Proposal summaries
B1153 - Traffic related air pollution and the development of childhood asthma - 28/04/2011
"Traffic-related air pollution as a risk factor for the development of childhood asthma"
This project, funded by AllerGen NCE, will bring together data on air pollution, and genetic and disease information from existing studies done in Canada, England, The Netherlands, Germany, and Sweden. (See listing below) Data from these studies (all of which have measured the development of asthma in children from birth) will be analysed together to address the question: Does exposure to traffic-related air pollution (TRAP) increase the risk of incident asthma in children? Data from these existing studies will provide important information that can be useful to develop preventive strategies related to childhood asthma and potentially to develop treatment approaches focused on a particularly vulnerable population, children with genetic profiles conferring particular risk.
B1152 - Meta- analysis of GWAS on educational attainment - 28/04/2011
Not available
B1148 - Genome-wide association of mothers genotype on offspring characteristics - 21/04/2011
(No outline provided).
B1143 - Genome-wide association of melanocytic naevi - 21/04/2011
A high melanocytic nevi count is the strongest known risk factor for cutaneous melanoma.Understanding the genetic bases of nevus formation is therefore an important step in understanding melanoma etiology. We propose a genome-wide association study of melanocytic nevi. Genome-wide association results will be combined with similar results from the Queensland Institute of Medical Researchand from Twins UK.
B1151 - Long-term effects of medication for ADHD - 21/04/2011
Project outline:
Research Questions
1) What are the long-term physical and mental health effects ofmedication treatment for ADHD?
2)Does medication treatment for ADHDhave an impact onsocial, behavioural and educational functioning in adolescence?
3) For children meeting criteria for ADHD at age 7 years, which factors best predict persistence of ADHD at age 15 years?
4) What are the prevalence and correlates of apparent 'new' or late onset presentations of ADHD after the age of 7 years?
B1144 - The Birth Experience and Oxytocin Pathways to Postpartum Depression - 14/04/2011
The specific aim is to explore potential relationships between synOT, birth/postbirth factors and postpartum depressive symptoms, while controlling for covariates (Fig 1).
H1: in 8000 cases, less optimal birth factors will predict elevated postpartum depressive symptoms at two months, and the negative influence will be lessened by more optimal postbirth factors.
H2: in a matched subset of postpartum women with or without elevated depressive symptoms, increased synOT dosage will predict elevated postpartum depressive symptoms at two months, and the negative influence will be lessened by more optimal birth and postbirth factors.
Our long term goal is to promote optimal birth experiences (birth-care that supports normal physiology and a woman's positive perception) that enhance postpartum maternal mood and healthy mother-infant interaction, thus supporting infant development.37
Collaborators include Aleeca Bell PhD, expert in midwifery, Jean Golding PhD, expert in perinatal epidemiology; John Davis PhD, neurobehavioral expert in psychiatric disorders; Sue Carter PhD, neurobehavioral expert in oxytocin; and Leah Rubin PhD, methods and statistical analysis expert.
B1150 - Genome-wide meta-analyses of leptin and leptin to adiponectin ratio - 14/04/2011
Leptin is an adipocyte-derived hormone of which the circulating levels correlate closely with body fat. Leptin acts as a chronic signal to 'inform' the brain about the stored body fat and is involved in the regulation of long-term energy homeostasis. GWAS of leptin may discover new loci predisposing to obesity and related traits.
Previous attempts to identify genetic signals for insulin resistance have had limited success and the majority of type 2 diabetes-associated loci established to date are associated with beta-cell function. Leptin-to-adiponectin ratio (LAR) has recently emerged as a useful measure of insulin resistance. A GWAS of LAR may discover new loci associated with insulin resistance, in particular those which have links to adipocyte function.
Inclusion of ALSPAC data will improve our power to detect loci associated with leptin and LAR. For both of the above traits, if novel associations are identified, inclusion of ALSPAC data will also allow us to investigate the effects of these SNPS on the trait in children to establish of they operate in the same manner.
B1142 - Cysteine in Relation to Obesity Genotypes and related Phenotypes in Alspac Children - 07/04/2011
Obesity is associated with elevation of circulating levels of several amino acids [1], but the mechanism of this elevation is unclear. Type of dietary protein influences risk of obesity [2], suggesting that specific amino acids could contribute to regulating weight gain. Plasma concentrations of cysteine (tCys), but not of other sulfur amino acids, correlate strongly with BMI [3, 4] fat mass [5], and odds of obesity [4] in men and women. Increase or decrease of tCys over 6 years is associated with change of BMI in the same direction [6].
Massive weight loss in bariatric surgery patients had minimal effects on tCys [7], suggesting a direction of causality from tCys to BMI. Rodent studies demonstrate that cysteine is a powerful modulator of adiposity and glucose, lipid and energy metabolism [8, 9]. Collectively, evidence shows that cysteine may be a modifiable, hitherto unrecognized risk factor for obesity [10].
