by DXA, MRI or CT scanning) are thought to better predict adverse outcomes than BMI. However, simple measurements of height and weight (that are used to derive BMI) are more feasible to complete in clinical and public health practice than methods that involve radiological examination, and BMI assessment is also likely to be easier and more reliable than measuring waist and hip circumference in clinical or public health practice. It is also possible that the best measure of adiposity (with respect to predicting adverse outcomes) differs by age and gender. To our knowledge very few studies have directly compared the magnitudes of association of BMI with other measurements of adiposity/fat distribution to determine the extent to which BMI may underestimate true associations with adverse outcomes. Several studies in adults have compared BMI and waist or waist to hip circumference but these have rarely made appropriate direct comparisons of standardised measurements. They have tended to include both measurements in multivariable models and conclude that the one remaining statistically significant is the better measurement. To our knowledge no study has attempted to make such comparisons across a range of cohorts of different ages. The aim of this project is to compare the magnitudes of association of different measurements of adiposity/fat distribution with metabolic and vascular outcomes and all-cause mortality (outcomes will vary and be appropriate to the cohort) in cohorts of different ages. Overall the project will use data from BWHHS, ALSPAC, Caerphilly, Speedwell, Boyd Orr (pending relevant permissions).

The specific aims of ALSPAC are:

1. To compare the magnitudes of association of BMI; waist circumference and DXA total and trunkal fat mass (all standardised), as measured at age 11 with each of the following outcomes:

a. Fasting insulin, glucose, lipids assessed at age 15

b. Blood pressure assessed at age 11, 13 and 15

We propose using anthropometry assessed at age 11 because a recent prosepective study (and meta-analysis presented at DoHAD conference) suggest clear associations of BMI assessed at this age and older in both girls and boys with future CHD risk. We think it important to assess associations with prospective outcomes but fasting blood assays for lipids, glucose and insulin are only available at age 15. Blood pressure will be assessed cross-sectionally (age 11) but also at 2 years and 4 years from the anthropometric assessment.

The final paper will have Amy Taylor as first author and Debbie Lawlor as last (supervising author) and co-authors from each study. We would be grateful if you could let us know who would be appropriate to include as co-authors from ALSPAC.

Date proposal received: 
Wednesday, 22 October, 2008
Date proposal approved: 
Wednesday, 22 October, 2008
Keywords: 
Metabolic
Primary keyword: 

B723 - Evaluation of prenatal and perinatal risk factors for tic disorders in the ALSPAC pre-birth cohort - 20/10/2008

B number: 
B723
Principal applicant name: 
Dr Jeremiah Scharf (Massachusetts General Hospital, USA)
Co-applicants: 
Dr Carol Mathews (University of California, USA)
Title of project: 
Evaluation of prenatal and perinatal risk factors for tic disorders in the ALSPAC pre-birth cohort.
Proposal summary: 

The ALSPAC study includes two different assessments for the presence of tic disorders in the offspring cohort. The first is a screening question for "tics or twitches that he/she [the child] can't control" which is asked in nine of the mother-completed questionnaires between ages 18 months to 11 years. The second, more detailed, tic assessment occurs in the Age 13 mother-completed questionnaire, in which a section entitled "Tics and Unintended Habits" asks five different questions about specific motor and vocal tics (face/head, neck/shoulder/trunk, arms/hands/legs/feet, repeated simple noises/sounds, and repeated words/phrases) as well as two additional questions about the pattern and frequency of these repeated movements. If record linkage or abstracted medical data are available for a subset of the Age 13 children, we will examinethe validity of these two different assessments by correlating questionnaire responses to a clinical diagnosis of TS or CT. While the Age 13 questionnaire will likely be more specific in identifying TS cases, the serial screening questions from age 18 months to 11 years may be able to detect children with chronic tics (those whose mothers endorse the presence of tics in two or more questionnaires spaced greater than 1 year apart) for whom symptoms may have abated by age 13. Since ~7500 mothers completed the study through Age 13 and the prevalence of either TS or CT is approximately 1-2% in the general population, we expect to find 75-150 cases of TS/CT in the sample.

