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1.  Dimensions of Parental Alcohol Use/Problems and Offspring Temperament, Externalizing Behaviors and Alcohol Use/Problems 
Alcoholism, clinical and experimental research  2013;37(12):10.1111/acer.12196.
BACKGROUND
Alcohol consumption (AC) and alcohol-related problems (AP) are complex traits. How many factors reflecting parental AC and AP are present in the large prospectively followed Avon Longitudinal Study of Parents and Children cohort? Would these factors be uniquely associated with various temperamental and alcohol related outcomes in the children?
METHODS
We factor analyzed multiple items reflecting maternal and paternal AC and AP measured over a 12 year period from before the birth of the child (n=14,093 families). We examined, by linear regression controlling for socio-economic status SES, the relationship between scales derived from these factors and offspring early childhood temperament, externalizing traits and adolescent AC and AP (n’s ranging from 9,732 to 3,454).
RESULTS
We identified 5 coherent factors: typical maternal AC, maternal AC during pregnancy, maternal AP, paternal AC, and paternal AP. In univariate analyses, maternal and paternal AC and AP were modestly and significantly associated with low shyness, sociability, hyperactivity, and conduct problems in childhood and early adolescence; delinquent behavior at age 15; and AC and AP at ages 15 and 18. AC and AP at age 18 were more strongly predicted by parental factors than at age 15. Maternal AC during pregnancy uniquely predicted externalizing traits at ages 4, 13 and 15.
CONCLUSION
Parental AC and AP are complex multidimensional traits that differ in their association with a range of relevant measures in their children. Controlling for background AC and AP, self-reported levels of maternal AC during pregnancy uniquely predicted externalizing behaviors in childhood and adolescence.
doi:10.1111/acer.12196
PMCID: PMC3855174  PMID: 23895510
ALSPAC; alcohol consumption; parental alcohol use; temperament; externalizing problems; fetal alcohol exposure
2.  Differences in risk factors for self-harm with and without suicidal intent: Findings from the ALSPAC cohort 
Journal of Affective Disorders  2014;168(100):407-414.
Background
There is a lack of consensus about whether self-harm with suicidal intent differs in aetiology and prognosis from non-suicidal self-harm, and whether they should be considered as different diagnostic categories.
Method
Participants were 4799 members of the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort who completed a postal questionnaire on self-harm with and without suicidal intent at age 16 years. Multinomial logistic regression analyses were used to examine differences in the risk factor profiles of individuals who self-harmed with and without suicidal intent.
Results
Many risk factors were common to both behaviours, but associations were generally stronger in relation to suicidal self-harm. This was particularly true for mental health problems; compared to those with non-suicidal self-harm, those who had harmed with suicidal intent had an increased risk of depression (OR 3.50[95% CI 1.64, 7.43]) and anxiety disorder (OR 3.50[95% CI 1.72, 7.13]). Higher IQ and maternal education were risk factors for non-suicidal self-harm but not suicidal self-harm. Risk factors that appeared specific to suicidal self-harm included lower IQ and socioeconomic position, physical cruelty to children in the household and parental self-harm.
Limitations
i) There was some loss to follow-up, ii) difficulty in measuring suicidal intent, iii) we cannot rule out the possibility of reverse causation for some exposure variables, iv) we were unable to identify the subgroup that had only ever harmed with suicidal intent.
Conclusion
Self-harm with and without suicidal intent are overlapping behaviours but with some distinct characteristics, indicating the importance of fully exploring vulnerability factors, motivations, and intentions in adolescents who self harm.
doi:10.1016/j.jad.2014.07.009
PMCID: PMC4160300  PMID: 25108277
ALSPAC; Adolescent; Self-harm; Suicide attempt; Longitudinal
3.  DataSHIELD: taking the analysis to the data, not the data to the analysis 
Background: Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK’s proposed ‘care.data’ initiative, and these issues reflect important societal and professional concerns about privacy, confidentiality and intellectual property. DataSHIELD provides a novel technological solution that can circumvent some of the most basic challenges in facilitating the access of researchers and other healthcare professionals to individual-level data.
Methods: Commands are sent from a central analysis computer (AC) to several data computers (DCs) storing the data to be co-analysed. The data sets are analysed simultaneously but in parallel. The separate parallelized analyses are linked by non-disclosive summary statistics and commands transmitted back and forth between the DCs and the AC. This paper describes the technical implementation of DataSHIELD using a modified R statistical environment linked to an Opal database deployed behind the computer firewall of each DC. Analysis is controlled through a standard R environment at the AC.
