Proposal summaries
B582 - Breastfeeding and Childrens outcomes - 13/11/2007
We are applying to use ALSPAC data as part of a large project for which we will be requesting funding from the ESRC. This project will not focus solely on ALSPAC data, but will also use data from the Millennium Cohort Study (MCS) which has already been made available to us, and the Infant Feeding Survey (IFS). We envisage our project as comprising four sub-projects. Not all of these will make use of ALSPAC data; however. In the proposal below, we include a brief outline of those parts of the project which involve other data sets, as this provides useful context for the investigations which do use ALSPAC.
There is already an extensive literature on the effects of breastfeeding on a number of outcomes: allergy and asthma; developmental delay in children; childhood blood pressure, and many others. There is also a recognition that standard multivariate analytical techniques may overestimate the positive effects of breastfeeding, due to a mother's propensity to breastfeed being correlated with unobservable (or simply unobserved) factors which are themselves associated with favourable child's outcomes. This problem of endogeneity is likely to lead to the effects of breastfeeding being overestimated. This project aims to carry out a causal analysis of the effects of breastfeeding: that is, an analysis which, as far as possible, overcomes the effects of endogeneity.
The ideal data with which to undertake such a causal analysis of the effects of breastfeeding would arise from a large-scale randomised experiment on infant feeding. However, the ethical considerations involved make such an experiment almost inconceivable. In order to study this issue, therefore, researchers must exploit variation in infant feeding patterns arising from other factors. Here, we propose to use two distinct analytical techniques to examine the extent to which estimates of the effects of breastfeeding are biased if one does not account for the endogeneity of the decision to breastfeed; and to attempt to uncover the causal effect of breastfeeding. We propose four inter-related projects, the first two of which examine children's cognitive outcomes, the third of which examines mothers' mental health, and the last of which examines parents' time off work looking after sick children.
1. The effect of breastfeeding on children's cognitive skills, using an Instrumental Variables approach
This project will identify the causal effect of breastfeeding on children's cognitive development, using an instrumental variables approach. The project will use data from the MCS, and will employ as instrument an exogenous variation in breastfeeding rates determined by whether or not the hospital at which a mother gave birth subscribed to the Unicef Baby Friendly Initiative (BFI). Several studies show that breastfeeding rates (initiation and/or duration) are higher in Baby Friendly hospitals. The IV method relies on the assumption that BFI status is exogeous. We believe this is a reasonable assumption: although mothers in the UK are free to choose the hospital at which they want to give birth, in most cases they are restricted in this choice by travel distance.
2. The effect of breastfeeding on children's cognitive skills, using a Propensity Score Matching approach
This project will also examine the relationship between breastfeeding and children's cognitive skills - but it will use a different data set (ALSPAC) and a different analytical technique (Propensity Score Matching, or PSM). This technique is described by Dehejia and Wahba (2002) and others, and has been used extensively in economics to assess causal effects. Using this technique, the analyst generates two samples of individuals who have and who have not undergone a "treatment" (here, breastfeeding), matched on a wide range of characteristics, as well as by their estimated propensity to breastfeed. The difference in outcomes between the two matched groups provides an estimate of the causal effect of breastfeeding. ALSPAC lends itself well to PSM, containing a wealth of data on parents' attitudes to breastfeeding, their prior intentions to breastfeed, and events during and after birth which may affect whether children are eventually breastfed.
The outcome variables on which we propose to focus are as follows:
* Key Stage 1 SATs results (we would like to use KS2 SATs results as well, but understand these are not yet available
* Results of school entrance assessments from the SATs files
* Teacher assessments: the child's ability group (Year 6); the Year 4 maths test; and teacher ratings of children's ability in Year 3.
* Parents' assessments of their children's development - particularly their assessments of vocabulary and other language-related skills - from the parent-completed questionnaires at 15, 24 and 38 months.
