Proposal summaries
B1530 - The interplay between fetal growth and ischemia-hypoxia regulated genetic variability in the development of ADHD - 14/03/2013
Association between fetal growth and ADHD. Low birth weight (less than 2500 grams) is a well-established risk factor for ADHD (Nigg et al., 2010). Across prospective case-control studies LBW cases are at approximately 2-times increased risk to developing ADHD or clinically significant ADHD symptoms (e.g., Breslau et al., 1996). Other fetal growth phenotypes such as small for gestational age, ponderal index, and head circumference at birth are also associated with ADHD symptomtatology (Indredavik et al., 2004; Lahti et al., 2006; Heinonen et al., 2011). The relationship between reduced fetal growth and prematurity exists after controlling for a variety of confounding child factors including: child sex, season of birth or duration of breast feeding (Elgen, Sommerfelt, & Markestad, 2003; Horwood, Mogridge, & Darlow, 1998); or by parental factors including: marital status, age, maternal education, paternal education, maternal stress, parental psychopathology, substance abuse, maternal smoking, or parental nurturance (Breslau et al., 1996; Elgen et al., 2003; Horwood et al., 1998; Indredavik et al., 2004; Linnet et al., 2006; Zubrick et al., 2000). Furthermore, evidence suggests that there is a dose-response relationship between birth weight and child behavioral problems (van Os et al., 2001; Wichers et al., 2002; see Wilens et al., 2006 for null findings), including ADHD (Boulet et al., 2009). Given the association between fetal growth and ADHD has been examined primarily in prospective case-control studies, it is necessary to utilize population birth cohorts to further understand the nature of the relationship across the full spectrum of fetal growth and ADHD symptom severity.
Fetal growth and ADHD neurodevelopmental risk. Growth restricted infants have reductions in overall white and gray matter compared to normally grown infants (Brown et al., 2009; Larroque et al., 2003; Tolsa et al., 2004). Such reductions relate to poorer performance on early measures of attention, negative neurodevelopmental outcomes (Peterson et al., 2003; Tolsa et al., 2004) and are consistent with findings in ADHD samples (Filipek et al., 1997; Kates et al., 2002; Mostofsky et al., 2002; Overmeyer et al., 2001). In addition to between group findings, neuroanatomical abnormalities, such as parenchymal lesions or ventricular enlargement, predict increased risk for ADHD within a LBW cohort (Whitaker et al., 1997; Whitaker et al., 2011). Together, these findings suggest that youth who have experienced restricted fetal growth, tend to display neurodevelopmental abnormalities which are functionally related to ADHD symptomatology and consistent with findings in ADHD samples.
Restricted fetal growth as a proxy for an ADHD environmental pathogen(s). Evidence from twin studies suggest that environmental factors that underlie fetal growth, increase vulnerability for ADHD and that this relationship is not confounded by genetic factors (Groen-Blokhuis et al., 2011). This suggests that restricted fetal growth is a proxy for a constellation of prenatal environmental risk factors which restrict fetal growth and are implicated in the complex pathophysiology of ADHD. Genetic factors, however, cannot be discounted and likely play an important role in modifying the relationship between fetal growth and vulnerability for ADHD.
Prenatal ischemia-hypoxia as a possible common pathway linking prenatal environmental risk with ADHD. Suboptimal maternal-placental-fetal nutrient transport is a main determinant of restricted fetal growth (Ghidini, 1996). Thus, prenatal ischemia-hypoxia is believed to underlie restricted fetal growth in the majority of cases, especially within well-nourished populations (Henriksen & Clausen, 2002). This suggests that prenatal ischemia-hypoxia may represent a common prenatal pathway which alters neurodevelopment (Schimdt-Kastner et al., 2012) and subsequent vulnerability for ADHD. For example, both prospective and retrospective case-control studies have shown that ADHD is associated with ischemia-hypoxia related obstetric complications (Pineda et al., 2007; Getahun et al., 2013). Furthermore, low neonatal cerebral blood flow is associated with greater dopamine receptor availability and increased ADHD-related executive functioning deficits (Lou et al., 2004). These findings suggest that prenatal ischemia-hypoxia and related neurodevelopmental and cerebral vascular sequelae may represent an early developmental pathway to ADHD.
Developmental Origins of Health and Disease Hypothesis. The Developmental Origins of Health and Disease hypothesis (DOHaD; Gluckman & Hanson, 2004) provides a framework to conceptualize how genetic and early environmental factors interact to confer vulnerability for ADHD. For example, neurodevelopmental delays or neurodevelopmental disruptions, which covary with restricted fetal growth, may result from a limited supply of nutrients and oxygen in utero. Within individuals exposed to prenatal ischemia-hypoxia vulnerability for ADHD may then be moderated by fetal and maternal genotype. Aberrant epigenetic regulation of gene expression is believed to mediate the relationship between gene x environment interaction with an observed phenotype. Therefore, to further understand developmental mechanisms linking prenatal ischemia-hypoxia with increased vulnerability for ADHD, it is essential to examine variation in both the epigenome and trascriptome.
In our previous research, we have showed that fetal growth moderates the relationship between genetic variants in ischemia-hypoxia regulated (IHR) neurotrophic and kynurenine genes and ADHD symptom severity (Smith et al., In preparation). This study included a limited number of candidate genes that are regulated by prenatal ischemia-hypoxia (Schmidt-Kastner et al., 2012). Therefore, there is a need to more comprehensively examine how IHR genes alter vulnerability for ADHD within a population birth cohort. Therefore, this project aims to leverage the size and scope of the ALSPAC database, along with an IHR gene database curated by Dr. Schmidt-Kastner (see Schmidt-Kastner, 2012) to examine the interplay between fetal growth, IHR genetic variation, and vulnerability for ADHD. The IHR gene database will include 388 genes that: 1) are up- or down-regulated in response to prenatal ischemia-hypoxia in microarray studies of the rodent brain; and 2) are either regulated by hypoxia inducible factor 1 or 2 (HIF-1; HIF-2 ) which regulate the cellular response to hypoxia or have a vascular function.
Summary. Although restricted fetal growth is a well-established risk factor for ADHD (Nigg et al., 2010), little is known about biological mechanisms that underlie the relationship between restricted fetal growth and ADHD. Therefore, the current proposal aims to explore the role of ischemia-hypoxia pathway (as indexed by IHR genetic and epigenetic variation) as an underlying mechanism linking restricted fetal growth and vulnerability for ADHD.
Aim 1. Estimate theproportion of genetic covariance between fetal growth and ADHD symptom severity that can be accounted for by genome-wide SNPs and separately within IHR SNPs using genome-wide complex trait analysis (GCTA; Lee et al., 2012).
Aim1.1. Examine the relationships betweenmeasured fetal and maternal SNPs within IHR genes on ADHD symptom severity, as well as pleiotropic relationships between IHR SNPs on both fetal growth and ADHD symptom severity (Hartley et al., 2012).
Maternal and fetal SNPs that have pleiotropic associations with ADHD symptom severity and fetal will inform gene-environment interaction models in Aim 2.
Aim 2. Model the interactive effects of IHR genetic variants (identified in Aim 1.1) and fetal growth on child ADHD symptoms.
Aim 3. Characterize the role of DNA methylation of CpG sites at birth within child IHR genes (identified in Aim 1.1) in mediating the relationship between fetal growth and ADHD symptom severity.
Aim 4. Examine the interrelationships between fetal growth, methylation profiles of IHR genes, ischemia-hypoxia gene expression and ADHD symptom severity.
Overall Hypothesis: These aims will examine the overall hypothesis that IHR genetic and epigenetic variability will partially explain the relationship between restricted fetal growth and increased ADHD symptom severity.
Exposure Variables: Fetal growth based on gestational age (birthweight, head circumference, crown-heel length) and ischemia-hypoxia related obstetric complications may be examined on a secondary basis (e.g., preeclampsia).
Outcome Variables: ADHD symptom severity is the primary outcome measure. From the ALSPAC site, ADHD (via parent report) is assessed multiple times with the DAWBA (ages 7, 10, 14) and SDQ (ages4, 7, 8, 10, 12, 13, and 17) providing a longitudinal measure of the primary outcome.
Genetic Determinants: Maternal and Child genome-wide data to be used in GCTA analysis. Child DNA Methylation Data at birth and 7 or 9 years of age. SNPs and CpG islands within IHR genes will be utilized in Aims 2 and 3. RNA expression data of IHR genes will be used in Aim 4. NOTE: IHR gene database (in consultation with Dr. Schmidt-Kastner) and results from Aim 1 analysis will be used to guide analyses in Aim 2, 3, and 4.
Confounding Variables: Placental weight, maternal blood pressure, hypertension during pregnancy, maternal smoking during pregnancy, prenatal alcohol use, socioeconomic status and pregnancy, delivery and neonatal health/complications.