Results: Based on this Opal/R implementation, DataSHIELD is currently used by the Healthy Obese Project and the Environmental Core Project (BioSHaRE-EU) for the federated analysis of 10 data sets across eight European countries, and this illustrates the opportunities and challenges presented by the DataSHIELD approach.
Conclusions: DataSHIELD facilitates important research in settings where: (i) a co-analysis of individual-level data from several studies is scientifically necessary but governance restrictions prohibit the release or sharing of some of the required data, and/or render data access unacceptably slow; (ii) a research group (e.g. in a developing nation) is particularly vulnerable to loss of intellectual property—the researchers want to fully share the information held in their data with national and international collaborators, but do not wish to hand over the physical data themselves; and (iii) a data set is to be included in an individual-level co-analysis but the physical size of the data precludes direct transfer to a new site for analysis.
doi:10.1093/ije/dyu188
PMCID: PMC4276062  PMID: 25261970
DataSHIELD; pooled analysis; ELSI; privacy; confidentiality; disclosure; distributed computing; intellectual property; bioinformatics
4.  Adolescent Alcohol Use is Predicted by Childhood Temperament Factors Before Age 5, with Mediation Through Personality and Peers 
Alcoholism, clinical and experimental research  2013;37(12):10.1111/acer.12206.
Background:
Very few studies chart developmental pathways from early childhood to adolescent alcohol-related outcomes. We test whether measures of temperament collected from mothers at multiple assessments from 6 months through 5 years predict alcohol-related outcomes in mid-adolescence, the developmental pathways that mediate these effects, and whether there are gender differences in pathways of risk.
Methods:
Structural models were fit to longitudinal data from the Avon Longitudinal Study of Parents and Children, an epidemiological sample of pregnant women with delivery dates between April 1991 and December 1992, with children followed longitudinally. Temperamental characteristics were assessed at 6 time points from 6 to 69 months of age. Alcohol use and problems were assessed at age 15.5. Analyses here utilize data from 6,504 boys and 6,143 girls.
Results:
Childhood temperament prior to age 5 predicted adolescent alcohol use and problems at age 15.5 years, even after controlling for socio-demographic factors and parental alcohol problems. In both boys and girls, 2 largely uncorrelated and distinct temperament styles—children who were rated as having consistent emotional and conduct difficulties through age 5, and children who were rated as consistently sociable through age 5—both showed elevated rates of alcohol problems at age 15.5, but via different mediational pathways. In both genders, the association between emotional and conduct difficulties and alcohol problems was mediated through reduced conscientiousness and lower emotional stability. The association between sociability and alcohol problems was mediated through increased extraversion and sensation-seeking for both genders. Boys also showed mediation for sociability and alcohol outcomes through friendship characteristics, and girls through lower conscientiousness and reduced emotional stability.
Conclusions:
Our findings support multiple pathways to alcohol consumption and problems in adolescence. Some of these pathways are shared in boys and girls, while other risk factors are more salient in one gender or the other.
doi:10.1111/acer.12206
PMCID: PMC3823677  PMID: 23841856
ALSPAC; Temperament; Alcohol; Adolescence; Sex Differences
5.  Prevalence of Chlamydia in Young Adulthood and Association with Life Course Socioeconomic Position: Birth Cohort Study 
PLoS ONE  2014;9(8):e104943.
Background
Few estimates are available of chlamydia prevalence in the general population. Existing studies have limited scope to explore potential selection bias or associations with socioeconomic position.
Methods
We examined the prevalence of Chlamydia trachomatis infection and associations with life-course socioeconomic position in the Avon Longitudinal Study of Parents and Children in England. Chlamydia infection was measured through nucleic acid amplification test of urine specimens.
Results
4864 (51%) of those invited attended the clinic (mean age 17.8; SD 0.37 years). (60%) provided a urine specimen. Prevalence was 1.0% (95% CI 0.6 to 1.6) among participants reporting sexual activity. Risk of infection was strongly associated with life course social disadvantage and with recent sexual behaviour. After adjustment for other measures of disadvantage and for sexual behaviour the strongest risk factors for infection were lower maternal educational attainment (OR 9.1 (1.1, 76.7)) and lower participant educational attainment at age 11 (OR 5.0 (1.5, 16.5)). Both clinic attendance and agreement to test were lower amongst the disadvantaged. Adjustment for selective participation based on detailed information on non-participants approximately doubled prevalence estimates. Prevalence was higher in sexually active women (1.4% (0.7 to 2.4) than men (0.5% (0.1 to 1.3)).
