Proposal summaries
B703 - The role of haptoglobin and amylase copy number in child and adolescent health - 16/09/2008
A novel method for high throughput genotyping of copy number variation (CNV) has been developed by Dr Philip Guthrie within Bristol Genetic Epidemiology Laboratories. This has been optimised for two CNVs: haptoglobin and salivary amylase. This project aims to genotype these two polymorphisms in the ALSPAC cohort.
Haptoglobin (HP) copy number
Haptoglobin acts as an antioxidant by limiting peroxidative tissue damage by free hemoglobin, which it specifically binds with high affinity. It has also been reported to associate with vitamin C level. Haptoglobin allele Hp2 comprises a 1.7kb duplication encompassing exons 3 and 4, relative to allele Hp1. Hp2 carriers form protein multimers which have reduced availability to tissues, and have been claimed to be associated with higher rates of diabetic vascular complications. Most genetic studies have been conducted by serum phenotyping since there remains a shortfall of DNA-based assays of the duplicon structure.
The only known qualitative difference of allele Hp2 from Hp1 is the presence of the junction sequence between the duplicated segments. We have developed a liquid-phase assay for this junction which is simple, robust, economical and high throughput, and we have applied it to analyse the BWHHS (female) and CAPS (male) cohorts. These studies revealed apparently gender-specific associations. For example, BWHHS showed associations between Hp genotype and haemoglobin level, erythrocyte count and coronary heart disease, whereas Caerphilly showed only a non-significant trend for haemoglobin level in the same direction as in BWHHS.
Analysis of the ALSPAC cohort for Hp genotype will greatly increase the power of this study and help to elucidate further the roles of sex difference in modulating the effects of genotype.
This assay would typically require 10ng genomic DNA. DNA from cell lines is unsuitable, as it may have additional variation in copy number not present in the original sample. We would, however, like to carry out a pilot study using e.g. 100-200 samples replicated between genomic and cell line DNA, to verify/quantify this phenomenon.
Salivary Amylase (AMY1) copy number
Amylase is the enzyme responsible for starch hydrolysis, and the salivary amylase gene AMY1 shows extensive variation in diploid copy number, varying from 2 to 16 copies. A recent study concluded that the pattern of variation in copy number of this gene is consistent with diet-related selection pressures. We have generated an additional hypothesis, which is that copy number of this gene is likely to be more strongly associated with selection pressures generated from interaction between the amount of gene product and some species of Streptococci, which capture amylase onto their coats for their own ends; this in turn influences which other pathogens can colonise or infect the mouth/pharynx, with possible disease-related outcomes due to competition between Streptococci and other buccal micro-organisms
We have developed a liquid-phase assay to determine copy number of this gene, which is simple, robust, economical and high throughput. This assay would typically require 10ng genomic DNA. DNA from cell lines is unsuitable, as it may have additional variation in copy number not present in the original sample. We would like to carry out a pilot study using e.g. 100-200 samples replicated between genomic and cell line DNA, to verify/quantify this phenomenon.
B701 - Unlocking the evidence of infant and maternal health and diet from tooth enamel - 12/09/2008
Tooth enamel represents a durable archive of developmental events in early life. Incremental growth markers laid down during the secretory (matrix formation) stage of enamel formation provide an exact record of the age of onset of mineralization of different areas of enamel. This can be used as an accurate chronological framework that can be related to developmental events such as birth and weaning.
The neonatal line is present in all deciduous teeth in humans and is an accentuated growth increment in enamel and dentine (Schour 1936, Skinner and Dupras 1993). It can be used to identify the portion of enamel that initiated formation before and after birth, and the expression of the neonatal line has been considered an indicator of the severity of neonatal stress during labor and birth. However, this assumption has not been properly tested and the underlying mechanism remains uncertain.
Accentuated striae of Retzius are growth disruptions which reflect a temporary disruption of enamel matrix secretion and have been regarded as a non-specific indicator of systemic stress (FitzGerald et al. 2005). The relationship between the number and distribution of enamel growth disruptions and factors such as socioeconomic status, infant diet, maternal smoking, maternal anxiety, and growth faltering has not yet been tested.
The chemical composition of deciduous tooth enamel is dependant on environmental exposure and physiological influences during the prenatal and postnatal stages of enamel formation. The distribution of trace elements such as strontium, lead and zinc within enamel reflect differences in the age of exposure and in the incorporation of each element into enamel. These patterns can be used to interpret dietary intake and other environmental influences (Humphrey at al 2008 a, b). Analysis of a well documented sample will be used to test assumptions and refine interpretations.
The objectives of the proposed project are to:
1) Evaluate the expression of the neonatal line in relation to mode of delivery (caesarian, spontaneous or instrument assisted delivery), parity status of the mother, maternal anxiety and APGAR score (where available).
2) Evaluate the position of the neonatal line within the enamel crown in relation to birth weight and gestation length.
3) Develop a longitudinal record of enamel growth disruptions in enamel secreted before and after birth for each individual using accentuated striae of Retzius, and relate these records to socioeconomic status, infant diet, maternal smoking, maternal anxiety, and growth faltering measured in the first year of life.
4) Develop spatial maps of the distribution of calcium normalized trace element intensities across each tooth crown, and relate these intensities to mode of feeding at birth, age of introduction of complementary foods, dietary intake, and other environmental exposures (e.g. maternal smoking) and outcomes.
Methods
This project will use naturally shed deciduous teeth donated by approximately 95 children from the core ALSPAC sample. One deciduous canine will be sampled from each child, and we will also select 20 incisors from the study population that have the least amount of wear. High resolution dental casts and micro-CT scans will be produced for each crown prior to sectioning to preserve information on internal and external morphology and ground sections of each tooth used will be returned at the end of the study to extend the usefulness of the collection.
A longitudinal thin section of enamel approximately 100 micrometers thick will be prepared and used for both chemical analysis and a detailed histological study. The neonatal line will be used to identify the portion of enamel that initiated formation before and after birth and also as a baseline for establishing a chronological framework within the enamel crown. Accentuated striae of Retzius (growth disruptions) will be identified following the criteria of FitzGerald et al (2006). Individual chronological records of growth disruptions experienced during the period of tooth crown formation will be established by relating the position of defects to normal incremental growth markers in enamel (Dean et al 1993, Dean 2000, Reid and Dean 2000).
The LA-ICP-MS (laser ablation inductively coupled plasma mass spectrometry) facility in the Department of Mineralogy at the Natural History Museum will be used to determine calcium normalised trace element intensities at approximately 60 sampling locations in each enamel cusp. LA-ICP-MS combines discrete microanalysis with exceptional spatial resolution and very low detection limits, and is minimally destructive. Data on the distribution of a range of trace elements, including strontium, barium, iron, magnesium, manganese, lead, selenium, and, if possible, cadmium will be collected simultaneously. Geographical Information Systems (GIS) will be used to visually and statistically compare normalised elemental intensities.
We will assess several measures of infant health and diet in relation to deciduous tooth enamel histology and chemical composition (Table 1). Detailed data on a range of attributes and behaviours potentially relevant to health have already been collected in this well-documented sample of children. These include measures of socioeconomic position at birth and in late childhood, parental smoking during pregnancy, birth weight, gestation length and APGAR score and infant diet. This project will address a number of specific and testable hypotheses concerning how these attributes are reflected in enamel structure and composition. The project will also provide baseline data on each of these enamel parameters in a contemporary population. It is also expected that this detailed study will inform appropriate sampling strategies for future epidemiological research using the ALSPAC cohort or other tooth collections.
References
Dean, M.C., Beynon, A.D., Reid, D.J. and Whittaker, D.K. (1993) Longitudinal study of tooth growth in a single individual based on long and short period incremental markings in dentine and enamel. International Journal of Osteoarchaeology. 3: 249-264
Dean, M.C. (2000) Incremental markings in enamel and dentine; what they can tell us about the way teeth grow. In: M.Teaford, M. Meredith Smith and M. Ferguson (eds) Development, Function and Evolution of Teeth. Cambridge University Press. pp. 119-130.
