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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B944 - Genetic association of ERAP2 with pre-eclampsia - 20/01/2010

B number: 
B944
Principal applicant name: 
Dr Eric Green (National Human Genome Research Institute (NHGRI), USA)
Co-applicants: 
Title of project: 
Genetic association of ERAP2 with pre-eclampsia
Proposal summary: 

(No proposal form received).

Date proposal received: 
Wednesday, 20 January, 2010
Date proposal approved: 
Wednesday, 20 January, 2010
Keywords: 
Genetics, Pre-eclampsia
Primary keyword: 

B968 - Examanation of time-varying confounding in the relationship between breastfeeding and wheezing - 18/01/2010

B number: 
B968
Principal applicant name: 
Prof Kate Tilling (Not used 0, Not used 0)
Co-applicants: 
Rolf Groenwold (University of Bristol, UK), Prof Jonathan Sterne (University of Bristol, UK)
Title of project: 
Examanation of time-varying confounding in the relationship between breastfeeding and wheezing
Proposal summary: 

Background:

In observational studies on causality, including non-randomised therapeutic studies, the exposure and confounders are often considered constant over time. However, this assumption may not be valid, especially in case of time-varying confounding [Robins 1992, Robins 2000]. When exposure status affects confounder status, and this confounder again affects future exposure, conditioning on the confounder (as is done in a regular regression analysis), might induce bias rather than correct for confounding. To adequately estimate causal effects of e.g. interventions, initiation or stopping of medical therapy during follow-up should be taken into account, for example using time-dependent analyses. Several time-dependent analyses have been proposed, such as Cox proportional hazards analysis with time-dependent exposure, GEE, and inverse probability of treatment weighting (IPTW). In empirical data (observational or trials), however, these have not been compared throughout. Furthermore, theoretically the method could give different results, for example in case of time/varying confounding. However, to what extent time/varying confounding will affect studies over a wide range of clinical fields, is unclear. We therefore, aim to compare analyses for time-varying exposure for the association between breastfeeding and wheeze in two examples on observational studies (the Whistler cohort and the ALSPAC cohort), and compare the results to those from a randomised trial.

Objective:

To compare methods to assess time-varying exposure in observational studies on the effects of breastfeeding on asthma/eczema, and compare the associations found to those from a randomised controlled trial.

Research questions:

1. What is the association between breastfeeding and wheezing? (potential confounders: maternal smoking, being in a smoky room, daycare, maternal wheeze/eczema, age, weight and height, pets)

2. What is the association between breastfeeding and eczema? (potential confounders: maternal smoking, being in a smoky room, daycare, maternal wheeze/eczema, age, weight and height, pets)

Methods:

Several time-varying analyses will be applied and compared:

1) Exposure = ever vs. never breastfed (dichotomous measure);

2) Exposure = total duration of breastfeeding (i.e.,exposure is a continuous measure);

3) Exposure is time-dependent (i.e. breastfeeding at different ages of follow-up) and effects will be estimated using survival analysis with this time-dependent exposure. Confounders are considered constant over time (e.g. maternal smoking during pregnancy is taken as the constant value for the confounder "maternal smoking");

4) Exposure and confounders are both time-dependent. Effects are estimated using survival analysis.Follow-up is divided in discrete intervals (i.e., 1-year intervals). Each period is considered an (independent) observation. Covariates can differ at the baseline of each period.

5) Exposure and confounders are both time-dependent. Effects are estimated using Generalized Estimating Equations, thus taking dependency between observations into account.

6) Exposure and confounders are both time-dependent. Effects are estimated using marginal structural models using inverse probability of treatment weighting [Robins 2000]

7) Exposure and confounders are both time-dependent. Effects are estimated using G-estimation [Tilling 2002].

Date proposal received: 
Monday, 18 January, 2010
Date proposal approved: 
Monday, 18 January, 2010
Keywords: 
Allergies, Diet, Respiratory, Atopy, Eating disorders
Primary keyword: 

B945 - Genome wide association study on pulse wave velocity in children Meta-analysis on Generation R and ALSPAC data - 15/01/2010

B number: 
B945
Principal applicant name: 
Dr Vincent Jaddoe (Erasmus University Medical Center, Rottterdam, the Netherlands, Europe)
Co-applicants: 
Layla de Jonge (Not used 0, Not used 0), Prof Debbie A Lawlor (University of Bristol, UK), Prof John Deanfield (University College London, UK), Nic Timpson (United States Department of Agriculture (USDA), USA)
Title of project: 
Genome wide association study on pulse wave velocity in children. Meta-analysis on Generation R and ALSPAC data.
Proposal summary: 

Increased arterial stiffness is a main determinant in the pathogenesis of hypertension and is a strong, independent predictor of cardiovascular events and mortality. Arterial stiffness is defined by a reduction in arterial distensibility and influences the speed of travel of the cardiac pulse wave. Carotid -femoral pulse wave velocity (PWV) is used clinically as a non-invasive measurement of arterial stiffness. Several studies have shown a substantial heritability of blood-pressure and arterial-stiffness, what suggests important genetic contributions (4, 5). Recently, genome wide association studies investigated the genetic component of pulse wave velocity.

There is limited information on the development of arterial stiffness and pulse wave velocity in healthy, community-based children. There is increased interest not only in the conventional environmental factors influencing the early vascular phenotype, but also in genetic influences. This study proposes a genome wide association study on pulse wave velocity in children ages 5 -10 years.

In two large population-based cohort studies, ALSPAC and Generation R, pulse wave velocity is measured in children at the ages of 5 years and 9 years. Both studies will genotype several SNP's and perform genome wide association studies on this phenotype, adjusted for gender and age at visit. Because ALSPAC and Generation R are the only cohorts with these data, combined analysis will be conducted to increase the number of available samples. Analysis will be performed as part of the EAGLE consortium.

Analysis Plan

Traits of interest

* Pulse Wave Velocity at the age of 5 years (range 60.9 - 87.1 months)

* Pulse Wave Velocity at the age of 9 years (range ...-... months)

Participating studies

* ALSPAC

* Generation R

Projected number of subjects

* PWV5: ~ 522

* PWV9: ~ #?

Genotyping + Imputation

* Genotyped SNPs (Affymetrix, Illumina, Perlegen)

* Imputation HapMap Phase II CEU SNPs. Preferred release 22 of HapMap, build 36. Predefined marker filters to apply before imputation (HWEPgreater than 10-6, MAFgreater than 0.01, SNP-callgreater than 95%). Suggestion left open to cohorts to apply specific filters but should be reported.

* Analyse all SNPs, no filtering on call rate/HWE/MAF/imputation quality (QC metrics to be reported, and filtering will be done at meta-analysis stage)

Model of association

* Additive model (SNP coded as allele dose from 0 to 2), which accounts for genotype imputation uncertainty by use of linear regression onto estimated dose (as included in MACHQTL, ProbABEL, SNPTEST), adjusting for population structure and covariates.

Data exchange

* See separate RESULTS_FORMAT file for details of results file formatting and file naming.

* Summary statistics to be uploaded to common server.

* Only summary statistics will be transferred, not individual level genotype or phenotype data.

Date proposal received: 
Friday, 15 January, 2010
Date proposal approved: 
Friday, 15 January, 2010
Keywords: 
Cardiovascular , Genetics
Primary keyword: 

B939 - Prediction of Drinking Outcomes in ALSPAC An Update and Extension - 13/01/2010

B number: 
B939
Principal applicant name: 
Prof Marc Schuckit (University of California, San Diego, USA)
Co-applicants: 
Title of project: 
Prediction of Drinking Outcomes in ALSPAC: An Update and Extension.
Proposal summary: 

We propose to evaluate data being gathered at the 17 Clinic using existing forms, most of which were developed through a collaboration between our group at UCSD and investigators at ALSPAC. Our goal is to use our expertise with SEM and with LR-based mediational model to analyse existing ALSPAC data to enhance our understanding of how mediators of LR to outcome function in the mid-teens. Eventually, we hope these analyses will contribute to our ability to develop programs to help diminish the risk for heavy drinking and alcohol problems in teenagers carrying a risk for these adverse alcohol outomes through a low LR.