Preliminary data shows that tCys is strongly associated with adiposity in overweight children. There is no data on association of tCys with obesity phenotypes in a general childhood population, or with obesity genotypes.
B1138 - Genetic liability for bullying victimisation A exploratory/GWAS study - 28/03/2011
Bullying refers to repeated and prolonged aggressive behaviours that are intentionally targeted
towards one or more weaker individuals. Victims may be persecuted through direct physical violence or
through indirectly harming social relationships. The prevalence of victimisation of children ranges from
approx. 10-25% across European countries. Victimisation is a powerful environmental stressor and adversely
related to concurrent children's well-being and mental health. Individual factors related to increased risk for
victimisation, however, are poorly understood: prospective studies are still rare and the mechanisms of how
genetic and family factors predict peer victimisation, and how victimisation relates to serious mental health
problems, are poorly studied.
It is proposed to investigate how family factors contribute to the development of bullying
victimisation in childhood and how environmental exposure to victimisation leads to common and severe
mental health problems in adolescence and early adulthood. The aetiology will be studied in four established
longitudinal cohort or panel studies in the UK and Germany. Study of the potential precursors of bullying
and mechanisms leading to serious mental health outcomes will include assessment of environmental and
genetic factors and experimental studies of bias in cognitive processing and effects on brain activation. The
study is highly cost-effective, utilising existing datasets, and ground-breaking in so far as it tests suspected
mechanisms in controlled studies. Understanding of the factors in families that increase the risk of
victimisation and their consequences will help to develop early interventions. Identification of malleable
environmental mechanisms will enable educators and clinicians to promote resilience and reduce the risk of
vulnerable children developing disabling and potentially life-long mental health problems. Ultimately, this
project intends to improve well-being across the life-span.
B1141 - Different methods of dietary patterns and their associations with bone development in childhood and adolescence - 24/03/2011
Background: Several studies have found positive associations between greater bone mineral density (BMD) and increased consumption of various dietary factors including potassium, magnesium and fruit and vegetables. However, due to the complexity of the foods and nutrients we eat and the inter-correlations between them, it is also important to assess the diet as a whole. Dietary patterns enable the assessment of the overall diet and may provide additional answers to the analysis of individual foods and nutrients.
Setting: The project will take advantage of the unique and extensive longitudinal data collected by ALSPAC. Detailed information on the ALSPAC study is available on the web site: http://www.alspac.bris.ac.uk
Data: Bone density has been collected via DXA scan at 9, 11, 13, 15 and 17 years of age. In addition. pQCT scans which assess volumetric density have been performed at 15 and 17. Three-day diet diaries were collected at 7, 10 and 13 years of age.
Aims: The main focus of this research will be to investigate the different methods of obtaining dietary patterns, focussing on Principal Components Analysis, Cluster Analysis and Reduced Rank Regression in determining optimum bone development in the ALSPAC cohort. In addition the performance of each method in predicting bone density will be tested.
Fat mass and physical activity have been shown to affect skeletal development in childhood; this project will further examine whether any effects of dietary patterns on bone development are mediated by altered body composition and activity levels.
B1140 - Pubertal timing and adolescent antisocial behaviour in girls - 24/03/2011
Extensive evidence now supports an association between early pubertal timing and increased risk of antisocial/externalizing behaviour in adolescent girls (Mendle et al, 2007). To date, the mechanisms underlying this association remain unclear. A recent review (Ge & Natsuaki, 2009) outlined four possible hypotheses: (i) a hormonal influence hypothesis, whereby increases in hormone levels at puberty lead to increased risk for psychopathology; (ii) a maturation disparity hypothesis, whereby the gap between physical, social, and psychological maturation in early maturers is thought to exact a toll on individual adjustment; (iii) a contextual amplification hypothesis, whereby experiencing early puberty in a disadvantaged context is argued to increase risk for psychopathology; and (iv) an accentuation hypothesis, whereby risk for early maturers is argued to derive primarily from pre-existing vulnerabilities.
Our on-going analyses of risks for adolescent onset conduct problems in ALSPAC (Project B235) have included early pubertal timing (operationalized as reaching Tanner stage IV by age 12) as a moderator of other potential risks. These preliminary analyses have convinced us that the ALSPAC data-set offers important opportunities to examine the mechanisms underlying associations between early puberty and girls' conduct problems/delinquency in a more general way. As a result, we are requesting agreement to undertake analyses for two papers in which pubertal timing would constitute the main exposure, the first focusing on the adolescent maturity gap (hypothesis (ii) above), and the second on elements of both the contextual amplification and the accentuation hypotheses (hypotheses (iii) and (iv) above).