FitzGerald, C. and Saunders, S. (2005) Test of histological methods of determining chronology of accentuated striae in deciduous teeth American Journal of Physical Anthropology 127: 277-290.
FitzGerald, C., Saunders, S., Bondioli, L. and Macchiarelli, R. (2006) Health of infants in an Imperial Roman skeletal sample: Perspective from dental microstructure. American Journal of Physical Anthropology 130: 179-189.
Humphrey, L.T., Dean M.C., Jeffries T.E. and Penn, M. (2008) Unlocking evidence of early diet from tooth enamel. Proceedings of the National Academy of Sciences 105: 6834-6839.
Humphrey, L.T., Jeffries T.E. and Dean M.C. (2008) Micro spatial distributions of lead and zinc in human deciduous tooth enamel. In: J.D. Irish and G.C. Nelson (eds) Technique and Application in Dental Anthropology. Cambridge University Press, pp 87-110.
Reid, D.J. and Dean M.C. (2000) Brief communication; The timing of linear hypoplasias in modern human anterior teeth. American Journal of Physical Anthropology. 113; 135-139.
Schour, I., 1936. Neonatal line in enamel and dentin of human deciduous teeth and first permanent molar. Journal of the American Dental Association. 23: 1946-1955.
Skinner, M. and Dupras, T. (1993) Variation in birth timing and location of the neonatal line in human enamel. Journal of Forensic Sciences, 38: 1383-1390.
B700 - Association of early rapid growth with neurodevelopment in childhood - 10/09/2008
Catch-up growth in early infancy is associated with overweight in childhood (1), but seems to lead to benefits in neurodevelopment in SGA infants (2, 3). This rises the question whether catch-up growth should be avoided or not (4). To our knowledge, there are no studies on the effect of early rapid growth on neurodevelopment in AGA and LGA infants.
We performed a pre-analysis on a merged dataset from four independent clinical trials originally designed to test the effect of LCPUFA supplementation in term and preterm infants (5-8). The data were provided in the framework of EARNEST (9) and included a total of 871 children (495 term, 376 preterm). Neurodevelopment had been assessed by Bayley Scales of Infant Development II (BSID II) at 18 months (10).
Our results indicate a possible benefit of rapid growth in respect to neurodevelopment in both term and preterm infants. However, the analysis is limited by its relatively small sample size and by the assessment of neurodevelopment by Bayley Scales at 18 months which may be an outcome variable of minor relevance.
Within ALSPAC, the required data to answer this research question are available. We would require the following variables from the data set:
o Weight, height and head circumference at birth, 4, 8 and 12 months
o Assessment of cognitive function (at the latest available age)
o Sex
o Gestational age
o Maternal age
o Maternal and paternal education / profession
o Smoking in pregnancy
o Breastfeeding
References:
1. Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 2000;320:967-71.
2. Lundgren EM, Cnattingius S, Jonsson B, Tuvemo T. Intellectual and psychological performance in males born small for gestational age with and without catch-up growth.Pediatr Res 2001;50:91-6.
3. Latal-Hajnal B, von Siebenthal K, Kovari H, Bucher HU, Largo RH.Postnatal growth in VLBW infants: significant association with neurodevelopmental outcome. J Pediatr 2003;143:163-70.
4. Postnatal growth, neurodevelopment and altered adiposity after preterm birth--from a clinical nutrition perspective. Acta Paediatr 2006;95:909-17.
5. Bouwstra H, Dijck-Brouwer DAJ, Boehm G, Boersma ER, Muskiet FAJ, Hadders-Algra M. Long-chain polyunsaturated fatty acids and neurological development outcome at 18 months in healthy term infants. Acta Paediatr 2004;94:26-32.
6. Lucas A, Stafford M, Morley R, et al. Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomised trial. Lancet 1999;354:1948-54.
7. Fewtrell MS, Morley R, Abbott RA, et al. Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants. Pediatrics 2002;110:73-82.
8. Fewtrell MS, Abott RA, Kennedy K, et al. Randomized, double-blind trial of long-chain polyunsaturated fatty acid supplementation with fish oil and borage oil in preterm infants. J Pediatr 2004;144:471-9.
9. Fewtrell MS; EARNEST consortium. Session 6: Infant nutrition: future research developments in Europe. EARNEST, the early nutrition programming project: EARly Nutrition programming - long-term Efficacy and Safety Trials and integrated epidemiological, genetic, animal, consumer and economic research. Proc Nutr Soc 2007;66:435-41.
10. Bayley N. Bayley Scales of Infant Development, 2nd edn.San Antonio, TX: Psychological Corporation; 1993.
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A growing body of epidemiological and experimental evidence indicates that the prenatal period is a sensitive period for later health outcomes, and prenatal priming is a term increasingly used to describe the long term effects on health outcomes programmed by prenatal and early postnatal factors (1). While the roles of maternal obesity (2), maternal smoking in pregnancy (3), gestational diabetes and birth weight (4) are established, there are only few publications assessing the association between gestational weight gain (GWG) and childhood obesity (5-8).
The potential impact of GWG is of particular interest since increases in GWG have been reported in several populations (9, 10), and because GWG may be modified by diet or exercise (11, 12).
A cooperative analysis of the ALSPAC data of Andy Ness and Richard Martin and collaborators from our institution to assess these interdependencies is proposed. We would require the following variables from the data set:
Child:
* Weight and height at latest available age
* DXA at age of 11 years
* Birth weight
* Sex and age
* Gestational age at birth
* TV consumption
* Physical activity (self-reported and objective, if possible)
* Energy intake (calories, protein, fat, carbohydrates, saturated / unsaturated fat)
Mother:
* Weight gain in pregnancy
* Age at delivery
* BMI before pregnancy
* Education / profession
* Smoking in pregnancy
* Breastfeeding
* Married / unmarried
* Gestational diabetes
* Diabetes mellitus
* Pre-eclampsia
* Maternal birth weight
* Parity
References:
1. Gillman MW. Developmental origins of health and disease. N Engl J Med. Oct 27 2005;353(17):1848-1850.
2. Whitaker RC. Predicting preschooler obesity at birth: the role of maternal obesity in early pregnancy.Pediatrics. Jul 2004;114(1):e29-36.
3. Von Kries R, Bolte G, Baghi L, Tochke AM.Parental smoking and childhood obesity - is maternal smoking in pregnancy the critical exposure? Int J Epidemiol. 2007;doi:10.1093/IJE/dym239.
4. Oken E, Gillman MW. Fetal origins of obesity. Obes Res. Apr 2003;11(4):496-506.
5. Moreira P, Padez C, Mourao-Carvalhal I, Rosado V. Maternal weight gain during pregnancy and overweight in Portuguese children. Int J Obes (Lond). Apr 2007;31(4):608-614.
6. Oken E, Taveras EM, Kleinman KP, Rich-Edwards JW, Gillman MW. Gestational weight gain and child adiposity at age 3 years. Am J Obstet Gynecol. Apr 2007;196(4):322 e321-328.
7. Schack-Nielsen L, Mortensen EL, Michaelsen KF, TIA S. High maternal pregnancy weight gain is associated with an increased risk of obesity in childhood and adulthood independent of maternal BMI [abstract]. Pediatr Res. 2005;58:1020.
8. Seidman DS, Laor A, Shmer J, Galr R, DK S. Excessive maternal weight gain during pregnancy and being overweight at 17 years of age. [abstract]. Pediatr Res. 1996;39:112A.
9. Schieve LA, Cogswell ME, Scanlon KS. Trends in pregnancy weight gain within and outside ranges recommended by the Institute of Medicine in a WIC population.Matern Child Health J. Jun 1998;2(2):111-116.
