Proposal summaries
B750 - PPAR-gamma-2 gene polymorphism Pro12Ala breastfeeding and early growth - 10/12/2008
The aim of the study is to examine the effect of PPAR-gamma-2 gene polymorphism Pro12Ala and early postnatal growth and to see whether the effect is modified by breastfeeding. For this purpose we will require birth weight and postnatal growth data, and PPAR-gamma-2 genotype.
First, we will look at cross-sectional differences of growth characteristics at various ages in both cohorts. Then, will we examine longitudinally differences in growth rate (defined as grams/months) from birth to 5 years (3 years in Generation R) between the genotypes. Finally, we will explore whether there is an interaction effect between breastfeeding duration and genotype on growth characteristics.
B751 - Anxiety and Depression During Pregnancy Measurement Course and Consequences - 09/12/2008
Mental disorders during the perinatal period have serious consequences for women and their offspring. The majority of research on perinatal mental health has focused on the postnatal period and particularly on postnatal depression. Depression and anxiety during pregnancy have been largely neglected despite evidence suggesting symptoms of these disorders are higher during pregnancy than the postnatal period (Evans et al., 2001; Heron et al., 2004; Lee et al., 2007; Ross, Evans, Sellers, & Romach, 2003). Furthermore, research in this area indicates that antenatal depression and anxiety increase the likelihood of postnatal mental health problems (Heron et al., 2004), and are associated with negative offspring outcomes in childhood (Deave, Heron, Evans, & Edmond, 2008; O'Connor, Heron, Glover, & the ALSPAC Study Team, 2002; O'Connor, Heron, Golding, Beveridge, & Glover, 2002; O'Connor, Heron, Golding, Gover, & the ALPAC Study Team, 2003). While existing research highlights the need for increased attention to anxiety and depression experienced during pregnancy, important questions remain. The current proposal seeks to use data from a longitudinal, community-based study, the Avon Longitudinal Study of Parents and Children (ALSPAC; Golding, Pembrey, Jones, & the ALSPAC Study Team, 2001), to investigate the following aims:
Aim 1. To examine the presentation of anxiety during the perinatal period.Analyses will be conducted to examine perinatal anxiety symptoms as measured by a commonly used perinatal depression rating scale, the Edinburgh Postnatal Depression Sale (EPDS), in comparison to the Crown Crisp Experiential Index (CCEI). The proportion of women with clinically significant anxiety symptoms at 18 and 32 weeks gestation and 8 weeks and 8 months postnatally, the contribution of the anxiety subscale to the total EPDS score, and the extent to which antenatal anxiety and depression are comorbid will be investigated. It is hypothesized that the EPDS will reveal patterns of perinatal anxiety that are similar to those previously seen with the CCEI and will be a valid measure of perinatal anxiety.
Aim 2. To assess the impact of antenatal anxiety, antenatal depression, and comorbid antenatal anxiety and depression on alcohol use during pregnancy and postpartum.Analyses drawing upon ALSPAC gestation data will be conducted to determine if women with antenatal anxiety, women with antenatal depression, and women with comorbid antenatal anxiety and depression have increased alcohol use during pregnancy and the postnatal period compared to women with no antenatal anxiety or depression. Antenatal mental health problems are hypothesized to predict increased use of alcohol both during and after pregnancy.
Aim 3. To examine the effects of antenatal anxiety, antenatal depression, and comorbid antenatal anxiety and depression on age 10 child behavioral and emotional problems. Reports from multiple informants (i.e., mothers and teachers) on the Development and Well-Being Assessment (DAWBA) and the Strengths and Difficulties Questionnaire (SDQ) will be included in analyses examining the association between antenatal anxiety, antenatal depression, and comorbid antenatal anxiety and depression and child behavioral and emotional problems at age 10. Antenatal mental health problems are hypothesized to increase risk for behavioral and emotional problems in offspring.
Deave, T., Heron, J., Evans, J., Edmond, A. (2008). The impact of maternal depression in
pregnancy on early child development. British Journal of Obstetrics and Gynaecology, 115, 1043-1051.
Evans, J., Heron, J., Francomb, H., Oke, S., & Golding, J. (2001). Cohort study of depressed
mood during pregnancy and after childbirth. British Medical Journal, 323, 257-260.
Golding, J., Pembrey, M., Jones, R., & the ALSPAC Study Team. (2001). ALSPAC - The Avon
Longitudinal Study of Parents and Children I. Study methodology. Paediatric and Perinatal Epidemiology, 15, 74-87.
Heron, J., O'Connor, T. G., Evans, J., Golding, J., Glover, V., & the ALSPAC Study Team.
(2004). The course of anxiety and depression through pregnancy and the postpartum in a community sample. Journal of Affective Disorders, 80, 65-73.
Lee, A. M., Lam, S. K., Sze Mun Lau, S. M., Chong, C. S., Chui, H. W., & Fong, D. Y. (2007).
Prevalence, course, and risk factors for antenatal anxiety and depression. Obstetrics & Gynecology, 110, 1102-1112.
O'Connor, T. G., Heron, J., Glover, V., & the ALSPAC Study Team. (2002). Antenatal anxiety
predicts child behavioral/emotional problems independently of postnatal depression. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1470-1477.
O'Connor, T. G., Heron, J., Golding, J., Glover, V., & the ALSPAC Study Team. (2003).
Maternal antenatal anxiety and behavioural/emotional problems in children: A test of a programming hypothesis. Journal of Child Psychology and Psychiatry, 44, 1025-1036.
O'Connor, T. G., Heron, J., Golding, J., Beveridge, M., & Glover, V. (2002). Maternal antenatal
anxiety and children's behavioural/emotional problems at 4 years. British Journal of Psychiatry, 180, 502-508.
Ross, L. E., Gilbert Evans, S. E., Sellers, E. M., & Romach, M. K. (2003). Measurement issues
in postpartum depression part 1: Anxiety as a feature of postpartum depression. Archives of Women's Mental Health, 6, 51-57.
B745 - Is a Meditteranean diet in pregnancy associated with childhood atopy and asthma - 04/12/2008
It has been shown in a Menorca birth cohort that scoring higher on the Mediterranean Diet Score [MDS] (1) during pregnancy is protective for persistent and atopic wheeze and atopy at age 6.5 years (2).
In the ALSPAC cohort, dietary patterns in pregnancy using PCA have been obtained (3). We found no association between these patterns and childhood asthma or atopy after adjustment for a wide variety of potential confounding factors (4). However, we have not examined any specific a priori scores.
Given the cultural differences in diet between these two cohorts it will be of interest to see how the two methods of examining dietary patterns compare within the cohorts (PCA and a prior MDS score).
Following discussion it was agreed between MT and KN that PCA would be performed on the Menorca dietary data, while MDS would be applied to the ALSPAC data to further examine the associations with atopy/asthma.
We will therefore calculate a MDS for the ALSPAC mother's during pregnancy and relate these scores to childhood atopy and asthma, as presented in our submitted paper (4). We will treat the MDS as both continuous and categorical (using a low and high score as presented by Chatzi etal (2)).
1. Trichopoulou A, Costacou T, Bamia C et al. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003; 348; 2599-2608.
2. Chatzi L, Torrent M, Romieu I et al. Mediterranean diet in pregnancy is protective for wheeze and atopy in childhood. Thorax 2008; 63: 507-513.