B1526 - Using Mendelian randomization to investigate the impact of maternal smoking during pregnancy on offspring obesity - 06/03/2013
Aim
To investigate whether smoking during pregnancy is causally associated with offspring dietary fat intake and obesity using a Mendelian randomization approach.
Hypotheses
There is strong observational evidence that maternal smoking during pregnancy is associated with higher adiposity in offspring. (1) It has also been suggested that prenatal tobacco exposure may lead to alteration of amygdala volume in the brain in utero, leading to changes in dietary fat intake and subsequent obesity.(2)
However, there is little robust evidence to suggest that the maternal smoking- offspring obesity association is causal and it is likely to be at least partly confounded by sociodemographic and lifestyle factors. Recent analyses in ALSPAC, comparing the associations of maternal and paternal smoking during pregnancy on offspring trajectories of height and adiposity demonstrated that whilst maternal smoking was likely to be causally associated with smaller birth length and adiposity in infancy, there was little evidence for causal effects on height and adiposity after 2 years.(3)
Mendelian randomisation analyses will allow further exploration of whether the maternal smoking offspring obesity and dietary fat intake associations are causal. Genetic variants in the CHRNA5-A3-B4 gene cluster (rs16969968/rs1051730) are robustly associated with smoking heaviness and to a lesser extent, smoking cessation. (4) These can be used as proxies for smoking behaviour during pregnancy in Mendelian randomisation analyses to investigate whether smoking during pregnancy is causally associated with outcomes in offspring. Within the ALSPAC cohort, the minor alleles of rs16969968/rs1051730 have been shown to be associated with increased heaviness of smoking in women who continued to smoke during pregnancy and reduced ability to quit smoking among women who smoked prior to pregnancy.(5)
We propose to investigate the associations of rs16969968/rs1051730 with trajectories of offspring BMI and trajectories of offspring dietary energy and fat intake, which have previously been developed in ALSPAC using random effects models. In these random effects models, age is the exposure and height, weight or adiposity (BMI or DXA-assessed fat mass) is the outcome. The SNPs will be included in the random effects models with an interaction parameter between the SNP and age, such that different mean trajectories are estimated for levels of the SNP. If an association between the SNPs and growth trajectories is observed, we will take this forward to a formal Mendelian Randomization analysis using two stage IV analysis.
Exposure variables
Mother
Genotype for rs1051730/rs16969968
Outcome variables
Child
Height (birth to 17 years)
Weight (birth to 17 years)
DXA scans (9 -17 years)
Dietary measures of fat intake (3 to 13 years)
Confounding variables
Age
Sex
1. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. International journal of obesity 2008;32:201-10.
2. Haghighi A, Schwartz DH, Abrahamowicz M et al. Prenatal Exposure to Maternal Cigarette Smoking, Amygdala Volume, and Fat Intake in Adolescence. JAMA Psychiatry 2013;70:98-105.
3. Howe LD, Matijasevich A, Tilling K et al. Maternal smoking during pregnancy and offspring trajectories of height and adiposity: comparing maternal and paternal associations. International journal of epidemiology 2012;41:722-32.
4. Munafo MR, Timofeeva MN, Morris RW et al. Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. Journal of the National Cancer Institute 2012;104:740-8.
5. Freathy RM, Ring SM, Shields B et al. A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy. Human molecular genetics 2009;18:2922-2927.
B1529 - Investigating the link between umbilical cord PUFAs and maternal and child genotypes - a genome wide approach - 28/02/2013
AIM: To investigate whether fetal cord plasma fatty acid levels are determined by fetal fatty acid conversion
HYPOTHESIS: We hypothesise that variants across the genome, both maternal and child, will be associated with fetal fatty acid levels.
VARIABLES: Levels of cord blood fatty acids will be the outcome variable, while imputed genotype (both maternal and child) will be the exposure. Additional potential confounders will include dietary data and gender of the child.
Previous research investigated the influence of maternal and child FADS genotypes on the levels of long chain polyunsaturated fatty acids (LC-PUFAs) present in umbilical cord venous plasma (Lattka et al., 2012). These levels were used as an indicator of fetal fatty acid supply during pregnancy and the paper suggested that fetal LC-PUFA levels are partly determined by fetal fatty acid conversion.
We propose to extend this to a genome-wide analysis of the maternal and child genotypes on cord blood fatty acids. Additionally, we plan to carry out a secondary analysis on plasma fatty acids levels collected in the children at age 7.
References:
Lattka, E., B. Koletzko, et al. (2012). "Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC)." British Journal of Nutrition FirstView: 1-15.
B1524 - Replication of Parent of Origin Effects in the North Finland Birth Cohort - 28/02/2013
The aim of this proposal is to replicate findings of a parent-offspring effect for BMI and height found in the Northern Finish Birth Cohort. Fourteen SNPs will be tested against either BMI or height (listed below).
The following SNPs will be tested for replication
Trait Chrom MarkerName (Or best proxy)
BMI 14 rs11160659
BMI 2 rs13013988
BMI 15 rs1345919
BMI 12 rs1718123
BMI 2 rs197088
BMI 17 rs208015
BMI 10 rs2358844
BMI 8 rs2471083
BMI 12 rs2904508
BMI 20 rs3092611
BMI 13 rs4883723
BMI 10 rs945491
Height 11 rs831630
Height 4 rs1277313
B1523 - MRC UNITE Programme 4 Using Genetics to Identify Causal Pathways that Influence Bone Related Phenotypes in Children and Young Adults - 28/02/2013
Aims:
(i) Identify genetic determinants of bone related phenotypes, in particular those affecting bone acquisition and growth, using a combination of cutting edge genetic technologies, high resolution phenotypes, and established and novel analytical approaches
(ii) Identify common and rare genetic variants that influence molecular phenotypes (methylation, expression, and the metabolome), and use these variants as well as allelic scores that index them, to identify potentially modifiable biomarkers that affect BMD, high bone mass and osteoporosis (i.e. "mining the phenome using allelic scores")
(iii) Utilize the MR approach and extensions of this methodology to determine whether the associations identified in (ii) are likely to represent causal relationships and to formally quantify these relationships through instrumental variables analyses
B1520 - Blood pressure effects on cognitive function and academic attainment in children - 28/02/2013
Aims
To better understand how blood pressure (BP) is related to cognitive function and academic attainment in childhood. More specifically, to investigate: (a) the relationship between BP and cognitive function (ages 4, 5, 9, 10, 11, 13 and 15 years) and academic attainment (reception, year 2, year 6, year 9 and year 11) in children, (b) the association between parental hypertension (HT) and cognitive functioning and academic attainment in offspring, (c) the contribution of vascular health (flow-mediated dilatation and pulse wave velocity) to BP-related cognitive functioning and academic attainment, (d) the impact of BP in pregnancy on offspring cognitive performance and academic attainment (e) how these four risk factors (i.e., children's BP, parental history of HT, vascular health and BP in pregnancy) jointly relate to cognitive performance and academic attainment, (f) if these potential risk factors predict future as well as current cognitive functioning and academic attainment.
Hypotheses
a) Paediatric BP will be inversely related to cognitive performance and academic attainment, after controlling for potential confounders.
b) Children with one or more parents diagnosed with HT will be more likely to show poorer cognitive performance and academic attainment than those without a parental history, after controlling for potential confounders.
c) Poorer vascular health (as measured by flow-mediated dilatation and pulse wave velocity) will confer additional risk, compared to elevated BP and parental history of HT, for reduced cognitive performance and academic attainment.
d) Higher maternal BP during pregnancy will be related to reduced cognitive performance and academic attainment in offspring, after controlling for potential confounders.
e) Parental history of HT, higher maternal BP during pregnancy and poorer vascular health will each confer greater risk for poorer cognitive performance and academic attainment than when paediatric BP is considered in isolation.
f) Risk for HT (based on elevated paediatric BP and/or parental history of HT) will be related to cognitive performance and academic attainment both cross-sectionally and longitudinally.
Exposure variables
a) Paediatric BP at ages 4-15: valid measurements of BP taken and expressed as BP percentiles accounting for age, sex, and height. All children with will be included in analyses.
b) Parental HT status: Based on latest evidence of a HT diagnosis (ideally verified by antihypertensive medication) and may review latest BP measurements if necessary. Latest evidence of diabetes diagnosis will highlight secondary HT.
c) Vascular measures: Brachial artery flow-mediated dilatation and pulse wave velocity.
d) Maternal BP in pregnancy and gestational HT.
e) HT Risk: based on paediatric BP (elevated BP >=90th BP Percentile) and parental history for HT (scored as presence of 2, 1, or 0 risk factors).