Exposures of interest will include prenatal and perinatal factors reported to be associated with either TS or tic severity in at least one previous study, including birth weight, Apgar scores, paternal age, hyperemesis of pregnancy, increased maternal stress during pregnancy, maternal smoking, alcohol, and caffeine use, as well as obstetrical complications (specifically forceps delivery and neonatal hypoxia). Three to five controls will be selected per case and will be matched based on gender, month and year of birth. Both univariate analysis and multivariate analysis using logistic regression will be performed. We hypothesize that maternal smoking, paternal age and perhaps other environmental variables will be associated with the development of TS/CT in this population.

Aim 2: In the subgroup of ALSPAC subjects with TS and/or CT, examine the non-genetic risk factors identified in Aim 1 for association with comorbid OCD and/or ADHD.

In addition to the above tic assessments, ALSPAC subjects have been screened for DSM-IV diagnoses of OCD and ADHD at three different time points thus far (ages 7, 10 and 14). In this aim, we will evaluate each subject with a chronic tic disorder (TS and/or CT) based on the criteria validated in Aim 1 for the presence of OCD and/or ADHD. We will then perform both univariate and multivariate analyses to test for an association between the presence of comorbid OCD and/or ADHD and the same previously reported prenatal and perinatal risk factors, focusing primarily on maternal smoking, alcohol and caffeine use during pregnancy as well as forceps delivery. We hypothesize that at least one of these variables will prove to be associated with TS-associated comorbidities, similar to the findings observed by Mathews and colleagues (Mathews et al., 2006).

Date proposal received: 
Monday, 20 October, 2008
Date proposal approved: 
Monday, 20 October, 2008
Keywords: 
Speech & Language, Risks
Primary keyword: 

B722 - Light Physical Activity and Energy Expenditure in Relation to Obesity in a Large Cohort of Children - 17/10/2008

B number: 
B722
Principal applicant name: 
Prof Jonathan Mitchell (University of South Carolina, Columbia)
Co-applicants: 
Title of project: 
Light Physical Activity and Energy Expenditure in Relation to Obesity in a Large Cohort of Children.
Proposal summary: 

The physical activity recommendations suggest that children should engage in 60 minutes of moderate-to-vigorous physical activity (MVPA) on most days of the week to help prevent numerous health outcomes (1). It has recently been shown that engaging in 15 minutes of MVPA was negatively associated with obesity in the ALSPAC cohort at 12 years old (2). The physical activity recommendations and the previous ALSPAC findings do not address the potential health benefits associated with light physical activity (LPA). There are indications that LPA may be of benefit to health outcomes, with a recent study noting that light physical activity was independently associated with improved blood glucose regulation in adults (3). The implications of LPA in terms of preventing obesity have not yet been extensively studied.

Considering the principles of energy balance - reducing or increasing the intensity of physical activity, while altering the duration of physical activity, to match the energy expended with 15 minutes of MVPA, should result in the same negative association with obesity in the ALSPAC children at 12 years old. In line with this hypothesis, a cross-sectional study involving children, determined that 45 minutes of moderate physical activity (MPA) and 15 minutes of vigorous physical activity (VPA) were both associated with lower body composition measures (4). However, different physical activity intensities may be negatively associated with obesity at varying levels of energy expenditure and this hypothesis requires further research.

Aim:

To determine the influence of the intensity and duration of physical activity with regard to obesity among a sample of 12 year old children participating in ALSPAC.

Objective 1:

To determine if LPA is independently associated with obesity in the ALSPAC children at 12 years old.

Objective 2:

To determine if the energy expended with 1 MET-hour (15 minutes of MVPA) is negatively associated with obesity, when achieved through LPA, MPA and VPA in the ALSPAC children at 12 years old.

Objective 3:

To determine if the energy expended with 2, 3 and 4 MET-hours is negatively associated with obesity, when achieved through LPA, MPA, MVPA and VPA in the ALSPAC children at 12 years old.