Conclusions
Chlamydia prevalence in this general population sample was low even after adjustment for selective participation in testing. These estimates of prevalence and patterns of association with socioeconomic position may both reflect recent screening efforts. Prevalence was higher amongst the disadvantaged who were also less likely to engage in testing. Our results reveal the importance of monitoring and addressing inequalities in screening programme participation and outcomes.
doi:10.1371/journal.pone.0104943
PMCID: PMC4143219  PMID: 25153124
6.  The association between depressive symptoms from early to late adolescence and later use and harmful use of alcohol 
European Child & Adolescent Psychiatry  2014;23(12):1219-1230.
Depressive symptoms and alcohol misuse contribute substantially to the global health burden. These phenotypes often manifest, and frequently co-occur, during adolescence. However, few studies have examined whether both baseline levels of depressive symptoms and change in symptoms are associated with alcohol outcomes. In addition, inconsistent findings could be due to sex differences or the use of different alcohol outcomes. Using data from a prospective population-based cohort in the UK, we estimated trajectories of depressive symptoms from 12 years 10 months to 17 years 10 months, separately for male and female participants. We assessed whether baseline and change in depressive symptoms were associated with use and harmful use of alcohol at 18 years 8 months. Among females, increasing depressive symptoms were associated with increased alcohol use; whilst for males, there was little evidence of this. When examining harmful levels of alcohol use, baseline levels of depressive symptoms in males were weakly related to later harmful alcohol use but this association was attenuated substantially through adjustment for confounders. In contrast, both baseline symptoms and increase in symptoms were associated with later harmful alcohol use in females and these associations were not diminished by confounder adjustment. Elevated depressive symptoms during adolescence are positively associated with increases in both use and harmful use of alcohol at 18 years 8 months. These findings differ between the sexes. Further research is needed to examine the mechanisms underlying the link between depressive symptoms and harmful alcohol use to identify potentially modifiable factors for intervention.
Electronic supplementary material
The online version of this article (doi:10.1007/s00787-014-0600-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00787-014-0600-5
PMCID: PMC4246124  PMID: 25130265
ALSPAC; Adolescence; Depressive symptoms; Alcohol; Longitudinal
7.  Conduct problem trajectories and alcohol use and misuse in mid to late adolescence 
Drug and alcohol dependence  2013;133(1):100-107.
Background
We consider the strength of the relationship between types of conduct problems in early life and pattern of alcohol use during adolescence.
Methods
Children from the Avon Longitudinal Study of Parents and Children, a UK birth-cohort, had their level of conduct problems assessed repeatedly from 4 to 13 years using the maternal report Strengths and Difficulties Questionnaire. Developmental trajectories derived from these data were subsequently related to (i) patterns of alcohol use from 13 to 15 years, and (ii) hazardous alcohol used at age 16.
Results
Boys with ‘Adolescent Onset’ or ‘Early Onset Persistent’ conduct problems were much more likely to be high frequency drinkers between 13 and 15 years (OR 5.00 95% CI = [2.4, 10.6] and 3.9 95% CI = [2.1, 7.3] respectively) compared with those with Low or ‘Childhood Limited’ conduct. Adolescent Onset/Early Onset Persistent girls also had greater odds of this high-alcohol frequency drinking pattern (2.67 [1.4, 5.0] and 2.14 [1.2, 4.0] respectively). Associations were more moderate for risk of hazardous alcohol use at age 16. Compared to 32% among those with low conduct problems, over 40% of young people classified as showing Adolescent Onset/Early Onset Persistent conduct problems were drinking hazardously (OR 1.52 [1.09, 2.11] and 1.63 [1.22, 2.18] respectively).
