Proposal summaries
B886 - RELATIONSHIPS BETWEEN MATERNAL BACKGROUND UVB EXPOSURE AND CORD BLOOD DNA METHYLATION - 05/10/2009
Background
We recently reported a positive association in ALSPAC between background levels of UVB in the third trimester of pregnancy, derived from meteorological office records, and subsequent bone development of the child based on DXA scans at age nine (1). UVB exposure as analysed in this way provides a measure of vitamin D status in utero (2), which is in turn thought to contribute to programming of development of several systems within the off-spring including the skeleton. Although the mechanisms which mediate these effects are unknown, one possibility is that these involve altered methylation status of as yet unidentified target genes, by virtue of effects of vitamin D on the activity of enzymes involved in DNA methylation. Following recent methodological advances which enable methylation status to be evaluated at multiple sites across the genome (3), proof of concept studies intended to examine the role of methylation are now feasible.
Hypothesis
Our overall hypothesis is that exposure to low levels of vitamin D in utero has adverse effects on subsequent skeletal development as a consequence of altered methylation of key regulatory genes. The present proposal aims to address one component of this hypothesis, namely that vitamin D exposure in utero affects DNA methylation at multiple sites.
Objectives/Design
1. Approximately 50 DNA sites showing the greatest variability in methylation status will be identified in collaboration with Caroline Relton (University of Newcastle), based on methylation status recently measured at 1500 sites (covering 800 genes) in cord blood samples from 174 ALSPAC children.
2. The genes represented by these sites will be classified according to what biological pathway or process they are likely to affect.
3. Relationships will be analysed between maternal UVB and extent of methylation for each of the 50 methylation sites in turn.
Techniques/approaches
Since last trimester UVB exposure and DNA methylation are both continuous variables, analyses will initially involve linear regression. Further analyses will be performed in which UVB exposure is treated as a dichotomous variable, eg by examining differences in methylation status between those in the upper and lower quartile of UVB (equivalent to birth in late summer and early spring respectively). Additional analyses may also be possible between DNA methylation and maternal vitamin D status in the last trimester in ALSPAC, based on direct measurement of vitamin D which is currently in progress. Whether relationships between maternal vitamin D status and DNA methylation vary according to biological pathway will be addressed by comparing these associations between different categories of genes. Positive findings will subsequently be replicated by repeating these analyses in a cohort from North Cumbria where equivalent information on cord blood DNA methylation and birthdate is available from approximately 200 off spring.
References
1. Sayers A, Tobias JH 2009 Estimated maternal ultraviolet B exposure levels in pregnancy influence skeletal development of the child. J Clin Endocrinol Metab 94:765-771
2. Sayers A, Tilling K, Boucher BJ, Noonan K, Tobias JH 2009 Predicting ambient ultraviolet from routine meteorological data; its potential use as an instrumental variable for vitamin D status in pregnancy in a longitudinal birth cohort in the UK. Int J Epidemiol
3. Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GH, Wong AH, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman, II, Martin NG, Petronis A 2009 DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41:240-245.
B885 - Near Term Birth and Long Term Cognitive Outcomes - 29/09/2009
Aim of the project
The aim of the project is to investigate the relationship between the infants born "near term" (32 to 36 weeks gestation) and IQ.
Background
The long term effects of prematurity are well recorded in infants born before 32 weeks corrected gestation. Extreme prematurity is associated with increased risks of cerebral palsy, speech[1], educational[1], and executive functioning[2] deficits as well as reduction in more global measures of cognition. The long term outcome of infants born at only moderately premature gestations however is less clear. Previous studies have suggested increased rates of educational concerns in infants born before 37 weeks gestation[3, 4] but little evidence exists on specific measures of cognition, particularly IQ, and other measures of neuro-development. At present these infants little specific educational input, and indeed recent recommendations have suggested that that only infants below 32 weeks of gestational age should be offered formal neuro-developmental follow-up.
Experimental design and methods to be used in investigating this problem
Infants born above 31 weeks gestational age will be identified from the ALSPAC cohort. The exposure of interest will be gestational age, categorized as near term (less than 37 weeks corrected gestation) or term (37 weeks or more). The primary outcome will be IQ (as measured by the WISC-II at 8 years). In addition measures of school performance, manual dexterity, attention, memory and language skills will also be assessed.
Covariates
Measures of neonatal wellbeing will be obtained from the STORK dataset (available for all infants born in St Michaels orSouthmeadHospital). Measures used in the analysis will be:
- Antenatal factors: Gender, maternal parity and maternal hypertension.
- Intrapartum factors: Birth weight, length and head circumference (corrected for gestation), mode of birth (i.e. spontaneous cephalic, emergency or elective caesarian section, instrumental or breech) and maternal pyrexia.
- Social factors: Maternal age, socioeconomic group and educational achievements, car ownership, housing tenure, crowding and ethnicity.
Any infants who are admitted to the neonatal unit will have further data on presence or not of neurological signs recorded from the Neonatal Data. Covariates will be added to the model in the blocks above.
Analysis Strategy
Exposure groups will be defined by completed gestational age (32-36 weeks). A reference groups will be defined of infants born at term (37 weeks or more completed weeks) who did not require admission to a neonatal unit.
Outcomes will be both the difference in mean value in the outcome variable (if normally distributed) and the proportion of infants in the lowest 10%. An IQ of less than 80 will be considered 'low'. Linear and logistic regression models will be used to assess the association between the exposure and the outcomes as appropriate.
A secondary analysis will be performed with the results stratified by the completed week of gestation and including all infants born at term (including those admitted to the neonatal units).
Chained Equations may be used to impute the value of any missing covariate data. All analysis will be performed using STATA 10 software (Stata Corp, TX,USA).
Study power
Assuming that around 5% of infants will be born moderately preterm and that there is IQ data available on 6000 infants within the cohort, we would have a power of greater than 99% to find a clinically important difference of 3.25 IQ points (a quarter of one standard deviation) with an alpha of 5%.
References
1. Wolke D, Samara M, Bracewell M, Marlow N, Group EPS: Specific language difficulties and school achievement in children born at 25 weeks of gestation or less.[see comment]. Journal of Pediatrics 2008;152:256-262.
2. Marlow N, Hennessy EM, Bracewell MA, Wolke D, Group EPS: Motor and executive function at 6 years of age after extremely preterm birth. Pediatrics 2007;120:793-804.
3. Chyi LJ, Lee HC, Hintz SR, Gould JB, Sutcliffe TL: School outcomes of late preterm infants: special needs and challenges for infants born at 32 to 36 weeks gestation. J Pediatr 2008;153:25-31.
B884 - Meta-analysis of genome-wide association studies of Eczema - 24/09/2009
Eczema is due to multiple genetic and environmental factors. Although variants in the fillagrin gene have been robustly associated with eczema risk, the vast majority of the genetic variance in this condition remains to be explained. It is our aim to construct a variable indicating whether an individual has ever suffered from eczema and to subject this variable to genome-wide association analysis. Similar data is also available from twins UK (Tim Spector) and Queensland Institute of Medical Research (Nick Martin) and both groups have expressed interest in the possibility of pooling results in a meta-analysis. We will aim to follow up significant associations in the remainder of the ALSPAC cohort and other cohorts for which this measure is available.
B880 - The association of vitamin D with cognitive function in childhood - 23/09/2009
Background: The role of vitamin D in calcium metabolism and bone health is well documented. Vitamin D enables normal bone mineralization and prevents hypocalcemic tetany. It is also necessary for bone growth and bone remodeling by osteoblasts and osteoclasts. Vitamin D deficiency is common and typically arises from inadequate intake, inadequate sunlight exposure, and limited absorption or conversion into active metabolites (often due to liver or kidney disorders). Recent studies suggest that vitamin D influences various health conditions (such as diabetes, heart disease and hypertension) and mortality. Accumulating evidence also suggests previously unsuspected roles for vitamin D in brain development and neuroprotection. Recent population-based studies link vitamin D deficiency in old age with cognitive function cross-sectionally (Buell, et al., 2009; Lee, et al., 2009; Llewellyn, et al., 2009) and prospectively (Llewellyn, et al., in review). Further research is needed to establish whether vitamin D deficiency influences cognitive development in children.
The mechanisms underlying these associations are unclear, and residual confounding is possible, particularly in cross-sectional studies. Vitamin D receptors are present in a wide variety of cells, including neurons and glial cells, and genes encoding the enzymes involved in the metabolism of vitamin D are also expressed in the brain (McCann & Ames, 2008). In a recent review, Buell and Dawson-Hughes (2008) emphasize that Vitamin D may be neuroprotective through antioxidative mechanisms, immunomodulation, neuronal calcium regulation, detoxification mechanisms and enhanced nerve conduction. Vitamin D may play a role in brain detoxification pathways by reducing cellular calcium, inhibiting the synthesis of inducible nitric oxide synthase and increasing levels of the antioxidant glutathione (Garcion, 2002). Vitamin D stimulates neurogenesis and regulates the synthesis of neurotrophic factors which are important for cell differentiation and survival (Brown, et al., 2003). Vitamin D is also an immunosuppressor and may inhibit autoimmune damage to the nervous system (Garcion, 2002). Calcitriol stimulates amyloid-beta phagocytosis and clearance while protecting against apoptosis (Masoumi, et al., 2009). Low levels of vitamin D may also be associated with an increased risk of neurological diseases such as multiple sclerosis (Munger, et al., 2006), and Parkinson's (Newmark & Newmark, 2007).
The majority of brain development occurs in utero and during childhood. Optimal cognitive development in early-life may confer resistance to late-life cognitive decline and dementia in late life through 'cognitive reserve' and higher levels of midlife functioning. To our knowledge no prospective study has examined the association between in utero or early childhood vitamin D levels and childhood cognition or educational attainment. We also intend to examine whether genetic variants associated with vitamin D levels are also associated with cognitive function in childhood using an instrumental variables approach.
We would envisage the following series of papers to result from this work:
1) Association of childhood vitamin D with childhood intelligence.
2) Association of childhood vitamin D with educational attainment (key stage and GCSE) and the possible mediation by intelligence.
3) Association of maternal vitamin D during pregnancy with childhood intelligence and educational attainment (taking into account childhood vitamin D levels).
4) Possible neuroimaging studies (in collaboration with Tomas Paus and others) to further explore the above.
This work fits very well with Debbie Lawlor's MRC funded vitamin D grant which had as a main focus vascular and metabolic outcomes but noted that we would also examine relevant associations with a wide range of other health outcomes for which causal claims for vitamin D have been made. In this respect bone and respiratory/atopy phenotypes were specifically mentioned (in the grant and original proposal to exec.) but IQ and educational outcomes were not and therefore we are submitting this request here.