3. Northstone K, Emmett P, Rogers I. Dietary patterns in pregnancy and associations with socio-demographic and lifestyle factors. Eur J Clin Nutr 2008; 62: 471-479.
4. Shaheen S, Northstone K, Newson R, et al. Dietary patterns in pregnancy and respiratory and atopic outcomes in childhood. Submitted.
B743 - The Dynamics of Domestic Violence - 04/12/2008
AIMS
In this project we will seek to map out the dynamic relationships between employment, health and domestic violence using all available relevant information in the ALSPAC data. The data will be analyzed using both generic statistical methods and specialised structural dynamic models. The purpose will be to understand not only the incidence of domestic violence, but also its timing and the causal linkages between violence, health, partnership status, and economic outcomes.
A second aim of the project is to consider the impact of domestic violence on child outcomes. There is evidence that living with violence has health, psychological, behavioural and emotional effects on children (see e.g. Mullender, 2001). However, a challenge in this literature is to separate out the effect of domestic violence from other unobserved family characteristics. For this purpose the ALSPAC data, which is rich in information both with respect to family background and with respect to child outcomes, can provide further insights into the true causal impact of living in a family characterised by abuse. The specific requirements for the project involve information from existing questionnaires. Measures of domestic violence will be based on the repeated question on occurrence of physical (and emotional cruelty) by the partner. However, we will also be making use of available information on health status, partnership status, economic activity. Hence will be making use of information from the questionnaires completed by the mothers (and partners) at all points in time. For the analysis of child outcomes we will be needing information from the child-based questionnaires, the child-completed questionnaires and the schools questionaires.
B744 - Investigating the relationship between symptoms of infection in early life and demographic factors - 30/11/2008
1 Background
Increasing levels of allergic disease amongst children in Westernised countries has lead to proposal of the 'Hygiene Hypothesis' [1, 2]. This suggests that a lack of exposure to common infection in early life leads to an increased risk of atopic sensitisation and allergic disease development. Investigation of the relationship between demographic factors (such as number of siblings, breastfeeding, hygiene levels, day care attendance) and infectious symptoms will lead to greater understanding of the factors that affect the level and type of infectious symptoms experienced in childhood.
Information on the incidence of overall common infection in infants is sparse, most data are collected relating to serious infections resulting in hospitalisation and serious morbidity or mortality. Others concentrate on one very specific, clinically diagnosed infectious disease, for example measles. Data from medical records will underestimate incidence of infections, as they do not include those that don't require a visit to the doctor. The ALSPAC study has collected data on the parental-reported information on various common medical conditions and occurrences that may lead to a visit to the GP including symptoms of infectious disease, accident, fits or wheezing [3]. Questionnaires were sent to parents when the child was 6, 18, 30, 42 and 57 months old with questions on 14 items. Previous research using the ALSPAC data-set has shown that levels of one symptom, cough, did not vary by maternal education but the percentage of those children taken to the GP or given medication decreased with increasing maternal education. The same paper also found children with a larger number of older siblings were more likely to have been reported to have a cough in the first 6 months of life [4]. Further description of the relationship between common infectious symptoms will help to investigate which children are most likely to have such symptoms and their relationship with attendance at the doctor.
2 Study aim and hypotheses
The aim of this research will be to use data collected within the Avon Longitudinal Study of Parents and Children to investigate relationships between reported levels of common infection requiring and not requiring a visit to the GP and demographic, social and environmental factors that may influence infection levels including day care attendance, hygiene practices, siblings and population mixing.
The hypothesis to be studied will be:
Do the number and type of infections reported in early life vary due to demographic factors such as number of siblings, day-care attendance and population mixing?
Within the United Kingdom there are few data available on the prevalence of common infectious symptoms experienced within early life in the general population and therefore little is known as to how well other factors relate them. The work carried out within this project will allow quantitative assessment of the most common infectious symptoms in young children and their relationship with proxy measures of infection used in epidemiology such as day care attendance. It will also allow an investigation into underlying classifications of infectious disease and symptom presentation.
3 Study design
3.1 Data
The work carried out will be using data already collected and available within the ALSPAC cohort. The ALSPAC study has collected data at 6 and 18 months on several symptoms and consultations in children including:
* Diarrhoea
* Vomiting
* Cough
* High temperature
* Snuffles/cold
* Ear ache
* Ear discharge
* Colic
* Rash
Parents then ticked one of the following choices for each symptom: 'yes and saw a doctor', 'yes but did not see a doctor' or 'no did not have'. Those listed above represent symptoms which could be linked to infections.
Information was also collected on the age and sex of other children living in the house when the child was aged 6 months and 18 months. At 15 months a questionnaire was administered including a section on childcare asking who regularly looks after the infant apart from the person completing the questionnaire. The choices were: partner, baby's grandparent, other relative, friend/neighbour, paid person outside the home, paid person in the baby's home, day nursery, other. Also collected were hours per week this occurred and age of the baby in months when it started. Also for each months of the child's life (up to 15 months) a chart is completed giving the number of hours of outside childcare, the person carrying this out and at what place. Residential postcode will be used to link to the 2001 census area in which the child resides and from this information about the area can be collected including population density, deprivation level and population mixing. Other general variables as used in other analyses (maternal age, time of questionnaire delivery, sex of the child etc.) will also be required.
3.2 Statistical analysis
Statistical analysis will be carried out including latent class analysis to investigate whether specific patterns of infectious symptoms are associated with any of the demographic variables recorded. The methods will allow the identification of the relationships between specific symptoms being present in early life and their relationship to different demographic factors e.g. Some demographic factors may be related to having a large number of mild heterogeneous symptoms whereas another may be related to having fewer, more severe infections with a specific symptom present such as a fever. The relationship between demographic factors and the likelihood of a parent taking a child to the doctors or giving the child medication can also be investigated. Previous analyses of symptom check-lists have been carried out using similar methods [5] and such analyses allow the identification of groups of individuals with similar behaviour or patterns of disease [6, 7] - in this case it will be those with similar infections and their relationship to demographic factors.
4 Experience of the research team
We are internationally recognised in the field of childhood cancer epidemiology and specifically current research into population mixing and other infectious measures and their association with childhood leukaemia (PMK/GL). The team have a large amount of experience in statistical analysis of epidemiological data including complex mobile phone record data in case-control studies of adult cancer (SH). Computer systems are already in place to allow the secure storage of data including a secure storage area on the Faculty of Medicine and Health server for keeping electronic data.
Within the Centre for Epidemiology and Biostatistics there are several internationally recognised statisticians specialising in structural equation modelling and the development of latent class analysis methods (Professor Mark Gilthorpe, Dr Yu-Kang Tu, Dr Robert West) and their expertise will be available for consultation on the best methods and use of statistical software.
5 References
1. Bloomfield SF, Stanwell-Smith R, Crevel RW, Pickup J (2006) Too clean, or not too clean: the hygiene hypothesis and home hygiene. Clinical and Experimental Allergy. 36: 402-25.
2. Strachan DP (2000) Family size, infection and atopy: the first decade of the "hygiene hypothesis". Thorax. 55 Suppl 1: S2-10.
3. Hay AD, Heron J, Ness A (2005) The prevalence of symptoms and consultations in pre-school children in the Avon Longitudinal Study of Parents and Children (ALSPAC): a prospective cohort study. Family Practice. 22: 367-74.