Dependent variable:

- Obesity (top 10% fat mass)

Independent Variables:

- LPA (objective 1)

- 30 minutes of LPA (objective 2)*

- 20 minutes of MPA (objective 2)*

- 15 minutes of MVPA (objective 2)*

- 10 minutes of VPA (objective 2)*

- 60 minutes, 120 minutes & 180 minutes of LPA (objective 3)*

- 40 minutes, 60 minutes & 80 minutes of MPA (objective 3)*

- 30 minutes, 45 minutes & 60 minutes of MVPA (objective 3)*

- 20 minutes, 30 minutes & 40 minutes of VPA (objective 3)*

*See appendix 1 for the calculation of the MET-hours

Covariates:

- Gender (model 1)**

- Social class, maternal education, smoked during pregnancy, maternal obesity, birth weight & gestational age (model 2)**

- TV viewing (38mo) & sleep pattern (30mo) (model 3)**

- Pubertal status (model 4)**

**Repeat models with the inclusion of sedentary behaviour and MVPA as covariates (objective 1)

Repeat models with the incusion of sedentary behaviour and either LPA, MPA, MVPA or VPA

(objectives 2 & 3)

Data Analysis:

- Descriptive statistics

- Logistic regression (obese: yes or no)

References:

(1) Haskell WL, Lee IM, Pate RR et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc. 2007;39(8):1423-34

(2) Ness AR, Leary SD, Mattocks C et al. Objectively measured physical activity and fat mass in a large cohort of children. PLoS Med. 2007;4(3):e97

(3) Healy GN, Dunstan DW, Salmon J et al. Objectively measured light-intensity physical activity is independently associated with 2-h plasma glucose. Diabetes Care. 2007;30(6):1384-9

(4) Wittmeier KDM, Mollard RC & Kriellaars DJ. Physical Activity Intensity and Risk of Overweight and Adiposity in Children. Obes 2008; 16: 415-420

Appendix 1- Calculation of MET-hours:

MVPA (4 METs):

15 minutes of MVPA = 1 MET-hour

30 minutes of MVPA = 2 MET-hours

45 minutes of MVPA = 3 MET-hours

60 minutes of MVPA = 4 MET-hours

LPA (2METs):

30 minutes of LPA = 1 MET-hour

60 minutes of LPA = 2 MET-hours

90 minutes of LPA = 3 MET-hours

180 minutes of LPA = 4 MET-hours

MPA (3 METs):

20 minutes of MPA = 1 MET-hour

40 minutes of MPA = 2 MET-hours

60 minutes of MPA = 3 MET-hours

80 minutes of MPA = 4 MET-hours

VPA (6 METs):

10 minutes of VPA = 1 MET-hour

20 minutes of VPA = 2 MET-hours

30 minutes of VPA = 3 MET-hours

40 minutes of VPA = 4 MET-hours

Appendix 2 - Variables Required to match current data:

30, 60, 90 & 180 minutes of LPA; Accelerometry; Children; 11 year clinic

20, 40, 60 & 80 minutes of MPA; Accelerometry; Children; 11 year clinic

30, 45 & 60 minutes of MVPA; Accelerometry; Children; 11 year clinic

10, 20, 30 & 40 minutes of VPA; Accelerometry; Children; 11 year clinic.

Date proposal received: 
Friday, 17 October, 2008
Date proposal approved: 
Friday, 17 October, 2008
Keywords: 
Physical Activity, Obesity
Primary keyword: 

B717 - The Predictors of Adolescent Well Being Every Child Matters Outcomes - 14/10/2008

B number: 
B717
Principal applicant name: 
Dr Leslie Gutman (Institute of Education, UK)
Co-applicants: 
Dr John Brown (Institute of Education, UK)
Title of project: 
The Predictors of Adolescent Well Being: Every Child Matters Outcomes.
Proposal summary: 