Methods
Existing data and planned (funded) vitamin D assays will be used. Analyses will be completed by Anna Tolpeinan with supervison by Debbie Lawlor and input (including development of analysis plan) from other applicants. Our preliminary analysis plan is to use multivariable regression models with adjustment for potential confounders. Potential mediators will be added as additional terms to fully adjusted models. Debbie Lawlor has access to all necessary data except educational attainment. We are aware that these data have been funded by the ESRC large grant and would be very keen to collaborate with the key person involved in the funding and collection of those data.
B879 - The association of childhood sedentary behaviour with cardiovascular risk factors - 23/09/2009
Among adults, excessive sedentary behaviour (as characterised by those activities that involve sitting, in particular screen (TV or computer) viewing) is linked to increased risk for cardiovascular events,(1,2) all-cause mortality,(1) obesity,(3,4) dyslipidemia,(5) higher plasma glucose levels,(6) and the metabolic syndrome.(7) These links seem to be independent of participation in moderate-to-vigorous physical activity (MVPA). For example, among adults who meet the MVPA guidelines, significant, detrimental dose-response associations of sedentary time exist with all-cause and cardiovascular mortality,(1) waist circumference and BMI,(3) systolic blood pressure, 2-hour plasma glucose, fasting plasma glucose, triglycerides, and HDL cholesterol.(8)
In children, it is less clear how sedentary behaviour relates to cardiovascular and metabolic health. There is cross-sectional evidence that sedentary behaviours, such as TV viewing relates to cardiometabolic risk,(9,10) but these cross-sectional relationships are not always independent of MVPA, especially when sedentary behaviour and MVP are measured objectively,(11) raising the possibility that research based on non-objective measurements is biased. However, cross-sectional evidence may be explained by reverse causation, for example there are indications that body weight status can predict sedentary behaviour but sedentary behaviour may not predict future obesity in adults.(12) There is very little work done on the longitudinal relationships of objectively measured sedentary behaviour and cardio-metabolic health indicators in children. Such evidence will provide clues as to whether sedentary behaviour should be targeted separately to MVPA to protect and improve children's health. If sedentary time is found to be independently associated with cardio-metabolic risk in children, UK physical activity recommendations should explicitly address sitting in addition to recommending 60 minutes of MVPA a day. Such recommendations currently exist in guidelines in USA and Canada(13) and Australia,(14) where it is recommended that children limit their TV viewing time to less than 2 hours per day.
The main purpose of the proposed project will therefore be to study the longitudinal associations between sedentary behaviour and cardio-metabolic risk factors in children with an emphasis on the interactions between MVPA. Specific objectives would be:
* To examine the association of sedentary behaviour (assessed by questionnaire and accelerometer) in earlier childhood with variation in fasting blood glucose, insulin & lipids assessed at age 15 and 17 years.
. To examine the extent to which any of these associations are mediated by adiposity
. To examine whether associations of sedentary behaviour with these metabolic risk factors varies by whether the person has high or low levels of MVPA
Manos Stamatakis is applying for a Wellcome Trust senior career scientist fellowship to address these issues using data from a number of cohort studies and National cross-sectional surveys. These are likely to include (permissions either obtained or currently being sought) the Health Survey for England, Whitehall II and British Women's Heart and Health Study. One overall aim is to examine how patterns of sedentary behaviour and their associations vary by age group. Relevant analyses in ALSPAC as one part of his planned work for this fellowship. This will use data already available/funded in ALSPAC, including collected accelerometer data (Chris Riddoch grants) and fasting blood sample data (Debbie Lawlor grants) and will not require new data collection or bio-assays.
This application has been discussed with Prof C Riddoch & we would work in close collaboration with him & with Professors S Blair & R Pate who are applicants on the grant that funds the accelerometer data.
Methods
All applicants will develop the analysis protocol, in collaboration with S Blair & R Pate
DAL will put together the dataset
MS will complete analyses
All applicants will contribute to papers for publication
References
1. Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting Time and Mortality from All Causes, Cardiovascular Disease, and Cancer. Med Sci Sports Exe. 2009;41:998-1005.
2. Stamatakis E, Hamer M, Dunstan DW. Television and other screen-based entertainment time and cardiovascular events: population-based study with ongoing mortality and hospital events follow up. Under Review
3. Stamatakis E, Hirani V, Rennie K. Moderate-to-vigorous physical activity and sedentary behaviours in relation to body mass index-defined and waist circumference-defined obesity. Br J Nutrit 2009;101:765-773.
4. Frank LD, Martin A. Andresen MA, et al. Obesity Relationships with Community Design, Physical Activity, and Time Spent in Cars. Am J Prev Med 2004;27:87-96.
5. Jakes RW, Day NE, Khaw KT, et al. Television viewing and low participation in vigorous recreation are independently associated with obesity and markers of cardiovascular disease risk: EPIC-Norfolk population-based study. Eur J Clin Nutr. 2003;57:1089-1096.
6. Healy GN, Dunstan DW, Salmon J, et al. Objectively Measured Light-Intensity Physical Activity Is Independently Associated With 2-h Plasma Glucose. Diabetes Care. 2007;30:1384-1389.
7. Chang PC, Li TC, Wu MT, et al. Association between television viewing and the risk of metabolic syndrome in a community based population. BMC Public Health 2008;8:193 doi: 10.1186/1471-2458/8/193.
8. Healy GN, Dunstan DW, Salmon J, et al.: Television time and continuous metabolic risk in physically active adults. Med Sci Sports Exerc 2008, 40:639-645
9. Ekelund, U; Brage, S; Froberg, K; et al. TV viewing and physical activity are independently associated with metabolic risk in children: The European Youth Heart Study. PLoS Medicine 2006; 3: 2449-2457.
10. Martinez-Gomez, D; Tucker, J; Heelan, KA; et al. Associations Between Sedentary Behavior and Blood Pressure in Young Children. Archives of Pediatrics & Adolescent Medicine 2009, 163 (8): 724-730.
11. Mitchell JA, Mattocks C, Ness AR, et al. Sedentary Behavior and Obesity in a Large Cohort of Children. Obesity 2009; 17: 1596-1602
12. Ekelund U, Brage S, Besson H, Sharp S, Wareham NJ. Time spent being sedentary and weight gain in healthy adults: reverse or bidirectional causality? Am J Clin Nutr. 2008;88:612-617.
13. American Academy of Pediatrics, Committee on Public Education. Children, adolescents, and television. Pediatrics. 2001;107:423-426.
14. Australian Government, Department of Health and Ageing. Australia's physical activity recommendations for 5-12 tear olds. Department of Health and Ageing 2004, Canberra, Australia.
B878 - Psychosocial Stress Growth Tempo and Pubertal Timing - 23/09/2009
A building body of research evidence suggests that intrauterine and early life exposures contribute to chronic disease risk in later life. While recent evidence supports the role of childhood adversities on reproductive lifespan,1-4 yet there is a limited understanding of mechanisms through which these adversities impact health. Researchers have established an association between psychosocial stressors in childhood and disruption of pubertal timing. The strongest literature is among girls, and using age at menarche (AAM) as a proxy measure for pubertal timing. Earlier age at menarche has been linked to all cause mortality,5 risk for breast cancer,6-8 cardiovascular disease,9 depression,10 metabolic syndrome11 and associated features, including overweight/obesity,12,13 insulin resistance,14 and polycystic ovarian syndrome,10 while later age at menarche is associated with depression,15,16 fractures,17-19 and lower bone mineral density.20-22 To date there has been limited exploration of psychosocial predictors of pubertal onset and the tempo of pubertal development among both girls and boys.
Psychosocial antecedents of age of menarche include: familial conflict,23 alterations in family structure,24 stressful home circumstances,25-27 paternal absence in childhood,28 and quality of familial relationships.29,30 3,25,31-34 A growing number of studies have demonstrated an association between child abuse and age at menarche.3,35-39 In the five studies to date sexual abuse has demonstrated a stronger and more consistent association with early menarche while physical abuse has had a weakly positive association in some studies.3,35-39 A shared limitation of these studies is the failure to account for additional childhood hardships, such as poverty, that are also associated with pubertal development.
The intent of this study is to investigate the independent and cumulative impact of multiple types of childhood adversities (including child abuse, neglect, family conflict, and socioeconomic status) on timing of puberty in this prospective birth cohort. We hypothesized that children exposed to higher cumulative adversities will be more likely to have altered timing of menarche-earlier or later age at onset. We proposed to investigate the relation between exposure to early life adversities and the tempo of pubertal development and timing of puberty. Specifically, we are interested in exploring the impact of exposure to physical abuse, sexual abuse, emotional abuse, neglect, and/or family conflict and the timing and tempo of pubertal development. We hypothesize that childhood adversities may impact pubertal development through influences on rate of change in BMI over time, lifestyles and health behaviours, including dietary habits, physical activity, and sedentary behaviours. Existing studies are limited by retrospective exposure assessment, and failure to consider multiple types of adversities.
Thus, a proposed mechanism linking exposure to child abuse and sexual maturation is through dysregulation of neuroendocrine systems that respond to environmental challenges (such as the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-gonadal (HPG) axes. Child maltreatment is a significant psychosocial stressor and therefore may influence responsiveness of the HPA and HPG axes, neuroendocrine functioning, hormonal milieu and ultimately influence timing of sexual maturation. In addition, child abuse may be associated with nutritional factors, energy expenditure, level of activity, and health behaviors in early life that impact AAM. Compelling evidence from several recent studies suggest a relation between childhood adversities and body mass index (BMI) in adulthood.40,41 Child maltreatment has been linked to both excessive weight control and obesity,40-47 and disordered eating.48-53
A second area of interest is the relation between pubertal development and disordered eating patterns and body dissatisfaction. Puberty is one commonly cited risk factor for disordered eating, body dissatisfaction, and eating disorders.10,54 Past studies which have investigated the timing of puberty in relation to the development of eating disorders, and body dissatisfaction have produced mixed findings.54-58 A common limitation shared by previous studies includes the use of cross-sectional methodology, clinical samples, or small community samples. The advantage of the AVON study is that it is robust and comprehensive in the measurement of disordered eating and puberty, the longitudinal methodology, sample size, and sample population. This secondary analysis will focus on the impact of characteristics of pubertal development, particularly timing and tempo, on patterns of disordered eating, eating disorders, and degree of body dissatisfaction.