(A) Paper 1: The adolescent maturity gap
The concept of the adolescent 'maturity gap' (the discrepancy between physical and sexual maturation on the one hand and continued material and legal dependence on caregivers on the other) has been widely canvassed as one explanation for increased rates of problem behaviour in adolescence (see e.g. Moffitt, 1993). We propose to examine pathways from variations in pubertal timing to adolescent problem behaviour (mother-reported Conduct Problems as measured by the Strengths and Difficulties Questionnaire) via a number of "advanced social behaviours", that is, behaviours that are normative in late adolescence and adulthood but less so in early adolescence. We propose to characterize such behaviours using indicators of spare-time activities (as assessed in Teen Focus 1), and early romantic relationships (as assessed in Teen Focus 2). Early pubertal timing will constitute the predictor for adolescent problem behaviours in these analyses, and we hypothesize any associations found will be partially mediated by engagement in these advanced social behaviours.
(B) Paper 2: Contextual amplification and accentuation effects
In the second paper we propose to examine: (i) the extent to which early maturers showed elevated rates of conduct problems prior to the onset of puberty (using the repeated Strengths and Difficulties measures completed by parents from age 4); (ii) the extent to which early maturing girls (a) come from socially disadvantaged family backgrounds, and (b) are differentially 'selected into' disadvantaged social contexts in adolescence, focusing specifically on peer deviance; (iii) whether these contextual factors moderate effects of early puberty on self-reports of delinquency at ages 12 and 15 years; and (iv) whether early pubertal timing is differentially associated with differing developmental trajectories of conduct problems (as typified by our past analyses of conduct problem trajectories [Barker & Maughan, 2009]) either as a main effect or a moderator of other contextual/environmental risks.
References
Barker, E. D., & Maughan, B. (2009). Differentiating Early-Onset Persistent Versus Childhood-Limited Conduct Problem Youth. American Journal of Psychiatry, 166, 900-908.
Ge, X., Natsuaki, M.N., 2009. In search of explanations for early pubertal timing effects on developmental psychopathology. Current Directions in Psychological Science 18, 327-331.
Mendle, J., Turkheimer, E., Emery, R.E., 2007. Detrimental psychological outcomes associated with early pubertal timing in adolescent girls. Developmental Review. 27, 151-171.
Moffitt, T.E. (1993). Adolescence-limited and life-course-persistent antisocial behaviour - a developmental taxonomy. Psychological Review, 100, 674-701
B1136 - Case study Combined analysis of maternal occupation and the risk of adverse birth outcomes across CHICOS birth cohorts - 22/03/2011
Background and objective
Occupational parental exposures before conception or during pregnancy may be hazardous to fertility and optimal child development and a number of chemical and physical agents, and factors related to work organization (work strain, work schedule, shift work), have been suspected to interfere with normal reproduction process. InEurope, there are many pregnancy and birth cohort that have collected information on maternal occupation but few of them have enough statistical power to examine the effects of specific occupational exposures and adverse birth outcomes in detail, and therefore pooling of data across European cohorts may be particularly valuable.
Assessment of occupational exposures in European birth cohorts has been summarized (ENRIECO WP2 protocol: "Methods and Approaches of Evaluating Occupational Exposures in European Birth Cohorts" - online available www.enrieco.org). Assessment across the cohorts is very diverse and ranges from simple occupational title, to questionnaires on specific exposures, application of job-exposure matrices or biological markers of exposure.
The aim of this case study is to evaluate the risk of adverse birth outcomes (reductions in birth weight and gestational age) for specific "at risk" maternal occupations using combined data from European birth cohorts and evaluate the heterogeneity between countries in such effects.
Methods
Selection criteria for cohorts inclusion
1. Birth cohorts having recorded maternal occupations held at any time during pregnancy (including collected at birth) and having already coded this information into occupational codes
2. Birth cohorts that started the enrolment after 1990
Exposure variables
From participating birth cohorts it is expected that they have collected information on maternal occupation(s) held between the period starting one month before pregnancy until birth; however, only but one occupation during pregnancy will be selected for the pooled analysis. If cohorts have asked occupation history once during pregnancy, they will have to provide the corresponding code of this occupation. In cases that cohorts have asked occupational history more than once during pregnancy, they will be asked to provide only one occupational code and specify the criterion of selection (the longest job, first interview, etc.).
We ask each cohort to indicate whether the mother worked during pregnancy or not. If yes, cohorts will provide the corresponding occupational code and specify if the job was held during each specific period: 1 month before pregnancy, 1st, 2nd or 3rd trimester and the date of end of work during pregnancy (maternity leave).
*Occupational code:
A list of final occupations for analysis (grouped in different occupational sectors) will be defined when data from cohorts has been received, and the prevalence of each occupation is known. The ENRIECO case study already identified a list of occupational sectors of a-priori of interest: 1) Health; 2) Day-care; 3) Cleaning; 4) Agriculture and gardening; 5) Electricity, electronic, optic workers; 6) Lab work and chemical industry; 7) Food industry; 8) Printing and painting; 9) Hairdressers and cosmeticians.