10. Bergmann RL, Richter R, Bergmann KE, Plagemann A, Brauer M, Dudenhausen JW.Secular trends in neonatal macrosomia in Berlin: influences of potential determinants. Paediatr Perinat Epidemiol. Jul 2003;17(3):244-249.
11. Artal R, Catanzaro RB, Gavard JA, Mostello DJ, Friganza JC. A lifestyle intervention of weight-gain restriction: diet and exercise in obese women with gestational diabetes mellitus. Appl Physiol Nutr Metab. Jun 2007;32(3):596-601.
12. Wolff S, Legarth J, Vangsgaard K, Toubro S, Astrup A. A randomized trial of the effects of dietary counseling on gestational weight gain and glucose metabolism in obese pregnant women. Int J Obes (Lond). Mar 2008;32(3):495-501.
B696 - Iron-related gene polymorphisms and birth weight - 09/09/2008
In a study in the North of England, we first confirmed the birth weight association in childhood ALL and hypothesized that iron-related gene polymorphisms may explain this association by increasing both birth weight and childhood ALL risk. We tested this hypothesis, on 995 infants and their mothers from The North Cumbria Community Genetics Project (NCCGP) and 168 cases with childhood ALL from the Newcastle Haematology Biobank in a comprehensive study of the hereditary hemochromatosis gene HFE and other selected iron-related genes including the transferrin receptor gene TFRC (Dorak et al, MS submitted). We found that certain materno-fetal genotype combinations involving HFE and TFRC that increase fetal iron exposure resulted in higher birth weight in boys only and elevated ALL risk mainly in girls. Maternal effect was evident in mother-child pairs when mothers were positive for HFE variants, presumably increasing the amount of iron available for materno-fetal transfer. Our interpretation was that iron-related gene polymorphisms affected placental iron transport and males were able to use excessive iron by increasing fetal growth but girls were not. Greater cell proliferation rate in male fetuses would cause this dichotomy. Ultimately, boys would suffer less from the genotoxic effects of (free) iron but girls would have high amounts of iron increasing their risk for leukemia. Limited data on cord blood iron levels suggested that that when (1) the mother was positive for any of the three HFE variants that increased birth weight, (2) the offspring was male and (3) the male infant was positive for HFE and TFRC variants, birth weight would reach extreme values and cord blood iron would still be high. Thus, only the materno-fetal genotype combinations that increase iron levels most extremely would increase both birth weight and ALL risk in boys. This study suffered from lack of statistical power, especially for the assessment of interactions, and lack of plasma samples in sufficient quantity from mother-child pairs. There was only limited opportunity to increase the sample size due to availability of DNA samples from further mother-child pairs.
We are applying to ALSPAC to replicate this study with greater statistical power in a larger cohort of mother-child pairs and to take advantage of (1) pre-existing data on iron levels at birth, especially in cord slices, and at intervals after birth, (2) pre-existing genetic data on other genetic polymorphisms influencing birth weight, (3) the availability of data on post-natal diet and growth as well as any health outcome. The ALSPAC cohort would also provide the study with data on gestational iron supplementation, birth order, sex of previous birth(s), maternal prepregnancy weight and maternal smoking, that have been reported to influence birth weight or may be relevant for the sex-specificity of the combined HFE and TFRC association with birth weight. For our purposes, the Children in Focus (CiF) subset of ALSPAC will be most useful. We propose to carry out initial studies on CiF samples and extend positive findings to the complete ALSPAC cohorts. Thus, initial genotyping studies will take place at HUMIGEN, Genomic Immunoepidemiology Laboratory (year 1) and any association found or suggested will be replicated in the whole cohort at K-Biosciences (year 2).
The Newcastle study and our ongoing studies in the Genomic Immunoepidemiology Laboratory in HUMIGEN have identified the low penetrance HFE mutations involved in iron overload, C282Y and H63D, to be relevant in birth weight and leukemia associations but have also identified an HFE intron 1 SNP (rs9366637) as a strong predictor of birth weight. In addition, a detailed analysis of the HFE region suggested new susceptibility markers for childhood leukemia. The SNP rs10425 outside HFE appears to be a marker for the wildtype HFE haplotype along with rs807212 and rs12346. In addition to the HFE SNPs, we plan to include the TFRC SNP rs3817672 (S142G), transferrin (TF) SNPs rs1049296 and rs4481157, hepcidin (HAMP) SNP rs7251432, hephaestin (HEPH) SNPs rs5919015, rs809363, rs4827365, ceruloplasmin (CP) SNPs rs710573, rs7652826, bone morphogenetic protein 2 (BMP2) rs235756, hemojuvelin (HFE2 / HJV) SNP rs4970862, ferroportin (HFE4 / SLC40A1) SNP rs2304704, solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2 (SLC11A2 / NRAMP2) SNP rs422982 and transmembrane protease, serine 6 (TMPRSS6) SNP rs733655. We will include these SNPs as a minimal set of iron-related gene polymorphisms and add any other SNPs that our ongoing studies may identify in these genes and other iron pathway genes as new candidates. We will include two HLA-G polymorphisms (rs16375 and rs1233334) also in the extended HLA class I region (between HFE and the HLA complex) because of their potential influence on fetal growth rates. HLA-G has been implicated as the human equivalent of the mouse Ped gene which regulates fetal growth rate. We will examine the HLA-G polymorphisms for their role in birth weight determination and to exclude as a confounder of the HFE association. To achieve these genotypings, we will need 200-250 nanograms of genomic DNA from each mother-child pair in the CiF group. Depending on the amount of already available data in cord blood iron parameters, we may need cord blood serum for iron and ferritin measurements.
If we get the expected results, genotypes or their combinations increasing materno-fetal iron transfer will correlate with birth weight increase in boys but not in girls except the HFE intron 1 SNP rs9366637, which appeared to associate with birth weight in boys and girls in the NCCGP cohort. We will seek correlations between genetic markers and maternal and cord (tissue/blood) iron levels to elaborate our preliminary observations on the NCCGP samples. We expect to find a weak inverse correlation between birth weight and cord iron parameters in boys because of iron depletion by increased growth rate. Seemingly paradoxically, however, we expect to find increased cord iron levels in boys in the presence of certain materno-fetal combinations of iron-related gene polymorphisms. It is this subset that we propose as the basis of birth weight association in leukemia. It will be of great interest to analyze pre-existing data on blood iron level changes during early childhood in these boys to find out whether any genotype maintains high blood iron levels throughout childhood. In a future study, these data can also be correlated with (iron-induced) oxidative stress and genotoxicity assay results.
Iron measurement in cord blood or tissue is an end-point analysis. Our preliminary data suggest that cord iron levels are a cumulative result of materno-fetal iron transfer, fetal cell proliferation rate and duration of gestation. The overall dynamic process of fetal iron levels cannot be reliably quantitated by a single end-of-pregnancy measurement. According to our model, the fetus may be exposed to high levels of (free) iron that causes the genotoxic damage but the cord blood iron level may be low due to accelerated growth towards the end of pregnancy. Since real-time monitoring of fetal iron levels is not possible in humans, ultimately animal experiments will be required to examine this hypothesis. At this stage, we are not planning to propose any animal studies till we obtain more robust data supporting our preliminary findings.
B692 - THE DEVELOPMENT OF MATHS CAPABILITIES AND CONFIDENCE IN PRIMARY SCHOOL - 28/08/2008
Four specific research questions will be addressed to attain the aims specified in the section justification of the method.
1. Are there differences in the development of specific types of mathematical understanding and, if so, how do these influence pupils' progression across the Key Stage 1-3 period?
Learning to think quantitatively and learning arithmetic are two different studies. One previous study with relatively few children has shown that their mathematical reasoning in Year 1 predicts KS1-Maths performance independently of the children's knowledge of numbers at school entry (Nunes et al., 2007) and that improving children's reasoning in Year 1 significantly enhances their KS1 results one year later. An analysis of the ALSPAC data could provide a demonstration of a predictive relation between mathematical reasoning measured in Years 4 and 6 and KS2 and KS3 achievement, independently of knowledge of arithmetic. This could provide much needed evidence regarding later mathematics learning.