There is major public concern about the well-being of children in the UK. Recently, this concern has been sharpened with a UNICEF 'report card' ranking the UK in the bottom-third for child well-being (United Nations Children's Fund, 2007). The Government's recent agenda reflects this concern, with the Every Child Matters: Change for Children programme of reforms placing a duty on local authorities and key partners to cooperate in order to improve the well-being of children. More information, however, concerning the factors mediating the development of wider well-being in young people is needed. This project proposes to provide an initial investigation into the development of wider well-being in young people through the childhood life course from infancy, through middle childhood to early adolescence. The maturation of the ALSPAC dataset, making available longitudinal detail of psychological and behavioural trajectories of children from birth to 14, offers the opportunity to study a broader spectrum of childhood life course well-being while taking into account socio-economic background, aspects of parenting and the home environment, and the school through a number of developmental dimensions. This work will first attempt to develop indices of well being based primarily on the Development and Well-being Assessment (DAWBA) from 8 and 14 years combining these with other measures collected from parent report, child report and clinical assessments. The indices will consist of separate dimensions of well being: emotional, social, behaviour, and school. For example, for the emotional component, scores will be used for DAWBA Particular Fears, Separation Anxiety 8 to 14, the parent report of Mood and Feelings questionnaire from 8 to 14, as well as items of Strength and Difficulties over the same period. The component for social competences is expected to include DAWBA Social Fears 8 to 14, Skuse Social Cognition 7, 11 and 14, Peer Relations 8 to 14, Bullying and Victimisation age 8 and 11. Measures for earlier childhood will be mapped onto these component areas. The second step in this study will involve modelling predictors of these component scores. This is intended to simultaneously control and test for the relative contribution of factors established in the literature that determine well-being from childhood to early adolescence. We will first examine how children's earlier components of well-being predict their later well-being. This stems from our earlier research (Gutman and Brown, 2008) indicating that children's social competence at age 4 predicted their later involvement in bullying and/or victimisation. We wish to expand this previous research by examining the processes that may mediate the relationship between earlier and later well-being, particularly in the social realm. Previous research suggests that children who have more social difficulties also have lower emotional well-being, which, in turn may contribute to greater problems with their peers and in school (Gutman and Brown, 2008; Gutman and Feinstein, 2008). We expect, therefore, that emotional well-being may mediate the relationship between social competence in early childhood and later social competence in primary school. We are also interested in the role of parenting behaviours in this process. Waylen (2008) found that health changes in ALSPAC affected parents' feelings and attitudes regarding their children and child rearing at 61 months, but socio-economic status was not an influence. Our recent work (Gutman and Brown, in progress) shows that parents' feelings and attitudes used by Waylen (2008) were one of the leading predictors of quality of parent-child interaction at 61 months (Thorpe) in addition to breast feeding and parental social competence. We are interested in testing a model wherein parental health predicts parents' feelings and attitudes, which, in turn, influences parenting and lastly predicts later child well-being, controlling for earlier well-being. We are also interested in examining whether specific developmental periods are more important in determining well-being than others. We expect, for example, that well-being is particularly vulnerable during the transition from primary to secondary school. Protective factors, such as teacher and friend support, may buffer the impact of such transition. We expect, therefore, that those pupils who have better relationships with their peers and teachers may experience fewer negative changes in their well-being during such transitions than other pupils. Lastly, we are interested in how such pathways may be moderated by gender and socioeconomic status. Our research has found that low socioeconomic boys are more likely to experience a trajectory of low and declining well-being compared to other primary school children (Gutman and Feinstein, 2008). Boys are also more likely to engage in bullying behaviours (Gutman and Brown, 2008). Therefore, we might expect that earlier factors such as child social competence are more important for boys than for girls in determining later well-being. This proposal mirrors elements of the ESRC large grant on adolescent development especially the components led by Anna Vignoles and Paul Greg on peer effects and socio-economic impacts. This study complements the larger studies by offering an initial examination of the predictors influencing the developmental trajectory from childhood to early adolescence. This study will be carried out in 6 months and therefore only offer baseline findings to will inform the larger scale investigations. Owing to the different time constraints and different client readership, the methodologies of this proposed study are very different from the exhaustive approach possible in the ESRC study. This proposal therefore aims to control for the primary background factors using regression analyses rather than refine large models using advanced statistical techniques. Our study offers a further benefit from a more constrained study to identify the main effects with publication in a shorter time frame, by spring 2009. Additionally, the DCSF have expressed great interest in less methodological-based description of the main findings of well being trajectories from childhood to adolescence in a format appropriate for a non-specialist policy-based readership and feel that it would make a significant contribution to the development of debate on how the state my intervene most effectively to improve life chances.