Please see the attached Excel spreadsheet which outlines the concepts, measures, source, and time points requested (as outlined in application item #8).
References
1. Mishra GD, Cooper R, Tom SE, Kuh D. Early life circumstances and their impact on menarche and menopause. Womens Health (Lond Engl) 2009;5(2):175-90.
2. Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 2003;24(5):668-93.
3. Romans SE, Martin JM, Gendall K, Herbison GP. Age of menarche: the role of some psychosocial factors. Psychol Med 2003;33(5):933-9.
4. Slyper AH. The pubertal timing controversy in the USA, and a review of possible causative factors for the advance in timing of onset of puberty. Clin Endocrinol (Oxf) 2006;65(1):1-8.
5. Jacobsen BK, Heuch I, Kvale G. Association of low age at menarche with increased all-cause mortality: a 37-year follow-up of 61,319 Norwegian women. Am J Epidemiol 2007;166(12):1431-7.
6. Hamilton AS, Mack TM. Puberty and genetic susceptibility to breast cancer in a case-control study in twins. N Engl J Med 2003;348(23):2313-22.
7. Bernstein L. Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia 2002;7(1):3-15.
8. Romundstad PR, Vatten LJ, Nilsen TI, Holmen TL, Hsieh CC, Trichopoulos D, Stuver SO. Birth size in relation to age at menarche and adolescent body size: implications for breast cancer risk. Int J Cancer 2003;105(3):400-3.
9. Remsberg KE, Demerath EW, Schubert CM, Chumlea WC, Sun SS, Siervogel RM. Early menarche and the development of cardiovascular disease risk factors in adolescent girls: the Fels Longitudinal Study. J Clin Endocrinol Metab 2005;90(5):2718-24.
10. Stice E, Presnell K, Bearman SK. Relation of early menarche to depression, eating disorders, substance abuse, and comorbid psychopathology among adolescent girls. Dev Psychol 2001;37(5):608-19.
11. Frontini MG, Srinivasan SR, Berenson GS. Longitudinal changes in risk variables underlying metabolic Syndrome X from childhood to young adulthood in female subjects with a history of early menarche: the Bogalusa Heart Study.Int J Obes Relat Metab Disord 2003;27(11):1398-404.
12. Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME.Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics 2001;108(2):347-53.
13. Adair LS, Gordon-Larsen P. Maturational timing and overweight prevalence in US adolescent girls. Am J Public Health 2001;91(4):642-4.
14. Ibanez L, Potau N, de Zegher F. Recognition of a new association: reduced fetal growth, precocious pubarche, hyperinsulinism and ovarian dysfunction. Ann Endocrinol (Paris) 2000;61(2):141-2.
15. Bisaga K, Petkova E, Cheng J, Davies M, Feldman JF, Whitaker AH. Menstrual functioning and psychopathology in a county-wide population of high school girls. J Am Acad Child Adolesc Psychiatry 2002;41(10):1197-204.
16. Herva A, Jokelainen J, Pouta A, Veijola J, Timonen M, Karvonen JT, Joukamaa M. Age at menarche and depression at the age of 31 years: findings from the Northern Finland 1966 Birth Cohort Study. J Psychosom Res 2004;57(4):359-62.
17. Fujiwara S, Kasagi F, Yamada M, Kodama K. Risk factors for hip fracture in a Japanese cohort. J Bone Miner Res 1997;12(7):998-1004.
18. Roy DK, O'Neill TW, Finn JD, Lunt M, Silman AJ, Felsenberg D, Armbrecht G, Banzer D, Benevolenskaya LI, Bhalla A, Bruges Armas J, Cannata JB, Cooper C, Dequeker J, Diaz MN, Eastell R, Yershova OB, Felsch B, Gowin W, Havelka S, Hoszowski K, Ismail AA, Jajic I, Janott I, Johnell O, Kanis JA, Kragl G, Lopez Vaz A, Lorenc R, Lyritis G, Masaryk P, Matthis C, Miazgowski T, Gennari C, Pols HA, Poor G, Raspe HH, Reid DM, Reisinger W, Scheidt-Nave C, Stepan JJ, Todd CJ, Weber K, Woolf AD, Reeve J. Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS). Osteoporos Int 2003;14(1):19-26.
19. Silman AJ. Risk factors for Colles' fracture in men and women: results from the European Prospective Osteoporosis Study. Osteoporos Int 2003;14(3):213-8.
20. Rosenthal DI, Mayo-Smith W, Hayes CW, Khurana JS, Biller BM, Neer RM, Klibanski A. Age and bone mass in premenopausal women. J Bone Miner Res 1989;4(4):533-8.
21. Varenna M, Binelli L, Zucchi F, Ghiringhelli D, Gallazzi M, Sinigaglia L. Prevalence of osteoporosis by educational level in a cohort of postmenopausal women. Osteoporos Int 1999;9(3):236-41.
22. Eastell R. Role of oestrogen in the regulation of bone turnover at the menarche. J Endocrinol 2005;185(2):223-34.
23. Moffitt TE, Caspi A, Belsky J, Silva PA. Childhood experience and the onset of menarche: a test of a sociobiological model. Child Dev 1992;63(1):47-58.
24. Pesonen AK, Raikkonen K, Heinonen K, Kajantie E, Forsen T, Eriksson JG. Reproductive traits following a parent-child separation trauma during childhood: a natural experiment during World War II. Am J Hum Biol 2008;20(3):345-51.
25. Wierson M, Long PJ, Forehand RL. Toward a new understanding of early menarche: the role of environmental stress in pubertal timing. Adolescence 1993;28(112):913-24.
26. Ellis BJ, Essex MJ. Family environments, adrenarche, and sexual maturation: a longitudinal test of a life history model. Child Dev 2007;78(6):1799-817.
27. Bogaert AF. Age at puberty and father absence in a national probability sample. J Adolesc 2005;28(4):541-6.
28. Belsky J, Steinberg L, Draper P. Childhood experience, interpersonal development, and reproductive strategy: and evolutionary theory of socialization. Child Dev 1991;62(4):647-70.
29. Ellis BJ, Garber J. Psychosocial antecedents of variation in girls' pubertal timing: maternal depression, stepfather presence, and marital and family stress. Child Dev 2000;71(2):485-501.
30. Ellis BJ, McFadyen-Ketchum S, Dodge KA, Pettit GS, Bates JE. Quality of early family relationships and individual differences in the timing of pubertal maturation in girls: a longitudinal test of an evolutionary model. J Pers Soc Psychol 1999;77(2):387-401.
31. Maestripieri D, Roney JR, DeBias N, Durante KM, Spaepen GM. Father absence, menarche and interest in infants among adolescent girls. Dev Sci 2004;7(5):560-6.
32. Saxbe DE, Repetti RL. Brief report: Fathers' and mothers' marital relationship predicts daughters' pubertal development two years later. J Adolesc 2008.
33. Tither JM, Ellis BJ. Impact of fathers on daughters' age at menarche: a genetically and environmentally controlled sibling study. Dev Psychol 2008;44(5):1409-20.
34. Mendle J, Turkheimer E, D'Onofrio BM, Lynch SK, Emery RE, Slutske WS, Martin NG. Family structure and age at menarche: a children-of-twins approach. Dev Psychol 2006;42(3):533-42.
35. Brown J, Cohen P, Chen H, Smailes E, Johnson JG. Sexual trajectories of abused and neglected youths. J Dev Behav Pediatr 2004;25(2):77-82.
36. Foster H, Hagan J, Brooks-Gunn J. Growing up fast: stress exposure and subjective "weathering" in emerging adulthood. J Health Soc Behav 2008;49(2):162-77.
37. Vigil JM, Geary DC, Byrd-Craven J. A life history assessment of early childhood sexual abuse in women. Dev Psychol 2005;41(3):553-61.
38. Wise LA, Palmer JR, Rothman EF, Rosenberg L. Childhood Abuse and Early Menarche: Findings From the Black Women's Health Study. Am J Public Health 2009.
39. Zabin LS, Emerson MR, Rowland DL. Childhood sexual abuse and early menarche: the direction of their relationship and its implications. J Adolesc Health 2005;36(5):393-400.
40. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, Koss MP, Marks JS. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med 1998;14(4):245-58.
41. Williamson DF, Thompson TJ, Anda RF, Dietz WH, Felitti V. Body weight and obesity in adults and self-reported abuse in childhood.Int J Obes Relat Metab Disord 2002;26(8):1075-82.
42. Lissau I, Sorensen TI.Parental neglect during childhood and increased risk of obesity in young adulthood. Lancet 1994;343(8893):324-7.
43. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, Koss MP, Marks JS. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med 1998;14(4):245-58.
44. Gunstad J, Paul RH, Spitznagel MB, Cohen RA, Williams LM, Kohn M, Gordon E. Exposure to early life trauma is associated with adult obesity. Psychiatry Res 2006;142(1):31-7.
45. Lissau I, Sorensen TI. Parental neglect during childhood and increased risk of obesity in young adulthood. Lancet 1994;343(8893):324-7.
46. Noll JG, Zeller MH, Trickett PK, Putnam FW. Obesity risk for female victims of childhood sexual abuse: a prospective study. Pediatrics 2007;120(1):e61-7.
47. Williamson DF, Thompson TJ, Anda RF, Dietz WH, Felitti V. Body weight and obesity in adults and self-reported abuse in childhood. Int J Obes Relat Metab Disord 2002;26(8):1075-82.
48. Johnson J, Cohen P, Kasen S, Brook JS. Childhood adversities associated with risk for eating disorders or weight problems during adolescence or early adulthood. American Journal of Psychiatry 2002;159(3):394-400.
49. Wonderlich SA, Wilsnack RW, Wilsnack SC, Harris TR. Childhood sexual abuse and bulimic behavior in a nationally representative sample. Am J Public Health 1996;86:1082-1086.
50. Everill JT, Waller G. Reported sexual abuse and eating psychopathology: a review of the evidence for a causal link. Int J Eat Disord. 1995;18:1-11.
51. Welch SL, Fairburn CG. Childhood sexual and physical abuse as risk factors for the development of bulimia nervosa. Child Abuse Negl. 1996;20:633-642.
52. Ackard DM, Neumark-Sztainer D, Hannan PJ, French S, Story M. Binge and purge behavior among adolescents: associations with sexual and physical abuse in a nationally representative sample: the Commonwealth Fund survey. Child Abuse Negl 2001;25(6):771-85.
53. Fonseca H, Ireland M, Resnick MD. Familial correlates of extreme weight control behaviors among adolescents. Int J Eat Disord 2002;32(4):441-8.