The ALSPAC dataset contains four types of predictors to be used in this investigation: (1) cognitive and (2) affective factors; (3) predictors related to teachers' and schools' practices; (4) a set related to the family and the socio-economic background.
The predictors relevant to this first research question are the cognitive measures, which include assessments of the children's:
a) mathematical reasoning (Years 4, 6 and 8 assessments);
b) knowledge of arithmetic (a sub-test of the WISC);
c) working memory (backward digit span), short-term memory (non-word repetition and forward digit span) and attention (a specific measure of attention and a scale within the Strengths and Difficulties Questionnaire);
d) general intelligence (Weschler Intelligence Scale for Children: WISC).
Regression analyses will be used to investigate whether each of the first three of these measures makes a distinct contribution to predicting students' mathematics achievement at each KS assessment, after controls for differences in general intelligence and in the other two variables. We hypothesise that children's mathematical reasoning will make a specific contribution to the prediction of KS results beyond what is predicted by the other factors. A positive result would provide the basis for a programme to promote children's mathematical reasoning with the aim to improve their mathematics achievement.
Separate scores for items within the mathematics assessments will be used to distinguish (a) additive and multiplicative reasoning; (b) reasoning about quantities and reasoning about relations; and (c) problems about extensive and intensive quantities. These will be used in analyses to investigate the extent of their relative power in the longitudinal prediction of maths and science attainment.
2. Is the development of some skills more important for progression than others?
There is a debate in education regarding the relative emphasis that should be given to computation and reasoning skills for later mathematics learning. It has also been suggested that spatial and visualisation skills are important for mathematics learning. The WISC contains sub-tests that allow for considering how arithmetic and spatial skills contribute to mathematics attainment.
There is also increasing interest in the role of attention in mathematics learning. The WISC subtest "Coding" is considered a measure of attention. Previous analysis of the ALSPAC data showed that the correlation between this sub-test and KS1 achievement was significant, though low. There are more specific measures of attention which will be used in this analysis.
3. Are there differences in the development of skills by gender, ethnicity, or socio-economic factors, such as parents' education or SES?
The dataset will be used for the analysis of these demographic variables considering both the impact of these variables at school entry and the possible augmentation of these effects if the home environment contains little academic incentive (e.g. books) and if the parents have low educational aspirations for the children.
Data from the teachers' questionnaires will be used to assess the effect of some school practices (streaming) and environment (number of pupils per class; number of students receiving free school meals; a specialist maths coordinator available) on students' mathematics progression.
4. How is development of understanding affected by children's self perception of their own ability in mathematics?
The ALSPAC measures of children's affective reactions to mathematics include questions on pupils' self-confidence, their liking for mathematics and its perceived usefulness, and their perception of the teacher's abilities and attitudes towards maths and teaching the subject. Different items were included at the different data collection points but it is possible to assess whether, according to different reports (i.e. by parents or by children), the students showed consistent liking, or not, for mathematics.
Some research has shown that pupils are reasonably accurate in identifying their position in their class as mathematics learners but their teachers' perceptions of them is just as important as their measured ability in influencing their self-perception as learners (Pretzlik, Olsson, Nabuco, & Cruz, 2003). Teachers' perceptions of their pupils' abilities in mathematics are influenced by the pupils' reading ability; the latter tend to be more accurate than their perceptions of the pupils' mathematics abilities. We need, therefore, to explore how pupils' abilities, their self-perceptions and their teachers' perceptions of them interact in the prediction of KS2-3 mathematics outcomes.
Final notes
In all of these analyses, we propose to test whether pupils' general ability and general self-confidence are better predictors of their attainment and later liking of maths than their specific mathematical reasoning capabilities and self-confidence. For this reason, measures of attainment in reading and in English, and self-confidence in and liking of English and Maths are required measures. It will also be necessary to analyse the data both including and excluding children with special needs (sensory, reading and language). The attainment of these groups of possible outliers could affect the results of the analyses.
The list of relevant variables is appended.
B688 - Childhood diet and adolescent depression - 16/08/2008
No outline received
B689 - The relationship between early speech and language development and later literacy - 13/08/2008
The most prominent explanation for specific reading difficulties is the phonological deficit hypothesis; that reading difficulties are caused by difficulties in accessing the phonological, or sound structure of speech. This makes it difficult for children to 'sound out' words in reading and spelling, and difficult to link spoken and written words in memory.
On the basis of this theory, it might be expected that children with early speech difficulties would be likely to show later literacy difficulties. In fact, many children with speech difficulties show good reading progress, and only a subgroup have literacy difficulties. Researchers have suggested various hypotheses to explain this fact. Most prominently, researchers have argued that only children with both speech and language difficulties are likely to go on to have literacy difficulties, and that therefore language difficulties are a more important risk factor than speech difficulties. This seems counter-intuitive given that speech is, on the face of it, more closely related to phonological processing. On this basis it seems that we need to consider carefully what we are measuring with standard language assessments.
Other researchers have argued that only children who show unusual or disordered speech errors are likely to go on to have literacy difficulties, or that only children who continue to have speech difficulties at the point at which they begin literacy instruction will be impaired. All of these alternative hypotheses can be examined using this dataset.
Previous studies have focused on group differences, and have generally used clinical samples referred through speech therapists or specialist schools. These methods will be subject to referral bias, and may underestimate the role of individual differences - for example, children with both speech and language difficulties tend to have more severe speech impairments than children with pure speech problems. A recent study of my own (Carroll & Myers, in preparation) showed that while children with both speech and language difficulties were more likely to have literacy difficulties, as previously suggested, language skills were not a significant predictor of growth in reading over time. This suggests that the link between the two could be explained by another third variable.
The ALSPAC study provides a way to investigate this possibility. Extensive background information is available on the families and children involved. There are repeated language assessments of a representative sample of children throughout the preschool years, together with clinical assessments of a smaller group at 24 months, 61 months and 8 years. These could be used to predict reading and spelling at 7, 9 and 12 years, and phonological skills such as nonword repetition, phoneme deletion and spoonerisms at the same time points. While the sample is considerably reduced by using measures from the 'children in focus' assessments, it remains a large sample in terms of clinical studies of this type.
The analyses will focus on using structural equation modelling and if necessary multiple regression to illustrate the relationships between the variables over time. Some group difference analyses examining those children in the sample showing significant difficulties will also be included. The measures requested for this analysis are shown on the following page
B687 - An FTO Gene Variant and Sedentary Behaviour in Children - 12/08/2008
An FTO Gene Variant and Sedentary Behaviour in Children
Purpose:
To examine any potential differences in the time spent sedentary at 11 and 13 years old in relation to a variant in the fat mass and obesity (FTO) gene. Secondly, to examine the changes in sedentary behaviour between 11 and 13 years old in relation to a variant in the FTO gene.
Background:
Genome-wide association studies have provided resounding evidence that variants in the FTO gene are associated with obesity. For instance, per A allele for the single nucleotide polymorphism (SNP) - rs9939609 - has been extensively associated with an increased odds of being obese, defined by several obesity phenotypes (1). The mechanisms whereby this gene induces the increased fat mass are now being investigated. Due to the FTO gene being highly expressed within the hypothalamus, hypotheses concerning energy intake have been developed and there is evidence that those with the risk allele may consume more energy (2). In terms of energy expenditure there have been contrasting reports with null (3) and positive (4) associations found between FTO gene variants and self-reported physical activity. While these initial reports are intriguing, the clinical measurements are far from robust. Specifically analysing the association between rs9939609 genotypes and sedentary behaviour, assessed by accelerometry, while adjusting for moderate-to-vigorous physical activity (MVPA), could reveal further insight into the role of the FTO gene in energy expenditure.