Date proposal received: 
Wednesday, 13 January, 2010
Date proposal approved: 
Wednesday, 13 January, 2010
Keywords: 
Alcohol, Drugs, Smoking
Primary keyword: 

B964 - Peer group influences on the relationship between depressive symptoms and substance use/misuse in adolescence - 06/01/2010

B number: 
B964
Principal applicant name: 
Dr Marianne van den Bree (University of Cardiff, UK)
Co-applicants: 
Prof Marcus Munafo (Not used 0, Not used 0), Dr Katherine Shelton (Not used 0, Not used 0), Dr Jon Heron (Not used 0, Not used 0)
Title of project: 
Peer group influences on the relationship between depressive symptoms and substance use/misuse in adolescence
Proposal summary: 

BACKGROUND

Alcohol-related harm (see Saraceno; Munafo; Heron; Craddock, and van den Bree 2009) for more detail and references).

Alcohol is the most frequently used substance and alcohol involvement in young people has been associated with increased risk of tobacco and drug use, academic failure, traffic and other accidents, delinquency, pregnancy and sexually transmitted disease. Teenagers in the UK have one of the highest rates of substance use in Europe (European Monitoring Centre for Drugs and Drug Addiction). 21% of those aged 11-15 years report having used alcohol in the past week (Institute of Alcohol Studies, 2007). It is estimated that 1% of 14-16-year-olds in the UK drink alcohol nearly every day and are therefore at high risk of alcohol use disorder. Adolescence is a key developmental period with respect to future risk of alcohol use disorder. Studies indicate young people may have lower alcohol tolerance levels and become dependent at lower doses than adults. There is also increasing concern that ethanol can affect normal brain development during adolescence and thus interfere with cognitive and emotional functioning.

Depressive symptoms

Depression is a common mental health problem during adolescence. In the UK 5% of those aged 11-16 are affected with clinically diagnosed major depressive disorder or anxiety disorder. Alcohol problem use has been associated with depressive symptomatology in a number of adolescent samples and there is an increasing research and clinical interest in the aetiological relationships between both traits. Many studies indicate that depression plays an important role in the development of alcohol use disorder, however, the developmental relations between the traits remain unclear, with a number of studies reporting symptoms of depression precede alcohol problem use, while others report the opposite. There is a dearth of studies that have addressed these issues in large, longitudinal samples of young people.

Peer group behaviour

Peer substance use represents one of the strongest risk factors for the initiation as well as continuation of substance use/ misuse in adolescence. Adolescence is characterized by high vulnerability to social influences. Peers may exert their influences by serving as role models and influencing attitudes towards alcohol use or they can provide opportunities and encouragement for drinking and heavy alcohol use. Adolescents may seek out or be sought out by deviant peers because they share traits in common (e.g. deviance, or similar drinking habits).

The adolescent peer group can also influence (or moderate) the relationship between a risk-enhancing trait and substance misuse (Glaser et al., in press; D'Amico et al, 2005). D'Amico et al. reported that the relationship between adolescent substance use and alcohol abuse/ dependence at age 29 was influenced by pro-drug social influences in early adulthood (D'Amico; Ellickson; Collins; Martino, and Klein 2005). We previously found that childhood deviance increased risk of alcohol misuse in adolescence, but only in adolescents with alcohol using peers (Glaser et al. in press). In addition, the peer group (particularly peer rejection and victimization by peers) also plays an important role in depression in young people.

Sophisticated methods are needed to disentangle the complex relationships between peer influences, depression and alcohol misuse over time. For example, a longitudinal study by Aseltine et al. found that close relationships with friends protect against the development of depression, however, friendships with deviant peers on the other hand, have been reported to correlate positively with adolescent alcohol problem use.

Work that has preceded this proposal

Despite the documented strong influences of peers on adolescents' substance involvement and depressive symptoms, as far as we know, only one study has explored these relationships in more detail (Saraceno et al., about to be submitted). This study was part of a 3-year PhD project which focussed on the relationships between depressive symptoms in childhood (age 10) and alcohol problem use in early adolescence (age 14) in the large population-based Avon Longitudinal Study of Parents and Children (ALSPAC). We found that children with high levels of depressive symptoms had a 27% greater risk of alcohol misuse at age 14. However, this relationship was considerably stronger for girls than for boys. In addition, we found that not all adolescents with high levels of childhood depressive symptomatology had the same elevated risk of alcohol misuse. Rather, the strength of this relationship depended on (was moderated by) the peer group. That is, adolescents who experienced depressive symptoms in childhood were only at increased risk of alcohol misuse in adolescence if: a) they were firmly linked in with a friendship network; b) alcohol use/ misuse was common within this friendship network.

Currently proposed study

This study focussed on two time points only and we also only examined the relationship between earlier depressive symptoms (age 10) and later alcohol problems (age 14). That is, we did not examine the development of the relationships between depressive symptoms and alcohol use/ problem use over time. We also did not explore the factors that may contribute to the enhanced sensitivity to the influences of peers in adolescents with higher levels of depressive symptomatology. ALSPAC is uniquely suited to address these issues, because it represents one of the world's largest and most comprehensive cohort studies. Relevant information on depressive symptoms, alcohol use/ misuse and peer factors has been comprehensively assessed (from multiple informants to increase report reliability), using well-established measures on a number of occasions throughout the relevant period of young people's development. In addition, detailed information on other relevant factors that are likely to contribute the relationships specified above is available, i.e., family socio-economic status (SES), parental substance use/ misuse, parental depression, relations between family members. We are proposing to use ALSPAC data to examine the issues above.

AIMS are to examine:

1. How the relationships between depressive symptoms and alcohol use/ misuse are related across time and to what extent depressive symptoms increase risk for alcohol problem use and vise versa?;

2. The moderating role of the peer group (peer deviance and substance use) on the relationships between depressive symptoms and alcohol use;

3. To what extent social processes (i.e., young people's social acuity and histories of social interaction) predict deviance and substance use in the peer group in later adolescence;

4. To examine the interplay between social cognition and peer behaviour in the prediction of depressive symptoms and alcohol use.

Date proposal received: 
Wednesday, 6 January, 2010
Date proposal approved: 
Wednesday, 6 January, 2010
Keywords: 
Alcohol, Depression, Drugs, Smoking
Primary keyword: 

B922 - Maternal levels of perfluorinated chemicals and markers of cardiovascular risk at age 7 - 30/12/2009

B number: 
B922
Principal applicant name: 
Dr Mildred Maisonet (Emory University, USA)
Co-applicants: 
Dr Michele Marcus (Emory University, USA), Ms Adrianne Holmes (Emory University, USA)
Title of project: 
Maternal levels of perfluorinated chemicals and markers of cardiovascular risk at age 7.
Proposal summary: 

To conduct analyses of existing data to assess the effects of maternal exposures to selected perfluorinated compounds and blood pressure and levels of serum lipids at age 7 in girls enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Date proposal received: 
Wednesday, 30 December, 2009
Date proposal approved: 
Wednesday, 30 December, 2009
Keywords: 
Cardiovascular
Primary keyword: 

B844 - Meta-analysis on filaggrin FLG nutrition and cat exposure on the development of eczema - 30/12/2009

B number: 
B844
Principal applicant name: 
Dr Chih-Mei Chen (Helmholtz Zentrum M?nchen, Germany)
Co-applicants: 
Dr Joachim Heinrich (Helmholtz Zentrum M?nchen, Germany)
Title of project: 
Meta-analysis on filaggrin (FLG) nutrition and cat exposure on the development of eczema.
Proposal summary: 

To perform a meta-analysis of the birth cohort studies which participated GA2LEN net work to determine whether cat exposure in early life enhance the effect of FLG mutation on the development of eczema and it's effect size.

Date proposal received: 
Wednesday, 30 December, 2009
Date proposal approved: 
Wednesday, 30 December, 2009
Keywords: 
Allergies, Skin
Primary keyword: 

B938 - Biological Maturity Status and Body Composition as Predictors of Physical Activity in British Youth - 21/12/2009

B number: 
B938
Principal applicant name: 
Dr Sean Cumming (University of Bath, UK)
Co-applicants: 
Dr Lauren Sherar (Loughborough University, UK), Prof Chris Riddoch (University of Bristol, UK), Prof Robert Malina (Tarleton State University, USA)
Title of project: 
Biological Maturity Status and Body Composition as Predictors of Physical Activity in British Youth.
Proposal summary: 

The subject of physical activity (PA) is of particular importance to those involved in the study and promotion of positive health in youth (1). In children, PA is considered a prerequisite for healthy growth and a positive predictor of psychosocial adjustment and well-being (2). To optimize the health benefits associated with regular involvement in PA, children should be encouraged to be (and remain) active from an early age. However, evidence from the past 40 years suggests that children have become increasingly less active in many domains, including leisure-time activities, physical education, and active transport (3).