54. Patton GC, Viner R. Pubertal transitions in health. Lancet 2007;369(9567):1130-9.
55. Ackard DM, Peterson CB. Association between puberty and disordered eating, body image, and other psychological variables. Int J Eat Disord 2001;29(2):187-94.
56. Kaltiala-Heino R, Rimpela M, Rissanen A, Rantanen P. Early puberty and early sexual activity are associated with bulimic-type eating pathology in middle adolescence. J Adolesc Health 2001;28(4):346-52.
57. Killen JD, Hayward C, Litt I, Hammer LD, Wilson DM, Miner B, Taylor CB, Varady A, Shisslak C. Is puberty a risk factor for eating disorders? Am J Dis Child 1992;146(3):323-5.
58. Mangweth-Matzek B, Rupp CI, Hausmann A, Kemmler G, Biebl W. Menarche, puberty, and first sexual activities in eating-disordered patients as compared with a psychiatric and a nonpsychiatric control group. Int J Eat Disord 2007;40(8):705-10.
B882 - Pathways to Alcohol Us Disorders in ALSPAC A Genetic-Developmental Study - 22/09/2009
There is considerable evidence suggesting that a wide range of childhood and adolescent externalizing behaviors are prospectively associated with the subsequent development of alcohol use (AU) and alcohol use problems (AUPs), including several dimensions on which data have been collected within the ALSPAC study: e.g., conduct problems, temperament, personality, sensation seeking, and impulsivity. Clearly, we would not expect these various aspects of externalizing behavior to act independently, but rather to operate on AU and AUPs through a dynamic system of influences, both within and across time. For example, early temperament has been shown to influence later conduct problems, for which there are also known associations with aspects of personality, impulsivity, and sensation seeking. There is little clarity, however, regarding how mechanistic associations between these facets ultimately influence AU and AUPs in adolescence and adulthood. Prior to examining the structural nature of these relationships, we must first establish the factor structures within each of the dimensions, independently. So, for example, ALSPAC has collected information on conduct problems assessed across several points in time, and with multiple instruments (e.g., the Revised Rutter Parent Scale for Preschool Children at 42 months and repeated assessments of the Strengths and Difficulties Questionnaire at ages 6.5, 9.5, and 11.5 years). In order to assess development within conduct problems, we must first confirm that the two scales tap into the same underlying construct. Toward this end, one strategy that we propose is to identify a set of "anchor" items/behaviors that are assessed within both measures (e.g., is inconsiderate of others, steals, destroys/damages property, fights, bullies, lies/cheats). We can then subject this common set of variables to within-wave confirmatory factor analysis, allowing us to differentiate between items that yield consistent parameter estimates across time (equivalent factor loadings across assessments) and those for which associations with the underlying construct vary across time (i.e., some items may reflect behavior that is more or less indicative of conduct problems at different stages of development). Time-specific factor score estimates (FSEs) can then be derived by specifying a model which equates factor loadings across time for those items displaying factorial invariance, while freely estimating loadings at each wave of assessment for those items displaying developmental inconsistency. Moreover, we propose to implement these procedures across the different dimensions of externalizing behavior that have been conducted in ALSPAC. The resulting FSEs, which capitalize on consistency while also recognizing the potential for specific behaviors to increase/decrease in relevance across development, can then be used as the unit of measurement in models addressing the complex structural relationships between individual dimensions of behavior, general domains of risk, and alcohol-related outcomes. Accordingly, the broad goal of this set of analyses will be to characterize the measurement of, and inter-relationships between, different domains of externalizing behavior that have been assessed in ALSPAC, in order to use this information to study how different facets of externalizing behavior relate to alcohol use. We have previously had a conference call with Barbara Maughan (and Glyn Lewis) and discussed her interesting work on trajectories of conduct problems and externalizing behavior in the ALSPAC sample, so we would plan to work with her (and other interested ALSPAC collaborators) on these efforts, so as to ensure there is no duplication of effort across the projects. Since our primary interest is in understanding how externalizing behavior relates to alcohol use (with the latter being our primary outcome of interest), and her interest is in the nature of externalizing behavior itself (her primary outcome of interest), we believe that our projects will be synergistic rather than overlapping in scope.
B876 - Association analysis between a high risk autism SNP and the broader autism phenotype in the ALSPAC cohort - 21/09/2009
Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder (ASD). We recently investigated up to 7313 ALSPAC children and studied association between rs4307059 and potential broader autism traits including early vocabulary and communication (MacArthur-Communicative-Development-Inventory/MacArthur-Toddler-Communication-Questionnaire; Denver-Developmental-Screening-Test), social behaviour and behavioural difficulties (Emotionality-Activity-Sociability-Temperament-Survey; Revised-Rutter-Parent-Scale for Preschool Children; Standard-Assessment-Tests of social skills; Strengths-and-Difficulties-Questionnaire, Cambridge Hormones-and-Moods-Project-Friendship-Questionnaire; Special-Educational-Needs assessment), social communication (Social-and-Communications-Disorders-Checklist; Children's-Communication-Checklist) and verbal intelligence (Wechsler-Intelligence-Scale-for-Children-III) assessed between 15-months and 12-years. Our results suggested that common variation in rs4307059 is associated with ASD-related phenotypes and support the role of rs4307059 as QTL for ASD. We aim to extend this approach and investigate the association between the SNP and ASD-related traits assessed in mothers. We therefore propose to genotype rs4307059 in the ALSPAC maternal sample.
B875 - Program Project Analysis of the Placenta in Fetal Origins of Adolesecent Health Neurocognitive Pulmonary and Somatic - 20/09/2009
We propose a program project that will permit the processing and analysis of all consented ALSPAC placentas that have follow-up data on at least one of the three outcomes proposed for the program project, as described below.
The program project will include an Administrative Core (details to be provided by ALSPAC).
A "Placental Core" will be headed by Dr Craig Platt, Senior... at BRI, with Dr Carolyn Salafia as Co-PI at Placental Analytics LLC. Dr Platt will be responsible for supervision and quality control of placental examination, photography, tissue sampling, and sample processing to wax blocks, Placental Analytics LLC will be responsible for image analysis of placental photographs, and preparation of all histologic slides deemed essential to study goals including routine (hematoxylin and eosin) and special (e.g., immunohistochemistry) stains, and will digitize all such slides in a standard and accessible format. At the completion of the program project, all data extracted from photographs of placentas and digitized slide files, plus the digitized slide files, slides and remainders of wax tissue blocks will be returned to ALSPAC/BRI (?) as a permanent archive.
Program subprojects:
Neurocognitive: "Placental structure and pathology and neurocognitive outcome"
PI Prof Jean Golding, Co-Investigators D Misra, J Miles, C Platt, C Steer, C Salafia
We propose to test the hypothesis that detailed markers within the placenta are related to specific cognitive, behavioural and psychological outcomes from early childhood to school leaving (see Annex, below). A range of statistical approaches including structural equation modelling, a method well known to the psychometric literature, will be used to determine the predictive value of the placental measures in regard to the outcomes. Particular attention will be paid to ways in which the placenta varies in regard to factors that have been shown to be related to adverse neurocognitive outcomes such as influenza in mid-pregnancy, alcohol in early pregnancy, maternal anxiety, maternal prenatal levels of lead and mercury, and paternal omega-3 intake. We will also assess the ways in which placental variation is observed in placentas of children with minor congenital defects (minor congenital malformations are found in excess among children with many different neurocognitive outcomes).
All the neurocognitive outcomes will be available, but the minor congenital malformations will need to be identified from the neonatal clinical records - for which this grant would budget to be extracted from existing medical records.
The placenta provides two routes of analysis that we propose will account for variation in neurocognitive development/developmental trajectory:
- Placental branching growth is determined by the branching growth of its vascular tree. The "neurovascular hypothesis of disease" summarizes recent recognition that the gene families, growth factors and molecular signals that promote and maintain neuronal health are the same factors that promote and maintain vascular health. We propose that measurement of the placental vascular tree, in terms of 2D chorionic surface, 3D placental volume, chorionic surface vascular networks and finer architecture of the placental fetal and terminal villi correlate with fetal neuronal growth and health and will therefore account for variability in neurocognitive outcome/developmental trajectory.
- Placental pathologies of inflammation and injury patterns that may indicate oxidative stress can be identified in clinically abnormal and in clinically "normal" pregnancies. These pathologies are measured by histologic features identified in tissue sections of the placenta. We propose that measurement of these features will provide quantitative estimates of fetal exposures to inflammation and oxidative stress, via fetal effects on the developing brain, will account for variation in neurocognitive outcome/ developmental trajectory.
Pulmonary: "Placental structure and pathology and pulmonary outcome"
PI Dr John Henderson, Co-Investigators D Misra, J Miles, C Platt, C Salafia
There is evidence from cohort studies that have measured lung function sequentially from childhood that decrements of lung volumes (FEV1) and flows (FEF25-75 and maximal flows at 75%, 50% and 25% remaining FVC) may become established by early childhood and then 'track' into adult life. The effect of this would be to diminish peak measures of lung function prior to the natural decline in lung function with age, thus hitting a threshold at which disease becomes manifest at an earlier age. This paradigm is compatible with additional insults, such as smoking, leading to more rapid decline of lung function & exacerbating early life deficits. Thus, there may be additive effects of early life factors and later insults leading to diseases such as COPD.
Birth cohort studies that have measured lung function shortly after birth have demonstrated differences in measures of airflow associated with different patterns of symptom presentation in early childhood (e.g. transient early wheezing is associated with decrements in V'maxFRC shortly after birth (before symptoms are manifest) but regresses to the mean during the first years after birth whereas children who develop wheeze in later childhood have normal V'maxFRC in infancy but lower values of FEV1 in later childhood than never-wheezers) and with in-utero exposure to maternal tobacco smoke - children exposed in utero have lower values of lung function after birth and are more likely to develop wheeze and asthma during childhood.
Following the work of Barker and others, who demonstrated that adult respiratory diseases and lung function (FEV1) is associated with birth weight, there is considerable interest in the notion that fetal growth restraint is associated with abnormalities of airway development during a critical window of exposure leading to canalisation of effects that persist through the lifecourse (but may manifest only in the context of a second insult, e.g. smoking or following the decline in lung function measures with ageing).