Outcome variables
a) Cognitive performance: including the following: (i) Aged 4: IQ (WPPSI- R) measures and short-term memory (digit span), (ii) Aged 5: short-term memory (digit span, non-word repetition, initial consonant recognition), (iii) Aged 9: maths and reading ability, (iv)Aged 10: working memory (counting span task) and inhibition (stop signal task), (v) Aged 11: attention (TEACh), (vi) Aged 13: CDR executive function tasks (simple RT, choice RT, digit vigilance), and (vii) Aged 15: WASI measures and inhibition (stop signal task).
b) Perception of ability: including (i) mother's perception of child's ability, (ii) child's perception of school ability/performance, reading and maths ability, (iii) teacher's perception of child's ability.
c) Academic attainment : including (i) External data for Entry and Key stage 1-4, (ii) Pupil Level Annual School Census, and (iii) Key stage 3 grades and qualifications.
To minimise confounding, the following variables form the basis of exclusion or statistical control as they are known to affect one or more of the exposure or outcome variables:
Covariates
a) Study child measures, including : (i) core variables: birth weight, sex, gestation, parity, (ii) age at clinic visit or school assessment, (iii) alcohol consumption, (iv) smoking habits, (v) pubertal development and menstruation (vi) body mass index, (vii) head circumference at 6 months, (viii) clinic anxiety: heart rate and tester rating where possible, (ix) depression, and (x) blood lead level.
b) Parent/caregiver measures (depending on the analysis it might be more applicable to use biological or caregivers information, if different), including: (i) core variables: Mothers age at delivery, ethnicity, parity, marital status, housing tenure, maternal and paternal social class in pregnancy, maternal education during pregnancy, smoking in pregnancy), (ii) mothers alcohol consumption during pregnancy, (iii) mothers and fathers/partners current/most recent occupation, (iv) mothers and fathers/partners current/most recent education, (v) father/partner living with study child, (vi) female caregiver is biological mother, (vii) current partner is biological father, (viii) household income, (ix) Mothers WASI IQ score at TF3, (x) diabetes during pregnancy, (xi) diabetes medical diagnosis in biological mother and father.
Exclusions:
a) Study child measures, including: (i) chronic health conditions (e.g., seizure disorder, obstructive sleep apnoea, chronic disease such as diabetes), (ii) prescription medication, (iii) use of illicit drugs, (iv) acute illness at time of assessment (e.g., infection), (v) demeanour inappropriate at clinic assessment, (vi) presence of special education needs and learning disabilities, (vii) attendance at non-mainstream school, (viii) presence of mental health problems/ symptoms, (ix) uncorrected visual or hearing problems or other problems that may affect cognitive/ academic performance, (x) first language not English.
b) Parent/caregiver measures, including: (i) illicit drug use during pregnancy, (ii) excessive alcohol consumption during pregnancy, (iii) HT status information from both biological parents not available (only for analyses using parental history of HT).
B1519 - Obstetric complications Immune Activation and Schizophrenia Susceptibility - 28/02/2013
The overall goal of this proposal is to advance current understanding regarding the mechanisms that mediate how second trimester maternal infection and peri-natal hypoxia may increase SZ susceptibility. The specific aims of this study are to leverage the unique strengths of the ALSPAC so as to test the inter-relationships between obstetric complications, serum immune biomarkers and phenotypic features of SZ (i.e. childhood behavioral disinhibition and psychotic symptoms). Our hypothesis is that these in utero stressors activate the immune system resulting in persistently elevated serum cytokines, increased behavioral disorders and psychotic symptoms in the offspring. The primary statistical analytic approach to test these inter-relationships will use path analysis or related methods. Regression models will estimate the direct, indirect and total effects of obstetric complications and of serum immune markers on phenotypic features of SZ (psychotic symptoms and behavioral disinhibition).
Exposure variables:
? Maternal infections during pregnancy (e.g. influenza, rubella)
? Peri-natal hypoxia (e.g. umbilical cord around neck, prolonged labor, baby hypoxic requiring resuscitation); vaginal bleeding during pregnancy, placenta abruptio
? Questionnaires of mothers (32 weeks gestation and 8 weeks)
? Obstetric clinical records at time of delivery of the child
Outcome variables:
? interluekin-6 (child); C-reactive protein (child)
? IGFI (maternal); IGFII (maternal); IGFBP3 (maternal)
? Teacher ratings of child's behaviors (Child's Behaviors & Abilities questionnaire at Year 3 and The Developing Child questionnaire at Year 6)
? Mother ratings of child's behaviors (Strengths & Difficulties Questionnaire at 4 yrs, 7 yrs, more yrs?)
? Go/No-Go behavioral measures at age 17 yrs
? Psychotic symptoms (PLIKS-Q at ages 11, 13, 14 and 16 yrs)
Confounding variables:
? Low socioeconomic status
? Immunological disorders in mother or child
? History of schizophrenia in the mother.
B1518 - Automated methods for data mining of causal associations in epidemiology - 28/02/2013
This project is an extension to a mini project that was carried out last year, where we sought to identify causal associations of BMI using Mendelian randomisation. The aim is to develop a proof of principle approach to automate the process of finding causal associations.
This project will involve searching for causal phenotypic associations for BMI and other variables, in a hypothesis free manner using Mendelian Randomisation. The instrumental variables will be automatically constructed from data retrieved from an online web source.
This is a MSc Computer Science project for Arnar Bergthorsson, who will need access to ALSPAC data.
B1517 - Assessment of growth delay in children with unilateral cleft lip and/or palate - 28/02/2013
Outline:
Cleft lip and/or palate (CL/P) is a common congenital anomaly in humans. About a thousand children are born in the United Kingdom (UK) each year with some form of CL/P. Some research has indicated that weight and in particular growth including height (length) and head circumference are reduced in children with clefts when compared with controls at birth and during the first stages of their development ?ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"dKMtKsJU","properties":{"formattedCitation":"{\rtf\super1\uc0\u8211{}5\nosupersub{}}","plainCitation":"1?5"},"citationItems":[{"id":2078,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/AG8DX9N5"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/AG8DX9N5"],"itemData":{"id":2078,"type":"article-journal","title":"Birthweight and gestational age of newborns with cleft lip with or without cleftpalate and with isolated cleftpalate","container-title":"The Journal of ClinicalPediatric Dentistry","page":"185-190","volume":"27","issue":"2","abstract":"Thebirth weight and gestational age of 1368 newborns with isolated cleft lip withor without cleft palate and 582 with isolated cleft palate were compared tothose of matched healthy controls. The results indicate that fetuses with oralclefts are at elevated risk of having low and very low birth weight, but not ofhaving a premature birth. Speculations on a relationship between these findingsand the presence of oral clefts arepresented.","note":"PMID: 12597694","journalAbbreviation":"JClin PediatrDent","author":[{"family":"Wyszynski","given":"DiegoF"},{"family":"Sarkozi","given":"Andrea"},{"family":"Vargha","given":"Peter"},{"family":"Czeizel","given":"AndrewE"}],"issued":{"year":2003}}},{"id":2008,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/WAUWUA52"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/WAUWUA52"],"itemData":{"id":2008,"type":"article-journal","title":"Associatedmalformations in cases with oralclefts","container-title":"The Cleft Palate-CraniofacialJournal: Official Publication of the American Cleft Palate-CraniofacialAssociation","page":"41-47","volume":"37","issue":"1","abstract":"OBJECTIVE
Infantswith oral clefts (OCs) often have other associated congenital defects. Thereported incidence and the types of associated malformations vary betweendifferent studies. The purpose of this investigation was to assess theprevalence of associated malformations in a geographically definedpopulation.
METHOD
The prevalences at birth of associated malformationsin infants with OCs were collected between 1979 and 1996 on all infants born inthe area covered by the registry of congenital anomalies of Northeastern Francein 238,942 consecutive births.
RESULTS
Of the 460 cleft infants bornduring this period, 36.7% had associated malformations. Associatedmalformations were more frequent in infants who had cleft palate (46.7%) thanin infants with cleft lip and palate (36.8%) or infants with isolated cleft lip(13.6%). Malformations in the central nervous system and in the skeletal systemwere the most common other anomalies, followed by malformations in theurogenital and cardiovascular systems. Weight, length, and head circumferenceof children with OCs and multiple associated malformations were lower than incontrols, as was the weight of the placenta. Prenatal diagnosis was rarely doneby fetal ultrasonographic examination in isolated clefts. However, even inmultiple associated malformations, prenatal diagnosis by fetal ultrasonographicexamination had a low sensitivity, 31.6%.