4. Dewey CR, Hawkins NS (1998) The relationship between the treatment of cough during early infancy and maternal education level, age and number of other children in the household. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Child Care Health Dev. 24: 217-27.
5. Sacker A, Wiggins RD, Clarke P, Bartley M (2003) Making sense of symptom checklists: a latent class approach to the first 9 years of the British Household Panel Survey. Journal of Public Health Medicine. 25: 215-22.
6. Steffen AD, Glanz K, Wilkens LR (2007) Identifying latent classes of adults at risk for skin cancer based on constitutional risk and sun protection behavior. Cancer Epidemiology, Biomarkers and Prevention. 16: 1422-7.
7. Spycher BD, Silverman M, Brooke AM, Minder CE, Kuehni CE (2008) Distinguishing phenotypes of childhood wheeze and cough using latent class analysis. European Respiratory Journal. 31: 974-81.
B741 - Does the ingestion of contraceptive progestins in breast milk have any harmful consequences for infants and children - 24/11/2008
The Human Reproduction Programme of the World Health Organisation (HRP) produces a series of guidelines relating to sexual and reproductive health including two aiming to improve the quality of care in contraceptive provision; The Medical Eligibility for Contraceptive use (which gives guidance on who can use specific contraceptive methods) and the Selected Practice Recommendations for Contraceptive Use (how to use the available methods safely and effectively). Both are available on the HRP website [1] and both have been updated in 2008.
The Guideline Development Group has struggled with giving guidance on use of hormonal contraceptives by women who are breastfeeding. Since there is good evidence that exogenous estrogens reduce the quantity of breast milk the guideline recommends that all combined hormonal contraceptives (the pill, patch, ring and combined injectable) should not be used at all during the first 6 weeks postpartum and can only be used if no other method is acceptable or available from 6 weeks to 6 months after childbirth. While there is no evidence that progestogen-only methods impair lactation, some group members have suggested that the ingestion of progestins in breast milk may interfere with the development of the brain and liver of neonates and infants. For this reason the guideline also recommends that progestin-only methods are avoided during the first 6 weeks post partum.
Many members of the group responsible for updating the guidelines are uncomfortable with limiting the use of progestin only contraceptives (POC) because the evidence for any harm is extremely limited and of poor quality. There is also very limited research evidence for their being no harm. However hundreds of thousands (perhaps millions) of women in both developed and developing countries have used POC in the early post partum period - in some countries high dose depot injections (Depo Provera(registered trademark) and Norethisterone-enanthate) have been routinely given on the day of delivery and there is no evidence for any serious consequences for neonatal health. An expert group was convened in late October 2008 to consider whether there is any compelling evidence for an effect of progestins in breast milk on development of the brain or liver of neonates and infants. The experts included, among others, a paediatrician and two basic scientists who have done a lot of research on the effect of estrogen and progestogen on the brain - but in rats! While the conclusion of the meeting was that there was no compelling evidence of harm, the experts pointed out that they could not exclude a subtle effect of contraceptive progestogens on behaviour (such as ADHD for example), cognition or even sexuality in later years. So we are stuck with not recommending POC for women during the first 6 weeks postpartum (and logic would ask why, if there could be a harmful effect, is it acceptable to use these methods after 6 weeks when the baby's brain is still developing rapidly).
Of course the chance of a breastfeeding woman conceiving before 6 weeks after delivery is remote. However in many developing countries it is difficult for women to negotiate condom use with their partners, intrauterine devices are rarely available and diaphragms are not used so this leaves not much else for effectively preventing pregnancy and short inter-birth intervals. The long-acting methods of POC give 3-5 years protection from pregnancy (or longer) but the only opportunity to start these methods, since they require a skilled health professional, is missed if the newly delivered mother leaves the place where she had her baby and does not have access to a skilled provider thereafter.
We are aware that the ALSPAC cohort of mothers and infants has collected data on a wide range of outcomes and wonder whether it may be possible to use your data to investigate the effects of contraceptive progestogens ingested in breast milk on infants and children. Breastfeeding women in the UK commonly start using the progestogen-only pill at 28 days after delivery and some who use Depo Provera(registered trademark) may start even earlier.
We are unsure as to whether ALSPAC has collected data on postpartum contraceptive use which is of sufficient detail to cast light on the possible effects on breastfeeding babies and infants (i.e. contraceptive method used and start (and stop) dates. If not there is no point in pursuing this further. If data are sufficiently detailed we would be interested in linking contraceptive use during breastfeeding with any subsequent pathology in the offspring.
1. http://www.who.int/reproductive-health/publications/family_planning.html)
B740 - Adjustment outcomes as a function of receptive nonverbal ability and locus of control orientation - 22/11/2008
The purpose of the propsed study is to use children's receptive nonverbal skill and locus of control orientation at 8 years of age to predict their personal and social adjustment when they are older. It is predicted (1) that children who are deficient in reading emotion in facial expression and tones of voice will develop problems in personal and social adjustment at 10, 13/14 and 15/16 and (2) that the type of problem children develop will depend on their locus of control orientation. If they are poor at reading emotion in faces and voices and internally controlled they will develop internalizing types of problems like anxiety, depression, and low self esteem; if they are externally controlled then they will develop externalizing difficulties such as acting out behaviors, conduct disorders and antisocial problems.
To evaluate these possiblities we would require the following data from the ALSPAC data set.
CONCEPT SPECIFIC MEASURE PERSON SOURCE TIME POINTS
Nonverbal information DANVA (faces/voices) CF CF 8 years
Locus of control PPNSIE CF Ques. 8 years
Separation anxiety DAWBA K Ques. 10 to 15/16
Phobias K Ques. 10 to 15/16
PTSD K Ques. 10 to 15/16
Obsessions/Compul. K Ques. 10 to 15/16
General anxiety K Ques. 10 to 15/16
Depression K Ques. 10 to 15/16
Atten/Activ K Ques. 10 to 15/16
Oppositional beh. K Ques. 10 to 15/16
Conduct problems K Ques. 10 to 15/16
Hyperactivity SDQ K&S Ques 10 to 15/16
Emotional Symptoms SDQ K &S Ques. 10 to 15/16
Conduct problems SDQ K &S Ques. 10 to 15/16
Prosocial behaviours SDQ K & S Ques 10 to 15/16
Antisocial behaviour Antisocial behaviour CF Ques. 10 to 12
Friendships CHAMP CF Ques. 10 to 14
Bullying Wolke et al(2000) CF Ques. 10 to 15/16
Romatic relations SexualActivity Index CF Ques. 10 to 15/16
Self esteem SPPC (Harter) CF Ques. 8 years
Self Image Self Image Profile CF Ques. 14
The above proposed study is based on research that has shown that the inability to read emotion in facial expressions and tones of voice has been found to be related to a wide variety of social difficulties such as lower popularity, lower teacher rated social competence, attention deficit disorder, nonverbal and verbal learning disabilities, externalizing problems and conduct disorder, emotional problems, depression, social anxiety, speech and language impairment, and aggression.The purpose of the present project is to see if children's locus of control orientation will help identify which children develop internalizing and which develop externalizing adjustment difficulties.
