Proposal summaries
B1259 - Prediction and prevention of poor condition at birth - 24/11/2011
Aims: The aim of this body of work is to develop a greater understanding of which infants are born needing support after birth and identify high risk infants who may benefit from interventions or changes in practice. This project also aims to provide greater understanding of these risks for women, from which they can make informed choices for their own births.
To do this we anticipate three components to the project:
1) Modeling of birth condition.
2) Gene polymorphisms
3) Placental examination
A final analysis will be designed after the 3 components are complete whereby a comprehensive model of poor condition at birth is derived.
Summary of proposed project: Through these three arms we hope to understand the processes through which infants are likely to be born in poor condition, and identify points at which the risk could be reduced or prevented.
B1251 - Gene -Environment Interactions and Childrens Reading and Language Skills - 24/11/2011
Aims: The aim of this project is to further develop the small literiture on such Gene*Environment interactions with reference to children's language and literacy skills. Hypotheses and research questions:Our goal is to establish whether the bioecological or diathesis-stress model holds in the context of children's language and literacy skills. In other words, is the association between genotype and children's outcomes stronger for those from enriched or deprived environments? One of the key contributions that we intend to make is through our thorough consideration of what constitutes "rich" and "deprived" environments with respect to children's reading and language skills, drawing upon evidence from educational research. Accurately defining this concept is critical to testing the validity of the bio-ecological versus the diathesis stress hypotheses. This issue has, however, thus far received relatively little attention in the literature.
Research question 1: Is the association between the genetic markers and children's language and literacy skills strongest for those children in particularly enriched or deprvied home environments? Research question 2: What are the factors that mediate the relationship between the genetic marker, children's home environment and their language and literacy skills? Research question 3: Is there an association between the genetic markers and the rate of change in children's test scores between the ages of 5 and 16? Does this depend on children's home environment?
B1266 - Antecedents and correlates of adolescent gambling behaviour at age 17 - 10/11/2011
Aims: To assess the association between gambling behaviours and other risk taking behaviours at age 17; To examine the extend to which these potential associations can be explained by the young person's/parental socio-demographic background characteristics, childhood antecedents such as hyperactivity and conduct disorders and parental gambling patterns.
Outcome variables: - Frequency of gambling (>= weekly)- Scope of gambling (4 or more gambling activites in the previous 12 months)- Problem gambling (Problem Gambling Severity Index score) .
Exposure variables:- Nicotine dependence (Fagerstrom Test of Nicotine Dependence)- Problematic Alcohol use (AUDIT scale)- Problematic cannabis use (CAST scale)- Inhalant use- Harder drug use- Sexual risk behaviour- Antisocial behaviour.
Variables proposed to be examined as potential mediating variables or confounders: - Socio-economic indicators - Gender- Ethnicity- Maternal alcohol, smoking and substance use- aternal depression (antenatal, postnatal)- Hyperactivity and conduct problems (SDQ) - Depressive symptoms or other indicators of mental health in YP- Parental monitoring- Parental gambling patterns- Stressful life events since age 12 (YP).
B1265 - Brain structure function and associated outcomes in young adults born late-preterm - 10/11/2011
This work will be part of a programme of research investigating neurocognitive, developmental and school performance outcomes in children born late preterm without significant neonatal medical problems or interventions.
Aims: To investigate differences in brain structure and function in young adults born late-preterm (32-36 weeks gestation), compared to those born at term. To investigate functional outcomes among children born late-preterm, including school attainment and measures of impulsivity and attention. To investigate correlations between imaging findings and outcomes from psychometric testing and questionnaires.
Outcome variables:Further analysis of school attainment will be carried out on Key Stage 2, 3 and 4 results, extending the previous work looking at Key Stage 1 results. Psychometric measures from ALSPAC clinics, such as the 'Stop-Signal' task will be compared between those born late-preterm and term. Other measures of impulsivity, such as the Strengths and Difficulties Questionnaire, measured at several time points within ALSPAC, will be examined.