B749 - Association of rs1051730 maternal smoking genotype on child development - 12/08/2008
Maternal smoking is a known teratogen (1) and is associated with complications of pregnancy (2). Furthermore there is robust evidence that maternal smoking in pregnancy is causally associated with low birth weight in offspring (3;4). Observational studies have also reported associations of maternal smoking in pregnancy with various child outcomes such as increased obesity (5;6), reduced stature (7), lower cognitive development and behavioural problems (8;9) and higher blood pressure (10). However, results for these outcomes have been inconsistent and there is evidence that some of these associations reflect confounding by socioeconomic factors (10-13) rather genuine biological effects of intrauterine exposure to smoke.
We have explored associations of maternal smoking on offspring outcomes observationally in ALSPAC and have previously reported no association with child obesity (11), no association with child blood pressure (14) and an inverse association with child stature (15). We recently gained approval to study the relationship between maternal smoking and offspring cognition.
We would like to build on these existing observational analyses and explore the role of confounding further by using the rs1051730 genetic variant as a means of testing the causality of putative associations between maternal smoking in pregnancy and offspring outcomes.
It has recently been observed that rs1051730 genotype is associated with variations in smoking behaviour in pregnancy. An analysis using pooled data from ALSPAC and The Exeter Family Study of Childhood Health has shown that each additional copy of the rs1051730 risk allele is associated with higher odds ratios of continuing to smoke during the first trimester (Freathy et al., in press). Thus this genetic variant can be used to explore causality in relation to maternal smoking in pregnancy and offspring outcomes.
In sum, we would like to explore the associations of maternal rs1051730 genotype (associated with continued smoking behaviour in pregnancy) with:
1) child adiposity
2) child stature
3) child blood pressure
4) child cognition
For table of requested variables, please see attached.
Reference List
1. Dwyer JB, Broide RS, Leslie FM. Nicotine and brain development. Birth Defects Res C Embryo Today 2008;84:30-44.
2. Andres RL, Day MC. Perinatal complications associated with maternal tobacco use. Semin Neonatol 2000;5:231-41.
3. Sexton M, Hebel JR. A clinical trial of change in maternal smoking and its effect on birth weight. JAMA 1984;251:911-5.
4. Brooke OG, Anderson HR, Bland JM, Peacock JL, Stewart CM. Effects on birth weight of smoking, alcohol, caffeine, socioeconomic factors, and psychosocial stress. BMJ 1989;298:795-801.
5. Chen A, Pennell ML, Klebanoff MA, Rogan WJ, Longnecker MP. Maternal smoking during pregnancy in relation to child overweight: follow-up to age 8 years. Int J Epidemiol 2006;35:121-30.
6. Al Mamun A, Lawlor DA, Alati R, O'Callaghan MJ, Williams GM, Najman JM. Does maternal smoking during pregnancy have a direct effect on future offspring obesity? Evidence from a prospective birth cohort study. Am J Epidemiol 2006;164:317-25.
7. Lampl M, Kuzawa CW, Jeanty P. Prenatal smoke exposure alters growth in limb proportions and head shape in the midgestation human fetus. Am J Hum Biol 2003;15:533-46.
8. Julvez J, Ribas-Fito N, Torrent M, Forns M, Garcia-Esteban R, Sunyer J. Maternal smoking habits and cognitive development of children at age 4 years in a population-based birth cohort. Int J Epidemiol 2007;36:825-32.
9. Wakschlag LS, Pickett KE, Cook E Jr, Benowitz NL, Leventhal BL. Maternal smoking during pregnancy and severe antisocial behavior in offspring: a review. Am J Public Health 2002;92:966-74.
10. Brion MJ, Leary SD, Lawlor DA, Smith GD, Ness AR. Modifiable Maternal Exposures and Offspring Blood Pressure: A Review of Epidemiological Studies of Maternal Age, Diet and Smoking. Pediatr Res 2008;63:593-8.
11. Leary S, Davey Smith G, Rogers I, Reilly J, Wells J, Ness A. Smoking during pregnancy and offspring fat and lean mass in childhood. Obesity 2006;14:2284-93.
12. Gilman SE, Gardener H, Buka SL. Maternal smoking during pregnancy and children's cognitive and physical development: a causal risk factor? Am J Epidemiol 2008;168:522-31.
13. Batty GD, Der G, Deary IJ. Effect of maternal smoking during pregnancy on offspring's cognitive ability: empirical evidence for complete confounding in the US national longitudinal survey of youth. Pediatrics 2006;118:943-50.
14. Brion MJA, Leary SD, Davey Smith G, Ness AR. Similar associations of parental prenatal smoking suggest child blood pressure is not influenced by intrauterine effects. Hypertension 2007;49:1-7.
15. Leary S, Davey Smith G, Ness A. Smoking during pregnancy and components of stature in offspring. Am J Hum Biol 2006;18:502-12.
B748 - An investigation of breast cancer in the ALSPAC cohort - 12/08/2008
The aim of this project is to investigate the relationship between exposures during pregnancy and subsequent breast density, a strong determinant of breast cancer risk. The project will be undertaken within the Avon Longitudinal Study of Parents and their Children (ALSPAC) cohort. The specific objectives of the proposal are to investigate the relationship between each of two measures of breast density, described in detail below, and the following exposures:
i. Biological markers of the insulin-like growth factor (IGF) axis during pregnancy
ii. Nutritional intake during pregnancy
iii. Pregnancy weight patterns
iv. Diabetes or indications of hyperglycaemia in pregnancy
v. Blood pressure (BP), hypertensive disorder of pregnancy and pre-eclampsia
vi. Smoking during pregnancy
We also plan to investigate the relationship between IGF gene variants and IGF levels, with future plans to relate each of these to breast density.
The data collection phase of the project requires obtaining, digitising and analysing the mammograms of eligible mothers from the ALSPAC cohort. We will only include women who have a mammogram taken under the NHS Breast Screening Programme, which offers free mammography to women aged 50 to 70. As a result of the current study, we are not proposing to expose any woman to unnecessary radiation.
Eligibility criteria: The following women will be eligible to take part in the study; those who
i) have had a mammogram under the NHS Breast Screening Programme, or have one prior to the end of 2011 (eight months prior to study end);
ii) have not previously had a mammogram or MRI investigation of the breast
iii) consent to us accessing their mammograms (only requested from women aged 48 years or over, as per ethical approval);
iv) currently reside in Avon (this restriction is necessary, since we will only obtain mammograms from the Avon Breast Screening Programme)
Obtaining consent: Women who attend the Focus on Mothers clinic will be requested to consent to us obtaining and analysing their mammograms. Women who do not attend the clinic will be contacted by post and asked to give consent to us accessing their mammograms. Other than this, we will not have any further contact with the women.
Obtaining the mammograms: We will set up a flagging system, so that whenever a cohort member who has given us consent to access their mammogram attends screening, the research team will be informed. We will purchase an Array digitiser, and install it at the Avon Breast Screening Clinic (the Central Clinic). The research associate (RA) will then spend time at the Central Clinic each week, digitising the relevant films (both cranio-caudal and medio-lateral oblique images will be obtained), and transferring digital images to the coordinating centre. Dr Lis Kutt of the Central Clinic has writte a letter of collaboration agreeing to this.
Analysing breast density: Breast density will be performed in two ways: i) using a validated, computer-aided, threshold method, and ii) an automated volumetric method (SMF).
Exposure measurements: The following exposure data will be analysed.
From obstetric records: blood pressure and proteinuria in pregnancy; pregnancy weight measures; pregnancy diabetes / hyperglycaemia; offspring birthweight (from birth notification and/or obstetric data).
From questionnaire data: self-reported pre-pregnancy weight and waist/hip measures, (12 weeks' gestation); food frequency questionnaire (32 weeks' gestation); self-reported regular smoking during the 1st and 3rd trimesters; mother's weight at 8 weeks post-partum;
Biochemical measures: The earliest serum or plasma sample taken during pregnancy will be used to for analyses of: insulin, insulin-like growth factors (I and II) and relevant binding proteins (BP3).