To better understand and promote PA in children, researchers and practitioners have studied the influence of various psycho-social variables and/or the characteristics associated with the physical environment. Although there is little doubt that factors such as motivation, lifestyle, family and peer support, and the built environment contribute to variation in PA in youth, it has been argued that PA has a biological basis (4-5), and that a true understanding of PA resides within the interactions of various biological, psychosocial, and physical factors (5). Physical activity is, after all, a biological process tdhat exists within a cultural setting in which various meanings and customs are ascribed to it (6).

Biological maturation has been identified as a potential contributor to involvement in PA, and may be particularly pertinent to those studying PA in youth. Maturation refers to progress towards the adult state and ca be viewed in terms of timing and tempo. There is good reason to believe that maturation may contribute to variance in PA in youth. First, the decline in PA with age is considered one of the most robust findings in PA epidemiology, with individuals become less active as they progress towards the mature state (i.e., adulthood) (5). Second, the physical and functional characteristics associated with early maturation in males and late maturation in females are considered more conducive to successful involvement in most forms of physical activity (6).

Although there is compelling evidence to suggest that biological maturation contributes to sex differences in PA among same age cohorts (7-10), evidence that variation in maturity status (i.e., timing of maturity) accounts for individual differences in PA within sex is limited. A recent review of literature pertaining to maturity associated variance in PA (11) noted that relations between biological maturity status and PA, within sex, were unclear, with only a limited number of having been published (N=9). Further, the available studies were largely restricted to females and had produced equivocal results. Whereas a few studies had documented an inverse relation between maturity status and PA in females, others had observed a positive, or no, relation between the constructs. Relations between biological maturity and PA are equally unclear in males. The inconsistent nature of these results has been attributed to a number of methodological and analytical limitations including a reliance on cross sectional data, modest sample sizes, variation in the measurement of PA and maturation status, and a general failure to consider, or control for maturity associated changes in body composition (11).

With the aforementioned limitations in mind, the purpose of the proposed study is to examine the independent and interactive effects of biological maturity status and body composition (i.e., relative fat mass) upon changes in PA and fitness in British youth. The Khamis-Roche (KR) method for estimating percentage of predicted adult stature attained at measurement will be used as an estimate of biological maturity status. The KR method has been used as an estimate of biological maturity status in US youth 4-17 years of age and has been validated against an established marker of biological maturity status (12). The median error bound (median absolute deviation) between actual and predicted mature height is 2.2 cm in males and 1.7 cm in females (13). The KR method has also been employed in studies of activity level (10), perceptions of physical and social competence in youth soccer players (14), and injury risk in youth football (15-16). Whole Body Dual X-Ray Absorptiometry (DEXA) will be used to determine body composition and daily PA will be measured objectively by the Actigraph accelerometer. Methods of analysis will included descriptive statistics, Pearson product moment correlations, and hierarchical multiple linear regressions. Linear growth modelling, using procedures described by Singer (17), will be used to examine the independent and interactive effects of biological maturity status and body composition upon changes in physical activity and fitness from the age of 11 to 13 years. Separate analyses will be conducted for males and females.

Date proposal received: 
Monday, 21 December, 2009
Date proposal approved: 
Monday, 21 December, 2009
Keywords: 
Physical Activity
Primary keyword: 

B937 - Genetic basis of moral utility - 21/12/2009

B number: 
B937
Principal applicant name: 
Philippe Tobler (University of Cambridge, UK)
Co-applicants: 
Title of project: 
Genetic basis of moral utility.
Proposal summary: 

Background. Moral behavior is a fundamental issue for human societies. We often make choices on the basis of the subjective value (utility) of the available options. Examples include animal foraging and human value-based decision-making. Utility comes in two flavours. Economic utility captures the personal value consequences of one's decisions whereas moral utility captures value consequences for others. Microeconomic theories of economic utility provide formal models of how economic utility relates to the objective properties of choice options such as their reward magnitude, probability, risk and delay. Crucially, the same economic models also capture moral utility, suggesting that economic and moral utility can be calculated similarly. For example, the expected economic and moral utility of an option can be calculated with: EU=sigma(u(m)*p), where p corresponds to objective reward probability, m to objective reward magnitude, and utility u to a subjective, monotonically increasing function of m. Despite the common formalism, it is an open question whether the behavioural and neural mechanisms underlying economic and moral utility calculations are the same. I have elaborated the framework for the present project more fully elsewhere (Tobler et al., 2008). My previous work revealed neural correlates of economic utility components, particularly in the dopamine system (Tobler et al., 2005, 2007, 2009).

Individual differences in economic and moral utility processing.

Individuals differ considerably in their sensitivity to economic and moral value. Previously, I have elucidated the role of dopamine neurons in economic reward processing (e.g. Tobler et al., 2005). Dopamine neurons project strongly to the striatum and the prefrontal cortex (PFC) and these regions process economic reward parameters as well (Tobler et al., 2007, 2009). The present project therefore focuses on the genetic basis of the dopamine system. There is a number of enzymes and proteins determining the availability and action of dopamine (synthesis: tyrosine hydroxylase (TH) and DOPA decarboxylase, reuptake: dopamine transporter (DAT), pre- and postsynaptic receptors: dopamine receptors 1-5 (DRD 1-5) and metabolism: catechol-O-methyl-transferase (COMT), dopamine beta hydroxylase (DBH) and monoamine oxidase (MAO)). A variety of genes controls these proteins and enzymes (e.g. Gasso et al., 2009). Single-nucleotide polymorphisms (SNPs) in such genes may explain some of the behavioral and neural variability in dopamine function and, by extension, in economic and moral value processing. Indeed, some previous genetic studies point to a role of lateral PFC and ventral stratum dopamine function, as indexed by polymorphisms of the COMT, DAT and DRD2 genes, in modulating individual differences in economic reward processing (Yacubian et al., 2007, Schmack et al., 2008; Dreher et al, 2009; Forbes et al., 2009). The rationale for the present project is to use genetic screening to study the genetic basis of individual differences in the behavioural processing of economic and moral utility.

Hypotheses and method. Individual differences in genetic make-up will be assessed with the hypothesis that genetic differences in the dopamine system predict behavioural differences in processing of moral and economic utility. More specicifically, two sets of alternative sub-hypotheses will be tested:

1a) Behavioral indicators (see below) of economic and moral value processing increase monotonically with SNPs leading to increases in prefrontal and striatal dopamine activity and availability

1b) Behavioral indicators follow an inverted-U function of such dopamine activity and availability, in analogy to previous findings that both too little and too much dopamine can be detrimental to cognitive functions (e.g. the Avon-based study of Barnett et al., 2009)

2a) Behavioural indicators of economic and moral value are modulated by the same genes of the dopamine system

2b) Behavioural indicators of economic and moral value are modulated by different genes of the dopamine system

The method will be to ask the children to answer a short (about 20 minutes) questionnaire that reveals individual differences in the following behavioural indicators of economic and moral utility processing: a) Sensitivity to magnitude, b) Sensitivity to probability, c) Risk attitude, and d) Temporal discounting (attitude to delay). In each question, participants will make a decision between two options. The questions are ordered in a systematic way, such that answering them is quick (see examples). Questions about economic value involve monetary amounts, probabilities, risk and time while questions about moral value in addition involve a moral dimension (choices involving stolen money (see examples) and giving to charity (e.g. Moll et al., 2006)). The questionaires will in turn be longitudinally informed by the ALSPAC measures of prosocial, asocial, illegal and impulsive behaviour. IQ and 2D:4D will serve as covariates. For all types of questions on moral and economic value, individual differences in equivalence points (switching-over from low to high risk/delay) and differences of such differences (sensitivity to magnitude and probability) will be taken and related to genetic differences in the dopamine system. Under hypo-thesis 1a), sensitivity to magnitude and probability, proneness to risk and unwillingness to wait would increase with genetic variation resulting in higher dopamine activity and availability. Conversely, these variables would peak at intermediate levels of dopamine activity and availability under hypothesis 1b).

Date proposal received: 
Monday, 21 December, 2009
Date proposal approved: 
Monday, 21 December, 2009
Keywords: 
Genetics
Primary keyword: 

B934 - Detection of Parent of Origin eQTLs using genome-wide expression - 17/12/2009

B number: 
B934
Principal applicant name: 
Dr Cecilia Lindgren (Wellcome Trust Centre for Human Genetics, UK)
Co-applicants: 
Dr Carl Anderson (Wellcome Trust Sanger Institute, London, UK), Dr Blanca Herrera (Wellcome Trust Centre for Human Genetics, UK), Andrew Morris (Not used 0, Not used 0), Dr Nic Timpson (University of Bristol, UK)
Title of project: 
Detection of Parent of Origin eQTL?s using genome-wide expression.
Proposal summary: 

Aim:

To identify alleles which influence gene expression through a maternal or paternal parent-of-origin mechanism and to correlate these observations to growth and development phenotypes in offspring.