Date proposal received: 
Tuesday, 14 October, 2008
Date proposal approved: 
Tuesday, 14 October, 2008
Keywords: 
Mental Health
Primary keyword: 

B716 - To what extent do maternal dietary patterns explain the variation in child dietary patterns - 08/10/2008

B number: 
B716
Principal applicant name: 
Dr Kate Northstone (Not used 0, Not used 0)
Co-applicants: 
Dr Kirstin Newby (Not used 0, Not used 0), Dr Pauline Emmett (University of Bristol, UK)
Title of project: 
To what extent do maternal dietary patterns explain the variation in child dietary patterns?
Proposal summary: 

We wish to examine the associations between maternal dietary patterns obtained using Principal Components Analaysis (1) with those obtained in the children at 3,4, 7 and 9 years of age (2-4). The development of children's food preferences is primarily influenced by parental control which in turn is likely to be most affected by parental dietary habits. We have already established that a number of social and lifestyle factors are associated with child dietary patterns and these will be taken into account in order to determine whether there are any direct associations between the way a mother eats and how she feeds her child or whether the variation in child dietary patterns can be explained purely by socioeconomic and lifestyle factors

Initially we will focus the current analysis on maternal dietary patterns obtained when the children were 47 months of age and the child dietary patterns at 54 months. Continuous scores were obtained for each dietary pattern for both mothers and children. Associations between these scores will be examined using correlations, weighted kappas (using quintiles of scores) and regression analyses.

To our knowledge no other study has examined such associations using dietary patterns with the exception of Robinson et al who showed that pre-pregnancy maternal dietary patterns were associated with infant dietary patterns at 6 and 12 months of age (5). It is important to examine dietary patterns in later childhood when children are beginning to exert their independence.

1. K Northstone, P Emmett, I Rogers. Dietary patterns in pregnancy and associations with socio-demographic and lifestyle factors. European Journal of Clinical Nutrition 2008; 62: 471-479.

2. K North, P Emmett and the ALSPAC Study Team. Multivariate analysis of diet among three-year old children and associations with socio-demographic characteristics. European Journal of Clinical Nutrition 2000; 54: 73-80.

3. K Northstone, P Emmett and the ALSPAC Study Team. Multivariate analysis of diet in children at four and seven years of age and associations with socio-demographic characteristics. European Journal of Clinical Nutrition 2005; 59: 751-760.

4. K Northstone, PM Emmett. Are dietary patterns stable throughout early and mid-childhood? A birth cohort study. British Journal of Nutrition 2008. AOP: doi: 10.1017/S0007114508968264.

5. S Robinson, L Marriot, J Poole, S Crozier, S Borland, W Lawrence. Dietary patterns in infancy: the importance of maternal and family influences on feeding practice. Br J Nutr 2007;98:1029-1037.

Date proposal received: 
Wednesday, 8 October, 2008
Date proposal approved: 
Wednesday, 8 October, 2008
Keywords: 
Diet
Primary keyword: 

B715 - Longitudinal profiles of dietary patterns in childhood - 08/10/2008

B number: 
B715
Principal applicant name: 
Dr Kate Northstone (University of Bristol, UK)
Co-applicants: 
Dr Kirstin Newby (Not used 0, Not used 0), Dr Pauline Emmett (University of Bristol, UK)
Title of project: 
Longitudinal profiles of dietary patterns in childhood.
Proposal summary: 

The proposed analyses are exploratory in nature and will use simple methods in an attempt to idenitfy groups of children who follow certain dietary patterns throughout childhood. Dietary patterns have been obtained using Principal Components Analysis at the ages of 3, 4, 7 and 9 years in the ASLPAC children (1-3). For each child a continuous score was obtained for each dietary pattern. It is envisaged that there will be children who consistently score highly on individual patterns, e.g. the 'health conscious' or 'processed' patterns over time. On the other hand there are likely to be children whose diets have changed, for example, they may have initially scored highly on the 'processed' pattern and low on the 'health conscious' pattern in early childhood but reversed this trend through mid-childhood. Identifying such groups may be useful for examining the longitudinal associations between diet and a wide variety of health outcomes, by offering an alternative dietary exposure.