Again, the placenta provides two routes of analysis that we propose will account for variation in pulmonary function:
- Placental trophoblast epithelial branching growth, determined by the branching growth of its vascular tree, parallels the branching of the pulmonary epithelium that is coordinated with the development of its parallel vascular tree. Major airways are laid down in the embryo/fetus at similar times as the major chorionic surface vessels, and more distal villous branching parallels later lung growth in utero. The close linkage of these two organ's development is highlighted by the difficulty in studying mutations of genes such as FGF and Notch that are key to lung development, as many of such muiutations are embryonic lethals because of failure of the development of the placenta. We propose that measurement of the placental vascular tree, in terms of 2D chorionic surface, 3D placental volume, chorionic surface vascular networks and finer architecture of the placental fetal and terminal villi correlate with fetal pulmonary growth and health and will therefore account for variability in pulmonary function.
- Placental pathologies of inflammation and injury patterns that may indicate oxidative stress can be identified in clinically abnormal and in clinically "normal" pregnancies. These pathologies are measured by histologic features identified in tissue sections of the placenta. Both inflammation, especially when cytokines are inhaled in the course of intraamniotic infections, and oxidative stress may alter pulmonary branching morphogenesis. We propose that measurement of these features will provide quantitative estimates of fetal exposures to inflammation and oxidative stress that will account for variability in pulmonary function.
More specifically, ALSPAC has detailed respiratory history at approximately 12 monthly intervals from birth and has measured lung function by spirometry at 8 and 15 years, allowing associations of both attained lung function pre- and (mostly) post-puberty and trajectory of lung function growth during adolescence (with a wealth of background information on exposures during this period, such as passive and active tobacco smoke exposure, validated with measurements of tobacco metabolites (cotinine).
Subproject 3 "Maternal overnutrition and offspring fat mass, metabolic and vascular function"
Principal Investigator: Dawn Misra, PhD, Co-Investigators: D Lawlor, J Miles, C Platt, C Salafia.
Dr. Lawlor's current grant aims refer to "offspring" generally; we have explicitly separated out the neonatal (birth outcomes) within our aims given the focus on the placenta.
SPECIFIC AIMS
Specific Aim 1: To investigate the influence of maternal BMI, weight gain, and diet during pregnancy on placental anthropometric measures. Specifically, we will assess and study the following placental parameters: placental weight, thickness, diameters; umbilical cord length; shape; symmetry measures; chorionic vascular branching pattern). The following null hypotheses will be tested:
1A. Maternal BMI does not explain variation in placental size and shape.
1B. Maternal weight gain does not explain variation in placental size and shape.
1C. Maternal diet does not explain variation in placental size and shape.
Specific Aim 2: To determine whether and how placental size and shape influences birth size. The following null hypotheses will be tested:
2A. Placental size and shape are not associated with birth size (e.g. weight, birth weight ratio, length, ponderal index).
2B. Associations between maternal factors and birth size are mediated by variation in placental size and shape.
Specific Aim 3: To determine whether and how placental size and shape influence offspring growth. Offspring growth was measured at multiple time points beginning at age 1 year up to 15 years of age and includes measures of adiposity (DXA assessed fat mass and fat distribution), vascular function (blood pressure, pulse pressure and endothelial function), and metabolic function (fasting glucose, insulin and lipids). The following null hypotheses will be tested:
3A. Placental size and shape are not associated with offspring childhood adiposity.
3B. Placental size and shape are not associated with offspring childhood vascular function.
3C. Placental size and shape are not associated with offspring childhood metabolic function.
3D. Associations between placental size and shape with offspring outcomes are mediated by effects of the placenta on birth size.
Specific Aim 4: To investigate the role of genetic variation on placental size and shape. DNA was extracted from mothers and offspring in the parent study. The following null hypotheses will be tested:
4A. Genetic variation does not explain variation in placental size and shape.
4B. Interactions between genes and the selected maternal factors (BMI, weight gain, diet) do not explain additional variations in placental size or shape.
Specific Aim 5: To develop and validate a placental index to identify offspring at risk for adverse outcomes with regard to adiposity, vascular function, and metabolic function.
Pilot analyses for the program subprojects will be generated using the placental data already collected from the Children in Focus subset (CIF, N=1050), and intermediate neurocognitive outcomes (TBD by Prof Golding), intermediate pulmonary function outcomes (TBD by Dr Henderson), and BMI, waist & fat & lean mass (DXA) at age 9 as previously determined by Dr Lawlor. These pilot analyses will provide strong support for our (generally well received) October submission, and we are optimistic about receiving funding based on our July resubmission. Dawn Misra and Jeremy Miles will work together on data analysis for the 3 subprojects, with Colin Steer additionally on the neurocognitive subproject.
Annex
1. Temperament and behaviour of child: Infant temperament using the Carey
at ages 6 and 24 months; EAS temperament scale at 42 months;
Behaviour measures of hyperactivity, antisocial/conduct problems, peer
problems, emotional behaviour and prosocial behaviour as well as overall
behaviour difficulties, measured at ages 4 - 13 years
2. Child development: mental and motor development measured annually
between 6 months and 4 years
3. Cognitive measures: IQ using the WISC at age 8; short term memory;
executive function;
4. Speech and language: Vocabulary measured from 15 months to 3 years;
Grammatical understanding; Phonological problems; Use of speech
tharapist
5. Motor coordination: Balance tests; fine motor coordination; Gross motor
coordination; Functional motor impairment, including DCD
6. Childhood growth: Height; Weight; Head circumference; Hip
circumference; Waist circumference; Body mass index - all at various time
points from 4 months to 15 years
7. Educational attainments: Results of SATS tests at 7, 11 and 14; GCSE
results; Results of ALSPAC's own tests ofReading, Spelling, Mathematics,
and Science understanding.
8. Attention and hyperactivity: Hyperactive and inattentive behaviour using
questions to parents and teachers from 4 to 11 years and to the children
at 13.
9. Hearing ability: Tests of hearing under standardised conditions at ages 7,
9 and 11 - using audiometry and otoacoustic emissions; Hearing of
speech discrimination at 3.5 and 5 years
10. Visual ability: Tests of visual acuity, stereoacuity, and other features of
visual ability at various ages from 8 months to 11 years
11. Other sensory outcomes (taste and smell): Taste test (PROP) results at
age 10; Smell test results at age 11
12. Childhood psychiatric disorders: Autism; ADHD; ADD; Anorexia nervosa;
Bulimia; Depression; Anxiety disorders; Conduct disorder;
B877 - Do associations between adolescent mental health and self-harm differ in males and females - 18/09/2009
Background:
Community-based research indicates that over 10% of adolescents aged 15-16 have self-harmed at some point their lives (1). As only a small proportion of young people who self-harm seek formal help, further research is required at a population level to explore potentially modifiable factors associated with this behaviour (1,2). There has been limited prospective research predicting adolescent self-harm in community samples, particularly in the UK (3-7). Functions of self-harm vary between people, and over time; including being a short-term release of passing distress, or an aspect of an enduring mental illness.
Self-harm is a strong predictor of later suicide (8-9) and further self-harm (10-11). The prevalence of self-harm varies by gender in adolescents, with substantially higher rates in girls (1-6). For example, a cross-sectional school-based survey in Oxfordshire reported that 11.2% of females and 3.2% of males aged 15-16 years had self-harmed in the previous year (1). This contrasts with the incidence of suicide being 3-4 times higher in males complared with females. The relationship between self-injurious behaviour and gender is not entirely clear. Self-harm may serve a different function for young males and females.
Analysis included in EK's recently submitted PhD examined data from longitudinal school-based study examining risk and protective factors for self-harm in a sample of 1023 East London adolescents (Research with East London Adolescents; Community Health Survey; www.relachs.org). Cross-sectional associations between self-harm and sub-clinical psychological distress, such as borderline scores on the SDQ, and longitudinal associations between self-harm, conduct problems (SDQ) and depressive symptoms (assessed with the Short Moods and Feelings Questionnaire), illustrated that self-harm may relate to different aspects of mental health, as well as different levels of symptom severity.
There was some evidence for a gender difference in the relationships between mental health and self-harm, with an association between previous depressive symptoms and self-harm in boys (OR 6.40, 95%CI 2.14-20.60, p=0.01), which was not evident in girls. The sample size limited the analysis and there was insufficient power to explore this further, thus research with a larger sample is required. Gaining more insight into whether adolescent self-harm has different implications in young males and females has potential to inform targeted interventions and responses to self-harm. Associations between self-harm and sub-threshold psychological distress may imply that interventions need to focus on general emotional health and well-being, not necessarily the recognition of and response to diagnosable mental health problems. The proposed analysis would examine gender differences in relationships between mental health in early adolescence (11-13 years) and self-harm at age 16.
Proposed analysis:
This proposal will constitute part of an application (by EK, mentored by DG and JK) for a 1 year ESRC postdoctoral fellowship, in which a limited amount of additional research related to PhD may be undertaken in addition to writing papers for publication from doctoral research.
The proposed analysis will aim to examine data already collected as part of ALSPAC, addressing two main research questions:
(i) Which aspects of mental health measured at ages 11 and 13 have prospective associations with self-harm at age 16?
(ii) Are there gender differences in the associations between mental health and self-harm?
Multivariable logistic regression would be used to examine associations with self-harm reported at age 16+, by gender. Potential predictors would include self-harm at age 11, assessed as a part of Borderline Personality Disorder, and subscales from psychological measures (DAWBA and SDQ) assessing depressive symptoms, emotional problems, conduct problems and oppositional behaviour at ages 11 and 13. Additionally, demographic data, and personality factors such as sensation seeking, locus of control and self-concept may be relevant to consider.
References:
1. Hawton, K. et al (2002) 'Deliberate self harm in adolescents: self report survey in schools in England', British Medical Journal, 325; 1207-11.
2. Fortune, S. et al (2008) 'Help seeking before and after episodes of self-harm: a descriptive study in school pupils in England', BMC Public Health, 8:369.
3. Evans, E. et al (2004) 'Factors associated with suicidal phenomena in adolescents: A systematic review of population-based studies', Clinical Psychology Review, 24:957-79.
4. Patton, G. et al (1997) 'Adolescent suicidal behaviours: a population-based study of risk', Psychological Medicine, 27: 715-24.
5. Young, R. et al (2006) 'Prevalence of deliberate self-harm and attempted suicide within contemporary Goth youth subculture: longitudinal cohort study', British Medical Journal, 332: 1058-61.
6. Martin, G. et al (2005) 'Perceived academic performance, self-esteem and locus of control as indicators of need for assessment of adolescent suicide risk: implications for teachers', Journal of Adolescence, 28:75-87.
7. Haavisto, A. et al (2005) 'Factors associated with ideation and acts of deliberate self-harm among 18 year old boys', Social Psychiatry and Psychiatric Epidemiology, 40:912-21.