Background:

Parent of origin effects (POE) are genetic effects that deviate from traditional Mendelian inheritance rules by affecting the expression of a phenotype/trait in offspring in a manner that is specifically determined by the sex of the parent from which the locus is inherited. Both maternal and paternal effects may arise via epigenetic mechanisms like imprinting.

Genomic imprinting is a common mechanism of gene regulation achieved through epigenetic modifications, which result in uniparental gene expression. "Epigenetic" refers to DNA changes/modifications, which do not affect the sequence of the genome directly, but can still be inherited. An epigenetic change located in/near a promoter can alter chromatin structure and obstruct transcription. Epigenetic modifications which result in gene silencing include:

-DNA methylation at the 5' position of cytosine residues in CG dinucleotides [1]

-Histone modification through acetylation, phosphorylation, methylation and ubiquitylation [2]

-ATP-dependent chromatin remodelling [3]

Epigenetic modifications are removed during meiosis and then reinstated in the zygote, in imprinted regions these modifications depend on parental origin. It has been suggested that imprinting evolved as the result of genetic conflict between maternal and paternal genes in relation to nutrient transfer to the offspring [4]. Which affect foetal growth in a potentially antagonistic manner, paternally expressed genes generally enhance foetal growth while maternally expressed genes reduce it [5].

To investigate POEs affecting gene expression, publically available expression and genotype data from HapMap families was used to establish the presence of parent-of-origin e-QTL (POE-eQTL) which affect expression through cis-acting mechanisms. Stranger et al [6] measured expression of 47,294 probes in 30 CEU and 30 YRI trios previously genotyped as part of the HapMap project [7]. We were able to map 18,139 of these probes to a genomic location using the UCSC database. Of these, 1,078 probes with a gene expression standard deviation greater than 0.5 were analysed. For each probe, SNPs located 500Kb upstream and 50kb of the transcription start site were tested for parent-specific effects on gene expression using a linear regression model [8]. This analysis resulted in 392 SNPs (annotating 60 genes) with evidence for uniparental effects on transcript levels (p-uncorrectedless than 5 * 10-5). Of these, 89 SNPs can potentially create or destroy methylation sites (meth-SNPs), these meth-SNPs annotate 31 genes across the genome including DAPK1, RIN2, FANK1, PRL for which there is already some evidence of methylation and specific maternal expression [9-12]. From our full set of 392 SNPs, we have selected a total of 83 independent SNPs (33 of which are predicted to generate or destroy methylation sites).

To replicate these findings, we propose to study a subset of 150 children from the ALSPAC cohort, For which gene expression data has been collected using microarrays at the Sanger Institute in Cambridge and for which parental DNA has been collected. We would like to genotype the 83 SNPs selected within the n=57 samples for whom there is complete trio data available, there is genomewide data available and where genomewide transcript data will be available (Dermitzakis expression data collection in ALSPAC) (i.e. DNA from child, mother and father - buccal DNA from fathers). For genotyping, the amounts of DNA required will depend on the genotyping set-up at Kbioscience (currently on their website as 1.5ul of DNA at a concentration of 3.3ng/ul. For 83 SNPs, we will require ~260ng of DNA per sample). The regression model [8] used in the discovery phase of the project will be applied, and bisulphite treatment based technology will be used to establish methylation profile of the suspected meth-SNPs for which findings are replicated at this atage of the study. We expect that some noise caused by clonality issues suggested to affect immortalized cell lines [13] might be detected in our expression study. However, we are confident that our tiered approach and the larger size of the follow-up cohort will reduce the number of false positive results.

As well as evaluating and confirming the presence of POE-eQTLs, we wish to investigate the hypothesis that specific POEs affect growth and development. Therefore, we would like to investigate correlations between genotypes/alleles at SNPs for which we demonstrate POE-eQTLs and a number of growth phenotypes including: birth weight, and other markers of foetal development, growth rate, BMI and anthropomorphic/body composition measurements available in the ALSPAC database.

The results from this study, as well as, enhancing our knowledge and understanding of the control of gene expression through parent-specific mechanisms, have the potential to identify novel imprinted genes which could serve to explain some of the current observed associations to growth phenotypes and represent an appropriate use of the vast resources available through ALSPAC.

Date proposal received: 
Thursday, 17 December, 2009
Date proposal approved: 
Thursday, 17 December, 2009
Keywords: 
Genetics
Primary keyword: 

B754 - An investigation of connexin-26 genetic mutations and hearing in the ALSPAC cohort - 15/12/2009

B number: 
B754
Principal applicant name: 
Dr Amanda J Hall (University of Bristol, UK)
Co-applicants: 
Prof Maria Bitner-Glindzicz (Great Ormond Street Children's Hospital, UK)
Title of project: 
An investigation of connexin-26 genetic mutations and hearing in the ALSPAC cohort.
Proposal summary: 

Purpose of the proposed investigation and statement of scientific value

1. To characterise the hearing status of the ALSPAC cohort at age 7, 9 and 11 years

2. To investigate the impact of the 35delG mutation on audiological measures at age 7, 9 and 11 years

3. To investigate the impact of the M34T mutation on audiological measures at age 7, 9 and 11 years

Background

The human gap junction b-2 gene (GJB2) that encodes the protein connexin-26 was the first autosomal gene for non-syndromic deafness to be identified(Kelsell et al, 1997). Connexin-26 is involved in recycling of potassium ions from the endolymph of the cochlea(Kikuchi et al, 2000) and mutations in this gene are by far the commonest cause of autosomal recessive non-syndromic sensorineural hearing loss (NSSNHL) (~50% in Europe). In addition mutations also contribute to both autosomal dominant NSSNHL and syndromic forms of hearing loss as well (Denoyelle et al, 1998; Gasparini et al, 2000, see references on http://davinci.crg.es/deafness/index.php?seccion=mut_db&db=synd&synd=cx26synd

). The mutation, 35delG, accounts for the majority of the mutations in the gene in Caucasian populations with an estimated carrier frequency of 1 in 80 in northern and central Europe (Gasparini et al, 2000).

The high frequency of the 35delG and the small size of the GJB2 gene (~ 5.5kb, 2 exons only 1 of which is coding) has facilitated the development of clinical mutation screening, which in turn has led to a fuller characterisation of the common variants in GJB2 than in other NSSNHL genes. A case in point is the GJB2 sequence variant 101 T(registered trademark)C (M34T), which has an UK heterozygote frequency of about 2% and changes a hydrophobic methionine residue in the first transmembrane region of the protein to a polar threonine. Functional data generated using the Xenopus laevis paired oocyte assay showed that M34TCx26 protein is a dominant disrupter of normal channel formation (White et al, 1998). Human genetic studies have shown that it is not a dominant mutation, but the role of M34T as a contributing recessive allele in NSSNHL is controversial and remains unclear despite both functional as well as clinical studies.

There have been few attempts to make carefully controlled audiological assessment of obligate heterozygotes from families with autosomal NSSNHL. Cohen and colleagues (Cohen, 1999; Cohen et al, 1997) found an increase in abnormalities in pure tone audiometry and otoacoustic emissions (OAE), but these did not correlate with the presence of the 35delG mutation. A small family study of Ashkenazi Jews (Morell et al, 1998) suggested that heterozygous carriers of GJB2 mutations (principally 167delT) with apparently normal hearing had significantly lower amplitudes of OAE than controls. A subsequent study of the same population showed significantly reduced suppression of OAE than control subjects, although no significant difference in OAE amplitude (Hood et al, 2000).

Within the ALSPAC cohort, Bitner-Glindzicz and colleagues have detected the 35delG and the M34T mutations of the GJB2 gene (unpublished). 1% (125 out of 9348) were heterozygote for the 35delG mutation and 2% (255 out of 9324) were heterozygote for the M34T mutation. Pilot analysis showed that the hearing status of the heterozygotes at age 7 and 9 were no different to the normal population. However the 35delG heterozygotes (but not M34T) had significantly reduced TEOAE amplitude indicating reduced cochlear function, at age 9 compared to the normal population.

The significance of the findings from the pilot study needs further investigation. We aim to evaluate whether being a carrier for 35delG and M34T has any functional significance on hearing.