3. Breastfeeding and mothers' mental health: A PSM approach
This section would use data from both ALSPAC and the MCS to examine the relationship between breastfeeding and mothers' mental health. Kendall-Tackett (2007) presents evidence that breastfeeding protects against post-natal depression via two mechanisms: reducing stress, and reducing inflammation. We propose to build on this by investigating the relationship between breastfeeding and maternal wellbeing, using the analytical techniques described above to control for the possible endogeneity of the decision to breastfeed, and to identify the causal relationships involved.
In ALSPAC, the outcome variables of interest would be:
* Crown-Crisp Experiential Scores from birth until 33 months, and subscales where available
* Edinburgh Post-Natal Depression Scores from birth until 33 months
* Other indicators of wellbeing and relationship to child (for example, J151, mum has felt unattached to study child, in the mother's questionnaire at 47 months).
4. Breastfeeding and mothers' work: a cost-benefit analysis
There is a considerable body of research looking at the return to work as a determinant of breastfeeding behaviour. Here, we propose to look at the relationship between breastfeeding and mothers' paid work, by allowing for causal effects in both directions. A mother's decision to breastfeed might influence the time at which she chooses to return to work, but recent research has shown that the length of the period of maternity leave may in turn affect decisions about initiation and duration of breastfeeding.
In addition, we propose to examine the effect of breastfeeding on the number of days parents take off work to look after sick children. Existing research shows that breastfed babies are at lower risk of a number of childhood illnesses; we propose to examine whether this translates to the parents of breastfed children taking less time off work to look after sick children. This is not an easy question to address, since data on this aspect are not available in all waves of ALSPAC. However, by combining data on hospital admissions, the number of illnesses (including ear infections and attacks of gastro-enteritis), and the amount of time parents have taken off work to look after children with ear and other general health problems (asked at 33 and 47 months), we may begin to make some informed assumptions about whether breastfeeding has economic benefits by reducing working parents' absenteeism rates and therefore is beneficial for employers as well as mothers and children.
B581 - Phenotypic effects from birth to adolescence of puttative causal genetic variants - 13/11/2007
No outline received
B610 - Investigating the role of a novel fasting glucose varient in fetal growth - 13/11/2007
B583 - Replication attempt of a signal observed in a genome-wide association study for childhood obesity - 09/11/2007
No outline received
B579 - Interaction of FLG and SPINK5 polymorphisms in exczema in children - 09/11/2007
Filaggrin is a barrier protein in the skin. Two common variants of the filaggrin gene were reported by Palmer et al (Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genetics 2006 Apr;38(4):441-6) to be strongly associated with eczema & these findings have been replicated by others, including us. SPINK5 (serine protease inhibitor Kazal-Type5) gene was discovered in association with Netherton Syndrome, a rare disorder that is ubiquitously associated with severe allergy.
Our collaborators have examined the associations of mutations in SPINK5 and FLG with eczema in a German population. The expected strong association between FLG and eczema was found. There appeared to be no strong evidence of a gene-only association of three mutations of SPINK5 and eczema in this cohort but there was evidence of a possible interaction between SPINK5 and FLG in association with eczema (see Appendix). We now wish to extend these observations by applying the same analyses to the data we have collected as part of our ongoing collaboration on FLG and allergis diseases.
The data are already available in a suitable form for analysis (Kate Northstone). THis proposal is to export these data (questionnaire and clinical assessments of eczema from birth to 13 years) to Dr Irvine & Mclean's German colaborators to carry out identical analytical methods to the attached. This will be more effieicient than analysing the data in-house. THe collaborators are willing to sign a confidentialiuty agreement and they will have access to a limited dataset (only that which is requred for this project under usual ALSPAC rules).
The genotyping costs of this project (FLG & SPINK5) have already been borne by the applicants. There are no additional resoucre issues for this project, which is part of an ongoing programme of analyses in collaboration with ALSPAC core personnel (JH, GDS, KN).
B578 - The role of genotype and maternal smoking during pregnancy on offspring smoking initiation - 09/11/2007
We will seek to definitively clarify the relationship between maternal cigarette smoking during pregnancy and subsequent offspring smoking behaviour, and specifically identify any critical risk periods during pregnancy when nicotine exposure is associated with increased risk of offspring smoking.