These specific occupations will be defined according to ISCO 88 code. We have chosen this occupational code because it has many national equivalents and appears to be the most frequently reported in the participating cohorts. Cohorts will send the corresponding occupational codes to CREAL (Maribel Casas: mcasas@creal.cat):
- cohorts that have already coded occupational information into ISCO 88: send ISCO 88 codes to CREAL;
- cohorts that have coded the occupational information into other codes that can be translated to ISCO 88 (case of ALSPAC): send the corresponding codes to CREAL and its staff will be responsible to translate these codes to ISCO 88. CREAL staff will also check that the definition of each occupational sector is equivalent to the definition of ISCO 88.
*Physical load
Based on the occupational codes for job titles, a specific job-exposure matrix will be developed for physical load by Lex Burdorf. This JEM will focus on heavy lifting, awkward back postures, and forceful movements. The development of the JEM will follow two different approaches. First, available information on self-reported aspects of physical load within the participating cohorts will be collected and, permitting sufficient comparability of questions, collated into a JEM ("internal JEM"). This procedure will also allow us to evaluate within-cohort variance in self-reported physical load. Second, a JEM currently under construction will be applied. This JEM is based on detailed information from the Health 2000 Study and the Finnish National Work and Health Surveys (FNWHS), which cover over 300 occupations.
Outcomes variables
The study will focus on reductions in birth weight and gestational age as the main outcome variables. Birth weight will be analysed as a continuous outcome expressed in grams and as low birth weight, defined as birth weight below2500 grams. Gestational age will be analysed as a continuous outcome expressed in weeks and as pre-term birth, defined as gestational age of less than 37 weeks.
Confounding variables
A list of potential confounders has been listed in section 8: Scientific outline.
Data analysis
A centralized approach for combined analyses will be followed, where possible. Each cohort will prepare the necessary information and variables dataset and send it to CREAL, where relevant variables will be harmonized. All the mothers included in each cohort, even if they have not been working during pregnancy (and 1 month before pregnancy), will be included in the dataset and send to CREAL.
The population samples will be limited to:
- live born infants
- AND singleton infants (in case of twin births, both twins - and their mother - should be excluded)
- AND with known values for birth weight, gestational age
Missing values do not need to be replaced by the birth cohort data managers. If necessary, a global approach to handle missing values will be developed centrally (CREAL).
Analyses will start with descriptive tables of all variables in each cohort. On the basis of this, a detailed analysis plan will be prepared and agreed by all cohorts before further analytical models will be applied (based on criteria such as the number of subjects in different occupations). This analysis plan will include the selection official occupations and occupational groups for analysis, the choice of reference/control group, the choice of confounding variables, and the analytical approach to be used (pooled and/or meta-analysis). Heterogeneity between cohorts will be explored using appropriate statistical models.
B1135 - Replication of Prominent Psychiatric G x E Reports - 21/03/2011
Two early reports of G x E effects on psychiatric outcomes, namely 5-HTTLPR and stressful life events on risk of depression, and MAO-A and early childhood maltreatment on conduct disorder, have generated considerable subsequent research investment and controversy.
We propose to attempt to replicate these findings by specifying our analyses to be as close as possible to the original study (the Dunedin sample). ALSPAC is ideally suited to this, being similar to the original study in that it is a prospective cohort study, but considerably larger.
The study team will consist of:
Marcus Munafo
George Davey Smith
Glyn Lewis
Stan Zammit
Anita Thapar
Jon Heron
This group will agree a phenotype specification and analysis plan which most closely matches that of the two original reports which we will seek to replicate, namely:
Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R. Role of genotype in the cycle of violence in maltreated children. Science. 2002 Aug 2;297(5582):851-4.
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003 Jul 18;301(5631):386-9.
This analysis plan will then be implemented. We believe that this approach will remove the possibility for "significance-chasing", so that any results we obtain will be a true replication (or failure to replicate).
The study team has been chosen to represent those who have been both supportive and critical of psychiatric G x E research.
B1132 - Is there evidence of paternal transmission of mitochondrial DNA in humans FELLOWSHIP - 21/03/2011
Mitochondria are small organelles present within every nucleated mammalian cell. They are the principal source of intracellular energy, in the form of adenosine triphosphate (ATP), which is generated by oxidative phosphorylation (OXPHOS). Mitochondria contain their own DNA- mtDNA - which codes for 13 essential components of the OXPHOS system, along with 22 RNAs required for intra-mitochondrial protein synthesis. In mammals, mtDNA is generally considered to be exclusively transmitted down the maternal line. This important feature has underpinned the use of mtDNA in population genetic studies of human migration and disease, along with widespread forensic use. However, several strands of evidence suggest that this might not actually be the case.