CONCLUSION
The overallprevalence of malformations, which was one in more than three infants,emphasizes the need for a thorough investigation of infants with clefts. Aroutine screening for other malformations especially skeletal, central nervoussystem, and cardiac defects may need to be considered in infants with clefts,and genetic counseling seems warranted in most of these complicatedcases.","DOI":"10.1597/1545-1569(2000)037less than 0041:AMICWOgreater than 2.3.CO;2","note":"PMID:10670888","journalAbbreviation":"Cleft Palate Craniofac.J.","author":[{"family":"Stoll","given":"C"},{"family":"Alembik","given":"Y"},{"family":"Dott","given":"B"},{"family":"Roth","given":"MP"}],"issued":{"year":2000,"month":1}}},{"id":2089,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/VXA3P79B"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/VXA3P79B"],"itemData":{"id":2089,"type":"article-journal","title":"Longitudinalstudy of growth of children with unilateral cleft-lip palate from birth to two yearsof age","container-title":"The Cleft Palate-CraniofacialJournal: Official Publication of the American Cleft Palate-CraniofacialAssociation","page":"603-609","volume":"46","issue":"6","abstract":"OBJECTIVE
Tostudy the growth of children with complete unilateral cleft lip and palate(UCLP) from birth to 2 years of age and to construct specific UCLP growthcurves.
DESIGN
Physical growth was a secondary outcome measure of aNational Institutes of Health-sponsored longitudinal, prospective clinicaltrial involving the University of Florida (United States) and the University ofS?o Paulo (Brazil).
PATIENTS
Six hundred twenty-seven children withUCLP, nonsyndromic, both genders.
METHODS
Length, weight, and headcircumference were prospectively measured for a group of children enrolled in aclinical trial. Median growth curves for the three parameters (length, weight,head circumference) were performed and compared with the median for theNational Center for Health Statistics (NCHS) curves. The median values forlength, weight, and head circumference at birth and 6, 12, 18, and 24 months ofage were plotted against NCHS median values and statistically compared at birthand 24 months.
SETTING
Hospital de Reabilita??o de AnomaliasCraniofaciais, Universidade de S?o Paulo, Bauru, Brazil(HRAC-USP).
RESULTS
At birth, children of both genders with UCLPpresented with smaller body dimensions in relation to NCHS median values, butthe results suggest a catch-up growth for length, weight, and headcircumference for girls and for weight (to some degree) and head circumferencefor boys.
CONCLUSIONS
Weight was the most compromised parameter forboth genders, followed by length and then head circumference. There was no evidenceof short stature. This study established growth curves for children withUCLP.","DOI":"10.1597/08-105.1","note":"PMID:19860503","journalAbbreviation":"Cleft Palate Craniofac.J.","author":[{"family":"Marques","given":"IlzaL"},{"family":"Nackashi","given":"JohnA"},{"family":"Borgo","given":"HiltonC"},{"family":"Martinelli","given":"AngelaP M C"},{"family":"Pegoraro-Krook","given":"MariaI"},{"family":"Williams","given":"WilliamN"},{"family":"Dutka","given":"JenifferC R"},{"family":"Seagle","given":"MichaelB"},{"family":"Souza","given":"TelmaV"},{"family":"Garla","given":"LuisA"},{"family":"Neto","given":"Jos? S M"},{"family":"Silva","given":"MarcosLN"},{"family":"Graciano","given":"MariaIG"},{"family":"Moorhead","given":"Jacquelyn"},{"family":"Piazentin-Penna","given":"S?lviaHA"},{"family":"Feniman","given":"MarizaR"},{"family":"Zimmermann","given":"MariaC"},{"family":"Bento-Gon?alves","given":"CristinaGA"},{"family":"Pimentel","given":"MariaCM"},{"family":"Boggs","given":"Steve"},{"family":"Jorge","given":"Jos?C"},{"family":"Antonelli","given":"PatrickJ"},{"family":"Shuster","given":"Jonathan"}],"issued":{"year":2009,"month":11}}},{"id":2097,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/NDG4EQTB"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/NDG4EQTB"],"itemData":{"id":2097,"type":"article-journal","title":"Lineargrowth characteristics of children with cleft lip andpalate","container-title":"The Journal ofPediatrics","page":"707-711","volume":"131","issue":"5","abstract":"OBJECTIVE
Tostudy the linear growth characteristics of children with isolated cleft lip(CL), cleft palate (CP), or both (CLP) and to determine whether this populationis at risk for short stature.
STUDY DESIGN
Retrospective chart reviewidentified 324 patients with CL, CP, or CLP that displayed no additionalcongenital anomalies. Longitudinal height and growth rate analyses wereperformed on routine anthropometric measurements gathered from hospital andclinic records. One-sample t tests (p less than 0.05) of average height percentileswere performed at yearly intervals. Analysis of variance was performed onclefting subgroups.
RESULTS
From birth to 10 years of age, the averageheight of both male and female white patients is consistently near the 40thpercentile. At yearly intervals, 60% of male and 70% of female average heightsdemonstrate statistical difference from the population mean. For all patients,64% of male but only 36% of female growth rates, from 2.5 to 12 years of age, wereabove the population mean.
CONCLUSIONS
White children from birth to 10years of age with isolated CL, CP, or CLP demonstrated a mean height below thepopulation mean. These data suggest that children with isolated cleftingmanifest an intrinsic tendency toward short stature. In addition, male patientsdisplay above-average growth rates, whereas female patients displaybelow-average growth rates, from 2 to 18 years of age. The data imply thatfemale patients may be at increased risk of overall short stature, whereas malepatients may eventually obtain mean populationheight.","note":"PMID:9403650","journalAbbreviation":"J.Pediatr.","author":[{"family":"Cunningham","given":"ML"},{"family":"Jerome","given":"JT"}],"issued":{"year":1997,"month":11}}},{"id":2104,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/JKPPZFQ3"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/JKPPZFQ3"],"itemData":{"id":2104,"type":"article-journal","title":"Failureto thrive in babies with cleft lip and palate","container-title":"BritishJournal of PlasticSurgery","page":"471-475","volume":"54","issue":"6","abstract":"Weestablished the frequency of failure to thrive (FTT) in children undergoingprimary cleft procedures by using growth charts and standard-deviation scores.Initially, 147 babies with cleft lip and/or palate undergoing 186 primarylip-and-palate repairs were studied between 1993 and 1996. Rates of FTT werecategorised according to cleft type. There was an increasing rate of FTT from32% for unilateral cleft lip and palate to 38% for bilateral cleft lip andpalate to 49% for cleft palate. There was a high incidence of FTT in palatalclefts, especially if these were associated with a syndrome or anomaly (P=0.001). The incidence of FTT with the Pierre Robin sequence was 100%. In viewof the high rates of FTT, two changes were instituted: a feeding-support nursewas appointed to supervise and monitor patients at risk and all patients withthe Pierre Robin sequence had supervised airway management. Thereafter, theincidence of FTT was prospectively studied in 68 babies undergoing 84 primaryprocedures between 1997 and 1999. There was a decrease in the incidence of FTTin comparison with the earlier cohort (9% for unilateral cleft lip and palate,20% for bilateral cleft lip and palate, 26% for cleft palate). There was asignificant decrease in the incidence of FTT in the group with the Pierre Robinsequence, from 100% to 40%. As a result of the provision of a feeding-supportnurse and airway management of patients with the Pierre Robin sequence, theincidence of FTT was reduced and the audit loopclosed.","DOI":"10.1054/bjps.2001.3618","note":"PMID:11513506","journalAbbreviation":"Br J Plast Surg","author":[{"family":"Pandya","given":"AN"},{"family":"Boorman","given":"JG"}],"issued":{"year":2001,"month":9}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}1-5. The evidence though is not entirely clear ?ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"GTTgUF2u","properties":{"formattedCitation":"{\rtf\super 6, 7\nosupersub{}}","plainCitation":"6,7"},"citationItems":[{"id":2071,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"itemData":{"id":2071,"type":"article-journal","title":"Evaluationof growth in patients with isolated cleft lip and/or cleftpalate","container-title":"Pediatrics","page":"e543-549","volume":"125","issue":"3","abstract":"OBJECTIVE
Thepurpose of the study was to evaluate the growth of patients with isolated cleftlip (CL), with or without cleft palate (CP), or CP during the first few yearsof life.
METHODS
A retrospective analysis of data from birth to 5 yearsfor 307 patients with isolated CL/CP or CP alone who were seen in a largecraniofacial center between 1980 and 2007 was performed. We analyzed growthpatterns and feeding interventions. Anthropometric values were plotted onto2000 Centers for Disease Control and Prevention charts. Longitudinal analyseswere performed to estimate age-related changes and to test whether feedinginterventions or early education influenced age-relatedchanges.
RESULTS
Including progressive weight, length, and headcircumference values, a total of 1944 data points were available. The mostfrequent diagnosis was unilateral CL with CP (165 [53.7%] of 307 cases). Nopatients experienced significant failure to thrive during the study period,although predicted weight and length percentiles for age had initial decreasesduring the first year of life, with nadirs at 5.2 and 15 months, respectively.These decreases were followed by recovery that started at approximately 12months for weight and at 20 months for length (P less than .0001). Patients who hadfeeding interventions had a significantly (P = .047) increased gain rate overtime for weight for length, compared with those who didnot.