Research questions:

1. Does being a carrier increase your risk of developing hearing loss?

a. Do carriers show significant changes in OAE between age 9 and 11 years?

b. Do carriers show significant changes in hearing (conventional and extra-high frequency thresholds) between 7 and 11 years?

2. Does being a carrier convey advantages in hearing function?

a. Are carriers more sensitive to sound (hyperacusis)?

b. Do carriers have lower acoustic reflex thresholds?

c. Are carriers less likely to report tinnitus?

ALSPAC measures required

1. Hearing thresholds at age 7, 9 and 11 years (child measure; focus clinic)

2. Otoacoustic emissions at age 9 and 11 years (child measure; focus clinic)

3. Acoustic reflex thresholds (ipsilateral) at age 7, 9 and 11 years (child measure; focus clinic)

4. Child report of tinnitus and hyperacusis at age 11 years (child measure; focus clinic)

5. Children in Focus hearing and tympanometry measures (child measure; focus clinic)

6. Tympanometry at age 7, 9 and 11 years (child measure; focus clinic)

7. Noise measures at age 11 years (child measure; focus clinic)

8. Connexin 26 genotypes

9. Measures of socio-economic status (maternal education status and others to be determined with statistician)

Research plan

1. To put the genetic results in context, we intend to categorise the normal hearing sensitivity of the ALSPAC cohort at age 7, 9 and 11 years. Most of this work was completed by Amanda Hall during her employment at ALSPAC, but requires additional funding to complete.

2. We intend to repeat the connexin 26 analysis using the age 11 year hearing and otoacoustic emission results. This will allow the repeatablity of the 9 year results to be checked.

3. We intend to investigate changes in the hearing and OAE for the carriers/non-carriers between age 7, 9 and 11 years.

4. We intend to compare measures of hearing function (tinnitus and hyperacusis) for the carriers/non-carriers.

Resources

* We require funding to process and prepare the 11 year otoacoustic emission and hearing data

* We require statistical support for the analysis

References

Cohen M, Francis M, Coffey R, Pembrey ME, Luxon LM. Abnormal audiograms and elevated acoustic reflex thresholds in obligate carriers of autosomal recessive non-syndromic hearing loss. Acta Otolaryngol 1997; 117: 337-42.

Cohen M. Auditory and vestibular studies in families with autosomal recessive non-syndromic hearing loss. PhD University of London 1999

Denoyelle F, Lina-Granade G, Plauchu H, Bruzzone R, Chaib H, Levi-Acobas F, Weil D, Petit C. Connexin 26 gene linked to a dominant deafness. Nature 1998; 393(6683): 319-320

Gasparini P, Rabionet R, Barbujani G, Melchionda S, Petersen M, Brondum-Nielsen K, Metspalu A, Oitmaa E, Pisano M, Fortina P, Zelante L, Estivill X. High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG. Eur J Hum Genet 2000; 8:19-23

Hood L, Berlin C, Morlet T, Goforth-Barter L, Tedesco S, Bordelon J, Picton T, Keats B, Friedman T, Morell R, Griffith A. Otoacoustic emissions in obligate carriers of genes for recessive hereditary hearing loss. Abstracts Association Research Otolaryngology 2000

Houseman MJ, Ellis LA, Pagnamenta A, Di WL, Rickard S, Osborn AH, Dahl HH, Taylor GR, Bitner-Glindzicz M, Reardon W, Mueller RF, Kelsell DP. Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss. J Med Genet 2001; 38: 20-25

Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 1997; 387 (6628): 80-83

Kikuchi T, Kimura RS, Paul DL, Takasaka T, Adams JC. Gap junction systems in the mammalian cochlea. Brain Res Brain Res Rev 2000; 32: 163-166

Morell RJ, Kim HJ, Hood LJ, Goforth L, Friderici K, Fisher R, Van Camp G, Berlin CI, Oddoux C, Ostrer H, Keats B, Friedman TB. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. New England Journal of Medicine 1998; 339: 1500-1505

White TW, Deans MR, Kelsell DP, Paul DL. Connexin mutations in deafness. Nature. 1998 Aug 13;394(6694):630-1.

Date proposal received: 
Tuesday, 15 December, 2009
Date proposal approved: 
Tuesday, 15 December, 2009
Keywords: 
Genetics, Hearing
Primary keyword: 

B933 - Early life nutrition ages 0-5 and physiological risk adiposity and neurocognitive development at ages 15-16 - 14/12/2009

B number: 
B933
Principal applicant name: 
Dr Rebecca Golley (University of South Australia, Australia)
Co-applicants: 
Dr Lisa Smithers (University of South Australia, Australia), Prof John Lynch (University of South Australia, Australia), Dr Karen Campbell (Deakin University, Australia, ROW), Dr Pauline Emmett (University of Bristol, UK), Dr Kate Northstone (University of Bristol, UK), Prof Andy Ness (University of Bristol, UK), Prof Debbie A Lawlor (University of Bristol, UK)
Title of project: 
Early life nutrition (ages 0-5) and physiological risk, adiposity and neurocognitive development at ages 15-16.
Proposal summary: 

We will examine whether very early life dietary patterns (age 0-3) influence childhood diet (age 5), and whether these patterns affect physiological risk profiles and cognitive performance in middle adolescence. If early life diet confers a risk for poorer physiological profile and cognitive ability in adolescence, then it is important to understand the parent characteristics and practices that influence early life diet quality (see figure 1 in appendix). These parenting factors should then become the targets of intervention in the period from birth to preschool. We have chosen ages 0-3 because it is in this period that the dietary patterns that may track through childhood start to emerge. Parents are also primarily in control of what children consume, with little external influence. This period may present an opportunity to provide more specific dietary advice to parents of infants and toddlers at a 'critical period' for later health and development. ALSPAC can help provide evidence from a high quality cohort on the effect of transition diet on later physiological risk and cognitive development. We will address the following objectives:

1 Characterise and compare methods of dietary characterisation across 0-3 years using principal components, cluster analysis, diet quality scores and single food/nutrient-based approaches

2 Evaluate whether dietary patterns across 0-3 years are related to dietary patterns at 5 years

3 Examine the relationship between different methods of dietary characterisation across 0-3 years and risk factors for chronic disease (obesity, blood pressure, lipids, insulin) at 15 years

4 Examine the relationship between different methods of dietary characterisation across 0-3 years and neurocognitive development and school attainment at 15 years

5 Identify parenting practices and characteristics of parent lifestyle and family structures that predict dietary patterns across 0-3 years.

This proposal is focussed on the role of early life diet on physiological risk factors for chronic disease (including adiposity) and cognitive ability in adolescence, both of which have implications for adult health and wellbeing (1, 2). Diet can be modified to improve disease risk factors in adults (3, 4), but it's not known if diet in the 0-3 year period matters either physiologically or developmentally for later health. However, given that prolonged breast feeding is associated with improved cognitive performance (5) it is plausible that other aspects of early life nutrition may be associated with later physiological and cognitive risk. Additionally, this is a period when parents are motivated to provide a good diet and may reflect a critical window when physiological and developmental risk profiles are 'programmed' with lasting effects into adult life (6).

1. Characterising the emergence of diet from birth to 3 years

In order to look at the association between diet at 0-3 years and later outcomes, we need to be able to characterise diet across this period. Diet is a complex mix of nutrients within a matrix of foods, which interact (7). The combined effect of nutrients and foods can be assessed by looking at dietary patterns, which may be useful for understanding the 'whole-of-diet' influence on disease. A number of methods are available to characterise dietary patterns (7). For example, cluster analysis divides individuals into different groups based on a particular characteristic (e.g. consumption of a food or nutrient). Whereas in factor analysis, individuals' diets are scored according to underlying patterns or 'factors' that explain variation in eating patterns. Neither method is designed to derive patterns that are predictive of disease, which is where diet indices or techniques such as reduced rank regression may be useful. Diet indices also enable assessment of intake against dietary recommendations which aim to promote health. By utilising these methods, the strengths of each method and its specific purpose can be exploited.

Most research involving dietary patterns has been conducted in older children and adults. Dietary research in the 0-3 year period has been dominated by studies on breastfeeding (8-12), weaning or toddler diet quality (9, 13-20), using largely a nutrient (14, 18-21), variety (13, 16) or food group (9, 14, 15, 17, 18) approach. However principal components analysis (PCA) has been used to describe dietary patterns in ALSPAC children between 3 and 9 years (22) and in infancy in the Southampton Women's Survey (23). As a tool, PCA can discern patterns associated with stage of development at 3 years (e.g. 'snacky') but also patterns similar to those characterised in later childhood and adult life (e.g. 'healthy/ prudent' 'junk') (22). Few attempts have been made to characterise dietary patterns, across the 0-3 year period which spans the transition from a milk- to food-based diet. Early life diet has also been characterised using an index based on how well parents adhere to guidelines, either at one point in time (24, 25) or across the infant to toddler diet transition (26). How well these or other methods relate to later diet or longer-term outcomes has not been established.