8. Hawton, K. et al (1999) 'Suicide in young people: a study of 174 cases, aged under 25 years, based on coroners' and medical records', British Journal of Psychiatry, 175:1-6.
9. Cooper, J. et al (2005) 'Suicide After Deliberate Self-Harm: A 4-Year Cohort Study', American Journal of Psychiatry, 162(2):297-303.
10. Hawton, K. et al (2000) 'Deliberate self-harm in adolescents in Oxford, 1985-1995', Journal of Adolescence, 23: 47-55.
11. Hawton, K. et al (2003) 'Deliberate self-harm in adolescents: a study of characteristics and trends in Oxford, 1990-2000', Journal of Child Psychology and Psychiatry, 44(8): 1191-1198.
B874 - Association of CHRNA3/A5 and COMT Genotypes with Smoking Cessation - 16/09/2009
We propose to test the hypothesis that genetic variation at two loci will reduce the likelihood of stopping smoking during the perinatal period. We expect these effects to be independent and will not investigate them in combination.
The first SNP (rs1051730) is located within the CHRNA3/A5 gene cluster, which encodes the nicotinic receptor alpha-3 and alpha-5 sub-units. Itwas originally reported to be associated with nicotine dependence in 2008 (Thorgeirsson et al., 2008), and this association has subsequently replicated in most (but not all) studies published since. It has also been investigated in relation to smoking cessation (e.g., Freathy et al., 2009). The National Institute of Drug Abuse (NIDA) has formed a working group to investigate the strength of evidence for the association of SNPs in chromosome 15 (including rs1051730) with smoking cessation. We propose to share the ALSPAC data published by Freathy and colleagues with this collaborative initiative, given the importance of including large, high-quality data sets of this kind.
The second SNP (rs4680) is located within the COMT gene, which encodes the catechol-O-methyltransferase enzyme, responsible for the degradation of extracellular dopamine, in particular in the prefrontal cortex. It has been widely investigated across a range of psychiatric phenotypes. We have recently reported an association between this SNP and smoking cessation in two clinical trials (Munafo et al., 2008; Johnstone et al., 2007), but subsequent attempts at replication have been inconsistent. One study found evidence of association in two independent samples of females only (Collila et al., 2005). Given evidence that oestrogen modulates COMT gene transcription (e.g., Jiang et al., 2003), it is possible that any effects of COMT genotype may be stronger in females.
Additional data on maternal depression over the same period are requested in order to explore whether any genetic associations with smoking cessation also predict change in depression symptom score, given the uncertainty regarding the direction of causation between cigarette smoking and depression.
Specific hypotheses:
1. The rs1051730 T allele will be associated with a reduced likelihood of smoking cessation;
2. The rs4680 G allele will be associated with a reduced likelihood of smoking cessation.
ALSPAC phenotypes required:
1. Maternal smoking status before, during and after pregnancy;
2. Maternal daily cigarette consumption and years smoked;
3. Maternal depression symptoms (EPDS) before, during and after pregnancy;
4. Maternal ancestry, age, educational attainment.
ALSPAC genotypes required:
1. rs1051730;
2. rs4680.
B873 - Investigation of the effect of maternal iodine status on cognitive and behavioural outcomes in the offspring - 08/09/2009
We note that there has already been an ALSPAC study showing an effect of fish intake during pregnancy on I.Q in the child. Fish is a rich source of iodine which may, at the very least, have contributed to the beneficial effects of fish observed. Therefore, this project would build on this association and evaluate the link between maternal iodine status during pregnancy and developmental scores in the offspring.
Background
Iodine is essential for the production of thyroid hormones, thyroxine (T4) and triiodityronine (T3). The mother is an important source of thyroid hormones to the developing fetus, particularly in the first trimester before the onset of fetal thyroid function. Thyroid hormones are required for the neurological development of the child.
The recommended intake of iodine in the UK is 140 mcg/day and no increment is recommended during pregnancy. However, more recently the World Health Organisation has advised 250mcg of iodine per day during pregnancy.
Iodine deficiency during pregnancy in the most severe form, leads to development of cretinism in the offspring. However, studies have also demonstrated that mild to moderate maternal iodine deficiency, and the subsequent effect on thyroid hormone concentration, can lead to a spectrum of disorders in the offspring including reduction in psychomotor development, reduction in IQ, and ADHD development.
The recommended method of assessing the adequacy of iodine intake in a population, is through urinary iodine concentration measurements. This is because over 90% of ingested iodine is ultimately excreted in the urine and therefore is a useful biological marker of recent iodine intake.
Historically iodine deficiency was common in several parts of the U.K, and a goitre belt was documented from the West Country up to the Cotswalds and Derbyshire, including the area of Avon. Though the UK is currently considered to be iodine sufficient, the status of iodine in the population is not monitored through urine measurements. Data on iodine from the National Diet and Nutrition Survey is based on food diary analysis, which is not as accurate as urinary measures. However, this indicates that young women (19-24 years) have mean intakes below the RNI and that 12% of this age group of women had intakes less than the lower reference nutrient intake. In addition to the NDNS data, other studies in the UK have measured urinary iodine in pregnant women, which revealed mild to moderate deficiency in some women. We have assessed iodine deficiency in a group of women of childbearing age from the University of Surrey: 33% of the women had an iodine intake below the reference nutrient intake (RNI) and had they become pregnant, 79% of them would have been below the current WHO requirements for pregnancy.
Study proposal:
To date, there are no studies in the UK which assess the impact of mild to moderate maternal iodine deficiency on child (or birth) outcome. It is therefore proposed to use the ALSPAC urine samples to measure iodine status in pregnancy and to link that to the existing ALSPAC data on pregnancy and birth outcomes, IQ and other developmental scores in the offspring. Through the use of the food frequency questionnaires, foods that contribute to iodine status can be evaluated against outcome measures in order to provide practical dietary advice for women during pregnancy.
In order to asses iodine in urine, approximately 1.2 ml of urine would be required from the frozen stored samples. We plan to analyse some 1000 urine samples and the outcomes listed above will be evaluated in the children of the pregnant women studied. (Sarah Bath, my PhD student, could assist in pulling th4 samples from the freezer if that would help.) The food frequency questionnaires would be assessed with particular attention to foods rich in iodine (fish, milk and dairy products) to determine the foods that contribute the most to the iodine status in this group of women.
Selection of urine samples will use that gestation (which should be as near to 12 weeks as possible) for individuals for whom most outcomes are available (especially for IQ at age 8, and where possible WPSSI at age 4).
The urine samples will be analysed in Southampton. Iodine determination will be carried out by ICP-MS.
The statistical analyses will be undertaken by the PhD student, Sarah Bath, under the guidance of Colin Steer.
B872 - Exposure to alcohol during pregnancy childhood development and teenage drinking a study of trans-generational effects - 06/09/2009
Aims
The main aim of the proposed study is to investigate the role of prenatal alcohol exposure on offspring cognition, neurological and motor development. I will also study maternal drinking patterns and how they influence offspring's alcohol behaviour including the onset of problem drinking, both directly and indirectly through a chain of biological effects on development and their consequences on educational attainment and choice of peer groups. The focus will be on causal effects and intergenerational determinants of health and health-related behaviours.
B869 - RELATIONSHIPS BETWEEN RANKL POLYMORPHISMS AND SERUM PROTEIN LEVELS - 02/09/2009
Background
A highly co-ordinated and regulated process known as bone remodelling maintains the structural integrity and mineral density of bone. During bone remodelling, worn or damaged surfaces of trabecular and cortical bone are resorbed by osteoclast cells and replaced by osteoblast cells 1,2. The extent to which bone resorption (osteolysis) and synthesis (osteogenesis) occur are dependent on the interaction of the following three principle cytokines: tumour necrosis factor ligand superfamily member receptor activator of nuclear factor-cob (NF-kB) ligand (RANKL); its cellular receptor, receptor activator of NF-kB (RANK), and the decoy receptor, osteoprotegerin (OPG) 3.
Osteolysis is initiated by RANKL/RANK signalling. RANKL is secreted by osteoblastic cells and specifically recognised and bound by RANK receptors of osteoclastic cells. RANKL binding catalyses the formation, activation and maintenance of multinucleated osteoclasts (osteoclastogenesis), which attach to and resorb bone 3. Bone resorption is in turn regulated by a third cytokine called OPG. OPG is a soluble decoy receptor that binds to and sequesters RANKL, thereby limiting the activation of RANK and reducing osteoclastogenesis and osteolysis3 4. As a result the ratio of RANKL/OPG is an important determinant of bone mineral density (BMD) and skeletal integrity. Inherent perturbations of this ratio contribute to a variety of pathological conditions ranging from osteoporosis (low BMD) to osteopetrosis (high BMD) 4. Recently allelic variants of Rankl and Opg have been correlated with varying gene expression profiles and bone mineral density in patients with osteoporosis 5 6. These observations highlight the potential effects allelic variation may have on RANKL/OPG ratios and BMD.
Our research group has recently completed a genome wide association study based on tibial pQCT scans obtained in ALSPAC children at age 15. We identified several allelic variants which are located within and adjacent to Rankl which show associations with cortical BMD at genome-wide significance levels We hypothesise that these allelic variants may influence the steady state levels of RANKL sufficiently to alter the bone remodelling process thereby influencing BMD.
Aims
1. To quantify the steady state levels of serum RANKL in a cohort of 200 ALSPAC subjects who are homozygous and heterozygous for a specific Rankl marker.
2. To determine if genotypic variation at a single Rankl marker accounts for variation in RANKL steady state level and BMD.
Methods
A small sub-group of children (~200 individuals) from ALSPAC will be selected on the basis of being homozygous for the common and rare Rankl allele which is most strongly associated with cortical BMD (as identified in our recent genome-wide association scan). It is proposed that these individuals will have their RANKL protein levels quantified using the ampli-sRANKL enzyme immuno assay kit (Biomedica, Geneva) at Professor J Holly's laboratory at Southmead Hospital. Statistical association between RANKL protein levels and Rankl genotypes will be tested. Association will also be tested between RANKL protein levels and bone mineral density (as assessed by DXA and pQCT measurements).
Literature cited
1. Teitelbaum, S.L. & Ross, F.P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet 4, 638-649(2003).
2. Martin, T.J. & Sims, N.A. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends in Molecular Medicine 11, 76-81(2005).
3. Boyce, B.F. & Xing, L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 473, 139-146(2008).
4. Simonet, W. et al. Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density. Cell 89, 309-319(1997).
5. Hsu, Y. et al. Variation in genes involved in the RANKL/RANK/OPG bone remodelling pathway are associated with bone mineral density at different skeletal sites in men. Human Genetics 118, 568-577(2006).