Conclusions
Whilst persistent conduct problems greatly increase the risk of adolescent alcohol problems, the majority of adolescents reporting hazardous use at age 16 lack such a history. It is important, therefore, to undertake alcohol prevention among all young people as a priority, as well as target people with manifest conduct problems.
doi:10.1016/j.drugalcdep.2013.05.025
PMCID: PMC3786043  PMID: 23787037
ALSPAC; Conduct problems; Alcohol use; Adolescence; Trajectory
8.  Mapping patient pathways and estimating resource use for point of care versus standard testing and treatment of chlamydia and gonorrhoea in genitourinary medicine clinics in the UK 
BMJ Open  2014;4(7):e005322.
Objectives
We aimed to explore patient pathways using a chlamydia/gonorrhoea point-of-care (POC) nucleic acid amplification test (NAAT), and estimate and compare the costs of the proposed POC pathways with the current pathways using standard laboratory-based NAAT testing.
Design/participants
Workshops were conducted with healthcare professionals at four sexual health clinics representing diverse models of care in the UK. They mapped out current pathways that used chlamydia/gonorrhoea tests, and constructed new pathways using a POC NAAT. Healthcare professionals' time was assessed in each pathway.
Outcome measure
The proposed POC pathways were then priced using a model built in Microsoft Excel, and compared to previously published costs for pathways using standard NAAT-based testing in an off-site laboratory.
Results
Pathways using a POC NAAT for asymptomatic and symptomatic patients and chlamydia/gonorrhoea-only tests were shorter and less expensive than most of the current pathways. Notably, we estimate that POC testing as part of a sexual health screen for symptomatic patients, or as stand-alone chlamydia/gonorrhoea testing, could reduce costs per patient by as much as £16 or £6, respectively. In both cases, healthcare professionals' time would be reduced by approximately 10 min per patient.
Conclusions
POC testing for chlamydia/gonorrhoea in a clinical setting may reduce costs and clinician time, and may lead to more appropriate and quicker care for patients. Further study is warranted on how to best implement POC testing in clinics, and on the broader clinical and cost implications of this technology.
doi:10.1136/bmjopen-2014-005322
PMCID: PMC4120370  PMID: 25056977
Genitourinary Medicine; Health Economics; Health Services Administration & Management; Sexual Medicine
9.  Polygenic Scores Predict Alcohol Problems in an Independent Sample and Show Moderation by the Environment 
Genes  2014;5(2):330-346.
Alcohol problems represent a classic example of a complex behavioral outcome that is likely influenced by many genes of small effect. A polygenic approach, which examines aggregate measured genetic effects, can have predictive power in cases where individual genes or genetic variants do not. In the current study, we first tested whether polygenic risk for alcohol problems—derived from genome-wide association estimates of an alcohol problems factor score from the age 18 assessment of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4304 individuals of European descent; 57% female)—predicted alcohol problems earlier in development (age 14) in an independent sample (FinnTwin12; n = 1162; 53% female). We then tested whether environmental factors (parental knowledge and peer deviance) moderated polygenic risk to predict alcohol problems in the FinnTwin12 sample. We found evidence for both polygenic association and for additive polygene-environment interaction. Higher polygenic scores predicted a greater number of alcohol problems (range of Pearson partial correlations 0.07–0.08, all p-values ≤ 0.01). Moreover, genetic influences were significantly more pronounced under conditions of low parental knowledge or high peer deviance (unstandardized regression coefficients (b), p-values (p), and percent of variance (R2) accounted for by interaction terms: b = 1.54, p = 0.02, R2 = 0.33%; b = 0.94, p = 0.04, R2 = 0.30%, respectively). Supplementary set-based analyses indicated that the individual top single nucleotide polymorphisms (SNPs) contributing to the polygenic scores were not individually enriched for gene-environment interaction. Although the magnitude of the observed effects are small, this study illustrates the usefulness of polygenic approaches for understanding the pathways by which measured genetic predispositions come together with environmental factors to predict complex behavioral outcomes.
doi:10.3390/genes5020330
PMCID: PMC4094936  PMID: 24727307
alcohol problems; adolescence; gene-by-environment; ALSPAC; FinnTwin12
10.  Validating childhood asthma in an epidemiological study using linked electronic patient records 
BMJ Open  2014;4(4):e005345.
Objective
To investigate the performance of parent-reported data in identifying physician-confirmed asthma.
Design and setting
Validation study using linkage between the Avon Longitudinal Study of Parents and Children (ALSPAC) and electronic patient records held within the General Practice Research Database (GPRD).