Extensive paternal transmission of mtDNA has been observed in other species, including the marine mussel (Mytillus edulis), and rarely in the fruit fly (Drosophila melanogaster), Lepidopteran insects and the honey bee (Apis mellifera). In mammals, the "leakage" of paternal mtDNA during transmission has only been observed in atypical situations such as inter-species breeding in mice (Mus musculus), or in vitro embryo manipulation in cattle (Bos taurus), or in abnormal embryos in humans. However, the recent description of a paternally-derived 2 base pair pathogenic deletion in the mtDNA ND2 (MTDN2) in a 28-year-old man with a mitochondrial myopathy, coupled with evidence of paternally transmitted mtDNA in healthy sheep (Ovis aries), questions the accepted dogma of exclusive maternal transmission in mammals.
In humans, the debate hinges on the analysis of mtDNA sequences at the population level. By studying partial or complete mtDNA sequences from individuals across the globe, some have argued that the co-occurrence of phylogenetically unrelated genetic variants indicates inter-molecular recombination between paternal and maternal mitochondrial genomes, but others have argued that the high mtDNA mutation rate confounds this analysis through the generation of homoplasy which can reach ~20%. The issue is unlikely to be resolved without direct experimental evidence showing paternal transmission of mtDNA in human pedigrees.
We therefore set out to study the potential transmission of paternal mtDNA in 10 trios where the mother and the father were known to have different mtDNA signatures (haplogroup backgrounds). Using sensitive PCR/RFLP-based techniques, our pilot work has shown that ~1 in 10,000 mtDNAs within the child is likely to be of paternal origin in ~50% of cases. We aim to confirm these findings in a larger cohort of trios using a different methodological approach before we consider published what would be potentially radical findings.
We are therefore seeking access to small aliquots of anonymised DNA from 100 ALSPAC trios. Using existing GWAS data on the mothers, we will be able to identify trios where the mother and the father have a different mtDNA haplotype, and thus study the child's DNA to determine whether any paternal mtDNA has "leaked through".
We will use ultra high depth next generation sequencing (IlluminaHiSeq 2000) to carry out this experiment, allowing the detection of 1 in 100,000 mtDNA molecules. We have already established the methodology to do this for mtDNA.
B1134 - Effects of prenatal alcohol exposure on mental health outcomes in adolescence - 18/03/2011
One out of every 100 live births in the United States is affected by fetal alcohol spectrum disorders - a range of physical, neurocognitive, emotional, and behavioral impairments caused by prenatal exposure to alcohol. Prenatal alcohol exposure has been associated with negative outcomes in diverse areas of functioning throughout the life span. Studies of negative outcomes associated with prenatal alcohol exposure, however, have largely focused on neurocognitive domains. Prospective studies of long-term psychosocial outcomes (particularly internalizing problems) are lacking. A few prospective studies on long-term psychosocial outcomes of prenatal alcohol exposure have focused on externalizing problems such as conduct problems, aggression and incarceration. Emerging literature indicates that prenatal alcohol exposure is associated with internalizing problems such as depression. However, it is not clear whether prenatal alcohol exposure effects on internalizing problems are independent from effects on externalizing problems and neurocognitive deficits. To better characterize prenatal alcohol exposure effects on internalizing problems, it is crucial to consider externalizing problems and neurocognitive deficits in a same model, because the effect of prenatal alcohol exposure on internalizing problems may be largely explained by its well-established effects on externalizing problems and neurocognitive functioning.
Long-term effects of prenatal alcohol exposure may differ depending on the degree of exposure to adverse environments later in life. First, individuals prenatally exposed to alcohol tend to initiate alcohol use at an early age and develop alcohol problems. Given that early onset of alcohol use has been shown as a risk factor for adverse mental health outcomes later in life, early initiation of alcohol use may exacerbate the effects of prenatal alcohol exposure on long-term psychosocial outcomes (including alcohol abuse and problems).
Second, disadvantages of social environments including family, neighborhood and school have been shown to affect mental health. Although a few studies have characterized adverse familial environments, neighborhood and school environmental effects rarely have been explored. Although the larger social environmental factors may have smaller effect sizes than familial environmental factors, the neighborhood and school disadvantages may exacerbate the effects of prenatal alcohol exposure on long-term psychosocial outcomes independent of familial disadvantages.