Locus of control was chosen because it plays a significant role in children's behavior. Locus of control refers to the connection individuals perceive between their behavior and what happens to them (Rotter, 1966). When they perceive a connection between their efforts and what happens to them, they are called internally controlled. When individuals do not see a connection between what they do and what happens to them, but rather they view what happens to them as the result of luck, fate, chance, or powerful others, they are seen as externally controlled. Whether events are perceived from more internal or external perspectives has been found in literally thousands of studies to be related to an extensive number of important personal, social and academic outcomes (Kalechstein & Nowicki, 1998; Rotter, 1990).
In the present study, we assume that children who are experiencing relationship failures with peers (and perhaps with adults, especially teachers) because of an inability to read emotional cues in facial expressions and tones of voice can view their failures one of two ways through the prism of locus of control. If children are internally controlled (so they believe that what happens to them is due to their efforts and how they behave), then they would be more likely to attribute their interpersonal failures to some aspect of themselves or their own behavior. And if children blame themselves for their interpersonal failures they would be more likely to develop feelings of depression and anxiety and low self-esteem; characteristics usually used to describe internalizing problems.
In contrast, children who are externally controlled (and believe that luck, fate or chance or powerful others determines what happens to them), would be more likely to blame others and not themselves for their interpersonal failures. Consistent with this kind of attribution, externally controlled children would be more likely to become angry and "act out" at those whom they believe are preventing them from attaining social success; characteristics of what have been used to describe externalizing problems.
Thus we are proposing that locus of control will act as a moderator between receptive nonverbal ability and personal and social outcomes gathered by ASLPAC after 8 years of age when nonverbal and locus of control measures were obtained.
We will examine boys and girls separately. Because there is some evidence especially from the preschool period that mothers talk more about sadness and with girls and anger with boys, it is predicted that girls will be better at identifying sadness and boys at identifying anger at age 8 (Adams, Kuebli, Boyle, & Fivush, 1991; Fivush 1991) and may lead girls to develop internalizing and boys externalizing problems.
B742 - Genome-wide association analysis in the Avon Longitudinal Study of Parents and their Offspring - 21/11/2008
The project will involve the genome-wide SNP typing of 6000 ALSPAC children at the CNG Paris on either the Illumina 370K or Illumina 610K SNP chip (depending on costing). If successful, it will mean that the entire cohort of ALSPAC children (for whom DNA is available) will have genome-wide data. The resulting genotypes will be linked with ALSPAC phenotype data and genome-wide association analysis will be performed. Loci showing genome-wide evidence of association (e.g. p less than 5.0 x 10-7) will be followed up in the Raine, Generation R and North Finland birth cohorts depending on the availability of similar phenotype measures. Bristol PIs who are experts in the relevant phenotypic measures will be offered involvement in the analysis, write up, and replication of the findings (e.g. Jon Tobias with the bone mineral density phenotypes).
LOGISTICS:
-Genotyping will be performed by CNG in Paris.
-I will require DNA for genotyping on the Illumina 370K/Illumina 610K platform (which platform is chosen will depend upon cost).
-I will require access to all children's phenotypes contained with the ALSPAC cohort.
B739 - Functional Genomic Variation Among Europeans EUROGENVAR - 21/11/2008
* To produce deep sequence information from eight European population-based biobanks including minority populations, to establish a catalogue of the genetic diversity of the complete human exome+ (all functional regions). The sequence information obtained will be 10-fold deeper than the goal of the 1000 Genomes project (www.1000genomes.org) on European samples, and will sample more regions of Europe.
* To produce a catalogue of known and new exonic CNVs in European populations, using a combination of array-Comparative Genomic Hybridisation (aCGH) in a subset of samples and sequence data in all samples. CNVs mined from sequence data will be extensively validated with aCGH data.
* To produce corresponding CNV and exome+ sequence variation catalogues from samples of European minority populations.
* To use these data to produce a much more detailed characterisation of genetic variation in Europe than available to date. This should result in an informatics platform for the future analysis of both rare and common disorders in European samples, including imputing low frequency coding and other functional sequence variants onto genotyped samples in a population specific manner.
* To provide candidate loci for follow-up association studies for disease end points through large international collaborations
* To produce information on functional variants that influence quantitative traits in different European populations. We aim to contribute to this goal by including the expression data from white cells or lymphocytes from 3300 individuals for which the exome+ sequence is produced (the remaining already have the transcriptomic data of lymphocytes on the same platform). Combining 1) the deep sequence information, revealing SNPs, small indels and CNVs and 2) the aCGH data from 320 individuals to cover more complex genome variation, with 3) the transcriptomics data, we should be able to determine the functional role of the majority of identified exome+ variations in expression and relate these to traits assessed in the cohorts.
* To make the collected anonymised sequencing data accessible to all investigators via the European Genotype Archive (EGA), as openly as possible subject to full ethical protection of the rights and privacy of the participants.
* To spearhead the technology needed to perform large scale sequencing and make methodological details and knowhow accessible to investigators via our website.
* To develop data analysis methods and tools to support accurate and reliable inference of population properties and functional quantitative trait variants from joint sequence, transcriptome and microarray datasets. These will include methodology for joint analysis, correlating our measurements with phenotypic and transcriptomic data.
* To characterize the distribution of rare and common functional sequence and copy number variants across European populations and its implications for the design of next-generation genome-wide genotyping and medical resequecing studies
* To quantify the strength of natural selection operating on different categories of genetic variants in the exome+ (i.e., non-synonymous changes, short indels, regulatory elements) and to predict the functional (i.e., benign, possibly damaging, probably damaging) and evolutionary importance (i.e., neutral, negatively selected, positively selected) of all genetic variants found by the project.
B738 - International Childrens Accelerometry Database ICAD - 18/11/2008
The Objective of this project is to:
1) Pool physical activity data (measured by accelerometry) and associated variables from 14 studies worldwide to create a large, diverse, and contextually rich database
2) Utilise the high level of statistical power to investigate predictors of physical activity and associations with health in a range of population sub-groups (e.g. gender, minorities, socioeconomic groups, urban/rural communities).
3) Use the cultural diversity of the data to generate new models of children's physical activity behaviour, within a 'socio-ecological' framework.
Specific research questions:
1. Levels and patterns of physical activity
a) What are the physical activity levels, patterns and characteristics of children from diverse social, cultural, ethnic and geographical backgrounds?
2. Predictors of physical activity
a) What are the social, cultural, ethnic and geographical predictors of physical activity?
b) What are the personal, social, cultural, ethnic and geographical predictors of different dimensions (e.g. light/moderate/vigorous activity, sustained bouts, sedentary time) and patterns (e.g. daily, weekly, seasonal, active travel, PE/sport) of physical activity?
3. Associations between physical activity and health outcomes
a) What are the dose-response relationships between physical activity levels and a range of health outcomes (e.g. obesity, CVD risk)
b) What are the dose-response relationships between differing dimensions & patterns of physical activity and a range of health outcomes (e.g. obesity, CVD risk)
c) How do these associations vary within age, gender, social, cultural, ethnic and geographical groups?
The pooled database
Datasets have been identified through personal contacts and scrutiny of published literature. Data sources comprise of 14 studies worldwide, including the European Youth Heart Study (EYHS), Personal
and Environmental Associations with Children's Health (PEACH) and Sport, Physical activity
and Eating behaviour: Environmental Determinants in Young people (project SPEEDY). The full age range of the children measured in the 14 studies encompasses the full childhood and adolescent period (4-18 years), with some measurements on young adults (18-21 years). We estimate that data are available on over 28,000 children. When repeat measures from the longitudinal studies are included, the potential total is above 35,000.