CONCLUSIONS
In this population, there were weight and lengthdecreases during the first year of life, which were not clinically significantand were followed by statistically significant recovery. Recovery seemed to berelated to successful education and feeding interventions. Head circumferenceand weight for length started at lower percentiles but showed consistent gainovertime.","DOI":"10.1542/peds.2009-1656","note":"PMID:20142284","journalAbbreviation":"Pediatrics","author":[{"family":"Zarate","given":"YuriA"},{"family":"Martin","given":"LisaJ"},{"family":"Hopkin","given":"RobertJ"},{"family":"Bender","given":"PatriciaL"},{"family":"Zhang","given":"Xue"},{"family":"Saal","given":"HowardM"}],"issued":{"year":2010,"month":3}}},{"id":2131,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/9ET5JDVA"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/9ET5JDVA"],"itemData":{"id":2131,"type":"article-journal","title":"Hospitalization,breast-milk feeding, and growth in infants with cleft palate and cleft lip andpalate born in Denmark","container-title":"The CleftPalate-Craniofacial Journal: Official Publication of the American CleftPalate-CraniofacialAssociation","page":"628-632","volume":"45","issue":"6","abstract":"OBJECTIVE
Toevaluate if the duration of postpartum hospitalization, duration of breast-milkfeeding, and growth during the first year of life in infants with cleft lip andpalate (CLP) and cleft palate (CP) are comparable to infants without facialclefts.
DESIGN
Prospective data collection using a registration chartdeveloped by the authors.
SETTING
Special health care of infants withCLP/CP born in Denmark.
PARTICIPANTS
All mature infants with CLP/CPborn in 2003 and 2004 were included. Of 165 infants, 115 participated in thestudy.
INTERVENTION
In Denmark, parents of children with CLP/CP receivecounseling. This counseling is managed by specially trained healthvisitors/nurses and is initiated at birth. The counseling seeks to supportparents' confidence in having an infant with CLP/CP and to initiate arelationship between the infant and the parents.
MAIN OUTCOMEMEASURES
Duration of postpartum hospitalization, duration of breast-milkfeeding, and weight and length at birth, 5 months of age, and 12 months ofage.
RESULTS
Hospitalization was 4 days and comparable to that ofinfants without CLP/CP. The infants with CLP/CP received breast milk but for ashorter period compared with infants without CLP/CP. Weights at birth, 5 monthsof age, and 12 months of age were identical with Danish growthreferences.
CONCLUSION
The authors find the results satisfactory andbelieve that the counseling provided by the health visitors/nurses plays a partin theresults.","DOI":"10.1597/07-007.1","note":"PMID:18956929","journalAbbreviation":"Cleft Palate Craniofac.J.","author":[{"family":"Smedegaard","given":"Lisa"},{"family":"Marxen","given":"Dorthe"},{"family":"Moes","given":"Jette"},{"family":"Glassou","given":"EvaN"},{"family":"Scientsan","given":"Cand"}],"issued":{"year":2008,"month":11}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}6, 7. Some studies however suggested that the initial "lag period", especially around birth, is then followed by a later "catch-up" period ?ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"2e763iojj2","properties":{"formattedCitation":"{\rtf\super 3, 6\nosupersub{}}","plainCitation":"3,6"},"citationItems":[{"id":2089,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/VXA3P79B"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/VXA3P79B"],"itemData":{"id":2089,"type":"article-journal","title":"Longitudinalstudy of growth of children with unilateral cleft-lip palate from birth to twoyears of age","container-title":"The CleftPalate-Craniofacial Journal: Official Publication of the American CleftPalate-CraniofacialAssociation","page":"603-609","volume":"46","issue":"6","abstract":"OBJECTIVE
Tostudy the growth of children with complete unilateral cleft lip and palate(UCLP) from birth to 2 years of age and to construct specific UCLP growthcurves.
DESIGN
Physical growth was a secondary outcome measure of aNational Institutes of Health-sponsored longitudinal, prospective clinicaltrial involving the University of Florida (United States) and the University ofS?o Paulo (Brazil).
PATIENTS
Six hundred twenty-seven children withUCLP, nonsyndromic, both genders.
METHODS
Length, weight, and headcircumference were prospectively measured for a group of children enrolled in aclinical trial. Median growth curves for the three parameters (length, weight,head circumference) were performed and compared with the median for theNational Center for Health Statistics (NCHS) curves. The median values forlength, weight, and head circumference at birth and 6, 12, 18, and 24 months ofage were plotted against NCHS median values and statistically compared at birthand 24 months.
SETTING
Hospital de Reabilita??o de AnomaliasCraniofaciais, Universidade de S?o Paulo, Bauru, Brazil(HRAC-USP).
RESULTS
At birth, children of both genders with UCLPpresented with smaller body dimensions in relation to NCHS median values, butthe results suggest a catch-up growth for length, weight, and headcircumference for girls and for weight (to some degree) and head circumferencefor boys.
CONCLUSIONS
Weight was the most compromised parameter forboth genders, followed by length and then head circumference. There was noevidence of short stature. This study established growth curves for childrenwith UCLP.","DOI":"10.1597/08-105.1","note":"PMID:19860503","journalAbbreviation":"Cleft Palate Craniofac.J.","author":[{"family":"Marques","given":"IlzaL"},{"family":"Nackashi","given":"JohnA"},{"family":"Borgo","given":"HiltonC"},{"family":"Martinelli","given":"AngelaP M C"},{"family":"Pegoraro-Krook","given":"MariaI"},{"family":"Williams","given":"WilliamN"},{"family":"Dutka","given":"JenifferC R"},{"family":"Seagle","given":"MichaelB"},{"family":"Souza","given":"TelmaV"},{"family":"Garla","given":"LuisA"},{"family":"Neto","given":"Jos? SM"},{"family":"Silva","given":"Marcos LN"},{"family":"Graciano","given":"MariaIG"},{"family":"Moorhead","given":"Jacquelyn"},{"family":"Piazentin-Penna","given":"S?lviaHA"},{"family":"Feniman","given":"MarizaR"},{"family":"Zimmermann","given":"MariaC"},{"family":"Bento-Gon?alves","given":"CristinaGA"},{"family":"Pimentel","given":"MariaCM"},{"family":"Boggs","given":"Steve"},{"family":"Jorge","given":"Jos?C"},{"family":"Antonelli","given":"PatrickJ"},{"family":"Shuster","given":"Jonathan"}],"issued":{"year":2009,"month":11}}},{"id":2071,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"itemData":{"id":2071,"type":"article-journal","title":"Evaluationof growth in patients with isolated cleft lip and/or cleftpalate","container-title":"Pediatrics","page":"e543-549","volume":"125","issue":"3","abstract":"OBJECTIVE
Thepurpose of the study was to evaluate the growth of patients with isolated cleftlip (CL), with or without cleft palate (CP), or CP during the first few yearsof life.
METHODS
A retrospective analysis of data from birth to 5 yearsfor 307 patients with isolated CL/CP or CP alone who were seen in a largecraniofacial center between 1980 and 2007 was performed. We analyzed growthpatterns and feeding interventions. Anthropometric values were plotted onto2000 Centers for Disease Control and Prevention charts. Longitudinal analyseswere performed to estimate age-related changes and to test whether feeding interventionsor early education influenced age-related changes.
RESULTS
Includingprogressive weight, length, and head circumference values, a total of 1944 datapoints were available. The most frequent diagnosis was unilateral CL with CP(165 [53.7%] of 307 cases). No patients experienced significant failure tothrive during the study period, although predicted weight and lengthpercentiles for age had initial decreases during the first year of life, withnadirs at 5.2 and 15 months, respectively. These decreases were followed byrecovery that started at approximately 12 months for weight and at 20 monthsfor length (P less than .0001). Patients who had feeding interventions had asignificantly (P = .047) increased gain rate over time for weight for length,compared with those who did not.
CONCLUSIONS
In this population, therewere weight and length decreases during the first year of life, which were notclinically significant and were followed by statistically significant recovery.Recovery seemed to be related to successful education and feedinginterventions. Head circumference and weight for length started at lowerpercentiles but showed consistent gain overtime.","DOI":"10.1542/peds.2009-1656","note":"PMID:20142284","journalAbbreviation":"Pediatrics","author":[{"family":"Zarate","given":"YuriA"},{"family":"Martin","given":"LisaJ"},{"family":"Hopkin","given":"RobertJ"},{"family":"Bender","given":"PatriciaL"},{"family":"Zhang","given":"Xue"},{"family":"Saal","given":"HowardM"}],"issued":{"year":2010,"month":3}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}3, 6 eliminating most of the growth differences compared with the norm at the latest by the age of 5 years ADDIN ZOTERO_ITEM CSL_CITATION{"citationID":"1m1i87p57t","properties":{"formattedCitation":"{\rtf\super6\nosupersub{}}","plainCitation":"6"},"citationItems":[{"id":2071,"uris":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"uri":["http://zotero.org/users/local/1XkiWLfQ/items/5852FGUE"],"itemData":{"id":2071,"type":"article-journal","title":"Evaluationof growth in patients with isolated cleft lip and/or cleftpalate","container-title":"Pediatrics","page":"e543-549","volume":"125","issue":"3","abstract":"OBJECTIVE
Thepurpose of the study was to evaluate the growth of patients with isolated cleftlip (CL), with or without cleft palate (CP), or CP during the first few yearsof life.