Participants
Participants were those eligible to participate in ALSPAC who also had a record in the GPRD; this included 765 individuals, just under 4% of ALSPAC-eligible participants. The analysis was based on 141 participants with complete parent-reported asthma data.
Primary and secondary outcome measures
The main GPRD outcome measure was whether a child had a diagnosis of asthma before they were nine. Parent-reported measures were doctor diagnosis of asthma (before mean age 7.5 years), various outcomes based on wheezing and breathlessness recorded longitudinally between 6 months and 8.5 years. Secondary outcomes were bronchial hyper-responsiveness (BHR), forced expiratory volume in 1 s/forced vital capacity ratio and skin prick test responses.
Results
Among the 141 participants with complete parent-reported data, 26 (18%) had an asthma diagnosis before age nine. Using general practitioner (GP)-recorded asthma as the gold standard, the question ‘Has a doctor ever diagnosed your child with asthma?’ was both sensitive (88.5%) and specific (95.7%). ‘Ever wheezed’ had the highest sensitivity (100%) but low specificity (60%). More specific definitions were obtained by restricting to those who had wheezed on more than one occasion, experienced frequent wheeze and/or wheezed after the age of 3, but these measures had low sensitivities. BHR only identified 50% of those with a GP-recorded diagnosis.
Conclusions
Parental reports of a doctor's diagnosis agree well with a GP-recorded diagnosis. High specificity for asthma can be achieved by using detailed wheezing questions, although these definitions are likely to exclude mild cases of asthma. Our study shows that linkage between observational studies and electronic patient records has the potential to enhance epidemiological research.
doi:10.1136/bmjopen-2014-005345
PMCID: PMC4010849  PMID: 24760357
Epidemiology; Primary Care
11.  Effects of Nutritional Supplementation during Pregnancy on Early Adult Disease Risk: Follow Up of Offspring of Participants in a Randomised Controlled Trial Investigating Effects of Supplementation on Infant Birth Weight 
PLoS ONE  2013;8(12):e83371.
Background
Observational evidence suggests that improving fetal growth may improve adult health. Experimental evidence from nutritional supplementation trials undertaken amongst pregnant women in the less developed world does not show strong or consistent effects on adult disease risk and no trials from the more developed world have previously been reported.
Objective
To test the hypothesis that nutritional supplementation during pregnancy influences offspring disease risk in adulthood
Design
Clinical assessment of a range of established diseases risk markers in young adult offspring of 283 South Asian mothers who participated in two trials of nutritional supplementation during pregnancy (protein/energy/vitamins; energy/vitamins or vitamins only) at Sorrento Maternity Hospital in Birmingham UK either unselected or selected on the basis of nutritional status.
Results
236 (83%) offspring were traced and 118 (50%) of these were assessed in clinic. Protein/energy/vitamins supplementation amongst undernourished mothers was associated with increased infant birthweight. Nutritional supplementation showed no strong association with any one of a comprehensive range of markers of adult disease risk and no consistent pattern of association with risk across markers in offspring of either unselected or undernourished mothers.
Conclusions
We found no evidence that nutritional supplements given to pregnant women are an important influence on adult disease risk however our study lacked power to estimate small effects. Our findings do not provide support for a policy of nutritional supplementation for pregnant women as an effective means to improve adult health in more developed societies.
doi:10.1371/journal.pone.0083371
PMCID: PMC3862758  PMID: 24349496
12.  Outcomes of childhood conduct problem trajectories in early adulthood: findings from the ALSPAC study 
Although conduct problems in childhood are stably associated with problem outcomes, not every child who presents with conduct problems is at risk. This study extends previous studies by testing whether childhood conduct problem trajectories are predictive of a wide range of other health and behavior problems in early adulthood using a general population sample. Based on 7,218 individuals from the Avon longitudinal study of parents and children, a three-step approach was used to model childhood conduct problem development and identify differences in early adult health and behavior problems. Childhood conduct problems were assessed on six occasions between age 4 and 13 and health and behavior outcomes were measured at age 18. Individuals who displayed early-onset persistent conduct problems throughout childhood were at greater risk for almost all forms of later problems. Individuals on the adolescent-onset conduct problem path consumed more tobacco and illegal drugs and engaged more often in risky sexual behavior than individuals without childhood conduct problems. Levels of health and behavior problems for individuals on the childhood-limited path were in between those for stable low and stable high trajectories. Childhood conduct problems are pervasive and substantially affect adjustment in early adulthood both in at-risk samples as shown in previous studies, but also in a general population sample. Knowing a child’s developmental course can help to evaluate the risk for later maladjustment and be indicative of the need for early intervention.