We plan to compare dietary patterns across 0 to 3 years characterised by cluster analysis, PCA and dietary indices (based on UK dietary guidelines) in the ALSPAC sample. In addition to enabling a direct comparison of methodology in the same sample, we will explore the predictive validity of these methods on physiological and cognitive outcomes (points 2-5 listed below). To our knowledge, comparisons between dietary pattern methods are limited, particularly in child samples, but would be useful in increasing the understanding of when to utilise various dietary pattern methodology.

2. Evaluate whether dietary patterns at 0-3 years are related to dietary patterns at 5 years

The ALSPAC cohort provides evidence that dietary patterns can be characterised from the age of 3 years and that these patterns track to some extent through middle childhood (22). This evidence is consistent with other cohort studies which show intake of nutrients (27, 28), foods (29, 30), food patterns (30) and food preferences (31) track across childhood , adolescence and into adult life (over 6 to 21 years of follow up). The rapid change in diet and learning about eating that occurs between birth and the toddler years may lay the foundation for future eating habits, food preferences and intake patterns (32). Part of our investigation will reveal whether diet in the 0-3 year period is related to diet at 5.

3. Early life diet and risk factors for chronic disease at 15 years

Risk factors for chronic disease, such as high blood pressure, serum lipids and adiposity show evidence of tracking from adolescence through adulthood (1, 33-36). This indicates that measures of risk during adolescence are a reasonable proxy for ascertaining life-long risk of chronic disease. Studies in adults have shown that diet can modify these risk factors and there is preliminary evidence that introducing weaning foods low in saturated fats can lead to reduced serum lipids by age 14 (37). Previous ALSPAC analysis has identified associations between fat and sodium intake in the weaning period, serum cholesterol at 3 years (38) and blood pressure at 7 years (21). Dietary patterns in ALSPAC childhood between 3 and 9 years have also been associated with later obesity (39). This proposal will extend previous ALSPAC analyses by looking at whole-diet across the period 0-3 years on adiposity and physiological risk factors in adolescence.

4. Early life diet and cognitive development and educational attainment at 15 years

Deficiency of specific nutrients (such as iron or iodine) in the postnatal period has permanent effects on cognitive development (40, 41). Rather than studying effects of nutritional deficiencies, emerging research is revealing dietary patterns associated with 'optimal' development. Data from ALSPAC shows that dietary patterns at 3 and 4 years are associated with later school attainment and hyperactivity (42, 43). Similarly, dietary patterns during infancy, when the brain is developing rapidly, suggests that a weaning diet rich in fruit, vegetables and home prepared foods benefit cognitive development at age 4 (44). This finding contradicts feeding guidelines, which emphasise iron-rich weaning foods at 6 months because breast milk is limited in iron. The ALSPAC cohort can help tease out the issue of whether diet between 0-3 years has longer-term effects on cognitive development.

5. The influence of parenting practices and characteristics on early life dietary patterns

While associations between socio-economic position, parental education, age, lifestyle or weight status and early life dietary patterns have been documented (23, 45), the mechanisms underpinning these relationships is less clear. For example, parenting- style, -practices and perceptions of children's diet are likely to influence early life diet quality. Parent decisions that affect the child's diet include the mode and duration of breastfeeding (8, 45), the age of solids introduction (46) as well as the variety, quantity and textures of foods provided (47). Interactions between the parent and child during feeding such as the responsiveness to appetite cues, repeated exposure, controlling and coercive practices, may also influence child diet (32). Whether family structure (e.g. family size, partner status, employment and domestic support) influences early life diet is unknown. There has been little large scale, prospective research in general populations on the role of parent characteristics and practices which shape children's dietary patterns. ALSPAC provides the opportunity to look at this comprehensively.

To date, analysis of ALSPAC data has included dietary assessments from age three or older and some outcomes in middle childhood. Our plan is to evaluate the effect of the earliest dietary exposure on adolescent outcomes.The period between 0-3 years is critical for establishing healthy growth in an under-nourished population (6), it is not known whether the same is true of children from developed countries. Our study will help determine whether dietary interventions should begin in pregnancy and continue through very early in life as a strategy for optimising adult outcomes.

Date proposal received: 
Monday, 14 December, 2009
Date proposal approved: 
Monday, 14 December, 2009
Keywords: 
Diet, Eating Disorder, Neurology, Nutrition
Primary keyword: 

B932 - A Prospective Investigation of the Impact of Timing and Chronicity of Exposure to Parent Conflict on Child Adjustment - 14/12/2009

B number: 
B932
Principal applicant name: 
Dr Amy R Ransom (Emory University, USA)
Co-applicants: 
Prof Stephen Nowicki (Emory University, USA)
Title of project: 
A Prospective Investigation of the Impact of Timing and Chronicity of Exposure to Parent Conflict on Child Adjustment.
Proposal summary: 

There is theoretical and empirical support suggesting exposure to interparental conflict has important implications for child adjustment; however, it is unclear the role other factors may play in mediating or moderating that relationship. Multiple theories hypothesize developmental differences in children's reactions to interparental conflict, but few studies have investigated these differences within a prospective longitudinal design. The purpose of the proposed study is to examine in detail the impact that the timing and chronicity of exposure to interparental conflict has on children's later adjustment difficulties. The effect of these factors will be investigated prospectively in a community sample of more than 6,000 families with varying degrees of interparental conflict and adjustment difficulties. We made three main hypotheses. First, we hypothesize that interparental conflict will positively predict subsequent child adjustment. Second, based on theoretical and empirical support, we hypothesize that children exposed to parent conflict earlier in their development will have worse emotional and behavioral outcomes when compared to children exposed to conflict at later age points. Finally, we predict that children exposed to chronic elevated levels of interparental conflict over the early and middle years of their development will show increased levels of subsequent adjustment problems. In addition, children's gender, nonverbal receptive skill, and locus of control will be examined as potential moderators of the parent conflict-child adjustment association. The results of this study may serve as a step toward a better understanding of how timing and chronicity of exposure to parent conflict impact the relationship between parent conflict and children's adjustment problems.

Date proposal received: 
Monday, 14 December, 2009
Date proposal approved: 
Monday, 14 December, 2009
Keywords: 
ADHD, Behavioural Problems, Parenting
Primary keyword: 

B931 - BIS funding for FE data linkage - 14/12/2009

B number: 
B931
Principal applicant name: 
Dr Charlie Ritchie (Department of Business, Innovation & Skills, Sheffield, UK)
Co-applicants: 
Ms Kerry Humphries (University of Bristol, UK), Mr Andy Boyd (University of Bristol, UK)
Title of project: 
BIS funding for FE data linkage.
Proposal summary: 

The £45,000 will go towards data linkage. The data linkage will focus on Further Education data. BIS have links with the National Pupil Database and the Data Service and can therefore help ALSPAC to get access to the ILR data (Individual Learners Record) that otherwise we wouldn't have access to. This data will follow on from the educational data that we hold already giving us a more complete picture of the young people's educational attainments.

Date proposal received: 
Monday, 14 December, 2009
Date proposal approved: 
Monday, 14 December, 2009
Keywords: 
Data Linkage
Primary keyword: 

B928 - Smoking behaviour and motor performance Original proposal was-Diet and socioeconomic circumstances in and balance ability in childhood - 11/12/2009

B number: 
B928
Principal applicant name: 
Mrs kate Birnie (University of Bristol, UK)
Co-applicants: 
Prof David Gunnell (University of Bristol, UK), Prof Richard Martin (University of Bristol, UK), Prof Yoav Ben-Shlomo (University of Bristol, UK)
Title of project: 
Smoking behaviour and motor performance (Original proposal was-Diet and socioeconomic circumstances in and balance ability in childhood).
Proposal summary: 

ESRC/MRC interdisciplinary postdoctoral fellowship

Title: Lifecourse exposure to socioeconomic circumstances and physical function

Main discipline: Statistics, Methods and Computing

Secondary discipline: Medical Sciences

Applicant: Kate Birnie

Mentor: Professor David Gunnell

Physical function refers to an individual's ability to undertake physical tasks needed for daily living. Measures such as gait speed and balance tests are simple, objective measures of physical function that have also been shown to act as markers of current health and predict subsequent disability and death in older people. The ability to carry out physical performance tests involves muscle strength, agility, speed, balance control and cognitive understanding of what the test requires.