METHODS
A retrospective analysis of data from birth to 5 yearsfor 307 patients with isolated CL/CP or CP alone who were seen in a largecraniofacial center between 1980 and 2007 was performed. We analyzed growthpatterns and feeding interventions. Anthropometric values were plotted onto2000 Centers for Disease Control and Prevention charts. Longitudinal analyseswere performed to estimate age-related changes and to test whether feedinginterventions or early education influenced age-relatedchanges.
RESULTS
Including progressive weight, length, and headcircumference values, a total of 1944 data points were available. The mostfrequent diagnosis was unilateral CL with CP (165 [53.7%] of 307 cases). Nopatients experienced significant failure to thrive during the study period,although predicted weight and length percentiles for age had initial decreasesduring the first year of life, with nadirs at 5.2 and 15 months, respectively.These decreases were followed by recovery that started at approximately 12months for weight and at 20 months for length (P less than .0001). Patients who hadfeeding interventions had a significantly (P = .047) increased gain rate overtime for weight for length, compared with those who didnot.
CONCLUSIONS
In this population, there were weight and lengthdecreases during the first year of life, which were not clinically significantand were followed by statistically significant recovery. Recovery seemed to berelated to successful education and feeding interventions. Head circumferenceand weight for length started at lower percentiles but showed consistent gainovertime.","DOI":"10.1542/peds.2009-1656","note":"PMID:20142284","journalAbbreviation":"Pediatrics","author":[{"family":"Zarate","given":"YuriA"},{"family":"Martin","given":"LisaJ"},{"family":"Hopkin","given":"RobertJ"},{"family":"Bender","given":"PatriciaL"},{"family":"Zhang","given":"Xue"},{"family":"Saal","given":"HowardM"}],"issued":{"year":2010,"month":3}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}6.
Aims: We aim to investigate whether there is still evidence for a growth delay within a sample of children with unilateral non-syndromic CL/P (Cleft Care UK) at the age of 5 years when compared with population based controls.
Methods: Using a univariate and or multivariate linear design, we will compare the risk effects of unilateral CL/P (case:control ratio 1:4) on differences in height, weight, BMI and head cirumference measured at the age of 5-7 years compared with age and sex-matched healthy children from the ALSPAC cohort, a sample which is representative of the general UK population.
Confounding issues: We are aware that secular trends in weight, length and head circumference might be associated with differences in birth years(ALSPAC: 1991/1992; Cleft Care UK: 2005/2007). However as our case sample was born ~15 years later than the control sample (ALSPAC), the hypothesis of a growth delay in CLP will, in the presence of a strong secular trend, either support the null hypothesis or show as an effect in the opposite direction (growth increase in CLP), and as such does not invalidate the proposed analyses. Furthermore, there is some evidence that secular trends with respect to adult height are largely stabilised during the last years8 in Northern Europe, and a similar trend might be expected for the UK. All analyses will be adjusted for socio-economic differences.
B1505 - Study of Learning Ability Development and Genes - 28/02/2013
Project outline:
Study of Learning Ability, Development and Genes
Background
Intellectual disability (ID) in childhood is common with a prevalence rate of around 2.6% (Emerson, 2003). Children with ID have substantially higher rates of persistent comorbid psychiatric disorders (ADHD, ASD, Conduct Disorders, Anxiety Disorders), around 4-7 times higher than the general population (e.g., Einfeld et al., 2006; Emerson, 2003; Emerson & Hatton, 2007; Emerson & Einfeld, 2010). The most strongly associated childhood diagnoses are ADHD (odds ratio=10 compared with non-ID controls) and autistic spectrum disorder (ASD; odds ratio=75; Emerson, 2003). Comorbid psychopathology in children with ID is important because it increases parent stress more than the severity of ID, raises the cost of care and has a long term impact on adult outcomes (Herring et al., 2006).
The majority of children with mild-moderate ID have no clearly identifiable cause for their ID (Einfeld et al., 2006). Although multiple common gene variants, comorbid neurological illness and psychosocial disadvantage contribute to the aetiology, there is growing evidence that the rate of subtle chromosomal anomalies (deletions and duplications), known as copy number variants (CNVs), is elevated in those with previously unexplained ID (Girirajan, et al., 2010; Ropers, 2008; Sagoo et al., 2009). As a result of this work, some UK clinical genetics services are offering array CGH diagnostic services and a recent consensus statement recommends using chromosomal microarrays in the first tier of investigating developmental delay (Miller et al., 2010).
In a recently completed study of ADHD (Williams et al., 2010) we found a significantly elevated rate of CNVs in those with ID + ADHD (36%) than amongst controls (7%) or those with ADHD alone (11%). This is actually a higher CNV rate than previously reported for idiopathic ID (around 10%-12% for significant CNVs) and leads us to postulate that in individuals with idiopathic ID, the presence of large, rare CNVs in ID is clinically important because it might increase the risk of comorbid neuropsychiatric disorder. We now propose to explicitly examine whether the presence of large, rare CNVs in children with idiopathic ID is associated with a broad range of psychopathology (not ADHD only).
Aims
* To investigate in children with mild/moderate Intellectual Disability (IQ test score less than 70) whether subtle chromosomal anomalies (CNVs) are associated with;
- The presence of psychopathlogy
- Higher levels of ADHD and autism scores
- Higher levels of aggression
- Lower levels of adaptive functioning
As such the primary outcome measures is the child's psychopathology and the main predictor is the presence of a Copy Number Variant (CNV).
Hypotheses
Children with Intellectual Disability and CNVs will have higher rates of psychopathology and lower levels of functioning
.
B1508 - Investigation on the mediating role of methylation in lipid pathways - 15/02/2013
Aims
To identify methylation variation mediating lipid pathways.
B1507 - Integrative systems analysis of omics data for outcome prediction and identification of molecular pathways - 15/02/2013
Aims
1. Development and application of Multiple Kernel Learning (MKL) approaches to the prediction of common outcomes using high density omics data
2. Identification of molecular "modules" and pathways by integrative analysis of high density omics data.
B1495 - The evolution and development of aggression in humans and other animals - 15/02/2013
GENERAL BACKGROUND
Aggression and violence are issues of global concern, identified by the World Health Organisation as a leading cause of death among young people and exerting considerable strain on individuals and society. Extensive research effort has been directed at understanding both the evolutionary origins of aggression and the factors affecting its development, but these two lines of research have proceeded largely independently. Developmental studies (mainly on humans) neglect how aggressive behaviour is shaped by evolutionary forces; while evolutionary studies (mainly on other animals) focus on fully developed,
adult behaviour and ignore how that behaviour develops during early life. This divergent approach
severely limits the conclusions we can draw about the root causes of aggressive behaviour. For a fuller
understanding of aggression, we urgently need an integrated approach in which developmental changes
in behaviour are seen as an outcome of evolved mechanisms organising behavioural development. My proposed project using the ALSPAC data forms part of a larger programme of research (5-year ERC Consolidator Grant application) aimed at understanding the evolution of developmental trajectories of aggression in humans and other animals.
AIMS
I plan to combine evolutionary theory with data on behavioural development to understand how natural selection has influenced developmental trajectories and how these interact with early life conditions to shape behaviour. Using the ALSPAC data, I will test some general predictions derived from a series of models of aggressive behaviour, in which individuals are uncertain of their own strength but can learn about this through their social experiences (see Fawcett & Johnstone 2010, Proc. R. Soc. B 277, 1427-1434). To refine the models and generate more specific predictions, I will incorporate data on patterns of physical development (growth in body size, strength etc.) and age-structuring of interactions in an attempt to explain age-dependent patterns of play fighting and aggressive behaviour. The underlying assumption of this work is that children learn about their physical capabilities through interactions with their peers.
HYPOTHESES
(i) In early childhood, there is little or no correlation between aggressive behaviour and proxies of physical strength.
(ii) As children mature, a positive correlation develops (at least in boys) between aggressive behaviour and proxies of physical strength: children (or at least boys) who are physically stronger than their peers tend to display higher levels of aggression.
(iii) As children mature, overall levels of aggression decline. The decline is more rapid for children (or at least boys) who are physically weaker than their peers.
(iv) Levels of aggression during adolescence are related to the timing of growth spurts: aggression increases immediately after growth spurts, particularly for those who undergo growth spurts earlier.