Genetic measures: We plan to investigate 14 SNPs which have previously been demonstrated to be related to IGF-I or IGFBP-3 levels . Thirteen are listed below; one further relevant SNP (rs2854744) has already been genotyped. If other SNPs are identified from the literature duting the study period, we may request that analyses of further SNPs are performed. Funding to cover this eventuality will be requested in the initial grant proposal.
B686 - Follow-up of bone phenotype associated loci from ALSPAC GWA within the complete ALSPAC cohort - 11/08/2008
The aim of this proposal is to perform follow-up genotyping of top, bone phenotype related, genotypes within the remaining ALSPAC sample in order to replicate findings from the original ALSPAC genome-wide analysis. Our definition of "top" signals of interest will take into account a three sources of information, original ALSPAC genomewide association testing, bioinformatics analysis of highest scoring SNPs and from collaborative exchange between ALSPAC and an established study for genomewide association in extremes of bone mineral density. This, in combination with results available from the one available publication on this topic, should allow us to confidently generate a list of potentially replicating loci for further follow-up. Our current estimations as to the number of loci to be followed up are approximate, however (considering the power of our studies and budget constraints) are likely to include up to 20 loci.
In terms of the recognition and analysis of reliable genetic associates of bone mineral density, this use of the ALSPAC cohort marks an important step. Given the precision and diversity of the measures available in the ALSPAC cohort, this will mark the first comprehensive analysis of top genomewide association signals from available evidence in any cohort in this way and an encouraging first use of ALSPAC genomewide genotype data.
B685 - Is there a relation between Developmental Coordination Disorder at 7-8 years and physical activity at 11 years - 11/08/2008
Background:
Children with Developmental Coordination Disorder (DCD; 5-6% of children) form a large group at risk of a less active lifestyle, social isolation, obesity and mental health problems1-3 with a higher prevalence in boys (Boy:girl ratio of 4:1 to 7:10) 4. The relationship between movement skill in children with DCD and physical activity participation has not been established in a UK population. Mediating factors of generalised self efficacy and peer relations have been shown to influence physical activity in children with DCD in Canada and Australia respectively 1,5. Many of these children, due to their motor coordination difficulties, are unable to cycle or swim and thus may not be able to take advantage of government initiatives to boost fitness through school sport schemes. Furthermore, health fitness may be compromised in individuals with low motor competence3,6.
Reduced levels of physical activity participation in typically developing children are of a concern7,8 as well as considering the levels of physical activity energy expenditure during the day which contribute to overall health fitness9. Children with DCD may be at an additional, increased risk of reduced physical activity participation, in part due to a lack competence and confidence in their movement skill performance. This may contribute to exclusion by peers in PE and playground activities which results in social isolation, further reducing opportunities for exercise2,10-11. Lonliness and lowered life satisfaction of boys with DCD has been linked with reduced participation in team sports which may result in reduced participation in moderate to vigorous physical activity with incrased time engaged in activities with low levels of physical activity 5,12.
There is emerging evidence to suggest that children with DCD, particularly boys, may have a two-fold risk of obesity with 70% showing low cardio-vascular fitness1,3,6. Other studies have highlighted the social isolation experienced by these children along and additional risks of associated psychopathology 11,13. It is not known how these factors interact with a developmental history of poor movement skill to influence physical activity.
Current assessments and interventions for DCD tend to consider the short term amelioration of movement difficulties rather than participation and enjoyment in physical activities.
Dr Green is a post doctoral academic occupational theapist with a research interest in activity participation. This project will dovetail with the work of Dr Lingam and Professor Emond who have defined DCD within the ALSPACcohort and are looking at the long term psychosocial and health effects of this condition. ProfessorsNessand Riddoch have extensive research experience with ALSPAC exploring levels and patterns of physical activity and energy expenditure in children.
This study proposes to analyse data collected as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study.It will analyse the relationship between movement difficulities at age 7 to 8 years with later activity participation at age 11 years, adjusting for other physical health, psychosocial indicators and potential confounding factors.
B683 - An investigation of breastfeeding protection on obesity based on FTO genotypes - 04/08/2008
Background. Childhood obesity is considered to have reached epidemic levels in developed countries. A number of studies have reported remarkably strong, replicable associations with obesity indices for the FTO gene.
We investigated the prospect of breastfeeding protection from obesity markers on a genotype dependent way for the FTO rs9939609 and rs11075989 polymorphisms in the GENDAI cohort - 1138 children attending fifth and sixth grade living in the Attica region of Greece (53% girls; mean age: 11.2+/-0.7 years) recruited from randomly selected elementary schools.
For both SNPs, children homozygotes for the risk allele presented higher values of BMI, waist, waist to hip ratio, skinfolds (triceps and subscapular) body fatness and TNF-a levels. Multivariate analysis showed that, after controlling for age, sex, physical activity, Tanner stage and energy intake, the impact of both SNPs on body composition variables and on TNF-a levels remained statistically important. We looked then on breastfeeding variable and we found that the prevalence of any breastfeeding was 80.6% with the majority of breast feeders reporting duration of 2-4 months. Including breastfeeding as a covariant in the model we revealed that breastfeeding was inversely associated with waist to hip ratio (beta+/-SE: -0.075+/-0.016, p=0.0004). Additionally to that a strong interaction was observed with both SNPs for waist to hip ratio and for body fatness.
We want to use a sample of the ALSPAC cohort to replicate our findingds in the GENDAI cohort. For this purpose we are requesting data on children for which there is available information on breastfeading (see below) and genotypes for SNP rs9939609.
In the GENDAI study data on the method of infant feeding were obtained from self-completion questionnaires sent to each mother. Information on breastfeeding duration was available as a categorical variable, and for this study we had information on the exclusivity of breastfeeding and of breastfeeding and formula on the same time. A positive answer was recorded if the duration of breastfeeding exceeded one month.
We would like to request
Breastfeading Mother Questionnaire Birth to 6 months
Sex Child
Body weight Child Clinic at the age of 10-12 years
Height Child '' ''
Waist circumference Child '' ''
Waist to hip ratio Child '' ''
TNF-a (pg/ml) Child '' ''
skinfolds
triceps Child '' ''
subscapular Child '' ''
body fatness Child '' ''
Genotype rs9939609 Child
B682 - Risk Factors and outcomes associated with bedwetting daytime wetting and soiling in late childhood and early adolesence - 04/08/2008
Summary
The overall aim is to increase an understanding of the impact of nocturnal enuresis, day wetting and soiling in late childhood/early adolescence (9-13 years) and to examine risk factors for persistent wetting and soiling in a prospective cohort study - the Avon Longitudinal Study of Parents and Children (ALSPAC). The two main threads are:
(i) the impact of persistent wetting/soiling problems on the everyday life of young adolescents on outcomes,including mental health, education/school attainment, peer relationships, social activities and goals/aspirations for the future
(ii) the risk factors for wetting and soiling problems continuing through the period of late childhood and into early adolescence
Within these threads, the specific research questions of the proposed project are:
Impact of wetting and soiling
* Do children with persistent wetting/soiling at 13 years have a higher risk of problems with mental health, self concept / image, education/school attainment, peer relationships and leisure activities than those with delayed bladder/bowel control (wetting/soiling that resolved during the period 9-13 years)?
* Are there long lasting negative outcomes associated with experiencing a delay in attainment of bladder/bowel control, or do the problems improve/resolve following resolution of wetting/soiling?
* Does the impact of wetting/soiling problems become more acute or distressing in late childhood/early adolescence compared to earlier childhood?
* Are adolescents with combined problems (wetting and soiling) at increased risk of negative outcomes compared to those with wetting or soiling alone?
Risk factors
* What is the impact and timing of negative life events on trajectories of bladder/bowel control?