We will use biochemical validation of smoking and both maternal and offspring genotype to accurately characterise foetal nicotine exposure and validate offspring smoking status, and to determine whether the association of nicotine exposure with subsequent smoking behaviour is explained by, or moderated by transmitted genotype.
We will assess offspring's response to first cigarette to investigate whether any association between foetal nicotine exposure and subsequent smoking behaviour is mediated by sensitivity to nicotine.
Specific research questions:
1. Is there an association between foetal nicotine exposure and subsequent offspring smoking behaviour, in particular initiation?
2. Is variation in nAChR and CYP2A6 genotype associated with subsequent offspring smoking behaviour?
3. Is any observed association between foetal nicotine exposure and offspring smoking explained by transmission of nAChR and CYP2A6 genotypes?
4. Does variation in nAChR and CYP2A6 genotype moderate the association of foetal nicotine exposure and offspring smoking behaviour?
5. Is any association betwee foetal nicotine exposure and/or genotype and subsequent offspring smoking behaviour mediated by subjective response to first cigarette?
Existing Data:
Maternal self-reported smoking status (pregnancy-15 years)
Paternal self-reported smoking status (pregnancy-15 years)
Offspring self-reported smoking status (11-15 years)
Offspring self-report subjective experience of first cigarette (15 years)
Maternal DNA
Offspring DNA
New Data:
Maternal self-reported smoking status (17 years)
Paternal self-reported smoking status (17 years)
Offspring self-reported smoking status (17 years)
Maternal urinary cotinine assay (pregnancy)
Offspring urinary cotinine assay (11-17 years)
B580 - Tonsillectomy for recurrent paediatric tonsillitis - does it work The ALSPAC experience - 06/11/2007
Background:
Debate continues as to the benefit of tonsillectomy. A recent Cochrane review found that there were insufficient trials to fully evaluate the effectiveness of tonsillectomy (1). However, the author of the only studies included in this review stand by their conclusion that tonsillectomy was efficacious in reducing sore throat episodes (1). Furthermore, recent comment from a leading ENT academic asks the pertinent question of the whether the perceived supremacy of this type of review for answering questions related to the use of surgical interventions is justified (2).
Primary question:
Is there a manifest, bias balanced benefit from tonsillectomy versus non-operative management for children with recurrent tonsillitis?
Rationale for using ALSPAC data:
Although there are many studies into the benefit of tonsillectomy, we believe that the ALSPAC database will contain information to add significantly to this debate. Last year there were nearly 30,000 tonsillectomies carried out across England in the 0-14 age group (3). Assuming the national average rate of tonsillectomy applies to the ALSPAC population we expect around 300 tonsillectomies to have been performed on this cohort of children. This study size is comparable with other studies (1).
The incidence of self-reported sore throat is included in the questionnaires, this is the primary outcome that has been previously used to assess benefit of the intervention. However, other outcome measures such as SAT scores and school attendance may be used to demonstrate an association with tonsillectomy. Also, confounders such as socio-economic and smoking status may be examined to balance any potential bias.
Plan of action:
1. We intend to review the ALSPAC database to ascertain the incidence of the exposure variable (tonsillectomy) and the outcome measure (primary being reported sore throat episodes, secondary measures being school attendance/performance).
2. Assess likely bias from confounders between groups.
3. Extract data.
4. Statistical analysis (3. and 4. to be supported by the ALSPAC statistics team, funded by the applicants).
5. Presented locally, regionally and nationally.
6. Publish in the ENT-UK journal (Clinical Otolaryngology).
B584 - Investigating the role of a novel fasting glucose varient in fetal growth - 06/11/2007
No outline received
B575 - Peri pubertal hip geometry in the ALSPAC Cohort - 25/10/2007
Several studies in ALSPAC have revealed significant effects of different factors on bone size as assessed by DXA measurements. Interestingly, effects such as social position persist after adjustment for height, suggesting an influence on bone width (1). This observation is important, since influences on bone width imply that bone shape and geometry are being affected, which may have important implications for the risk of sustaining osteoporotic fractures in later life. Therefore, we are keen to explore potential influences on bone geometry in ALSPAC in more detail.