We wish to recall a subgroup of ALSPAC participants who were born late-preterm (n=60), and a control group born at term (n=60), and carry out MRI brain imaging. This will involve three different resting state scans: a) structural brain imaging, b) diffusion tensor imaging, c) resting functional MRI.
B1263 - The clustered world - are the properties of genetic variants really suitable for instrumental variable analysis - 10/11/2011
Aims: The aim of this project is to comprehensively assess the properties of genomic variation in light of their use for Mendelian Randomisation. It will follow on from research conducted by Davey-Smith et al (2007, PLoS Med) using Genome-wide data that was outside the scope of the paper when it was published. For more information see 'Justification' section.
Hypotheses: We hypothesise that clinic variables taken at any one age will show high levels of correlation (greater than would be expected by chance). In contrast, one would not expect the same inter-correlations to exist either within a collection of genotypic data or across genetic variation and randomly selected phenotype data.
Exposure, outcome and confounding variables: This is not an association study for risk, per se, rather an assessment of the properties of genetic and phenotypic data. As such there will be no outcomes and exposures.
Data: The data that is required for this study will be all that is contained within a "standard" ALSPAC clinic assessment at around age 7 year along with genome-wide common variation for individuals found within that clinic.
B1231 - Intergenerational Transmisson of Mental Health - 10/11/2011
Firstly, we want to investigate the hypothesis of an intergenerational transmission of mental health disorders from parents to children once genetics are controlled for. Secondly, we want to document the potential existence of income ingradient in child's mental health. Hypotheses: (i) children's psychological health is indeed determined by parents' genetic characteristics, social conduct and socio-economisc status; (ii) being stronger the trasmission that takes places from mother to child rather than through the father; and (iii), there is an income gradient in child's mental health and it gets steeper with age. The variables we are interested in refer to measures of health status, physical health, mental health indicators and development of parents and child, and the confounding variables include age gender, economic status, education, occupation, and location primarily.
Our main milestone is to be able to produce scientific evidence that will contribute to the economics and social policy debate that is in the search of a clear proof that individuals' preferences are not choosen but shaped by parental charactiristics, i.e. mental health status, and especially mothers' emotional health state at the time of conception and afterwards. This type of research has important implications for health and social policy, where well being indicators play a crucial role.
B1262 - A Mendelian Randomisation Study of Iron Status ADHD and IQ - 27/10/2011
Aims: Iron deficiency has been associated with ADHD and low IQ in epidemiological studies (Froehlich et al., 2011), but this association is likely to be confounded with social class and other demographic variables and health behaviours. Our aim is to use Mendelian randomization to test the hypothesis that iron deficiency is a causal risk factor for ADHD and low IQ. A number of genotypes have shown replicated associations with serum transferrin and/or soluble serum transferrin and related phenotypes (Benyamin et al., 2009; Kamatani et al., 2010; McLaren et al., 2011; Oexle et al., 2011; Pichler et al., 2011) and could be used as instruments for iron status. Although our focus is on ADHD and IQ, we are requesting a broader set of outcome variables that represent related phenotypes (e.g., motor and language abilities, conduct problems).
Hypotheses: We hypothesise that if iron deficiency is a causal risk factor for ADHD and low IQ, then (1) selected gene variants will be associated (in predicted directions) with haemoglobin levels (measured at 8, 12, 18, 31, 43, 61 months and 7 yrs) and/or serum ferritin levels (measured at 8, 12, 18 months); (2) haemoglobin levels (measured at 8, 12, 18, 31, 43, 61 months and 7 years) and serum ferritin levels (measured at 8, 12, 18 months) will be associated with ADHD symptom scores, clinically-signficant levels of ADHD and IQ scores (measured from 7 to 10 yrs); and (3) selected genotypes will be associated with ADHD symptom scores, clinically-significant levels of ADHD, and IQ scores.