The preferred method for assessing trajectories of dietary patterns throughout childhood would be to use a technique such as latent profile or latent trait modelling. However, specialised software is required and time does not allow adequate learning of this application: It is anticipated that preliminary results will be presented at the ICDAM7 conference in June 2009 (abstract deadline is November 13th). We therefore propose to apply cluster analysis to the dietary pattern scores. This technique places individuals into distinct, non-overlapping groups based on the similarity of their dietary pattern scores. We will also investigate grouping children "by hand", based on quintiles of dietary pattern scores and compare the results obtained.

Depending on the results we hope to investigate the associations between a wide variety of variables and the 'trajectories' obtained, these will include social and parental lifestyle factors, feeding difficulties and other behaviours. This exploratory analysis will also set the scene for future analyses using the optimal methods of latent profile/trait modelling.

1. K North, P Emmett and the ALSPAC Study Team. Multivariate analysis of diet among three-year old children and associations with socio-demographic characteristics. European Journal of Clinical Nutrition 2000; 54: 73-80.3.

2. K Northstone, P Emmett and the ALSPAC Study Team. Multivariate analysis of diet in children at four and seven years of age and associations with socio-demographic characteristics. European Journal of Clinical Nutrition 2005; 59: 751-760.4.

3. K Northstone, PM Emmett. Are dietary patterns stable throughout early and mid-childhood? A birth cohort study. British Journal of Nutrition 2008. AOP: doi: 10.1017/S0007114508968264.5.

Date proposal received: 
Wednesday, 8 October, 2008
Date proposal approved: 
Wednesday, 8 October, 2008
Keywords: 
Diet
Primary keyword: 

B714 - Effects of soy infant formula on gender-specific early childhood vocabulary acquisition and time to onset of puberty - 07/10/2008

B number: 
B714
Principal applicant name: 
Ms Margaret Adgent (University of North Carolina, USA)
Co-applicants: 
Dr Julie Daniels (University of North Carolina, USA)
Title of project: 
Effects of soy infant formula on gender-specific early childhood vocabulary acquisition and time to onset of puberty.
Proposal summary: 

The aims of the proposed project are to assess the effects of exposure to soy-based infant formula in infancy on 1) vocabulary acquisition in males and females at ages 15 and 24 months, and 2) the time to onset of puberty in males and females. The rationale for this investigation is that soy-based infant formula contains hormonally active phytoestrogen compounds (specifically, genistein and daidzein) which may have the capacity to influence various aspects of neurological and physical development. It is of particular interest to observe how early life exposure to these estrogenic compounds may differentially effect development in boys and girls.

The longitudinal nature of the ALSPAC data makes it an ideal resource for looking at the effects of early life exposures on developmental outcomes occuring later in childhood. This data set contains infant feeding data that would inform us with respect to our exposure of interest [soy, or 'soya,' formula]. Additionally, ALSPAC documentation indicates that vocabulary has been assessed at both 15 and 24 months using the MacArthur-Bates Communicative Development Inventories. Ideally, these vocabulary outcome measures will be combined to develop language acquisition trajectories that can be analyzed via mixed model regression to compare rates across exposures and genders. Multiple measures of pubertal onset (age at menarche, Tanner staging) have also been repeatedly assessed at 5 time points between 97 and 157 months. Survival analysis will be implemented in the analysis of time to onset of puberty.