Initial time constraints in the focus clinics limited the acquisition of all three bone scans (Total body and Hip DXA, and PQCT) mainly due to the unfamilarity of the PQCT scanner, therefore we were limited to using only total body DXA and PQCT. However now the operators have become more familiar with the PQCT scanner the length of time required complete this section has been reduced. Therefore at the end of, and breaks in each clinic session there is now time to perform a unilateral hip DXA scan.
Currently total body DXA scans are being performed, and although total body DXA provides important information about bone density in the body it does not provide any information about the shape and strength of the bone. Other groups are currently measuring physical activity within the cohort and it is postulated that bone adapts to the functional requirements placed upon it. The hip is a key area linking the peripheral and axial skeleton together, and due to the geometric orientation of the hip functional stress and strains are very large, and therefore have the potential to show the greatest adaptation to these stresses and strain.
We are currently investigating the effects of physical activity on bone shape and geometry using pQCT as part of a welcome grant. However pQCT is confined to the use of the peripheral skeleton and we can only measure the tibia. Whilst the information gained from this part of the investigation is important due to the direct measurement of shape and geometry, it can not be used to infer information about the hip. Although hip DXA does not directly measure geometry unlike the pQCT, these parameters can be estimated, therefore we are keen to incorporate this scan into the current clinic, especially as there are no extra associated costs incu
We would like to include a unilateral hip DXA, time permitting, in the densitometry element of the data collection clinic. We are proposing to perform all 3 scans in the Age 17 clinic, and have previously collected information on hip geometry at age 13/14. By collecting hip geometry information at age 15/16 we will be better able to investigate the growth and development of bone whilst the young people are going through puberty, and how this may influence osteoporotic fractures later in life.
Hip DXA uniquely estimates the strength and cross sectional area of the hip, this aspect of bone geometry cannot be obtained via the PQCT or the total body DXA. The hip is commonly associated with osteoporotic fractures later in life and th
B577 - Public Health Consequences of Modifiable Maternal Exposures Offspring Obesity and Cognitive Health in the UK and Brazil - 24/10/2007
Research Programme.The aim of his project is to:
1)Increase the strength of causal inference regarding associations between modifiable maternal exposures (medication and supplement use, diet, smoking, alcohol consumption, physical activity) and offspring obesity, psychological health and cognitive function.
2) Formally compare these associations in a cohort from LMIC (Brazil) and one from HIC (Britain).
I (under the supervision of Professors Davey Smith, Victora, Lawlor, and Drs Lewis and Matijasevich) will implement this utilising:
1) Maternal and child data collected prospectively in the ALSPAC cohort in Britain and Pelotas cohort in Brazil.
2) Using two methods that can provide more robust causal inference regarding effects of maternal intrauterine effects that can be obtained from conventional observational epidemiology approaches11.
a. Comparison of maternal behaviour-offspring outcome associations to paternal behaviour-offspring outcomes. The idea behind this approach is that specific maternal intrauterine effects should result in stronger associations between maternal behaviour-offspring outcome and paternal behaviour-offspring outcome. I have used this approach once in my PhD work12 and would like to develop this relatively novel approach, including more sophisticated statistical modelling (e.g. to account for possible non-paternity further).
b. Use of genetic variants that are related to maternal modifiable exposures as instrumental variables to determine the causal effect of the maternal modifiable exposure. Mendelian randomisation has been proposed as one way of overcoming confounding by utilising the random allocation of alleles from parent to offspring13. Certain genetic variants can be found to affect behaviours e.g. LCT genotype and lactose-containing foods14. Genetic variants such as these can be used as instrumental variables for maternal behaviours, and provide a means for testing an unconfounded and unbiased association with components of offspring health.