Exposure variables: serum ferritin (8, 12, 18 months), haemoglobin (8, 12, 18, 31, 43, 61 months and 7 years), HFE C282Y (rs1800562); TMPRSS6 (rs855791), PCSK7 (rs236918), TF (rs3811647)
Outcome variables: We propose to look at variables in early childhood and later childhood capturing IQ (e.g., WISC, WPPSI), externalizing problem behaviours (e.g., DAWBA ADHD and conduct disorder scores, SDQ scores), attentional problems, motor ability, and language ability.
Confounding variables: We are aware that previous ALSPAC publications have reported associations between demographic variables (e.g., maternal education) and serum ferritin and haemoglobin levels at 18 months (Sherrif et al., 1999). We are requesting the measure of maternal education so as to replicate the association with haemoglobin levels at 7 years (for the purpose of justifying, in part, the need to use MR). We are also requesting gestational age, child sex, child ethnicity, birth weight, childhood weight & height (8, 12, 18, 31, 43, 61 mos; 7 years), recent infection status, child iron supplements (up to 10 yrs), iron in diet (8, 18, 43, 61 mos; 7 & 10 yrs).
Note: We are aware of ALSPAC publications looking at the relationship between Hb and ferritin with neurodevelopmental outcomes in early childhood (e.g., locomotor activity; Sherriff et al., 2001), but not with outcomes in later childhood. If the associations between iron status and later childhood outcomes have already been examined and found to be non-significant, then we would not want to take this application forward.
References
Benyamin, B., McRae, A. E., Zhu, G., Gordon, S., Henders, A. K., Palotie, A. et al. (2009). Variants in TF and HFE explain ~40% of genetic variation in serum-transferrin levels. American Journal of Human Genetics, 84, 60-65.
Froehlich, T. E., Anixt, J. S., Loe, I. M., Chirdkiatgumchai, V., Kuan, L., & Gilman, R. C. (2011). Update on environmental risk factors for attention-deficit/hyperactivity disorder. Current Psychiatry Reports, 13, 333-344.
Kamatani, Y., Matsuda, K., Okada, Y., Kubo, M., Hosono, N., Daigo, Y. et al. (2010). Genome-wide association study of hematological and biochemical traits in a Japanese population. Nature Genetics, 42, 210-U25.
McLaren, C. E., Garner, C. P., Constantine, C. C., McLachlan, S., Vulpe, C. D., Snively, B. M. et al. (2011). Genome-wide association study identifies genetic loci associated with iron deficiency. Plos One, 6.
Oexle, K., Ried, J. S., Hicks, A. A., Tanaka, T., Hayward, C., Bruegel, M. et al. (2011). Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels. Human Molecular Genetics, 20, 1042-1047.
Pichler, I., Minelli, C., Sanna, S., Tanaka, T., Schwienbacher, C., Naitza, S. et al. (2011). Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. Human Molecular Genetics, 20, 1232-1240.
B1261 - Causal inference of cannabis and tobacco with education variables within ALSPAC - 27/10/2011
Substance abuse has been shown to be associated with reduced academic attainment, anti-social behaviour and psychological health problems, although the causal pathway for this association has not been appropriately established. Causal inference for substance abuse has to be determined to discover the reason why it is such a common place problem, allowing us to understand what environmental factors precedes and proceeds the abuse of substances in a causal chain. Within the literature there are several schools of thought for the causal inference between substance use and education variables. These are a direct cause between substance abuse and education, either as the use of substances effects education or that academic underachievers are more likely to use substances15. The other school of thought is that there is an indirect cause, perhaps academic underachievement and substance abuse is a common syndrome of problem behaviours4. The main problem the literature has with defining causal inferences between substances and academics is the problems with uncontrolled confounding1. Confounding may be underestimated or perhaps not taken in to account (such as genetics).
The overall aim for this research is to evaluate causal inference using different statistical techniques and culminating in a Mendelian Randomisation approach to reduce the effect of confounding to infer causation between education and substance abuse.
B1245 - The relation of prenatal psychosocial stress with the childs cardiovascular biomarkers and vascular function - 27/10/2011
AIMS: At this time, we aim to 1) study the association between prenatal psychosocial stress and BP in the child in another cohort, 2) study whether the timing of stress indicates a more vulnerable period for programming of BP and 2) study whether the potential higher blood pressure is accompanied by impaired vascular function and alterations in lipid and inflammation markers that would be indicative of a more general cardiometabolic disturbance.