6. Takacs, I. et al. Allelic variations of RANK/RANKL/OPG signaling system is related to bone mineral density and in vivo gene expression. Bone 44, S116(2009).
B871 - MATERNAL DEPRESSION AND SOCIAL SUPPORT - 27/08/2009
BACKGROUND
Depression is much commoner in women than men (Weissman, 1995). The high prevalence of depression in women is most likely due to a combination of gender-related differences in cognitive styles, certain biologic factors and a higher incidence of psychosocial and economic stresses in women (Korstein,1997). Depression during the perinatal period is common and it is debated if it is of a different type. Perinatal depression is often divided into antenatal and postnatal depression.
Postnatal Depression: Depression up to one year after delivery is called postpartum depression or postnatal depression. Postnatal depression is a mental and behavioural disorder associated with the puerperium, typically commencing within 6 weeks of delivery according to the International Classification of Disease-ICD-10(World Health Organisation, 1992). It is characterised by episodes of irritability, guilt, exhaustion, anxiety, sleep disorders and somatic symptoms which have a disabling effect on mothers, children and families of sufferers, following childbirth (Green et al., 1990). The cause of postpartum depression remains unclear with diverse researchers suggesting a multi-factorial aetiology (Ross et al., 2004). However, epidemiological studies strongly support the importance of psychosocial variables (O'Hara & Swain 1996, Beck 2001). In particular, a recent meta-analysis of 84 studies showed several risk factors including low levels of social support, stressful life events, childcare stress, low self esteem, low income, and marital dissatisfaction (Beck 2001). Buuljen (2007) concluded that one of the most notable explanations for PND was the lack of social support.
Social support: Social support is defined as help in difficult life situations. Social support is a concept that is generally understood in an intuitive sense, as the help from other people in a difficult life situations. There are different types and sources of social support. House described four main categories of social support: emotional, appraisal, informational and instrumental (House, 1981). Based on Barrera's (1981,2000) theoretical model, social support in the perinatal period can be defined as activities directed at assisting pregnant women and new mothers in mastering emotional distress, sharing tasks, giving advice, and teaching parenting skills, including the provision of material aid.
Social support seems to be one of the most important protective factors against depression in women at all periods of their lives; lack of social support has been consistently associated with depression in women of childbearing age. In order to understand better the relationship between social support and postnatal depression in women, I did a systematic review.
Social support and postnatal depression: In my sytematic review I was able to identify 20 papers that used a longitudinal design to assess the association between social support in pregnancy and postnatal depression. Among those that measured social support during the antenatal period, Brugha et al (1998), Glasser et al (2000), Bernazzani at al (1997) and Webster at al (2000) measured social support at less than 28 weeks of gestation; whereas Rahman et al (2003) and Chee et al (2008) took their measurements at the third trimester, between thirty four to forty weeks of gestations. Brugha et al (1998), Glasser et al (2000) and Webster et al (2000) found strong association between low social support at antenatal period and high EPDS score at postnatal period. Rahman et al (2003) found that support related to childcare by at least one of family member was associated with less PND, and the finding was almost similar to the study done by Chee et al (2000) when she found low instrumental support was associated with less PND but not for emotional support. Therefore from the studies we noticed that the measurement of social support was quite general when it was measured at early gestations, but when it was measured at late gestations the authors started to focus on type of social support.
Therefore my proposed study will be base on the objectives below.
OBJECTIVES
1. To study the association between social support in pregnancy and postnatal depression
2. To investigate the association between different types of social support in pregnancy and postnatal depression
3. To study if other psychological and social factors in pregnancy may contribute to postnatal depression in the presence of good social support.
METHODOLOGY
The proposed project will benefit from the rich and extensive longitudinal data obtained by Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC is an ongoing population based study. This study will investigate the importance of social support in the ALSPAC mothers during pregnancy and the postnatal period.
Measures:
1. Depressive symptoms (mothers); antenatal and postnatal
2. Social support and social network measures
3. Personality
4. Religiosity
5. Locus of control
6. Life events
Analysis plan:
We will use complete datasets for the variables of interest. Initially I will perform a descriptive analysis of the main variables of interest during pregnancy and one year of postnatal period. I will then perform some basic cross-tabulations between social support measures during pregnancy and postnatal depression. Chi-square tests for these associations will be estimated. I will then examine the possible influence of confounding variables such as personality and life events. After this descriptive phase I will perform multivariate regression analysis to examine the association between postnatal depression and social support in pregnancy before and after adjusting for possible confounders. Potential moderating and mediating factors will also be examined. Finally I will explore applying other statistical approaches using more sophisticated models such as structural equation modelling.
B867 - Lead and child health development - 24/08/2009
Although in the past there was concern over the dangers to children of blood lead levels over 25 microg/dL, there is increasing evidence that much lower levels (as low as 5microg/dL have a deleterious effect on child development (see an ALSPAC paper about to be published in Archives of Disease in Childhood).
Further studies are needed to answer the following questions: (a) when in development does the exposure have the most harmful effects? (b) where does the majority of the lead come from? (c) which biological samples are most useful in epidemiological studies of child development?
The programme will use various samples from the ALSPAC survey and develop appropriate measurement methodologies for testing the different sample types. It will compare lead exposure measured in children's teeth over time, distinguishing between levels laid down prenatally, in infancy and later childhood, with maternal whole blood prenatal levels, infant hair and toenails, childhood levels from age 2.5 years, and 7 years. Lead isotope levels will also be measured to assess the likely exposure sources. The aim will be to develop appropriate methods for studies of other population surveys and, when appropriate, for screening the population for appropriate intervention.
In parallel, the epidemiological data concerning maternal prenatal levels of lead, 5000 of which are currently being measured at CDC in Atlanta, will be analysed statistically to determine (i) how closely the prenatal maternal levels correlate with the 2.5 year old measures; (ii) whether the maternal prenatal lead levels are associated with outcomes of pregnancy such as preterm delivery; (iii) whether the relationships with adverse neurocognitive outcomes are predicted with more efficiency using prenatal assays than later measures of child blood.[if so this would be an important time to screen for lead levels].
B868 - Tracking Accelerometry Derived Sedentary Behaviour and Obesity from Childhood to Adolescence - 19/08/2009
Purpose:
To determine the extent that sedentary behaviour and measures of obesity track from childhood to adolescence.
Background:
Tracking of sedentary behaviour from childhood to adolescence has not been extensively studied, and few studies have tracked accelerometry derived sedentary behaviour (1). Using objectively acquired sedentary time at repeated time points is important since the reliability of self-reported sedentary behaviour is likely to vary with age. The study by Baggett et al. (1) found fair-to-moderate tracking of sedentary behaviour, from 12 to 14-years, in sample of girls (kappa=0.17). A second study regarding accelerometer derived sedentary time found that, from 6 to 9-years, there was moderate tracking (r=0.37-0.52) (2).
The use of DXA derived fat mass as a measure of obesity is highly advantageous over certain anthropometric measures of obesity, as adolescence is a period when lean mass is increasing in addition to fat mass (especially among males). The findings by Cheng et al. (3) found that the tracking of fat mass, from 11 to 18-years, was good (r=0.65); however, only Finnish girls (n=396) were included in the analysis.
Dependent Variable:
- Sedentary Behaviour (Tertiles)
- Obesity [Percentiles: 90th (obese), 80th (overweight) & 10th - 79th (normal)]
Indpendent Variables:
- Age (time)
Covariates:
- Maturation (Tanner)
- Parental occupation (SES)
- MVPA
Data Analysis:
- General Estimating Equations (GEE)
- Analyses will be conducted by gender (due to the different stages of maturation) and by SES (to determine the extent of tracking according to SES)
Target Journals:
MSSE
British Journal of Sports Medicine.
B865 - Developing algorithms for assessment referral and management of childhood obesity in primary care - 14/08/2009
Background:
NICE has called for greater support for frontline staff for the management of childhood obesity, who are often limited in dealing with these patients by lack of time and specialist training. However, whilst guidance statements and generic advice are available, few practical management tools for untrained staff currently exist. A detailed clinical tool based on a series of validated questions has been shown to be feasible in the secondary care setting in New Zealand. A similar tool for the management of adult obesity has been piloted in one PCT in England. The use of an electronic tool in the management of childhood obesity could assist practice nurses in the management and appropriate referral of childhood obesity, overcoming the issues of lack of time and training.
Aim:
To develop algorithms for use in the assessment, referral and management of childhood obesity in primary care.
The algorithms will: 1) help to identify those young people at greatest risk of obesity co-morbidities; and 2) identify characteristics of patients that will aid management decisions, e.g. child's current diet, level of physical activity, or psychological state.
The algorithms developed in this project will be incorporated into an electronic tool to assist practice nurses in the referral and management of obese children.
Methods:
- Potential data items for analysis will be identified through expert interviews and systematic reviews of the literature on childhood obesity management, co-morbidities, co-morbidity risk factors, and existing clinical algorithms for risk assessment and referral.
- Based on the preliminary list established through systematic reviews, data items from ALSPAC will be selected and analysed to identify variables that best predict obesity co-morbidities in this population. Data will also be analysed to identify characteristics of patients that will aid practice nurses in management decisions (including readiness to change, diet, activity, sedentary behaviours, sociodemographic characteristics).
- From these lists, eligible data items will be short-listed through a pre-defined selection process, which will include assessment of face validity, relevance, and sensitivity/specificity/predictive value in the UK population and feasibility of data collection in the primary care setting, to produce a list of approximately 20 items. Algorithms based on these items will be generated and incorporated into an electronic tool that identifies children at risk of co-morbidities, and generates personalised management plans.
Potential data items for the tool:
Assessment of co-morbidities
- Sex
- Age
- Ethnicity
- BMI
- Family history of disease/treatment/hospitalization/medical diagnoses
- Premature puberty
- Learning difficulties, syndromic obesity
- Skin - acanthosis nigricans
- Blood pressure
- Body fat distribution - wiast circumference, thigh circumference etc
Childhood obesity co-morbidities
- Nonalcoholic fatty liver disease (ALT)
- Impaired thyroid function (TF3, TF4)
- Components of metabolic syndrome:
- Hyperinsulinemia/insulin resistance
- Dyslipidemia
- Hypertension
- Proteinuria
- Prediabetes/type 2 diabetes
- Gastroesophageal reflux
- Musculoskeletal disorders, e.g. slipped capital femoral epiphysis and Blount disease
- Gallstones
- Asthma
- Polycystic ovarian syndrome
- Obstructive sleep apnoea
- Mood disorders/depression
Factors affecting treatment decisions
- Diet: level of consumption, consumption of fruit/veg, fizzy drinks, snacks between meals, portion size
- Activity: hours of organised activity, leisure activity, walking
- Sedentary behaviours: screen time, eating in front of TV
- Mood/depression
- Willingness to change
- Self-efficacy/confidence
- Family/environmental circumstances: free school meals, access to play area, who cooks at home
- Previous interventions
- Learning difficulties
- Behavioural problems
- Age, sex, ethnicity
- Degree of overweight.