* Is there an increased vulnerability to negative outcomes in children with wetting/soiling who experience socioeconomic disadvantage
* Does onset of puberty have an impact on wetting/soiling problems? Is puberty associated with a resolution of wetting/soiling?)
* Is there a higher rate of cognitive impairments in children with persistent wetting/soiling compared to delayed bladder/bowel control?
B781 - Interactions between early diet and filaggrin and FADS mutations on risk of eczema asthma and allergen sensitisation - 01/08/2008
Asthma, eczema and other allergic disorders are common among children in industrialized countries, and their frequency is increasing. Changes in diet provide one possible explanation for this increase, but the results of dietary intervention trials in older children have been disappointing, and it has been suggested that diet during pregnancy and infancy may be critical to the development of atopy(1). In particular it has been suggested that the age of introduction of solids, duration of breastfeeding, and the balance of n-3/n-6 PUFAs in the pregnancy and infant diet may be important. Traditionally, the advice given on feeding infants at high risk of atopy is that to minimize risk they should be breastfed for at least six months, and that solid foods should be avoided for at least 4-6 months, with possible further delays in the introduction of particularly allergenic foods such as egg and peanuts(2-4). However, the efficacy of all aspects of this advice is questionable. There are a number of mechanisms by which early diet could be associated with the development of atopy. There could be a causal relationship, whereby early introduction of solid foods either induces an allergic response, or alternatively induces immune tolerance and so reduces the risk of allergy/atopy. It is possible that atopic parents, or parents noticing early symptoms of allergy in their child might delay the introduction of solids, generating a spurious association between the early introduction of solids and allergy/atopy (reverse causation). It is also possible that prolonged breastfeeding or delayed introduction of solids might increase the rates of allergy/atopy by affecting the development of mature immune response mechanisms in the infant - either by a direct reduction in exposure to immune stimulants such as bacteria, or in the case of breastfeeding by passive transfer or immune responses from the mother (hygiene hypothesis). There are relatively few studies of the associations of early diet with eczema and asthma and the results are very variable. Some studies have found early introduction of solids to be associated with wheezing and eczema, others have found no association, and some have found later introduction of particular solids to increase the risk of eczema and food sensitization (5,6).
One possible reason for the variability in the results of these studies is interaction of these dietary factors with the child's genotype. Loss of function mutations in the filaggrin gene have been shown to confer a greatly increased susceptibility to eczema, eczema plus asthma, and allergic sensitisation(7). This genotype has been shown to interact with environmental factors, with exposure to cats only being a risk factor for infant eczema among FLG deficient infants(8) Filaggrin has been detected in both human oral cavity and pharynx and rodent gut (9), and indeed the gut has been characterised as a key site for peanut absorption and sensitisation (10). However, as far as we are aware there is no data on how filaggrin genotype might interact with early dietary factors to determine the risk of allergic and atopic disorders.
Atopic sensitisation and inflammation are related to plasma levels of the 2-series prostaglandins and 4-series leukotrienes, which are derived from arachidonic acid(9). Common polymorphisms in the fatty acid delta-5 delta-6 desaturase gene cluster FADS1 and FADS2 have been linked with both altered plasma levels of arachidonic acid and clinical symptoms of adult atopy(10). There is no data on how FADS genotype is associated with the risk of wheeze and eczema in children and infants, nor on how this genotype may interact with early dietary factors such as PUFA intake.
Proposed project:
We propose to investigate the relationship between early dietary factors and atopic outcomes in the ALSPAC cohort, considering possible interactions with filaggrin and FADS genotype. Statistical analyses will take account of the possibility of reverse causation.
Data requested
1. Outcome variables:
Wheeze in the first 3 years of life (assessed by questionnaire at 6m, 18m, 30m and 42m)
Wheeze at 7 1/2 years of life (self-reported)
Questionnaire data on doctor-diagnosed asthma at 7 years
Lung function by BHR at 8 years (clinic assessment)
Results of skin prick tests at 7 years (clinic assessment)
Eczema assessed by questionnaire at 6, 18, 39, 42, 57 and 81 months of age.
Flexural dermatitis assessed by observation annually from 7y to 11y (clinic assessment).
2. Infant dietary predictor variables (all assessed by questionnaire at 6m and 15m):
Duration of breastfeeding
Age of introduction of formula milk.
Age of introduction of any solids.
Number of solids introduced at 4m and 6m.
Age of first introduction of egg, fish, meat, fruit, vegetables
Pregnancy dietary predictor variables (assessed by FFQ at 32 wks gestation):
PUFA intake in pregnancy
fish intake in pregnancy
3. Other predictor variables:
Fillagrin genotype
FADS genotype
4. Confounding variables:
Maternal education (assessed by questionnaire at 32 wks gestation)
Maternal age (assessed by questionnaire)
Smoking in pregnancy (assessed by quesitionnaire at 32 wks gestation)
Maternal parity (assessed by questionnaire)
Pet exposure (assessed by questionnaire)
Gestation (assessed by questionnaire)
Sex
ETS in first four years (assessed by questionnaire)
Crowding (assessed by questionnaire)
Child's BMI
Parental atopy (assessed by questionnaire)
References
1. Devereux G. The increase in the prevalence of asthma and allergy: food for thought. Nature Reviews Immunology 2006;6:869-874.
2. Pediatric Nutrition Handbook. 2004 Elk Grove, IL: American Academy of Pediatrics.
3. World Health Organisation. Fifty-Fourth World Health Assembly. WHA54.2 Agenda Item 13.1. Infant and Young Child Nutrition. 2004. Geneva, Switzerland: World Health Organization.
4. Murano A et al. Dietary prevention of allergic diseases in infants and small children: part III - critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatric Allergy and Immunology, 2004;15:291-307.
5. Tarini B et al. Systematic review of the relationship between early introduction of solid foods to infants and the development of allergic disease. Archives of Pediatric and Adolescent Medicine 2006;160:502-507.
6. Zutavern A. et al. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitisation at the age of 6 years. Results from prospective birth cohort study LISA. Pediatrics 2008;121:e44-e52.
7. Henderson J et al. The burden of disease associated with filaggrin mutations: A population-based longitudinal birth cohort study. Journal of Allergy and Clinical Immunology 2008 (In Press).
8. Bisgaard H et al. Gene-environment interaction in the onset of eczema in infancy: Filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PloS Med 2007;5:e131.
9. Makino T et al. Expression of hornerin in stratified squamous epithelium in the mouse: a comparative analysis with profilaggrin. J Histochem Cytochem 2003;51:485-492.
10. Anonymouse. Absorption of peanuts. N Engl J Med 1981;304:359-360.
11. Behrendt H et al. Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergen sensitization. Int Arch Allergy Immunol 2001;124:121-125.
12. Schaeffer L et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Human Mol Gen 2006;15:1745-1756.
B680 - Molecular Phenotyping in the Avon Longitudinal Study of Parents and their Children A resource for understanding Molecular genetic pathways underlying phenotypic variation in humans - 30/07/2008
ObThe aim of this application is to develop a world-class resource for systems biology that elucidates the molecular pathways underlying genotype-phenotype associations in the UK's largest, most densely phenotyped, prospective cohort. Specifically, 1000 adolescents from the Avon Longitudinal Study of Parents and their Offspring (ALSPAC) who have been measured repeatedly in a prospective study across a wide range of biological, sociological and behavioural variables, and for whom pre-existing genome-wide SNP data and genome-wide expression levels in transformed lymphoblastoid cell lines are also available, will be assayed on a range of molecular phenotypes including: (a) level of small molecule metabolites, (b) serum protein concentrations, and (c) methylation profiles. This information will then be entered into a database and made available to bona fide researchers, through data sharing systems that already exist within ALSPAC and that facilitate rapid access with clear variable definitions. The database will not only comprise the world's largest collection of molecular phenotypes to date, but also the first publicly available resource for systems biology which allows users to integrate genetic and molecular data with end stage phenotypes.