HYPOTHESES: 1) The presence of maternal psychosocial stress is associated with higher systolic and diastolic BP in the offspring. 2) First trimester stress exceeds third trimester stress effects on offspring BP. 3) The presence of maternal psychosocial stress is associated with impaired vascular function and alternations in lipid and inflammation markers in the offspring.
OUTCOME VARIABLES: - Blood-based assays in children at the mean age of 9.9 years. * Lipid markers: high density lipoprotein cholesterol (HDLc); non-high density lipoprotein cholesterol (N-HDLc); triglycerides. * Markers of inflammation: C-reactive protein; interleukin-6 (IL-6). * Apolipoproteins: Apolipoprotein A1 (ApoA1); apolipoprotein B (ApoB). - Vascular measurements in children at the mean age of 10.7 years.Systolic blood pressure (SBP); diastolic blood pressure (DBP); flow-mediated dilatation (FMD); pulse wave velocity (PWV); distensibility coefficient (DC); brachial diameter (BD)
B1257 - Exposome Noise and air pollution in European cohort studies ENACT - 13/10/2011
AIM: The aim of this four year EU project is to analyse existing large cohort studies, with appropriate data already available on air pollution and other relevant risk factors, and to supplement with environmental data on environmental noise exposure. The specific workpackage outlined below relates to a workpackage on Cognition, being managed by Clark, which aims to examine associations between both air pollution and environmental noise exposure on children's cognitive abilities.
HYPOTHESES: This study would link environmental stressors (air pollution & environmental noise exposure) and educational outcome data from the ALSPAC databases, to examine both cross-sectional and longitudinal associations where possible. The following questions would be examined: 1.Is air pollution associated with poorer cognitive abilities? 2. Is noise exposure associated with poorer cognitive abilities? 3. Do any significant effects remain, after taking the co-exposure into account? 4. Is there an interaction effect of air pollution and noise exposure on children's cognitive abilities?
B1256 - An obesogenic dietary pattern and cardiovascular risk factors in ALSPAC - 13/10/2011
AIMS:
Examine longitudinal relationships between an obesogenic and other hypothesis-driven dietary patterns and early markers of CVD risk.
B1255 - Childhood neurodevelopmental factors and risk of psychotic-like symptoms in 12-year-olds genetic variation and development - 06/10/2011
Paper 1: Childhood Literacy skills and psychotic-like-symptoms in a non-clinical population at 12 years of age. (1) Are here any associations between the selected literacy skills (language and speech functioning domains) of a child at ages 7, 8, 9, 10, and PLIKS (interview) at the age of 13 in the ALSPAC cohort? (2) What are the significant predictors of PLIKS after adjustment for confounding variables if there is any? (3) Are any associations stronger with stricter definitions of PLIKS?
Paper 2: Childhood literacy, neurocognition, , motor functioning and psychotic-like-symptoms trajectories in a non-clinical population. (1) Are there any significant associations of literacy variables, neurocognitive variables and motor functioning with PLIKS trajectories? (2) Out of (a) literacy variables, (b) neurocognitive variables, and (c) motor skills, what are the significant predictor variables of PLIKS trajectories?
Paper 3: Genetic variation and childhood social cognition, neurocognitive functioning as predictors of psychotic-like symptoms . Aim: examine the joint relationship between two exposure variables, (a) child genotype and (b) social cognition, neurocognition in the prediction of PLIKS (mean age 12.9). specifically, the purpose is to examine the prediction of PLIKS at age 12 as a function of (a) social cognition measures, (b) neurocognition measures, and (c) genetic variation.
B1254 - Gene-environment interactions with growth rate in myopia - 06/10/2011
Aim: To investigate whether myopia is associated with a gene-environment interaction with environmental factors related to growth rate.