B864 - Gene Environment Processes Underlying the Development of Conduct Problem Trajectories SUPERCEDED BY B0990 - 13/08/2009
1. SUMMARY
Conduct problems (CP) include behaviors such as bullying/intimidating, initiating physical violence towards others, assault (stealing with confrontation), theft, vandalism, and running away from home. An estimated 5-10% of youth engaging in CP follow an early onset and persistent (EOP) trajectory, and account for over 50% of crime within a given community (Moffitt, 2006). The cost to both victims and communities is considerable (Foster). Nevertheless, well designed longitudinal studies converge on the finding that the development of CP is a heterogeneous process: at least two other trajectories have been consistently identified (Barker & Maughan, 2009; Odgers et al., 2007; 2008; Raine et al., 2005), neither of which appear to be completely free of risk in childhood nor adjustment problems thereafter. Preliminary findings from epidemiology studies suggest that youth may encounter environmental risk at different developmental periods, and that these risks (or protective factors) may interact within an individual's genotype to confer the onset or offset of CP.
Using previously published CP trajectories from ALSPAC (Barker & Maughan, 2009) as an outcome, we propose to examine environmental risk exposures, from gestation to the teens, and potential gene-to-CP effects, and gene-environment interactions. With regard to candidate polymorphisms, we propose to examine certain single nucleotide polymorphisms (SNPs) and variable number tandem repeats (VNTRs) that have been shown to associate to variation in stress response and/or CP. We also propose to examine a meta-analytic genome wide association study (GWAS), between ALSPAC and the Twins Early Development Study.
2. BACKGROUND
Well designed longitudinal studies converge on the finding that the development of CP is a heterogeneous process: beyond the EOP subtype, at least two other trajectories of CP have been consistently identified (Barker & Maughan, 2009; Odgers et al., 2007; 2008; Raine et a., 2005), a childhood limited (CL) and an adolescent-onset (AO) subtype. Taken together, the results of these studies suggest heterogeneity in development poses a serious challenge for clinicians, interventionists, and researchers alike. Understanding etiologic pathways underlying these distinct trajectories is a significant public health concern and efforts should be focused not only on prevention, but on ensuring that children who present CP have the best possible outcomes.
Gaps in the current knowledge on the etiologies of these CP pathways are at least three. First, to date, studies typically have examined sets of risk at specific (or aggregated) developmental periods, but rarely have these risks incorporated the prenatal period and early postnatal periods, crucial times in child development that may bear on the timing and impact of important risks on the development of biological systems, and hence an individual's susceptibility to subsequent environmental risk exposure(s). Second, no matter the severity and duration of risks experienced by children, evidence highlights individual differences in response, with some individuals apparently protected, or more vulnerable, to later adverse outcomes (Rutter, 2009). That is, there is consensus that risk factors are likely to be complex and involve interplay amongst genetic vulnerabilities and environmental risk exposure. The third limitation is that most studies to date have examined the EOP pathway, highlighting the need for further studies to examine etiologies underlying the CL and AO pathways. Indeed, differences in the development of CP amongst these trajectories suggests that the variation and timing of environmental risk, and presumably genetic vulnerabilities (or protective factors), as key features for refining current knowledge of these taxons.
We propose to test the extent to which variations in development of CP is related to the developmental interplay of genetic and environmental child-based risks. Specifically, we propose to conduct theoretically driven analysis where the research focus includes environmental risk exposure during pregnancy (18 wks and 32 weeks), early postnatal (birth to age 2; age 2 to age 4), school entry (age 7-8), adolescence (age 15-16), as well as candidate genes.
3. METHODS
3.1 Overview
Phase 1. Examine developmental continuity (and discontinuity) of environmental risk exposures during the following developmental periods: antenatal, early childhood, primary school and adolescence.
Phase 2. Examine both direct effects (polymorphism-to-CP trajectory) and interactions between polymorphisms and the environmental risks (i.e., examine if the relationship between a polymorphism and a trajectory is moderated by environmental risk exposure). SNPS and VNTRs prioritized via previous CP studies and studies on variation in stress response will be typed in the Avon Longitudinal Study of Parents and Children (ALSPAC, PI: G. Davey-Smith; Golding, Pembrey, & Jones, 2001). These data will be used to test hypotheses of direct gene, gene-environment interaction and haplotype-environment interactions where the outcome is the the odds of following the different CP trajectories. The availability of prospective information on environmental exposure in this sample will allow hypotheses to be tested about the impact of timing of environmental stress for these different CP trajectories.
Phase 3. GWAS meta-analysis. I have negotiated access to the Twins Early Development Study (TEDS, PI R. Plomin; Trouton, Spinath, & Plomin, 2002). Dr. Beate Glaser, of ALSPAC, has agreed to collaborate and wil estimate the GWAS on ALSPAC. Dr. Glaser will also combine GWAS estimates obtained from TEDS with those from ALSPAC.
3.2 Data collection.
We propose to genotype SNPs and VNTRs, as well as haplotypes of CRH-R1 (e.g., Lake et al., 2003) in ALSPAC.
3.3 Existing Data Required
Environmental risks are located in the previous section. The SNPs and VNTRs we propose to genotype are located in the next section.
3.4 Data Analysis.
Phase 1: We will estimate and examine the configuration of risk within each development period by way of Latent Class Model (McCutcheon, 1987). Continuity of environmental risks will be examined via latent transition models (Muthen & Muthen, 2001-2006).
Phase 2: Examination of gene-environment processes
Phase 3: GWAS meta-analysis
3.5 Work already completed
We have already published a paper on the trajectories and antenatal and early postnatal risks associated to the EOP vs CL pathways (Barker & Maughan, 2009). We will soon submit a follow-up to this paper (Barker, Bonamy & Maughan, in preparation) for approval to the ALSPAC exec. These two papers create the substantive background for this application.
References
Barker, E. D., & Maughan (2009). Differentiating early-onset persistent versus childhood-limited conduct problem youth. American Journal of Psychiatry, 166, 900-908.
Barker, E. D., Bonamy, B., & Maughan, B. (in preparation). Time-varying covariates of conduct problem trajectories.
Golding, J., Pembrey, M., & Jones, R. (2001). ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology. Pediatric and Perinatal Epidemiology, 15, 74-87.
Lake, S. L., Lyon, H., Tantisira, K., Silverman, K. E., Weiss, S. T., Laird, N.M., Schaid, D.J. (2003). Estimation and Tests of Haplotype-Environment Interaction when Linkage Phase Is Ambiguous. Human Heredity, 55, 56-65.
Moffitt, T. E. (2006). Life-course persistent versus adolescence-limited antisocial behavior. In D. Cicchetti & D. J. Cohen (Eds.), Developmental Psychopathology (2nd ed., Vol. 3: Risk, disorder, and adaptation, pp. 570-598). NY: Wiley.
Muthen, L. K., & Muthen, B. O. (1998-2006). Mplus. Statistical analyses with latent variables. User's guide (4.1 ed.). Los Angeles: Muthen & Muthen.
Odgers, C. L., Caspi, A., Broadbent, J. M., Dickson, N., Hancox, R., Harringthon, H., et al. (2007). Conduct problem subtypes in males predict differential adult health burden. Archives of General Psychiatry, 64, 476-484.
Odgers, C. L., Moffitt, T. E., Broadbent, J. M., Dickson, N., Hancox, R. J., Harrington, H., et al. (2008). Female and male antisocial trajectories: From childhood origins to adult outcomes. Development and Psychopathology, 20, 673-716.
Raine, A., Moffitt, T. E., Caspi, A., Loeber, R., Stouthamer-Loeber, M., & Lynam, D. R. (2005). Neurocognitive impairments in boys on the life-course persistent antisocial path. Journal of Abnormal Psychology, 114, 38-49.
Robins L. N. (1966). Deviant children grown up. Baltimore: Williams & Wilkins.
Trouton, A., Spinath, F. M., & Plomin, R. (2002). Twins Early Development Study (TEDS): A multivariate, longitudinal genetic investigation of language, cognition and behavior problems in childhood. Twin Research, 5(5), 444-448.
B860 - ALSPAC mercury project - 07/08/2009
Methylmercury appears to have irreversible, adverse effects on the nervous system that are much more
widespread and serious in children than in adults, but better dose-response information is needed. The
proposed project will analyze 1,000 to 1,500 stored umbilical cords for mercury to determine the impact
of prenatal mercury exposure from maternal fish intake during pregnancy on the nervous system
development, which has already been assessed in the cohort subjects during 16 years of follow-up. This
information will be useful for future recommendations and guidelines on optimal seafood diets during
pregnancy.
The cords will be freeze-dried before analysis to obtain the dry-weight-based total mercury concentration
as the best available indicator of prenatal methylmercury exposure. This methodology has been
standardized and validated using large sample materials from birth cohorts in the Faroe Islands (where
cord tissue, cord blood, and other samples were available and were analysed for mercury).
Samples will be selected among the approximately 7,500 available to represent those that alfready have
GWAS data or otherwise the most complete phenotype data.
Follow-up through age 16 years will be utilized in regard to neurodevelopment and associated markers of
heart function as indicators of neurotoxicity. Possible adverse impacts of prenatal methylmercury
exposure on highly relevant neurodevelopmental functions will be examined, as will the possible
interactions caused by beneficial nutrients from maternal fish diets and the significance of relevant
heterogeneities involved in methylmercury metabolism and/or brain development processes that may be
susceptible to methylmercury toxicity.
The following three hypotheses will be examined: 1) Methylmercury-associated deficits in sensitive
domains are present at low-level prenatal methylmercury exposures and remain detectable through to
adolescence. 2) Beneficial nutrients from maternal seafood intake affect the same outcomes to
counterbalance methylmercury-associated deficits. And 3) Heterogeneities for metabolic and
neruodevelopmental genes affect the degree of methylmercury neurotoxicity.
Data analysis will be carried out jointly and will also include similar data from the largest Faroese birth
cohort (N = 1,000).