B684 - Role of Growth Hormone pathway SNPs in childhood obesity - 28/07/2008
Aim:
We intend to analyse genetic variants in genes of the growth hormone pathway for their association with childhood fat mass and measures of obesity in adulthood.
Rationale:
This is a continuation of a project which has already identified an association between a genetic variant in the the growth hormone gene cluster and fat mass in ALSPAC children. We wish to expand this research to include other genes in the same pathway that may have additional effects on fat mass in order to determine (a) the importance of this pathway in childhood obesity and adult cardiovascular risk and (b) whether there is any potential for therapeutic developments. Genetic variants have been selected on the basis of functional candidacy and nominal association (pless than 0.01) with type II diabetes in the WTCCC genome-wide data. This combines the notion of prior biological knowledge with significance values in genome wide data, as typified for example by the appearance of key pharmacogenetically important genes such as PPARG in genome wide data. The growth pathway includes several drugged, druggable or possibly nutritionally modifiable targets and these may be lower down the order of hundreds of genes with modest effects in polygenic disease although potentially of more practical utility as targets..
Methods:
Genetic analyses will be carried out by KBioscience according to the standard ALSPAC arrangements for SNP genotyping. Data analysis will be carried out in STATA using regression to test per allele genetic effects.
Genetic variants and phenotypes are listed below.
Expected value of results:
Understanding the genetic mechanisms underlying obesity is an important component of researching the obesity epidemic. We hope this project will direct us to genetic variants that are both important in childhood obesity and in predisposition to adult cardiovascular disease. This work will help clarify the role of a candidate genetic pathway and provide valuable information for future research.
B679 - Sedentary Behaviour and its Impact on Physical Fitness in Adolescents - 19/07/2008
Purpose:
To examine any potential, independent, association between sedentary behaviour and physical fitness among the ALSPAC adolescents at 13 years old
Background:
Cardiorespiratory fitness (CRF) is an important component of overall physical fitness and low CRF was found to increase the risk of mortality, in adults, independent of fat mass (1). Therefore improving physical fitness should perhaps be a priority, and may have a greater impact upon health outcomes than if weight reduction is solely targeted. Engaging in physical activity is of great benefit to CRF, especially vigorous physical activity (2). However, physical activity does not explain all the variance in CRF (2). Therefore, specifically reducing the time spent sedentary may be of importance. Previous studies involving adults and children have shown sedentary behaviour to be independently associated with various health outcomes (3, 4). However, there is a lack of research concerning the independent effects of sedentary behaviour upon CRF, and this information could potentially help ameliorate morbidity and mortality rates seen in later life (1).
Variables
- Dependent Variable:
? Physical Fitness (PWC 170; 13 year olds; clinical)
- Independent Variable:
? Sedentary Behaviour (hours per day, accelerometry; 13 years old; clinical)
- Covariates:
? Age, pubertal status (chronological and biological maturation; 13 years old; child-response questionnaire)
? Birth length, birth weight, gestation, TV viewing (38mo) and sleep patterns (30mo) (intrauterine factors and early life factors; parental/birth records, 30 and 38 month questionnaire)
? Parental height, parental BMI, social class, maternal smoking during pregnancy, maternal education at time of birth (parental and sociodemographic factors; 32 week questionnaire)
? Adolescents total fat mass (body composition measure; 13 years old; DXA)
? MVPA (physical activity, accelerometer; 13 years old; clinical)
B678 - Childhood negative early life events and pain in adolescence a birth cohort study - 16/07/2008
Aims and purpose of the proposed research
The proposed study will examine whether negative early life events in childhood predict pain in adolescence. To do so the study will examine the following hypotheses:
1) Negative early life events in childhood (pre-natal, birth and early childhood) predict musculoskeletal pain in adolescence
2) Negative early life events in childhood (pre-natal, birth and early childhood) predict chronic widespread pain in adolescence
3) These relationships are moderated by physiological and psychological factors including HPA axis dysfunction, sleep, anxiety and depression.
B677 - Physical activity in pregnancy and offspring neurodevelopment - 14/07/2008
Background
Physical activity has been associated with improvements in cognitive function in both animals and humans. In adult rats and mice, voluntary physical activity has been associated with neurogenesis in the hippocampus (1, 2) and with an increase in long-term potentiation of synaptic efficacy (2). In adult humans, cardiovascular fitness is associated with better performance on cognitive functioning tests (4). In rats and mice, maternal exercise during pregnancy appears beneficial to offspring neurodevelopment. In mice, voluntary wheel running during pregnancy led to differences in offspring's hippocampal cell proliferation (5). In rats, maternal swimming once a day for 10 minutes was associated with offspring having higher levels of neurogenesis in several regions of the hippocampus, higher levels of brain-derived neurotrophic factor, and better short-term memory (6).
The hippocampus may play a key role in the mechanism underlying these beneficial effects of physical activity. Traditionally, the hippocampus has been thought to preserve episodic memories (memories of events) while its role in memorization of facts (semantic memory) is less established. However, recent research has implicated the hippocampus in semantic memory potentially through its role in associative thinking (7, 8). As an example, the hippocampus was recently implicated in acquiring a unique and imaginary lexicon through visual images. Thus, language acquirement through associative learning, as is done in children, may be mediated by the hippocampus (9).
In humans, the effects of physical activity during pregnancy on the neurodevelopment of offspring have been inadequately studied. Three studies of the subject of three slightly different samples of women have been done by JF Clapp. In one study of healthy women with a history of engaging in regular physical activity, women who continued to exercise throughout pregnancy had neonates (N=34) who scored higher in terms of orientation behavior and their ability to regulate state at 5 days after birth as measured by the Brazelton Neonatal Behavioral Assessment Scales when compared to neonates born to women who did not exercise (N=31) (10). In a similar study design, infants of exercising mothers (N=52) at one year of age scored slightly (non-significantly) higher on the mental performance domain of the Bayley Scales of Infant Development when compared to infants of non-exercising mothers (N=52). For psychomotor score, however, infants of exercising mothers scored statistically significantly higher, though the effect was small (11). In the third study, 5 year-old children of women who exercised during pregnancy (N=20) were compared to women who did not exercise (N=20) using the Wechsler Preschool and Primary Scale of Intelligence-Revised, the Peabody Picture Vocabulary Test, the Expressive One Word Picture Vocabulary Test, and the Clinical Evaluation of Language Fundamentals. The children of exercising mothers scored higher in the domains of general intelligence (p=0.01) and oral language skills (p=0.01) (12). The difference in language skills is particularly intriguing given the potential role of the hippocampus in vocabulary acquisition.
Investigation is needed on physical activity during pregnancy in relation to offspring neurodevelopment in humans. Animal evidence supports a biological mechanism for such an effect but the previous human studies suggest a positive association yet are not convincing.
Project Description
We propose an investigation of physical activity during pregnancy in relation to neurodevelopment in offspring using data from ALSPAC. This cohort is ideal for this project for several reasons. We expect that if physical activity influences neurodevelopment the effect may be small and the large sample size in ALSPAC will improve power. Physical activity was assessed by self-administered questionnaire at approximately week 18 of pregnancy for nearly 12,000 women. Of these, we expect over 4,000 will have had IQ measured at age 8 years.
Several questions in section G of the 18 week pregnancy questionnaire have questions on physical activity. Most importantly, question G19 ascertains the number of hours per week, at present, that the woman participated in any of 11 specific exercise-intensive activities.
With respect to outcome, ascertainment was of especially high quality at age 8 compared with other large cohorts that rely on parent-completed questionnaires only. We will follow the analytical plan as presented by Hibbeln et al. (13), in their recent paper on pregnancy seafood consumption in relation to neurodevelopmental outcomes in childhood (except with physical activity scale(s) as the main exposure variable). Their results were adjusted for 26 potentially confounding factors; we might also want to adjust for pregnancy seafood intake.