Hypothesis: We hypothesise that the genetic effect on myopia is moderated through an environmental interaction with environmental factors which affect childhood growth rate. This hypothesis is suggested by the following three observations: First, we note that myopia is common. Estimates of prevalence vary across countries and subpopulations, but a prevalence of around 30% in the US is a reasonable. Second, myopia is highly heritable. Heritability estimates vary, but twin studies have estimated heritability as high as 80% though population based estimates are lower. However, even the lower estimates suggest a significant genetic component. However, the clear evolutionary disadvantage of myopia makes it likely that much of the genetic component does not act directly, suggesting that we look for an interaction effect. Third, most cases of mild to moderate myopia are associated with elongation of the eye's axis relative to the optimum for its refractive power. This is effectively a problem with the shape of the eye which suggests a developmental or growth related background.
We plan to scan for genetic variants which are associated with myopia in the presence of environmental factors which affect growth. Specifically, we intend to use head circumference and other growth related phenotypes as a proxy measure for those environmental factors.
B1253 - CNVs and psychosis-related neurodevelopmental phenotypes - 06/10/2011
There is strong evidence that rare copy number variants (CNVs) are associated with increased risk of schizophrenia (1-4) and autism (4-7), and a number of lines of evidence point to a shared genetic component to schizophrenia and autistic spectrum disorders. Aims: 1) To examine the frequency of CNVs within a population-based birth cohort. 2) To examine whether individuals with large/rare CNVs are at increased risk of developing autistic traits during childhood. 3) To examine whether individuals with large/rare CNVs show reduced cognitive ability during childhood and adolescence. 4)To examine whether individuals with large/rare CNVs are at increased risk of developing psychotic experiences during adolescence, and whether this association if present is mediated through autistic traits or impaired neurocognitive or social cognitive ability.
Hypotheses: We hypothesise that psychotic experiences, autistic traits, and impaired cognitive function will be more common in individuals with large, rare CNVs. We hypothesise that some CNVs will be shared across all neurodevelopmental outcomes (eg deletions in NRXN1), whilst others will show unique associations with these phenotypes. We hypothesise that autistic traits and impaired cognitive ability are unlikely to mediate any association between CNV burden and psychosis.
Outcomes: 1) Psychotic experiences at age 17 (definite psychotic experiences, and clinical/prodromal states). 2) Autistic traits. 3) Cognitive function.
B1252 - Ophthalmic associations of Developmental Co-ordination Disorder - 06/10/2011
Is the prevalence of the following conditions increased in children aged 7 who concurrently meet the DSM-IV criteria for DCD, compared to those who do not?
a.Reduced stereoacuity
b.Best eye visual acuity 6/18 or worse
c.Abnormal motor and sensory fusion at near or distance
d.Strabismus
e.Refractive error
f.Inter-ocular difference in acuity or refraction
g.Decreased visuo-spatial ability (according to maternal questionnaire at age 13). The answers to these will inform clinically important questions such as:
If a patient is diagnosed with DCD is there an indication for referring them routinely to either an ophthalmologist or an orthoptist?
In any given patient with DCD what is the likelihood of them having one of the above ophthalmic conditions?
Could any of the ocular problems listed in question 1 be used as a risk marker for DCD?
Methods: The primary exposure variable will be the presence of DCD according to the DSM-IV criteria at age 7 Cross-tabulations, then Univariate and Multivariable linear regression or logistic regression models will be used to look at the associations between DCD and the listed ocular abnormalities accounting for potential confounding and mediating factors identified from the literature. Adjustment will be made for the bias introduced by missing data using multiple imputation by chained equation.
B1249 - Engagement Science - 75th Anniversary Awards - 27/09/2011
A project team of administrative and research staff will invite our stakeholders to tell us in words/images what ALSPAC means to them. It could be a midwife's account of delivering one of the first babies, a participant's full-body scan or a researcher recalling their first major breakthrough using our data. This collection will be uploaded to a website and curated by a local artist who will use the material to create an artwork, which we will present to the local community at an event this autumn and at future events in 2012 when we celebrate our 21st birthday year.