Thus, this proposed research has three specific aims:
(1) To examine the effect of prenatal alcohol exposure on psychosocial outcomes (both externalizing and internalizing problems) in adolescence, after controlling for neurocognitive functioning;
(2) To examine a moderating effect of alcohol use in childhood;
(3)To examine a moderating effect of adverse school and neighborhood environments, after controlling for familial disadvantages
In order to achieve the above study aims, I will estimate three structural equation models, each of which is designed to address each of the above study aims. The first model (Model 1 as shown below) will include a manifest variable of prenatal alcohol exposure. The model also will include two latent factors of internalizing problems and externalizing problems in adolescence, each of which will be estimated using manifest variables of diverse mental health measured available in ALSPAC data. The internalizing and externalizing problem factors will be allowed to covary. Thus, an estimate of the path from prenatal alcohol exposure on the each problem factor will represent an unique effect of prenatal alcohol exposure on one problem factor after accounting for its effect on the other problem factor.
B1133 - The role of different conceptual skills in predicting KS2 and 3 science achievement - 18/03/2011
The aim of this project is to analyse the conceptual skills that predict KS2 and 3 science achievement. Research on cognitive development has identified key understandings that students must attain in order to make progress in learning mathematics and science. Some of these key ideas are common to mathematics and science learning. For example, ratio and proportion are important in both domains. In mathematics, ratio and proportion are crucial for understanding linear functions; in science, some measure of quantities, such as density, velocity and temperature, are based on ratio and proportion. Similarly, the understanding of relationships between variables is of huge importance in mathematics as well as in science. Mathematical modelling relies entirely on one's understanding of how the relations between variables are represented mathematically. Scientific theories also involve models that require understanding, for example, whether a quantity increases or decreases when another increases.
Other concepts may be more important for scientific than for mathematical learning. Empirical sciences depend on experimentation, and thus understanding what makes a good experiment is an essential part of scientific learning and discovery. In contrast, mathematical experiments are more like simulations than experimentation. The idea that all variables must be controlled, except for one, in order for an experiment to produce unambiguous results is more important in science than in mathematics. Research on cognitive development supports the idea that some mathematical concepts are independent of this aspect of scientific reasoning. Cousins et al (1993) carried out a factor analytic study of measures of young people's understanding of proportionality, probabilities and control of variables in empirical situations. They found that the first two measures loaded on one factor whereas the third loaded on a separate factor.
In brief, some conceptual skills are common to mathematics and science learning whereas others are more important for science learning. This analysis leads to two hypotheses regarding the prediction of children's science achievement.
The first hypothesis is that children's science learning will be based on (at least) two conceptual skills: one that is quantitative in nature and includes reasoning about relations between variables and mathematical concepts such as ratio and proportion, and a second non-quantitative skill that is related to the understanding of the need to control variables. Thus, measures of each of these conceptual skills should make significant and independent contributions to the prediction of achievement in KS2 and 3 Science, after controlling for general intelligence.
The second hypothesis is that children's understanding of the control of variables will be a strong predictor of KS2 and 3 science achievement but not of KS2 and 3 mathematics and English achievement.
Method
The ALSPAC dataset includes:
* a measure of general intelligence, obtained when the children were in Year 4;
* measures of children's understanding of the relations between quantities, including their understanding of proportionality, obtained when the children were in years 6 and 8;
* a measure of the children's understanding of the control of variables, obtained when the children were in year 6.
These measures will be used as predictors of the children's attainment in KS2 and 3 Science, and also KS2 and 3 Mathematics and English, in order to test both predictions. We will use regression analyses and structural equation models to test the predictions. We will use fixed order regression analyses, with the children's age at time of testing and their general intelligence entered as first and second steps, respectively. The third and fourth steps will be the children's mathematical reasoning and understanding of control of variables. These measures will be entered separately, each being entered once as the third and once as the fourth step, in order to test whether each one makes a contribution to the prediction of KS2 and 3 science, after controlling for the other one. The outcome measures will be the KS2 and 3 science, mathematics and English achievement. We expect that the understanding of control of variables makes a significant contribution to predicting KS2 and 3 science but not mathematics and English achievement. The data will also be scrutinised to see to what extent other variable (working memory, SES and reading ability) account for variance in KS2 and 3 science achievement and these variables will be controlled for, when necessary.
The analysis of the cognitive data will be complemented by an analysis of how much children say that they like science and mathematics, in order to see whether children's liking contributes to the prediction of achievement above and beyond an analysis of their cognitive skills.
The results will contribute to the understanding of the cognitive skills that support science learning. If both measures are strong predictors of science achievement, the implication is that both aspects of scientific concepts should be considered when new science topics are introduced in the classroom.
B1131 - Do behavioural emotional and school problems predict early sexual debut - 15/03/2011
Background
Although sexuality is a normal "developmental task" of adolescence, early sexual debut (before age 16) is well known as a "risk behaviour" with negative public health consequences in terms of greater STIs and teenage pregnancy compared to later debut. There is some evidence that early sexual behaviour shares common antecedents with other teenage risk behaviours such as substance use and antisocial behaviour. The proposed study would explore two areas highlighted for further research in a recent major review of US longitudinal research on sexual development [1]:
* Behavioural, emotional and school problems as predictors of early sexual debut: which factors are important, and when do they become predictive? (at early primary stage, or not until the age of transition from primary to secondary school?)