(v) There is a hump-shaped relationship between the age to which boys continue to playfight and their level of aggression later in life; boys who stop playfighting earlier show either a high or a low level of aggression, whereas those who continue to playfight until a later age show intermediate aggression.
EXPOSURE VARIABLE(S)
None.
OUTCOME VARIABLE(S)
Levels of aggression in interactions with peers, both in terms of play fighting and genuine fighting. Assessed through questionnaire responses about the tendency to start fights, hit/kick/bite other children, etc.
CONFOUNDING VARIABLE(S)
In the longitudinal analyses I wish to conduct, the principal confounding variables are age and collinear measurements of body size, such as height, weight and BMI. To deal with this issue I will centre the body size measurements around the mean for each age group, and compute residuals from the regression of weight on height. I will also need to control for the effects of socioeconomic status, fatness (obesity) levels and peer victimisation.
METHODOLOGY
To take account of the repeated-measures design inherent in longitudinal datasets, I will use multilevel models (Bryk & Raudenbush, 1992) with a first-order autoregressive error structure (Goldstein et al., 1994). This statistical approach retains individual-specific measures of growth and behaviour and therefore uses all of the available longitudinal information.
B1522 - Mining the phenome using allelic scores A new framework to dissect the biological basis of Ankylosing Spondylitis - 14/02/2013
The aim of this proposal is to specify formulae for allelic scores that index levels of expression, methylation and the metabolome and subsequently construct these scores in a large sample of AS cases and controls with GWAS data, and test to see whether the scores correlate with affection status, potentially identifying interesting biological pathways.
This analysis involves two distinct stages:(i) Genome-wide association analysis of genome-wide methylation, expression and metabolomic data. This will involve association analysis of both common and low frequency variants derived from genome-wide SNP chip platforms (Illumina 550K or 660K) and low density genome-wide sequencing, as well as imputed variants from the thousand genomes and UK10K projects. Because of computational constraints associated with the extremely large number of phenotypes modelled, statistical analysis will proceed using SNPTEST on a cleaned set of 8365 unrelated individuals of confirmed British ancestry. (ii) Construction of allelic scores to serve as genetic proxies for these molecular variables. I will investigate how allelic scores can best be constructed using a variety of approaches from simple weighted counts of strongly associated variants, to genome-wide allelic scores- an approach which I have pioneered in the context of individual risk prediction, to more sophisticated methods involving machine learning and lasso regression. The predictive validity of these measures will be assessed by cross validation, and/or using them to predict the same outcome in cohorts with similar data (e.g. TwinsUK in the case of genome-wide expression; Kettunen et al. (2012) in the case of metabolomic data). Please note, that this part of the project is pretty much identical to that proposed in MRC Unite Programme 4. Once the formulae for generating allelic scores has been validated, these scores will be derived and correlated with a large sample AS cases and controls with GWAS data.
B1521 - The impact of adolescent sleep disorders upon neurocognitive function and the development of chronic pain conditions - 14/02/2013
The impact of adolescent sleep disorders upon neurocognitive function and the development of chronic pain conditions.
Childhood and adolescence is a critical period for developing homeostatic sleep-wake patterns. There is a growing body of evidence to suggest that childhood sleep problems may precipitate difficulties in later life. For example, sleep restriction in children can result in memory and verbal function deficits (Randazzo et al, 1998). Objective actigraphy monitoring also indicates that children (between ages 9 and 12) with higher levels of sleep fragmentation show diminished neurocognitive function on tests such as the continuous performance test and symbol digit substitution (Sadeh, Gruber and Raviv, 2002). Furthermore, Gregory et al (2009) found that sleep problems at ages 5 and 9 could predict neuropsychological deficits at age 13; specifically, tasks requiring a high demand of mental flexibility and working memory. Similar deficits in attentional capacity, memory and cognitive function have also been found in children with sleep-related breathing disorders (Blunden, Lushington and Kennedy, 2001; Beebe, 2006; Lewin et al, 2002). Overall, these studies highlight the importance of managing sleep disorders in childhood.
Pain is an interruptive but adaptive stimulus alerting us to potential threat or danger. Chronic pain patients, however, find it difficult to disengage from the constant threat of pain. Therefore, it is common for pain-related cognitive biases to develop as patients become increasingly vigilant to pain stimuli. Such maladaptive attention processes can unfortunately, prolong pain states. Neuropsychological complaints are common amongst chronic pain patients (Hart et al, 2001) and are assumed to stem from the attention-demanding interference of pain. It may be that pre-existing neuropsychological impairments can precipitate the transition from acute to chronic pain disorders however. If childhood sleep disorders can result in diminished neurocognitive capacity, this may induce a cognitive vulnerability wherein attention towards pain will already be enhanced due to problems with distraction and inhibition.
Psychosocial measures such as depression and negative beliefs about pain have been shown to increase one's probability of transitioning from an acute to a chronic pain condition (Casey, Greenburg et al, 2008; Pincus, Burton, Vogel and Field, 2002). Whether neuropsychological factors pose a risk for the development of chronic pain has yet to be addressed. If such risk factors are identified, early psychological interventions could be critical in preventing the development of certain pain conditions.
Aim and Objectives
To consider whether sleep problems in childhood and adolescence impact upon neurocognitive function and the subsequent development of chronic pain disorders. Using regression methods, results from the study will highlight whether poor sleep in adolescence will contribute increased rates of chronic pain conditions in later life.
It is expected that those with higher incidences of sleep problems will show reduced neurocognitive function. Links between these diminished functions and the development of chronic pain conditions will then be explored.
Hypotheses
Poor sleep will be associated with an increased level of chronic pain reports. Poor sleep will also result in diminished neurocognitive function. The association between sleep and chronic pain will attenuate after the control of neurocognitive function.
Exposure Variables
Early life/adolescent sleep problems
Outcome Variables
Chronic pain condition (y/n)?
Confounding Variables
Gender, socio-economic status, depression, neurocognitive function.
B1516 - Establishing the link between omega 3 fatty acids and postpartum depression using Mendelian Randomisation - 14/02/2013
AIM: To establish whether there exists a causal association between omega 3 polyunsaturated fatty acids (PUFAs) and depression
HYPOTHESIS: We hypothesise that maternal levels of omega 3 PUFAs could be a contributing factor in postnatal depression (PND)
VARIABLES: Genetic variants will be used as instrumental variables for the omega 3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The outcome variable will be PND as measured by the Edinburgh Postnatal Depression Scale (EPDS) completed at 8 weeks postpartum.
Literature surrounding the association between PUFAs and depression reports conflicting results regarding efficacy. A number of observational studies reported in the psychiatric literature suggest that a deficiency of maternal DHA can lead to the development of major depressive disorder (MDD) during pregnancy and postpartum, whereas clinical benefits of supplementation with EPA are reported in more intervention studies (Mozurkewich et al., 2011). In an attempt to clarify the situation, meta-analyses of supplementation with omega 3 PUFAs have been performed which point to EPA, rather than DHA, being the key PUFA associated with depression (Martins et al., 2012; Freeman et al., 2006). However, these analyses may be limited due to issues including small sample sizes and heterogeneity between studies.
We plan to use Mendelian Randomisation (MR) to explore the association between maternal genotype and occurrence of postnatal depression. Genetic variants discovered through genome-wide association studies (GWAS) (Lemaitre et al., 2011; Tanaka et al., 2009) will be used as instrumental variables for the PUFAs. The use of MR should help to eliminate the issues with confounding and reverse causation to which conventional observational studies are subject.
Women completing the EPDS at 8 weeks postpartum will be classified as cases or controls depending on their score, with those scoring greater than 12 being designated as cases (Cox et al., 1987). This threshold will help to distinguish women who are likely to be suffering from a depressive illness of varying severity. Given the nutritional demands of breast feeding on the mother, we will investigate whether the effect of fatty acids differs according to the occurrence of breast-feeding. A secondary analysis will be carried out using EPDS scores at 8 months postpartum.
Participants will be excluded from the study if they experienced a stillbirth or early neo-natal death (within 27 days).
B1515 - Is complement factor H genotype associated with recognised AMD-related traits and serum inflammatory markers - 14/02/2013
Background
ALSPAC is a vital resource in the study of child development and has contributed to much influential work on the topic of child development and paediatric disease.