B1247 - Does high protein intake in infancy associate with rapid growth beyond infancy - 22/09/2011
We aim to investigate protein intakes and dietary sources of protein at 8 months of age and relate these to growth trajectories up to 10 years. In addition we will assess the tracking of protein throughout childhood
Research questions: We will use the diet diary data collected in ALSPAC at 8 months (n greater than 1100) to calculate protein intake and assign infants to quintiles of protein intake. Within these quintiles we will evaluate:
1 What are the sources of protein in the diets of eight-month-olds?
2 Does high protein intake track though childhood?
3 Is high protein intake within the context of the whole diet associated with more rapid growth during infancy?
4 Is there any difference in rates of growth between quintiles of protein intake into later childhood?
Outcome measures: Weight, height and BMI through out infancy and childhood.
B1246 - Dietary patterns in infancy and their associations with growth - 22/09/2011
We aim to examine dietary patterns obtained through Principal Components Analysis (PCA) from diet diary data collected at 8, 18 and 43 months and determine how these patterns relate to each other over time from infancy to the preschool period. We will examine associations between these dietary patterns and nutrient intakes and various familial socioeconomic and lifestyle factors. We will determine whether the early dietary patterns are related to rapid early weight gain, which has been shown to be associated with higher body fatness in these children at 5 years of age (Ong et al, 2000)
Research questions: We will use the diet diary data collected in ALSPAC at 8, 18 and 43 months (n ~ 800 with complete data) to:
1.Establish dietary patterns using PCA;
2.Examine associations between patterns and nutrients at each time point;
3.Examine associations between patterns and lifestyle factors at each time point;
4.Determine to what extent the patterns obtained over time are associated with each other;
5.Determine whether any particular pattern is associated with early rapid weight gain.
B1244 - Adolescent active and passive tobacco exposure and cardiometabolic health - 22/09/2011
The overall aim of this study is to examine the relationship between active and passive smoking and cardiometabolic risk factors (blood pressure, fasting glucose, insulin, lipids and inflammatory markers) in adolescence. Methods
The exposure variables are (a) serum cotinine levels in the ALSPAC YP (young person) assessed at teen-focus 3 (TF3; age 15-16 years); (b) self-reported smoking of YP at TF3; (c) self-report of the parents of the YP from their most recent (relative to TF3) questionnaire; we will also consider YP adiposity (BMI, waist and DXA fat mass) as an exposure for objective d and examine whether it interacts with smoking/cotinine in their associations with cardiometabolic outcomes or whether they combine independently
The outcome variables are systolic and diastolic blood pressure, fasting glucose, insulin, lipids and CRP in the YP assessed at TF3
We will consider the following as potential confounding factors: YP age, YP gender, YP pubertal status, maternal age at birth, maternal parity, head of household (parental) occupational social class, maternal and paternal education, ethnicity. YP adiposity will also be considered a potential confounding factor for objectives a-c and e but we will decide just how to model this after exploring the joint associations of this and smoking/cotinine with outocmes
B1243 - The Genetic Epidemiology of Atopic Dermatitis - 22/09/2011
Aim to address the current gaps in the knowledge of the genetic architecture of AD using a comprehensive programme of genetic epidemiological analysis, incorporating state-of-the-art technology and analysis methods, denser genetic information and better phenotype definitions, using existing collections of phenotype and genotype data. Identifying new genetic variants and biological pathways for AD and more fully characterising the genetic contribution of AD will improve the understanding of the underlying mechanisms involved in AD pathogenesis and identify targets for future drug discovery.
Objectives include: Refine the phenotype definition of AD using latent class analysis in ALSPAC, Carry out a large-scale genome-wide association (GWA) meta-analysis including analysis using improved AD definitions and subtypes, Refine existing signals and investigate the role of lower frequency variants in AD using next-generation sequence (NGS) data, Investigate parent-of-origin effects in AD using multi-generational data, Quantify the overall contribution made by common genetic variants to AD susceptibility & identify important pathways, Investigate 'geneXgene' (GxG) and 'geneXenvironment' (GxE) interactions in AD, Functional follow-up of AD associated variants.