Measurement of physical activity:
We will pool raw physical activity data derived from the MTI Actigraph accelerometer, model WAM
7164 (Actigraph LLC, Pensacola, FL) and its various predecessor models, which generate comparable data.
Data pooling procedures:
We expect that although data collection procedures have been consistent across studies, data reduction procedures will have differed. We will therefore wish to obtain raw accelerometer data from each study and apply standard data reduction software. This will create a standardised set of physical activity variables across the full dataset. Data sets have been selected, which fulfil the following criteria:
1) Have used the MTI Actigraph, WAM or GT1M accelerometer.
2) Have obtained a minimum of 3 days of 600 minutes/day of valid recording
3) Can contribute other data, including demographic (e.g. age, gender, ethnicity, socioeconomic position), psychosocial (e.g. self efficacy), anthropometric (e.g. obesity), educational (e.g. school type, attainment), physiological (e.g. fitness), health risk factors (e.g. obesity CVD risk factors), and environmental (e.g. urban/rural, travel to school, local amenities).
All variables will be renamed and re-labelled. Differences in coding structures will be investigated and re-coding performed where appropriate. A technical manual will be created fully describing all variables.
Specific ALSPAC requirements:
From ALSPAC we are requesting raw Actigraph DAT files from Focus 11+, TF2 and TF3, and corresponding anthropometric, fitness, body composition, psychosocial, socio-demographic and enviromental variables for these testing occasions. Limited parental and birth variables will also be requested.
B734 - ALSPAC Substance Use Trajectories - 13/11/2008
Substance use though typically initiated in adolescence is heterogeneous. There are likely to be different patterns or trajectories of substance use which have implications for research on aetiology, prevention, and later outcomes. Specific trajectories of substance use may have different aetiological pathways and maybe more likely to lead to poor adolescent and adult outcomes, which maybe missed if average "values" of substance use are used. Research, therefore, into this area needs to identify the common types of substance use trajectory in order then to test and explore specific hypotheses on aetiology, or on who may benefit or needs to be targeted by prevention activities and the type of intervention that maybe effective, and then to carry these forward into determining their impact on adult substance dependence and other outcomes.
The Avon Longitudinal Study of Parents and Children (ALSPAC) is the largest birth cohort with detailed biological and behavioural data from before birth through till late adolescence in the world. ALSPAC is organised as a resource for the whole scientific community and provides the most detailed phenotypic, genotypic and environmental assessments of parents and their children across the life course of any comparable study available to scientists studying early life influences on health (www.alspac.bris.ac.uk). Approximately 14,000 children along with their parents were recruited to ALSPAC between 1991 and 1992. Since this time these participants have been assessed regularly, mainly through questionnaires and clinics. Since the age of ten years these assessments have included measurement of self-reported substance use (tobacco, alcohol, cannabis and other illicit drugs) and since the age of 15 years these self-reports have been augmented by hair-based toxicology. The current assessment sweep at age 17 years is due to be completed in 2010. Approximately 10,000 ALSPAC participants have DNA stored to allow genotyping, and for 2,000 information from a full genome wide scan is available. Existing ALSPAC support will allow the collection and preliminary processing of data on adolescent substance use at 17, and the drug testing of hair specimens collected at 15 and the future clinic at 17. The current application is for the statistical support necessary to consolidate these data and create an accessible research resource for future secondary analyses by researchers with an interest in drug use and dependence. The value of this resource will be demonstrated through the analysis and identification of trajectories of substance use to age 17, a preliminary genome wide association study in relation to these trajectories, and the identification of key risk and protective factors collected in ALSPAC that are relevant to different hypotheses and their bivariate association with the drug use trajectories. The project has the following aims:
1.) To identify different trajectories of adolescent substance use - both drug specific (i.e. alcohol, tobacco, and cannabis) and an overarching analysis of any adolescent substance use.
2.) To compare and validate self-reported data on selected substances with toxicological evidence based on hair analysis (cannabis, amphetamines, ecstasy, opiates, benzodiazepines, ketamine, methaphetamine) and urinalysis (cotinine)
3.) To create an accessible database of self-reported substance use amongst ALSPAC participants from ages ten to 17 years, including specific trajectories of substance use, and hair analysis.
4.) To compare case participants exhibiting the above phenotypes with study controls in a subset of approximately 2000 study members in whom whole genome scan data are available in order to identify genetic loci of possible influence on trajectories of adolescent substance use in order to inform more detailed genetic investigations.
5.) To identify, collate, and make available information on key predictors, mediating factors, and confounders of substance use collected in ALSPAC including measures of:- social position, family adversity, parental and prenatal substance use, impulsivity (conduct problems and antisocial behaviour), subjective response, peer substance use, depression and anxiety, educational performance, life events, sexual maturation, and neighbourhood.
6.) To provide bivariate analyses of these factors on substance use trajectories in order to support researchers and research clusters test specific hypotheses on causal pathways determining adolescent substance use.
B735 - Motor development in infants and children in relation to body mass index - 12/11/2008
BACKGROUND:
Obesity is a growing problem in the developed world. It is thought to have its roots in rapid growth in infancy and early childhood[i], and is associated with a range of physical and psychosocial problems. Anecdotal evidence suggests that babies with a higher than average weight may experience mild gross motor delay of their developmental attainment. From a biomechanical viewpoint, it seems reasonable to hypothesize that obesity might lead to impairments in motor development, but few studies have investigated this relationship, and results are conflicting. Graf et al. found a small but significant inverse correlation between gross motor performance and BMI in first grade children (boys and girls) (r=-0.164; pless than 0.001). Similarly, in their study of 9415 schoolchildren, Mond et al.[ii] found a significantly higher prevalence of impairment of motor development amongst obese boys as compared to non-obese boys. However, this relationship was not found for girls, and Jones et al.[iii] found no difference in the motor abilities of normal weight and overweight children. The current literature has looked at the effects of obesity in children aged 2-14 years. It has not been possible to determine the direction of effect i.e. whether obesity leads to impairment of motor development or vice versa.
AIMS:
To test the hypothesis that infants with a higher than average weight at 6 months of age take longer to attain their gross motor milestones. To attempt to determine the direction of effect by carrying out analyses using data collected at more than one time point.
[i] Eriksson J, Forsen T et al., Obesity from cradle to grave, Int J Obes Relat Metab Disord, 2003 Jun, 27(6), 722-727
[ii] Mond JM, Stich H et al., Associations between obesity and developmental functioning in preschool children: a population-based study, Int J Obes 2007, 31, 1068-1073
[iii] Jones RA, Okely AD et al., Relationships between weight status and child, parent and community characteristics in preschool children, Int J Pediatr Obes 2008, 26, 1-8
B736 - Associations Of BMI Fat Mass and Lean Mass With Asthma In Childhood Mendelian Randomisation Study - 11/11/2008
Many studies have reported an association between body mass index (BMI) and asthma that is stronger in girls than boys. However, it is difficult to prove the direction of causality. Genomewide association studies have identified a common variant in the FTO gene chromosome 16 that is associated with BMI and, in particular, fat mass. We used a Mendelian Randomization approach to assess evidence for a causal effect of BMI or fat mass on asthma.