We do recognize that the prevalence of soy-based infant formula usage is lower in the UK than in the United States, and expect that this will be reflected to some degree in the ALSPAC data. However, given the substantial size of the ALSPAC cohort, we are confident that the proportion of soy exposed infants in ALSPAC will be sufficiently informative and allow for the conduct of sound and meaningful analyses.

An alternative design would be to conduct a randomized control trial of soy-based formula, cow milk formula and breast milk infant feeding regimes. However, this alternative study method is not feasible for the current investigators due to time and other resource limitations. Time is particularly prohibitive for our second outcome of intrest (time to onset of puberty), where approximately 10 or more years would be necessary for all relevent data to be collected. Given that the ALSPAC data has already been collected, using it in the proposed study is certainly the most effecient approach possible.

Date proposal received: 
Tuesday, 7 October, 2008
Date proposal approved: 
Tuesday, 7 October, 2008
Keywords: 
Nutrition
Primary keyword: 

B713 - The Foetal Programming Hypothesis Examining Prenatal Determinants of Neuroendocrine Activity in the ALSPAC cohort - 07/10/2008

B number: 
B713
Principal applicant name: 
Prof Kavita Vedhara (University of Bristol, UK)
Co-applicants: 
Prof Stafford Lightman (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK), Dr Chris Metcalfe (University of Bristol, UK)
Title of project: 
The Foetal Programming Hypothesis: Examining Prenatal Determinants of Neuroendocrine Activity in the ALSPAC cohort.
Proposal summary: 

According to the foetal programming hypothesis, factors influencing growth and development in the prenatal and early postnatal periods may affect vulnerability to chronic diseases (e.g., type 2 diabetes, coronary heart disease, etc.). Animal studies suggest that the neuroendocrine system, in particular the hypothalamic pituitary adrenal (HPA) axis, is the primary biological pathway through which this occurs. This has prompted interest in the factors that may affect the foetal HPA axis in humans. Several plausible candidates exist including: prenatal maternal factors that may affect the intra-uterine environment (e.g., depression, smoking etc.) and genes affecting foetal development by regulating the maternal axis (e.g., glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isoforms1 and 2 genes). However, the human evidence regarding foetal programming of the HPA axis remains equivocal. This is due, in part, to (i) limitations of existing approaches to assessing the human neuroendocrine system and (ii) a paucity of relevant data on potential environmental determinants of prenatal maternal HPA activity.

This study has sought to overcome these limitations by undertaking a more rigorous assessment of the neuroendocrine system than has previously been possible, through the implementation of the CO2 test. This test provides measures of HPA, sympathetic and parasympathetic reactivity and recovery to a stressor. Furthermore, as our enquiry is based in the ALSPAC (Avon Longitudinal Study of Pregnancy & Childhood) cohort in which environmental data are available on mothers and their offspring, we will be able to examine the relationship between foetal and early life factors (in both mother and offspring) & neuroendocrine activity in offspring at 16 years.

Data we have collected/already have approval to access (ALSPAC proj. B277):

An acute novel stressor (the 'CO2 test') was used in a sub-sample of ALSPAC (N=142). The test involved a single inhalation of 65% oxygen/35% CO2. This acts as a transient physiological challenge activating the key stress-responsive neuroendocrine systems. Consequently, the task produces increases in cortisol, blood pressure and plasma noradrenaline concentrations and an immediate reduction in heart rate that precedes the rise in blood pressure.

In order to explore inter-individual differences in sympathetic and parasympathetic reactivity and recovery, blood pressure and heart rate were recorded every minute from 5 minutes prior to the inhalation and for the 5 minutes post inhalation. Heart rate variability was recorded by the use of a Polar watch over this same time period as the R-R intervals provide assessments of the dynamic vagal regulation of the heart and dynamic changes in baroreceptor sensitivity. HPA activity was captured by the measurement of salivary cortisol (using salivettes) immediately pre-inhalation (-1 minute) and 10, 20, 30 minutes post-inhalation.

In order to control for factors known to affect salivary cortisol: all analyses will allow for time of day when samples were collected and stage in menstrual cycle will be considered for inclusion in the analysis. Participants were also asked to refrain from food and caffeine for at least 1 hour prior to the CO2 task until the final saliva samples have been taken.