ALSPAC. ALSPAC data that would be required for this proposed outline include maternal and paternal questionnaire data on health and behaviours during pregnancy (medication and supplement use, diet, smoking, alcohol) and clinic data in the children relating to size and obesity (BMI, body fat, lean mass, trunk fat etc) as well as psychological measures (depression, anxiety, cognitive function). In addition, genetic data from the DNA samples that are currently being collected in both mothers and children would be required.Pelotas cohort, Brazil.One of the largest and longest running birth cohorts in the developing world, this cohort consists of 5914 infants born in 1982 in the Brazilian city of Pelotas. Follow-up assessments (in varying numbers of children) have been carried out at varying stages of development ranging from at birth, infancy and childhood (age ranges from less than 1 year to 5 years), adolescence (12 to 19 years) and young adulthood (22 to 24 years). A wide range of information is available, including family socioeconomic position, maternal characteristics, maternal health and behaviours in pregnancy, infant perinatal data, environmental factors, infant nutrition, as well as physical and psychological measures in infancy, childhood and adolescence. Similar data is also available in another Pelotas cohort initiated in 1993.DNA samples will be collected in a planned follow up study in 2008.Existing collaborations between ALSPAC and Pelotas.There is enormous potential (given the similarity of design and measurements in the two studies) for scientifically valuable collaborations between these two cohorts, and the two scientific directors (Davey Smith and Victora) are eager to facilitate and support such collaboration. With an award by the Wellcome Trust for Dr Alicia Matijasevich, who works with Professor Victora on the Pelotas cohort to spend six months in Bristol on a project comparing socioeconomic differentials of maternal and childhood outcomes between the two cohorts. I intend to build upon this work in the current proposal and further strengthen collaborations between the two cohorts.
B576 - Dietary patterns in early childhood and IQ - 23/10/2007
There have been several studies showing the effects of vitamin supplementation, nutrient deficiency and recent dietary intake on IQ in children [see 1 for a review]. We have recently shown in the ALSPAC cohort that overall dietary patterns in early childhood are associated with both later child behaviour and school performance [2,3]. There appears to be little known about the long-term effects of early diet (with the exception of infant feeding) on later child cognition, as assessed by IQ. The use of dietary patterns aims to overcome the inherent problems of examining individual food and nutrients associations, namely, the inter-correlations between these foods and nutrients. The proposed analysis provides a novel approach to examining the effects of dietary intake on cognitive development.
A preliminary analyses assessing the effects of childhood dietary patterns on IQ has already performed in order to feed into a grant proposal to be submitted to NIH in Feb 08 by Tomas Paus (Nottingham), a primary aim of which is to evaluate the role of nutrition during the first five years of life on brain structure in adolescence.
At his request, I examined the associations between dietary patterns in early childhood (at ages 3, 4, 7 and 8 years [4,5]) and overall IQ assessed at 8 years of age. Initial results suggest that there may be an effect of overall dietary patterns in childhood and IQ. In particular a 1 SD increase in the 'processed' component score at each age (3, 4, 7 and 8) was associated with a decrease of between 2 and 4 points on the WISC IQ scale, while a 1 SD increase in 'health conscious' component score at each age resulted in a 2 point increase. After adjustment for a limited number of confouding or mediating factors the effect sizes were attenuated, though strong relationships remained the 3-year data; as such further analyses is required to take into account additional factors which may be important after a thorough review of the literature. This will determine whether the observed effects are real or due to residual confounding.
Proposed further anlaysis will include:
1. Examining the verbal and performance components of the WISC;
2. Examining the results of the subtests of the WISC;
3. Further adjustment for other factors, including maternal diet, aspects of which have been shown to be associated with IQ in this sample [6];
4. Using cut-offs for IQ in order to determine the risk of poor performance.
Although this work is unfunded it will be of particular use to the NIH grant and is a natural follow-on to the work constituting my PhD. It will also feed into other funding opportunities to investigate the effects of diet on other cognitive and neuro-developmental outcomes.