* Different developmental pathways to early sexual debut - what is the role of behavioural, emotional and school problems in these?
Behavioural, emotional and school problems as predictors of early sexual debut
The Zimmer-Gembeck and Helfand review ("ZGH review") found that behavioural, emotional and school problems appear uniquely associated with early, rather than later, sexual debut. The reviewers called for more research: fewUSstudies were able to examine these predictors, and existing research focused on children around the age of puberty, rather than earlier in childhood.
There is now a handful of population studies conducted since or outside the terms of the ZGH review indicating that behavioural problems (conduct and hyperactivity) in early childhood are predictive of early sexual debut [2-6]. None was conducted in the UK. We have found no studies looking at early depressive symptoms, which the ZGH review also suggests may predict early debut, especially in girls (relevant studies in review are all of early teens). Existing studies of school problems (low grades, negative attitudes to school and low educational aspirations) in relation to early sexual debut have measured problems around ages 10 to 13. This "transition" period is likely to be a particularly vulnerable time in terms of pubertal development, move to secondary school, and greater autonomy from parents. There is limited UK longitudinal research on school problems in relation to sexual debut and risk-taking for this age group [7].
The proposed study would examine behavioural, emotional and school problems as predictors of early sex reported in clinics up to and including the 15+ teen clinic. It would look at problems at different ages from the start of primary school, with a particular interest in whether any effects on early sexual debut may be traced back to early primary school, or do not emerge until the "transition" years.
For behavioural and emotional problems, the study would use SDQ and DAWBA scores and child's early antisocial behaviour including substance use (mother and teacher reports). For school problems, the study would use attitudes to school (mother and child reports) and SATs results (linked data). The analysis would adjust for well-established predictors of early sexual debut, including stage of pubertal development, socio-demographics, family adversity, romantic involvement, and parental monitoring. As school problems are one of the main areas of interest, it will also be important to adjust for IQ.
Different developmental pathways to sexual debut, and the role of behavioural, emotional and school problems
The ZGH review put forward the idea of different developmental pathways to sexual behaviour. Its interest was in different predictors of early (pre-16), mid (16-18) and late (post 18) sexual debut. Behavioural, emotional and school problems were suggested as "unique" predictors of early sexual debut. Mid adolescent sexual debut did not seem to have these antecedents characteristic of the development of a "problem behaviour" syndrome, but fitted a "biosocial" model of sexual development (emphasis on biological and social factors, and much less involvement in other risk behaviours). However, many biosocial predictors of mid debut were shared with early debut: these included physical maturity, not living with both biological parents, low parental monitoring, greater involvement in dating behaviour, and having friends who use substances. This raises the question of whether teenagers reporting early sexual debut are a heterogeneous rather than homogeneous group, making it possible to distinguish between those following biosocial and problem behaviour pathways. Other US work has found different developmental pathways to two groups of adolescents with high or low sexual risk-taking 'profiles', in keeping with a problem behaviour/biosocial pathway division [8].
The proposed study would attempt to categorise teenagers according to level of involvement in other risk behaviours around/just before sexual debut, and could also take account of later risky early sexual behaviour (eg condom use, partners). We would explore the hypothesis that early behavioural, emotional and school problems predict early sexual debut for teenagers with a high concurrent level of involvement in other risk behaviours, but are not important for teenagers without this risk involvement.
For this part of the study, information would be required on teenager's sexual risk (condom use, partners, etc), engagement in other risk behaviours including substance use and delinquent behaviour, from clinics up to and including the teen 15+ clinic and postal questionnaires at the same age.
References
1. Zimmer-Gembeck, M.J. and M. Helfand, Ten years of longitudinal research on U.S. adolescent sexual behavior: Developmental correlates of sexual intercourse, and the importance of age, gender and ethnic background. Developmental Review, 2008. 28(2): p. 153-224.
2. Fergusson, D.M., L.J. Horwood, and E.M. Ridder, Show me the child at seven: the consequences of conduct problems in childhood for psychosocial functioning in adulthood. Journal of Child Psychology and Psychiatry, 2005. 46(8): p. 837-849.
3. Ramrakha, S.M.A., et al., Childhood Behavior Problems Linked to Sexual Risk Taking in Young Adulthood: A Birth Cohort Study. Journal of the American Academy of Child and Adolescent Psychiatry, 2007. 46(10): p. 1272-1279.
4. Schofield, H.L.T., et al., Predicting Early Sexual Activity with Behavior Problems Exhibited at School Entry and in Early Adolescence. Journal of Abnormal Child Psychology, 2008. 36(8): p. 1175-1188.