Physical capability, and the body systems on which it depends, shows rapid growth in early life to reach a peak or plateau in young adulthood and declines with age in most people. This research proposal is extends work from my PhD investigating diet and socioeconomic circumstances in childhood and physical function in old age, measured by walking speed and balance ability in the Boyd Orr and Caerphilly studies, supervised by Professors Yoav Ben-Shlomo and Richard Martin. We found, for example, that accumulating socioeconomic disadvantage from childhood to adulthood is associated with worse physical function in old age. Participants who moved from a low socioeconomic position in childhood to a high socioeconomic position in adulthood had walking times that were 3% (95% CI: -2%, 8%) slower than people who had a high socioeconomic position in both periods. Participants who moved from a high socioeconomic position in childhood to a low adulthood socioeconomic position had walking times that were 5% (95% CI: -2%, 12%) slower. People with low socioeconomic position in both childhood and adulthood had walking times that were 10% slower (95% CI: 5%, 16%; P for trend less than 0.001). Higher body mass index was associated with reduced ability to perform the flamingo balance test; a standard deviation increase in midlife body mass index and in old age body mass index was associated with a 4% slower walk time in old age.

To understand the dynamics of poor functioning in old age, we wish to study physical performance in childhood and consider its lifetime determinants; this may offer possibilities for intervention in earlier life to develop and maintain peak levels of performance or to slow its rate of decline with age. Early life factors may influence both the development of biological capital promoting physical capability, and, alongside adult factors, the timing and rate of decline.

There is evidence that early growth and development affect functional measures, such as muscle strength. A hormonal pathway such as variations in insulin / insulin-like growth factor (IGF) levels, could link growth and nutrition in early life with physical function. The IGF system includes two nutritionally-influenced peptides (IGF-I and -II), important regulators of fetal and post-natal growth, and their binding proteins (IGFBP 1 to 6). Both IGF-I and IGF-II increase muscle mass and strength and hence might influence measures of physical function. There is little previous research on this topic.

There is a strong inverse association between smoking behaviour and Parkinson's disease (PD) a neurodegenerative disorder of later life associated with dopamine deficiency. This finding is strong and consistent across different populations where the confounding structures would be expected to be different. It is also seen amongst young onset cases suggesting it cannot be due to selective mortality. Two possibilities remain (a) causal effect of nicotine or smoking products that are neuroprotective; (b) dopamine levels are also associated addictive prone behaviour so tht non-smoking is a crude proxy measure of a pre-clinical susuceptibility to later PD. We can examine whether subtle differences in motor behaviour prior to onset of smoking is associated with initiation and maintenence of smoking in adolesence. Our prior hypothesis is that non-smokers will perform worse after conditioning on other determinants of smoking behaviour.

Data from ALSPAC would be used investigate the following hypotheses; that poor balance/motor ability at ages 7-11 years is associated with:

1. Socioeconomic disadvantage

2. Poor diet and short stature (a marker of poor nutrition during the growing years) in childhood

3. Adiposity in childhood

4. Low IGF-I and IGF-II levels (controlling for IGFBP-2 and IGFBP-3)

5. Non-smokers will have worse pre-smoking motor function.

This work would form part of an ESRC/MRC postdoctoral fellowship to produce publications, disseminate research findings and carry out additional research linked to the PhD. Data from ALSPAC would greatly contribute to the evidence base of lifetime exposures on physical function.

Date proposal received: 
Friday, 11 December, 2009
Date proposal approved: 
Friday, 11 December, 2009
Keywords: 
Alcohol, Drugs, Smoking
Primary keyword: 

B927 - The influence of a variety of environmental exposures on the methylation of cord blood - 10/12/2009

B number: 
B927
Principal applicant name: 
Prof Jean Golding (University of Bristol, UK)
Co-applicants: 
Prof Marcus Pembrey (University of Bristol, UK), Prof Alan Emond (University of Bristol, UK), Prof John Henderson (University of Bristol, UK), Dr Susan Ring (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK), Prof Debbie A Lawlor (University of Bristol, UK)
Title of project: 
The influence of a variety of environmental exposures on the methylation of cord blood.
Proposal summary: 

Aims of the study

The primary aim of this project is to identify the methylation pattern across the genome of cord bloods of children taking part in ALSPAC, and identify how they vary with features of the environment. The environments to be considered include not only the exposures during pregnancy, but also the parental exposures during their own childhood and even that of their parents where available.

Having identified these patterns, the project will be available for a variety of programmes to be funded in the future:

(a) To test the ways in which the methylation patterns in cord blood are associated with health and developmental outcomes measured throughout childhood and adolescence;

(b) To determine how environmental influences between birth and 7 years influence changes in methylation from birth

(c) To assess the differential influences of the two methylation records (birth and at 7) on the childhood outcomes.

Methodology

Currently there are only about 3500 {Sue will update} DNA samples obtained from cord blood. However there are still xxxx white cell pellets from which DNA can be extracted. It is proposed that these pellets be extracted as phase 1 of this project. The funding for this will be included in the proposal.

Once the DNA is available, around 500ng per child will be delivered to the laboratory that will carry out the assays, probably using the new Illumina chip. However, that will very much depend on which genes are included on the chip. The other task for the first year of the project will involve identifying the key genetic variants that need to be included. [N.B. Marcus has suggestions as to who will do the chip assays, but is in Japan at the moment. I will get back to you when he is back]

The methylation patterns will be analysed by statistical experts employed by this project, and linked to the various exposure variables that will have been prepared by JG and team as an exposome. The methylation patterns and the exposome variables will be fully documented and deposited wherever the Exec deems appropriate.

It is envisaged that a number of collaborators will be involved in the initial writing up of the results. The exposures and likely collaborators are listed on the next pages.

Date proposal received: 
Thursday, 10 December, 2009
Date proposal approved: 
Thursday, 10 December, 2009
Keywords: 
Environmental Exposure, Genetics
Primary keyword: 

B926 - Participation in organised sports during childhood and the association with adolescent physical activity - 10/12/2009

B number: 
B926
Principal applicant name: 
Chris Penfold (University of Bath, UK)
Co-applicants: 
Prof Chris Riddoch (University of Bath, UK), Mr Calum Mattocks (University of Bristol, UK), Dr Alex Griffiths (University of Bristol, UK), Prof Kate Tilling (University of Bristol, UK), Dr Sam Leary (University of Bristol, UK), Prof Andy Ness (University of Bristol, UK), Dr Steven Blair (University of South Carolina, Columbia)
Title of project: 
Participation in organised sports during childhood and the association with adolescent physical activity.
Proposal summary: 

Aims:

* The primary aim of this study is to investigate whether organised sports participation during childhood is associated with adolescent PA.

o This study will also investigate whether this association is moderated by parents' levels of PA and the extent to which children are active with siblings.

* The secondary aim of this study is to investigate whether organised sports participation during childhood is associated with change in PA between 12 and 16 years.

Date proposal received: 
Thursday, 10 December, 2009
Date proposal approved: 
Thursday, 10 December, 2009
Keywords: 
Physical Activity, Physical Fitness, Exercise & Fitness
Primary keyword: 

B925 - Genetic influences on stability and change in childhood psychopathology - 04/12/2009

B number: 
B925
Principal applicant name: 
Prof Marcus Munafo (University of Bristol, UK)
Co-applicants: 
Prof Christel Middeldorp (Vrije Universiteit, Amsterdam, Europe), Prof Dorret Boomsma (Vrije Universiteit, Amsterdam, Europe), Dr Beate St. Pourcain (University of Bristol, UK), Prof Barbara Maughan (Institute of Psychiatry, King's College London, UK)
Title of project: 
Genetic influences on stability and change in childhood psychopathology.
Proposal summary: 

The main aim of this study is to provide insight into genetic risk factors influencing the stability of and change in symptoms of psychopathology across childhood and adolescence. This will include the identification of a) symptom clusters and trajectories of change in these clusters over time, and b) genetic risk factors associated with these clusters and trajectories.

The primary discovery sample for these aims will be the Young Netherlands Twin Register. For both the psychometric and genetic results, it is proposed to use the ALSPAC cohort as a replication sample, focusing on DAWBA data at ages 7, 10, 13 and 15 years.

This proposal shares some overlap with ongoing projects, but is distinct due to the focus on symptom clusters rather than diagnostic categories. It is proposed that the project would be complementary to these ongoing projects.