B672 - Enviromental determinants of physcial activity - 22/10/2007
B572 - Enviromental determinants of physcial activity - 22/10/2007
B571 - The ontogeny of paranoid delusions - 22/10/2007
No outline received
B467 - Prevalence of antimicrobial resistance in bacteria in healthy humans and identifying risk factors that are contributing to the carriage andpersistence of antimicrobial genes in human - 19/10/2007
No outline received
B573 - Preterm Birth Whole Genome Association Study - 16/10/2007
No outline received
B569 - Genetic and environmental influences on developmental trajectories of alcohol use misuse and related behaviours - 15/10/2007
No outline received
B574 - Variants in the cannabinoid receptor gene and their influence on alcohol and drug consumption - 10/10/2007
The CB1 receptor of the endocannabinoid system is known to modulate the endocrine hypothalamic-peripheral endocrine axes. Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism and drug consumption. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity (Basavarajappa, 2007). Several small studies investigated a potential association between variants on the CNR1 gene and alcohol and/or drug consumption yielding inconsistent results (Herman et al. 2006; Racz et al. 2003; Schmidt et al. 2002; Zhang et al. 2004, Zuo et al. 2007).
We used data from the BWHHS study to evaluate whether two different single nucleotide polymorphisms of the CB1 receptor of the endocannabinoid system (CR1=rs1049353; CR2=rs2023239) are associated with obesity (2 variables), blood measures (9 variables), food intake (22 variables), drug consumption (6 variables) or mood (3 variables). There was no evidence that body mass measures, food intake or mood were related to genetic variants. However the results concerning alcohol and tobacco use are intriguing and merits further clarification.
Methods
Data from the ALSPAC study will be used to evaluate a potential association between variants of the CNR1 gene and alcohol consumption. We will genotype the two SNPs from the previous study (rs1049353; rs2023239) as well as to additional SNPs: rs806368 & rs12720071.The following data from the mother's forty seven month post-natal questionnaire will be investigated: alcoholic drinks (B22), own smoking (F4), passive smoking (D2, F5), drug/cannabis consumption (A3), being currently pregnant (A8).
The data will be analyzed using established statistical methods for genetic studies, primarily via regression models adjusted for potential confounding factors. Potential population admixture will be allowed for in the analysis. Genotyping will be done until end of November. Subsequently the analysis will be performed. The results will published in a scientific journal.
Significance
The ALSPAC study has considerable larger sample size than every other previous study on this topic. This candidate gene study will help to understand the role of the endocannabinoid system in the process of addiction. In addition,the study results are relevant regarding the application effects of cannabinoid (CB1) receptor antagonists. For instance a recent Cochrane review found that Rimobanant is helpful for quitting smoking (Cahill & Ussher, 2007).
B568 - The influence of the enviroment on face shape - 10/10/2007
No outline received
B592 - Predictive Value of Questionnaire Data for Assessing Atopic Status - 06/10/2007
Background: In epidemiological studies, questionnaire data are often used to determine atopic status of participants. When children are study subjects, the information on atopic status is provided by the parents. However, there does not appear to be a literature on the predictive value of a parent's report of allergies. To address this issue, questionnaire data regarding a child's allergy status need to be compared with objective data such as skin prick tests or specific IgE. In addition to obtaining both questionnaire and objective data, the temporal sequence is important for calculating predictive value.
Because of its prospective design, the ALSPAC cohort is ideal for addressing this question. Mothers were asked about their study child's specific allergies at ages 54 months and 81 months. At age 7 years, children attended Focus @7, which included skin prick testing.
Variables related to allergies and allergy symptoms will be used from earlier questionnaires (i.e., 54 months and 81 months) and compared with results of skin prick testing at age 7 years for children who attended the allergy clinic. Wheal size will also be considered. Predictive values of mother's responses at the 54 month and 81 month questionnaires will be calculated. Other variables that may influence a mother's report of child's allergic status will be considered, including mother's self-report of allergy and asthma, paternal allergy and asthma, mother's report of child's asthma, and child's history of wheezing and eczema at younger ages.
Again, I will not need to obtain any variables. All necessary variables were included in the dataset obtained for a project which will be submitted for publication by the end of December, 2007.