A total of 4690 children enrolled in the ALSPAC birth cohort had measures of FTO genotype, BMI at age 7 years, asthma at age 7.5 (defined as a physician diagnosis together with a report of either wheezing or asthma treatment in the last year), and confounding variables. Fat and lean mass were measured at 9 years by dual energy x-ray absorptiometry (DEXA), in 4145 of these children. Associations with fat and lean mass were adjusted for height, height2 and gender. Fat mass was rescaled so that its standard deviation was similar to that for BMI.
There was clear evidence of associations of BMI (OR per kg/m2 1.07 (95% CI 1.02-1.11) and fat mass (OR per 500g 1.08 (1.04-1.13)) with asthma. The association with lean mass was weaker (OR per kg 1.05 (0.99-1.11)). Associations with BMI and lean mass appeared stronger in girls than boys, but the association with fat mass did not differ. BMI and fat mass, but not lean mass, were strongly associated with FTO genotype (Pless than 0.001). However, there was little evidence for an association of FTO with asthma (ORs 0.94 (0.78-1.14) for A:T and 1.19 (0.92,1.53) for A:A compared with T:T).
A Mendelian Randomization test did not support a causal link between asthma and fat mass or BMI. However, given that Mendelian Randomization tests have low power, these results do not exclude a causal effect. The discovery of further genes related to BMI and fat mass may increase the power of the Mendelian Randomization approach.
We therefore would like to investigate nine more BMI related SNPs that are now available in ALSPAC (see details of SNPs below).
B737 - Postdoctoral study of gene-diet interactions on the development of atherosclerosis and osteoporosis - 10/11/2008
This project is a collaboration between GENDI (expanding from the Cardiovascular Risk in Young Finns Study) and ALSPAC. It will be the postdoctoral project of the applicant. The main objective is to study associations of dietary intakes on body weight, body composition and obesity, specifically according to the variants of candidate genes for obesity and/or body composition, such as melanocortin-4 receptor gene MC4R, fat mass and obesity associated-gene FTO and beta3-adrenergic receptor gene ADRbeta3. All these have been suggested to have interaction effects with macronutrient intake on the risk of excessive body fat. The postdoctoral project will take place at the University of Bristol; the applicant will work as a visiting researcher. Her personal funding comes from the Academy of Finland.
Gene-diet interactions in the development of atherosclerosis and osteoporosis (GENDI) is an ongoing consortium project funded in the Academy of Finland programme on Nutrition, Food and Health. The project aims to test and find gene-diet interactions in the development of atherosclerosis and osteoporosis and to obtain new information on the mechanisms and congruencies in the etiology of these diseases. The research expands from the Cardiovascular Risk in Young Finns Study, an ongoing large cohort study in Finland. The first cross-sectional study was performed in 1980, and included 3,596 children and adolescents aged 3 to 18 years. The latest follow-up was carried out in 2007 (n=2,204).
The collaboration between the two projects and their longitudinal data will offer a fruitful environment to achieve the objectives effectively. The genetic data will be combined with cumulative information on nutrition, and these will be related to later anthropometric measurements. The research will be carried out using existing data from ALSPAC and GENDI. From ALSPAC, the use of following data is required:
Dietary data: Food frequency data from age 7 onwards, assessed with questionnaires completed by the child.
Lifestyle data: Information on physical activity from age 7 onwards, assessed with questionnaires completed by the child.
Genetic data: Genotypes of relevant SNPs: MC4R rs17782313 and FTO rs9939609from the children.
Outcome data: Anthropometric data from age 7 onwards, assessed in clinics.
In addition, the applicant will apply for extra funding from the Academy of Finland for new genetic analyses to be performed. If granted, this funding will cover the costs of three SNPs among the ALSPAC offspring cohort. These will include beta3-adrenergic receptor gene ADRbeta3 rs1042714 and two other obesity related SNPs. Also, the applicant will apply from the academy for another EUR 2,500 for data management costs in ALSPAC.
B733 - Inferring Epidemiological Causality using Mendelian Randomisation - 07/11/2008
Public health interest often centres around the causal effect of an exposure on a particular outcome. For ethical, practical, or financial reasons, randomized controlled trials (RCTs) to investigate such an effect may not be possible and inferences must be drawn from observational data. These may be distorted by reverse causation, measurement errors, or the presence of socioeconomic and behavioural confounding factors that are difficult to measure even if known. Mendelian randomization is an instrumental variable (IV) method that permits estimation of the exposure-outcome causal effect in the presence of confounding. The assumptions required, i.e. all variables are continuous and all relationships between variables are linear, are often violated in epidemiological applications where the outcome (e.g. disease status) is typically binary and hence cannot have a linear relationship with the exposure. This is especially relevant to case-control data where the exposure-outcome relationship is usually logistic. The aim of this project is to develop theoretically sound methods for dealing with non-linear models and to investigate the practical implications of weakening, or even violating, some of the more restrictive conditions, given the type of data that we expect to arise in these settings. Theory must inform practice but applications should drive the theoretical investigation. This is not always the case and we view this as one of the main strengths of our proposal.
IV methods for binary outcomes are often used in econometrics to estimate causal effects when the exposure is subject to measurement error. We will investigate the adaptability of these approaches to epidemiological settings. Relevant methods also exist for RCT data when the effect for a particular subgroup is of interest. We will clarify when these are useful in Mendelian randomization applications and what conditions are required. The causal literature has shown that bounds on the average causal effect can be calculated without making restrictive distributional or relational assumptions. We will extend these to measures of casual effect that are more likely in epidemiological settings (e.g. causal odds ratios) and identify the data conditions under which they will be useful in practice. In order to get more precise estimates, data are often combined from different epidemiological studies. This pooling of data raises all the classic issues associated with meta-analysis and existing meta-analytic methods will be extended to take account of these. Finally, models that allow for more complex biological pathways will be developed to cater for multiple exposure and disease endpoints.
B752 - The prevalence of hyperandrogenism in teenage girls developmental origins and association with cardiovascular risk - 06/11/2008
(1) Aim of the project:
Our overall aim is to determine the prevalence of hyperandrogenism (clinical and / or biochemical evidence of androgen excess) in two large cohorts of post-menarchal adolescent girls followed prospectively prenatally and from birth in the UK and Finland. We will determine the extent to which androgen levels are related to early developmental changes (pre natal androgen exposure, early postnatal weight gain), familial factors (maternal history of PCOS) and whether hyperandrogenism is independently associated with cardiovascular risk factors during adolescence.
(2) Objectives:
1. Main objectives:
a. To determine the prevalence of hyperandrogenism in two populations of post-menarchal adolescent girls from the UK and Finland.
b. To explore the nature of the association between serum androgen levels and clinical features of polycystic ovary syndrome (PCOS) such as ovulatory dysfunction and hirsutism in postmenarchal adolescence.
2. Secondary objectives:
a. To determine the relationship between serum androgens at adolescence with early developmental factors (birth weight, cord blood androgen levels, rates of early postnatal weight gain).
b. To determine the relationship between serum androgen levels at adolescence with maternal history of PCOS (irregular periods, hirsutism, sub-fertility) and maternal serum androgens and anti-Mullerian hormone (AMH) levels.
c. To determine the relationship between serum androgens and cardiovascular risk factors at adolescence (lipids, insulin sensitivity, hsCRP, Adiponectin) and whether this is independent of BMI and body fat mass.
d. To use genetic information (including genome-wide scan data available for both cohorts) to make inferences about causal relationships through Mendelian randomisation approaches.