Data will be analyse by factor analysis on separate questionnaire items, followed by a latent class analysis on factor scores. Previous studies have suggested seven syndromes identified on the basis of symptom clusters: anxious depression, withdrawn behaviour, somatic complaints, attention problems, aggressive behaviour, rule-breaking behaviour, and thought problems / intrusive thoughts

Date proposal received: 
Friday, 4 December, 2009
Date proposal approved: 
Friday, 4 December, 2009
Keywords: 
Genetics
Primary keyword: 

B924 - A comparison of the caries risk of prematurely born children and full term children - 03/12/2009

B number: 
B924
Principal applicant name: 
Dr Laura Birch (University of Bristol, UK)
Co-applicants: 
Dr Beth Tucker (University of Bristol, UK), Dr Sam Leary (University of Bristol, UK)
Title of project: 
A comparison of the caries risk of prematurely born children and full term children.
Proposal summary: 

The aim of this study is determine the caries risk in 5year old children born prematurely compared to full-term children. The type of study we will be a retrospective cohort study.

Our project will consist of:

1. A thorough literature search on publications related to our project. From the searches completed already we have found conflicting conclusions. An example of a paper which shows there is a relationship is 'National Pathfinder Survey on children's oral health in Italy: Pattern and Severity of caries disease in 4 year olds. Campus et al: Caries res 2009;43:155-162'. An example of a paper, which shows there isn't a relationship is 'Dental caries in pre-term and low birth-weight children and related factors. Ghasempour et al: J contemp Dent Pract.2009:10.'

2. From the papers collected in the literature search, we can compare how each of the studies were conducted and compare the anaylsis undertaken; and therefore how valid there conclusions are.

3. We will then be able to choose the appropriate confounders.

3. Obtaining the ALSPAC data would allow us to identify our variables, which will also include confounding factors. We would then anaylse the data using logistic regression, adjusting for the confounding variables, using the data package STATA.

4. We would then discuss our results, and draw a conclusion showing our outcome in the context of the existing literature.

Time-permitting we will further our research to investigate gestation as a continuous variable, following a similar outline to above.

Date proposal received: 
Thursday, 3 December, 2009
Date proposal approved: 
Thursday, 3 December, 2009
Keywords: 
Obstetrics, Birth Outcomes
Primary keyword: 

B918 - Is physical activity a protective factor for emotional wellbeing in young people - 03/12/2009

B number: 
B918
Principal applicant name: 
Mrs Sarah Gunn (University of Bristol, UK)
Co-applicants: 
Prof David Gunnell (University of Bristol, UK), Prof Ashley Cooper (University of Bristol, UK)
Title of project: 
Is physical activity a protective factor for emotional wellbeing in young people?
Proposal summary: 

Is physical activity a protective factor for emotional wellbeing in young people?

Background

WHO(1) state that mental health problems are a worldwide public health concern and consequently, promotion of mental health is a key component of UK public health policy(2,3). Foresight(5) recently published a report which has drawn together evidence in this field and provides a framework for further developments.

Mental illness has a long-term impact on people and is a risk factor for mortality and morbidity(5), costing the UK economy £100 billion a year(6). In 2004, 10% of children and young people aged 5-16 years had a clinically diagnosed mental disorder, the majority of which were either emotional (anxiety or depression) or conduct disorders(7). However, many more young people are thought to suffer from poor emotional wellbeing. This was demonstrated in a report by UNICEF(8) in which the UK ranked bottom for children's wellbeing in comparison with North America and 18 European countries. A number of policies have been developed with a specific focus on the health and wellbeing of young people (9-11) and recently, NICE published guidance for promoting social and emotional wellbeing in primary(12) and secondary(13) schools. These key documents clearly demonstrate the need for a focus on improving the emotional wellbeing in young people in the UK.

Knowledge about factors that protect against mental health problems and improve emotional wellbeing in young people is required. There is some evidence of a positive although guarded association between physical activity and emotional health outcomes in adults(14,15), but young people are seldom studied. There are two relevant Cochrane reviews, the first by Larun et al(16) who examined the evidence for physical activity reducing or preventing common mental health disorders (anxiety and depression) amongst children and adolescents. They concluded that there was some evidence for a beneficial effect although the evidence was not robust enough, given the heterogeneity in the populations studied, to draw any conclusions. Ekeland et al(17), in a related Cochrane review, concluded that exercise had positive short-term effects on self-esteem in children and adolescents. However, neither review directly examined the association between physical activity and general emotional wellbeing. Similarly, some longitudinal studies have examined the relationship between depression and physical activity in adolescence(18-20) yet only two have explored the relationship between physical activity and emotional wellbeing(21,22). Predominately, the evidence is based on cross-sectional studies(23-26).

Clear conclusions about the association between physical activity and emotional wellbeing are difficult to make largely due to the use of different definitions and measures of physical activity and failure to investigate the dose-response relationship - the optimal amount and type of physical activity (incorporating information on the frequency, duration and intensity of such activity) to achieve emotional health benefits(27,28). Moreover, there have been a number of terms used to refer to emotional wellbeing (e.g. psychosocial health, mental health) and a range of different self-report questionnaires for measuring emotional wellbeing, which also makes it difficult to compare findings between studies. Furthermore, little is understood about the mechanisms that may underlie an association between physical activity and emotional wellbeing(22).

The proposed analysis will form part of an NIHR doctoral fellowship supervised by Professor Rona Campbell (co-supervised by Professor David Gunnell and Dr Ashley Cooper).

The research will analyse data already collected as part of ALSPAC to address the following aims:

* To determine whether physical activity is a protective factor for emotional wellbeing in young people

* To investigate the dose-response relationship between physical activity and emotional wellbeing in young people

* To determine whether emotional wellbeing is a barrier to physical activity in young people

Hypotheses will be tested through analysis of data from 2000 children in the ALSPAC cohort and 1000 children in the AHEAD cohort. Baseline physical activity was measured in the ALSPAC cohort at 12 years and then at follow-up age 14 then 16 years; AHEAD at 12 years then 15 years. Emotional wellbeing was measured at baseline in ALSPAC at 11 years and then at follow-up age 13 years; AHEAD at 12 years then 15 years.

Outcome data

The primary outcome is total difficulties score as measured by the SDQ (Strengths and Difficulties Questionnaire) http://www.sdqinfo.com/b1.html (29). This scale was selected as it is a valid and reliable instrument suitable for young people aged 11-16 and it can also be completed by parents or teachers (30). The 25 items in the SDQ comprise of 5 scales (emotional symptoms, conduct problems, hyperactivity/inattention, peer relationship problems, and pro-social behaviour) with 5 items in each. A 'total difficulties score' is calculated for the first four sub-scales (range 0-40). A high score (20+) on the total difficulties score can be used to identify those that may have mental health disorders. The 5 sub-scales will also be investigated independent of each other (each sub-scale ranges from 0-10). Child self-reported SDQ data collected from the AHEAD cohort and maternal and teacher reported data from the ALSPAC cohort will be analysed and also compared to explore the quality and content of the SDQ data from different informants.

Exposure data

Accelerometers are objective physical activity measurement devices which provide precision of measurement, as they overcome children's lack of ability to recall and quantify physical activity (31). The Actigraph accelerometer was selected for use with both the ALSPAC and AHEAD cohorts as it has been validated in both children and adolescents. Two main physical activity variables will be derived- total physical activity and time spent in moderate or vigorous physical activity (MVPA). Appropriate cut-points will be used to determine moderate and sedentary levels of activity.

Linear regression analysis (for continuous outcomes) and random effects logistic analysis (for dichotomous outcomes) will be used. Potential confounding factors will be controlled for e.g. age, gender, socio-economic markers and ethnicity in AHEAD and a number of additional confounders available from the ALSPAC data. Gender-specific effects will be formally tested.

In the AHEAD cohort (n=1000), an odds ratio of 1.36 can be detected with 80% power (at 5% significance). ALSPAC will have a minimum of 2000 participants in any analysis (due to a smaller number with physical activity data at 16 years compared to 12 and 14 years). If n=2000, an odds ratio of 1.24 can be detected with 90% power (at 5% significance).

The possibility of using the longitudinal nature of the data more fully can be explored by using repeated measures analyses. The role of e.g. social support as a potential mediator of this association (using number of close friends reported in the ALSPAC data, and peer nominations in the AHEAD data) could be investigated and the potential pathways using path analysis examined.

Date proposal received: 
Thursday, 3 December, 2009
Date proposal approved: 
Thursday, 3 December, 2009
Keywords: 
Diet, Eating disorders, Physical Activity
Primary keyword: 

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