5. McLeod, J., D. and S. Knight, The Association of Socioemotional Problems With Early Sexual Initiation. Perspectives on Sexual and Reproductive Health, 2010. 42(2): p. 93-101.
6. Galera, C., et al., Disruptive behaviors and early sexual intercourse: The GAZEL Youth Study. Psychiatry research, 2010. 177(3): p. 361-363.
7. Bonell, C., et al., The effect of dislike of school on risk of teenage pregnancy: testing of hypotheses using longitudinal data from a randomised trial of sex education. Journal of Epidemiology and Community Health, 2005. 59(3): p. 223-230.
8. Siebenbruner, J., M.J. Zimmer-Gembeck, and B. Egeland, Sexual Partners and Contraceptive Use: A 16-Year Prospective Study Predicting Abstinence and Risk Behavior. Journal of Research on Adolescence (Blackwell Publishing Limited), 2007. 17(1): p. 179-206.
B1130 - Contribution of polar overdominance to the missing heritability of common complex diseases in humans - 10/03/2011
One of the mainobjectives ofourprojectisto evaluate the contribution of polar overdominance-like effects to inherited predisposition to common complex diseases in human.
Details of this part of our project is as follows:
Genome-wide association studies (GWAS) have uncovered tens of loci influencing nearly all studied common complex diseases, and this has lead to essential new insights in disease pathogenesis. However, the identified risk loci typically explain <= 20% of inherited predisposition, raising the so-called "missing heritability issue". Understanding the missing heritability is viewed one of the most important objectives of modern medical genetics. Several hypotheses have been formulated to account for the missing heritability and are presently being evaluated. These include the quasi-infinitesimal architecture of complex traits and the role of rare, highly penetrant genetic variants, to name just the most publicized ones.
One alternative explanation is the contribution of non-Mendelian modes of inheritance, including parent-of-origin effects. While studying a muscular hypertrophy of sheep, known as the callipyge phenotype, we discovered one such completely novel non-Mendelian inheritance pattern, referred to as polar overdominance: only heterozygous animals inheriting the CLPG mutation from their father express the phenotype. Recent studies conducted in human, mice and domestic animals indicate that polar overdominance-like effects may be more common than initially suspected.
We are in the process if submitting a grant to the ERC, referred to as the SOLID GOLD project. The objectives of the Solid Gold project are (i) to use state-of-the-art genomic approaches to achieve a comprehensive understanding of the molecular mechanisms underlying polar overdominance at the ovine callipyge locus, and (ii) to evaluate the contribution of polar overdominance-like effects to inherited predisposition to common complex diseases in human.
We are requesting access to the ALSPAC data in the context of the second objective. Indeed, (i) having genotype mother-child duos will allow determination of the parental origin of the marker alleles inherited by the child, which is needed to test for parent-of-origin effects including polar overdominance, (ii) the exceptional size of the ALSPAC cohort provides excellent detection power, and (iii) the broad spectrum of recorded phenotypes increases the probability of detection of positive results.
B1127 - KCTD8 and head circumference at birth - 08/03/2011
This project seeks to replicate findigns obtained in the Saguenay Youth Study on the relathionship between genetic variation in KCTD8 and brain size in offspring exposed to maternal smoking during pregnancy (see below for the summary).
We propose to use head circumference at birth as a proxy of brain size.
"The most dramatic growth of the human brain occurs in utero and during the first two years of post-natal life. Genesis of the cerebral cortex involves cell proliferation, migration and programmed cell-death (apoptosis), all of which may be influenced by prenatal environment. Here we show that a particular variant of KCTD8, a gene involved in tetramerisation of potassium channels, is associated with brain size in females (top single-nucleotide polymorphism in a genome-wide scan: rs716890, p=5.40E-09). Furthermore, we found that KCTD8 interacts with prenatal exposure to maternal cigarette smoking during pregnancy vis-a-vis cortical area and cortical folding: in exposed girls only, KCTD8 genotype explains up to 21% of the phenotype. We speculate that KCTD8 moderates adverse effects of smoking during pregnancy (hypoxia, flow of nutrients) on brain development via apoptosis triggered by low intra-cellular levels of potassium, possibly reducing the number of progenitor cells and, in turn, cortico-genesis in the exposed individuals." (From Paus et al., in preparation).
B1126 - Analysis of 4 SNPs associated with permanent tooth eruption in additional growth phenotypes - 08/03/2011
We performed a genome-wide association study of permanent tooth eruption and identified four associated genetic variants. ALSPAC data provide an excellent opportunity to check these 4 SNPs in other growth related phenotypes to answer the question whether the variants are involved in growth in a more general way. Therefore, we are interested in the analysis of these four SNPs in dentition related, growth and developmental phenotypes within ALSPAC. The results will after discussion with Drs Timpson and Evans be mentioned in the manuscript on permanent tooth eruption and displayed in the Supplementary Material.