B728 - Adolescent cognition and substance abuse Relationships over time proposal for PhD studentship application - 06/11/2008
Introduction
Relations between cognition and substance abuse in adolescence
A number of studies have indicated that specific aspects of cognitive function may play a role in risk of substance abuse in young people1. For example, studies have reported that children at high risk for substance abuse, who have not yet started using substances (for example, children of substance dependent parents) may have specific cognitive deficits, including lower academic achievement, lower verbal and visuospatial ability, and reduced attention span and executive function. These findings have been extended in adoption studies, in which cognitive impairments were found in children of substance abusing parents, even though these children were adopted at birth and raised in an environment without substance abuse. These findings suggest that potential cognitive impairments that may predispose to later substance abuse may have a biological component and can not be entirely explained by rearing circumstances. Tarter et al. (2004) have hypothesized that cognitive tasks tapping into prefrontal cortex (PFC) dysfunction in particular may contribute to the liability to substance dependence2. However, there is a lack of studies that examine the relationships between cognitive functioning and the development of substance involvement over time, and take account of the influences of other potentially important factors, such as a youngster's personality, behavioural problems and family-related factors.
Personality, behavioural problems and family-related factors
Certain aspects of personality, including impulsivity, sensation-seeking motivation and low locus of control, have been related to increased risk of substance abuse in adolescence. However, few studies have examined how personality and cognition may work in conjunction to increase adolescents' risk of substance abuse. One cross-sectional study, which was limited to girls, reported that personality (i.e., temperament) acted as a mediator in the relation between executive function and substance use in adolescence3. It is however, also conceivable that cognition can act as a mediator in the relationship between personality and risk of substance abuse. In further disentangling these relationships, a longitudinal study design would provide major advantages in resolving the temporal relationships between cognition, personality and the development of substance abuse. Another study found that specific combinations of cognitive impairment and personality (i.e., disinhibition) posed the greatest risk for the development of substance abuse4. It would be important to replicate these findings and extend them by also examining other personality traits, such as sensation seeking and low locus of control. Relationships could first be explored for each trait individually and subsequently for combinations of personality traits. Furthermore, it would be important to take into account other aspects of a youngster's behaviour such as symptoms of conduct disorder and attention-deficit-hyperactivity disorder.
Family-related factors can also play an important role in adolescent substance abuse. For example, it is relatively well-established that young people who have a poor relationship with their parents or are poorly monitored by their parents have increased risk of substance abuse5. Young people's family background can also influence cognitive function. For example, Silveri et al. (2004) reported that parental substance abuse has a pronounced impact on young people's emotional and cognitive development6. Yet, few studies have examined to what extent the relationship between substance abuse and cognitive function in adolescence is influenced by family factors.
Genetic influences
A large literature of family, adoption and twin studies has indicated that genetic influences play a role in substance use and abuse as well as in cognition. Specific genetic variants have been studied in relation to cognitive function and substance abuse. A considerable literature indicates that the neurotransmitter dopamine plays a role in many if not all addictive phenotypes7 as well as in cognitive processes mediated by the PFC8. There has been a flurry of studies examining the role of the COMT gene in executive function. COMT encodes the enzyme catechol-o-methyltransferase (COMT) and is critical for dopamine metabolism in the PFC. For example, a study based on children participating in the ALSPAC study found that the COMT Val158Met polymorphism was associated with IQ as well as executive function (particularly cognitive tasks tapping into PFC function)9, although the effects may be stronger for IQ than for certain specific cognitive tasks10. Studies to date, however, have not tended to take into account potential differences between tasks tapping into affective (or 'hot') versus non-emotional (or 'cold') cognitive processes11. Furthermore, findings to date have largely been limited to the COMT Val158Met polymorphism, while there is evidence that the study of COMT haplotypes may be more promising in accounting for phenotypic variability12;13.
COMT has also been associated with substance abuse, although there are negative findings as well14. Some of the discrepancy may be related to personality, for example, in a sample of polysubstance abusers, the Val158Met polymorphism was found to be associated with addiction through impulsivity or dyscontrol15. When explaining the relations between cognition and substance abuse it will be important to include genetic information. This will contribute towards clarification of these relations and may also provide some insight into the reasons for the underlying discrepancies in genetic studies of substance abuse.
Aims of the proposed study:
We propose to study the relations between cognition and substance use/abuse in a large and representative UK-based sample of adolescents. The specific aims are to:
1. Examine the relations between aspects of cognition, specifically IQ and PFC functioning, and the development of substance involvement over time;
2. Examine the influences of personality, problem behaviour and family-related factors (including relations with parents, parental monitoring and parental substance abuse) on these relationships;
3. Investigate whether genes that have been related to both cognition and substance abuse (e.g., COMT) moderate the association between both phenotypes.
Sample and statistical analysis
The Avon Longitudinal Study of Parents and Children (ALSPAC) is an ongoing UK-based longitudinal study, comprising 14,541 mothers recruited in 1991 who have been followed with their offspring from before birth up to age 16 (www.alspac.ac.uk). DNA samples are available for ~10,000 children and COMT has already been typed in this cohort. Typing of other genes that may play a role in the relationship between cognition and substance abuse is currently taking place.
We would be interested in studying the following variables:
Concept Person Source Timepoints
Substances
Alcohol use Child Child/ parent Childhood/ adolescence
Cigarette use Child Child/ parent Childhood/ adolescence
Cannabis use Child Child/ parent Childhood/ adolescence
Cognition
IQ Child Child Childhood/ adolescence
Verbal ability Child Child Childhood/ adolescence
Working memory Child Child Childhood
Attention Child Clinic Childhood/ adolescence
Executive function Child Clinic Childhood/ adolescence
Inhibition/ impulsivity Child Clinic Childhood/ adolescence
Mediating/ moderating factors
Personality
Temperament Child Parent Childhood
Sensation seeking Child Child Adolescence
Locus of control Child Child Childhood/ adolescence
Family-related variables
Parental substance abuse Parent Parent Childhood/ adolescence
Parent-child relations Child/ Parent Parent/ child Childhood/ adolescence
Parental monitoring Parent Parent/ child Childhood/ adolescence
Child problem behaviour
Conduct problems Child Parent/ child Childhood/ adolescence
Attention-Deficit- Child Parent/ child Childhood/ adolescence
Hyparactivity Problems
Genetic influences
COMT Child
Relations between variables will be evaluated using linear/ logistic regression analysis and path analysis. Latent class analyses will be used to define clusters of cognitive and other variables with different predictive relationships with substance abuse. Latent growth curve modelling will allow the study of predictors of change and individual trajectories over time.