Age-related macular degeneration (AMD) is the most frequent cause of blindness in Europe and accounts for severe visual loss in around 25 million people worldwide.(1) It is characterised by reduction in visual acuity and contrast sensitivity with subsequent loss of central vision. There are two categories of AMD: wet (neovascular and exudative) and dry. Wet AMD accounts for 90% of blindness due to AMD (2) and if untreated results in an average loss of approximately 4 lines of visual acuity with 2 years of disease onset.(3) Timely identification and treatment of those with neovascular ARMD improves visual outcomes.(4) The economic burden of AMD in terms of direct and indirect costs is significant.(5)
A meta analysis by Chakravarthy et al in 2010 found that risk factors for AMD include major risk factors (with a strong, consistent association): increasing age, current cigarette smoking, previous cataract surgery and family history of AMD. Risk factors with a moderate and consistent association include history of cardiovascular disease, hypertension, raised plasma fibrinogen and high body mass index. Weak, inconsistent association was found between AMD and gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease and serum total and HDL cholesterol and triglyceride levels.(4) The same study identified 73 potential risk factors for late age-related macular degeneration including nine genetic factors. Increased sun exposure and low dietary intake of zinc and vitamin E were also highlighted by Smith et al using data pooled from three continents.(6)
More recently the link between genetics, environment and AMD has become far better understood with the discovery of potential AMD susceptibility genes. One such gene is Complement Factor H (CFH), a variant of which is rs1061170 (T1277C, Y402H) which is characterised by substitution of histidine for tyrosine at codon 402 on the long arm of chromosome 1, region 31. This is a missense mutation, which results in altered binding of the CFH protein to sulphated polysaccharides and may contribute to the pathogenesis of AMD through complement dysregulation. In individuals of European descent the Y402H variant was found to confer a 2-fold higher risk of late AMD per copy.(7,8)In homozygous individuals, those with neovascular AMD may have a decreased treatment response, particularly to anti-VEGF agents, when compared to individuals who are homozygous for the T-allele.(9) Along with another common variant (rs1410996), Y402H is thought to explain around 17% of AMD liability.(10)
There is evidence that chronic low-grade inflammation is key in the pathogenesis of AMD.(11) Raised serum inflammatory markers have been identified as possible indicators of increased risk of developing AMD, including C-reactive protein (CRP), interleukins (IL)-2 and -6, tumour necrosis factor (TNF)-a, soluble intercellular adhesion molecule (sICAM)-1 and C3a-desArg as have raised levels of urinary pro-inflammatory cytokines, including transforming growth factor (TGF)-b1 (OR 1.24 CI 1.02-1.50; Pless than 0.031) and macrophage chemoattractant protein (MCP)-1 (OR 1.07 CI 1.02-1.12 pless than 0.008) in early AMD and MCP-1 (OR 1.10 CI 1.03-1.17 pless than 0.003) in geographic atrophy.(11,12) Linked to this is the finding of the Blue Mountains Eye study that there is reduced renal function in AMD demonstrated by decreased estimated glomerular filtration rate and creatinine clearance.(13) Urinary MCP-1 levels above median levels were 2.5 times more likely to be found in individuals who were heterozygous or homozygous for the C-allele (Y402H) (Pless than 0.040).
The study team are experienced in working with ALSPAC data and among them have a wealth of epidemiological, genetic and ophthalmological clinical experience. The existing ALSPAC data contains snps directly associated with the Complement factor H and we will therefore be able to address the research question with existing data. This is a proposal for a small pilot study of the potential association between complement factor H genotype and AMD-related traits, which will inform the direction of future work.
B1514 - Puberty and adolescence as sensitive period in the development of cardiovascular risk - 14/02/2013
Background & Aim:
Adolescence is characterised by pubertal development, changing body composition, decline in health-promoting behaviours and uptake of potentially harmful behaviours. Blood pressure (BP) increases in adolescence, and changes are observed in levels of circulating lipids, glucose and insulin. Adverse levels of BP and lipids in adolescence are associated with greater adult risk of cardiovascular diseases. Adolescence thus represents a potentially sensitive period in the development of cardiovascular risk. However, the causal mechanisms linking adolescence-related changes with cardiovascular risk are not well understood. We propose to study this in the Avon Longitudinal Study of Parents and Children. Specifically, we will assess whether pubertal development, genetic variants, adiposity and behavioural factors are associated with patterns of change in BP, lipids, glucose and insulin from 7-17 years; and explore how puberty and changes in BP, lipids, glucose and insulin are associated with cardiovascular structure and function measured at age 17.
Our key hypotheses (numbered) will each be addressed by relevant objectives (letters) as follows:
1. Age at puberty will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence, with earlier age at puberty resulting in a more adverse cardiovascular profile
a. To assess the association between age at puberty (measured using age at peak height velocity, measures derived from height for mid-parental-height and age at menarche) with patterns of change in SBP and DBP from 7 to 17 years (measures at 7, 9, 11, 13, 15 and 17 years), and patterns of change in lipids, glucose and insulin from 9 to 17 years (measures at 9, 15 and 17 years), and gender differences in these associations
b. To test the causality of associations between age at puberty and SBP, DBP, lipids, glucose and insulin, using genetic variants related to puberty in a Mendelian Randomisation analysis
c. To assess the age at which associations between genetic variants related to puberty and trajectories of SBP, DBP, lipids, glucose and insulin become apparent, and how these associations change across childhood and adolescence.
2. Changes in adiposity will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence
a. To assess the associations of changes in BMI (from age 7 to 17), DXA-assessed fat mass (age 9 to 17) and waist circumference (age 7 to 17) with changes in SBP, DBP, lipids, glucose and insulin across childhood and insulin (ages as in 1a above), and whether these differ between males and females
b. To assess the association of genetic variants related to BMI and waist circumference with changes in SBP, DBP, lipids, glucose and insulin across childhood and insulin
3. Modifiable behavioural risk factors will influence the patterns of change in BP, circulating lipids, glucose and insulin across childhood and adolescence
a. To investigate the associations of dietary intake (ages 7 to 13), physical activity (ages 11 to 15) and smoking (ages 9 to 17) (and changes in these across childhood and adolescence) with changes in BP, lipids, glucose and insulin (ages as in 1a above, but starting at age 11 for physical activity and age 9 for smoking)
4. Genetic variants robustly associated in adult populations with BP, lipids, glucose and insulin will exhibit stronger associations with these traits later in adolescence (after puberty) compared with in childhood and earlier adolescence
a. To assess the relationship between an allelic score of BP-related SNPs and changes in BP
b. To assess the relationship between an allelic score of lipid-related SNPs and changes in lipids
c. To assess the relationship between allelic scores for i) type II diabetes, ii) fasting glucose levels and iii) circulating insulin levels and changes in glucose and insulin
5. Age at onset of puberty will be associated with cardiovascular structure and function
a. To assess the association of age at pubertal onset with measures of cardiovascular structure and function (measures detailed in section 4) at age 17
b. To determine the associations of changes in BP, lipids, glucose and insulin across childhood and adolescence with measures of cardiovascular structure and function at age 17
c. To assess the extent to which changes in BP, lipids, glucose and insulin across childhood and adolescence mediate the relationship of age at pubertal onset with measures of cardiovascular structure and function at age 17.
Statistical analysis will mainly involve multilevel models (including multivariate multilevel models) as well as standard regression techniques.
B1513 - Do hypertensive disorders and anaemia in pregnancy increase the risk of respiratory and atopic diseases in childhood - 14/02/2013
Background:
We have previously found a negative association between umbilical cord iron concentration and early childhood eczema in ALSPAC[1], but associations between maternal anaemia and childhood atopic outcomes have not been reported. Other studies have reported that maternal hypertension in pregnancy is associated with impaired infant lung function[2] and, along with preeclampsia, with an increased risk of early childhood wheezing[3], but data are lacking on whether these conditions predict asthma and impaired lung function later in childhood. It would be interesting to know whether any effects of maternal hypertension/preeclampsia on these outcomes are mediated through lower birth weight and whether preeclampsia might explain any of the well-known birth order/parity association with atopy. Clearly, if anaemia and maternal hypertension/preeclampsia are causes of childhood asthma and atopy there may be important opportunities for primary prevention.
Aims:
To analyse the associations between maternal anaemia and hypertensive disorders of pregnancy and respiratory and atopic outcomes in the offspring.
Hypotheses:
* Anaemia is associated with increased risk of atopic disease
* Hypertension and preeclampsia are associated with increased risk of asthma and impaired lung function.
Variables needed for primary analyses:
Derived exposure variables of interest:
* Hypertensive disorder of pregnancy (gestational hypertension plus preeclampsia)
* Preeclampsia
* Gestational hypertension
* Pre-existing hypertension
* Early pregnancy Hb
Confounders and outcomes: We have all potential confounder variables with the exception of gestational weight gain. Outcomes will include asthma, hayfever, eczema, atopy and total IgE at 7 years, and lung function at 8-9 years (we have these variables too).
If we confirm associations with hypertension it might be of interest to carry out secondary analyses to explore associations with changes in blood pressure at different stages of gestation using the appropriate derived variables.
B1512 - Is the effect of maternal smoking on childhood lung function mediated by nicotine A Mendelian Randomisation approach - 14/02/2013
Aims:
To investigate the association between child (fetal) CYP2A6 genotype and lung function and interactions with reported maternal smoking.