In addition 2 psychological measures were administered prior to the CO2 test, the profile of mood states for adolescents (POMS-A) and the 10 item perceived stress scale (PSS-10). This was necessary to allow for inter-individual differences in mood on the day of the stress test.

Existing data on mothers and children will be collated as previously agreed. For mothers, this will focus on prenatal self-reports of social and emotional exposures captured through: (i) indices of quality of social environment; (ii) social support; (iii) distress and (iv) stressful life events. Data on health behaviour exposures (i.e., diet, smoking and alcohol consumption) will also be collated to examine the extent to which the effects of social and emotional exposures on offspring neuroendocrine activity are mediated by health behaviours.

For children, information will be extracted on birth weight, ponderal index and birth weight corrected for gestational age. While the effects of puberty on the neuroendocrine system are not expected to be significant, we will collate growth information from birth and, for girls, data on start of menses so that the effects of pubertal development on neuroendocrine outcomes can be examined.

What biological samples we would like access to and why:

We are seeking to extend the scope of our original application by requesting access to the fasting bloods samples for the 142 volunteers who participated in the stress test at the most recent recall of the cohort (2007/08). We propose to assay plasma cortisol from these samples in order to address the following issues:

1. Explore the relationship betweeen a measure of basal HPA axis function (i.e., plasma cortisol) and measures of HPA reactivity and recovery (i.e., salivary cortisol responses to the CO2 stress test).

2. Examine the relationship between foetal and early life factors and plasma cortisol and whether and how this relationship differs from relationships observed with salivary cortisol.

In addressing these issues, we will also be able to explore the 'added value' conferred by 'stress testing' in this cohort and the most appropriate primary outcomes for future research.

Thus, we are requesting access to 25 ul of the plasma samples collected in heparin containers, from the 142 participants who have participated in our preliminary study. These assays would be conducted in Clinical Biochemistry at the University of Bristol under the supervision of Professor Stafford Lightman.

Date proposal received: 
Tuesday, 7 October, 2008
Date proposal approved: 
Tuesday, 7 October, 2008
Keywords: 
Endocrine
Primary keyword: 

B709 - Association of brain structure with high risk phenotype for schizophrenia - 03/10/2008

B number: 
B709
Principal applicant name: 
Prof Mark Drakesmith (University of Cardiff, UK)
Co-applicants: 
Prof Glyn Lewis (University of Bristol, UK), Prof Steve Williams (King's College London, UK), Dr Anirban Dutt (King's College London, UK), Dr Stanley Zammit (University of Bristol, UK), Prof Anthony David (King's College London, UK)
Title of project: 
Association of brain structure with high risk phenotype for schizophrenia.
Proposal summary: 

Aims:

We propose to carry out a study examining the neural substrate of an operationally and psychometrically-defined high risk (HR) or intermediate phenotype for the later development of schizophrenia spectrum disorders. This will recruit subjects from the ALSPAC birth cohort and apply structural MRI and voxel-based morphometry. The proposed HR phenotype comprises the combination of persistent (or recurrent) psychosis-like symptoms (PLIKS) between ages 12 and their current age (17), and evidence of stable cognitive deficits at age 8 and age 15. Thus the main aim is: to carry out MRI on a unique epidemiologically based sample of 30 high-risk non-prodromal, non-helpseeking, non-highly familial individuals and 30 matched controls in a nested case-control design within the cohort. Controls will be selected to have either, normal IQ and PLIKS, or, below average IQ but no PLIKS. Such a study will be a once-only opportunity to gather data prior to the peak age of risk. It is essentially a pilot study but will yield important results in its own right and will point the way for work in other modalities (eg spectroscopy and neurochemical imaging). A subsidiary aim is to explore the acceptability of this kind of research to participants in this cohort to offset future attrition.

Date proposal received: 
Friday, 3 October, 2008
Date proposal approved: 
Friday, 3 October, 2008
Keywords: 
Neurology, Schizophrenia
Primary keyword: 

Pages