References
1. N. Z. Weinberg, J Am Acad Child Adolesc Psychiatry 36, 1177-86 (1997).
2. R. E. Tarter, L. Kirisci, M. Habeych, M. Reynolds, M. Vanyukov, Drug Alcohol Depend 73, 121-32 (2004).
3. P. R. Giancola and A. C. Mezzich, J Child Psychol Psychiatry 44, 857-66 (2003).
4. L. Kirisci, R. E. Tarter, M. Vanyukov, M. Reynolds, M. Habeych, Drug Alcohol Depend 76, 125-33 (2004).
5. K. H. Shelton et al., (In Press (J Youth Adolesc)).
6. M. M. Silveri , G. K. Tzilos, P. J. Pimentel, D. A. Yurgelun-Todd, Ann N Y Acad Sci 1021, 363-70 (2004).
7. A. I. Leshner and G. F. Koob, Proc Assoc Am Physicians 111, 99-108 (1999).
8. E. M. Tunbridge, P. J. Harrison, D. R. Weinberger, Biol Psychiatry 60, 141-51 (2006).
9. J. H. Barnett et al., Am J Psychiatry 164, 142-9 (2007).
10. J. H. Barnett, L. Scoriels, M. R. Munafo, Biol Psychiatry 64, 137-44 (2008).
11. A. Kerr and P. D. Zelazo, Brain Cogn 55, 148-57 (2004).
12. S. Shifman et al., Am J Hum Genet 71, (2002).
13. A. G. Nackley et al., Science 314, 1930-3 (2006).
14. M. B. van den Bree, Curr Psychiatry Rep 7, 125-32 (2005).
15. D. J. Vandenbergh, L. A. Rodriguez, I. T. Miller, G. R. Uhl, H. M. Lachman, Am J Med Genet 74, 439-42 (1997).
B732 - Follow-up analysis of signals associated with early developmental traits ALSPAC GWAS within the complete ALSPAC cohort - 05/11/2008
The aim of this proposal is to perform follow-up genotyping of the top associated signals associated with early developmental traits within the remaining ALSPAC sample in order to replicate findings from the original ALSPAC genome-wide analysis. The signal at each respective locus will be represented through 1-2 common SNPs identified from the original ALSPAC genomewide association testing in conjunction with bioinformatics analysis. The selected SNPs will also be subjected to further analysis in other large birth cohorts.
B731 - Modelling Obesity Through Simulation MOTS - 05/11/2008
Childhood overweight and obesity has emerged as an epidemic. In 2003-2004, over 33% of US children and adolescents were overweight or obese, and over 17% were obese. As the cohort born since 1980 moves into adulthood and middle age, we will see increasing incidence of diabetes, heart disease, kidney failure, and related metabolic disorders. Considerable research effort has been expended to identify the causes of childhood obesity, a necessary first step in suggesting potential prevention strategies to mitigate or reverse this growing problem. However, to date only particular subsets of the problem have been addressed.
Some of the identified factors related to obesity are clearly nested within others. For example, characteristics of the built environment vary by race-ethnicity, and obesigenic factors are more prevalent in disadvantaged communities; this may increase the risk of obesity and low physical activity levels in children. Likewise, metabolic processes are nested within individuals, who are further located within neighborhoods; as a result, insulin resistance may also follow proximity to healthy neighborhoods and their amenities.
Disentangling the web of causation of childhood obesity is a formidable task, and both available data and standard epidemiologic analyses may be inadequate to capture multiple and interacting levels of causation. Furthermore, the presence of feedback loops precludes standard approaches to causality, which are based on acyclicity and SUTVA assumptions. For example, obese children are more likely to be socially isolated, spending more time watching television, and less time engaged in sports and clubs than non-obese children. Causality is difficult to assess in this situation: obese children may be shunned by peers, making them more likely to spend isolated recreation time watching television, and less likely to participate in sports and clubs. Alternatively, participation in clubs and sports may prevent obesity by giving children opportunities for social interaction and physical activity.
In response to RFA-HD-08-023 (Innovative Computational and Statistical Methodologies for the Design and Analysis of Multilevel Studies on Childhood Obesity), we propose a novel multilevel study design and analysis plan to address this problem. In particular, we propose a three-stage strategy based on simulation, confirmation, and manipulation.
We propose the following specific aims:
1. Generate a series of simulated datasets based on knowledge obtained from the literature.
The simulations will be created using both a statistical simulation approache and an agent-based modeling approach, whereby social interactions follow explicit rules. The characteristics [heterogeneity] of individuals and environments will be specified using existing literature. We will focus on the following levels:
(1) Proximal determinants of obesity, which are in feedback and through which other determinants operate.
* Energy expenditure, which is a weakly correlated, negative, and linear determinant of adiposity
* Energy intake, which is a strongly correlated, positive, and nonlinear determinant of adiposity
* Energy expenditure and intake jointly determine BMI through complex feedback
(2) Distal demographic determinants of energy intake and expenditure:
* Household income, parental education level, gender, and race-ethnicity
(3) Family/household behavioral and biologic characteristics of energy intake and expenditure.
* Preparing meals at home; eating meals together; parental adiposity; genetic factors (e.g., FTO)
(4) Social network characteristics as they relate to energy intake and expenditure
* Homophily: on race, gender, parental education, adiposity; centrality, prestige
* Network formation: p* models for obesity as an explanation of friendship; sport/club affiliation
(5) Characteristics of neighborhood
* SES, school funding, and the built environment (supermarkets, fast food, and recreation outlets)
Characteristics 3 through 5 will further incorporate rules of social interaction between heterogeneous agents with each other and with the social and build environments. Institutions may themselves be agents. In order to be realistic, the construction of these simulated datasets will require a thorough understanding of the mechanisms and processes by which obesity and obesegenic environments are produced, not merely an ability to predict the shape of the obesity outcome.
2. Test the agreement between the simulated models and actual (observed) patterns of obesity.
Tests will be against available data, based on the characteristics cited in Aim 1, as well as overall U.S. and regional overweight and obesity rates. Data will come from the literature as well as representative datasets (NHANES, Add Health, ALSPAC). Tests must be limited to what data are available; ALSPAC will be used primarily to understand the longitudinal dynamics of obesity, while Add Health will focus on the role of social networks. Agreement between the regression-based and agent-based models may indicate that agent-based models are unnecessary.
3. Perform pseudo-experiments using the simulated data that manipulate individual characteristics and/or rules of agent interaction.
The true significance of simulated data comes not only from demonstrating how properly specified properties and rules create realistic patterns of obesity, but in the ability to artificially manipulate these properties and rules to provide counterfactual contrasts. We may then ask questions that are impossible to answer (or would yield implausible results) using the traditional multilevel approach, e.g.: what would be the effect on childhood eating habits of adding a supermarket to a "food desert", or eliminating the stigmatizing effects of overweight on friendship formation and club participation?
A related approach involves the application of structural equation models to the simulated and longitudinal datasets (ALSPAC, Add Health). [Palloni's Monte Carlo method for SEM]
We note that only existing ALSPAC data will be used for the proposed work; there is no need for further data collection.
B702 - Follow-up analysis of signals associated with language comprehension ALSPAC GWAS within the complete ALSPAC sample - 05/11/2008
The aim of this proposal is to perform follow-up genotyping of the top associated, listening language comprehension related SNPs within the remaining ALSPAC sample in order to replicate findings from the original ALSPAC genome-wide analysis. The signal at the candidate locus will be represented through common SNPs (r2 less than 0.6; N <= 5) identified from the original ALSPAC genomewide association testing in conjunction with bioinformatics analysis. The selected SNPs will also be subjected to further analysis in another large birth cohort.
No other GWAS on listening language comprehension has been published yet. The recognition and analysis of reliable genetic associates of listening language comprehension in the ALSPAC cohort marks therefore a crucial step towards the identification of biological correlates underlying complex neurocognitive processes such as the understanding of the human language.