Electronic supplementary material
The online version of this article (doi:10.1007/s00787-013-0488-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00787-013-0488-5
PMCID: PMC4172989  PMID: 24197169
Conduct problems; ALSPAC; Trajectory outcomes
13.  Prenatal alcohol exposure and offspring cognition and school performance. A ‘Mendelian randomization’ natural experiment 
Background There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance.
Methods We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring’s IQ score had been assessed in clinic (N = 4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N = 6268), contributed to the analyses.
Results Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers’ genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification.
Conclusions Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.
doi:10.1093/ije/dyt172
PMCID: PMC3807618  PMID: 24065783
Alcohol dehydrogenase; causality; cognition; confounding factors; educational measurement; ethanol; Mendelian randomization analysis; pregnancy
14.  Socio-economic position and childhood multimorbidity: a study using linkage between the Avon Longitudinal study of parents and children and the general practice research database 
Introduction
In adults, multimorbidity is associated with social position. Socially disadvantaged adults typically experience more chronic illness at a younger age than comparable individuals who are more advantaged. The relation between social position and multimorbidity amongst children and adolescents has not been as widely studied and is less clear.
Methods
The NHS Information Centre (NHS IC) linked participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) to the General Practice Research Database (GPRD). Multimorbidity was measured in three different ways: using a count of the number of drugs prescribed, a count of chronic diseases, and a person’s predicted resource use score; the latter two measures were derived using the Johns Hopkins ACG system. A number of different socio-economic position variables measured as part of ALSPAC during pregnancy and early childhood were considered. Ordered logistic and negative binomial regression models were used to investigate associations between socio-economic variables and multimorbidity.
Results
After mutually adjusting for the different markers of socio-economic position, there was evidence, albeit weak, that chronic condition counts among children aged from 0 to 9 years were higher among those whose mothers were less well educated (OR = 0.44; 95% confidence interval 0.18-1.10; p = 0.08). Conversely, children whose mothers were better educated had higher rates of chronic illness between 10 and 18 years (OR = 1.94; 95% CI 1.14-3.30). However, living in a more deprived area, as indicated by the Townsend score, was associated with a higher odds of chronic illness between 10 and 18 years (OR for each increasing decile of Townsend score = 1.09; 95% CI 1.00-1.19; p = 0.06).
Conclusions
We have found some evidence that, in younger children, multimorbidity may be higher amongst children whose parents are less well educated. In older children and adolescents this association is less clear. We have also demonstrated that linkage between prospective observational studies and electronic patient records can provide an effective way of obtaining objectively measured outcome variables.
doi:10.1186/1475-9276-12-66
PMCID: PMC3751770  PMID: 23962118
Multimorbidity; Socio-economic position; Determinants; Childhood; Adolescence; Chronic conditions; ALSPAC; Linkage; GPRD
15.  Association of Maternal Smoking With Child Cotinine Levels 
Nicotine & Tobacco Research  2013;15(12):2029-2036.
Introduction:
Our aim was to understand the strength of association between parental smoking and child environmental tobacco smoke (ETS) exposure in order to inform the development of future tobacco control policies. ETS was measured using child cotinine levels below the active smoking threshold.
Methods:
Participants were drawn from the Avon Longitudinal Study of Parents and Children and included 3,128 participants at age 7 years and 1,868 participants at age 15 years. The primary outcome was cotinine levels of nonsmoking children, to investigate the relationship between maternal smoking and child cotinine levels. The secondary outcome was cotinine levels of all individuals to investigate the relationship between child smoking and child cotinine levels. Maternal and child smoking behavior was assessed by self-report questionnaire. We adjusted for several sociodemographic variables.
Results:
We found an association between maternal smoking and child cotinine at age 7 years (mean cotinine = 1.16ng/ml serum, ratio of geometric means = 3.94, 95% CI = 2.86–5.42) and at age 15 years (mean cotinine = 0.94ng/ml serum, ratio of geometric means = 5.26, 95% CI = 3.06–9.03), after adjustment for potential confounders.
Conclusions:
The magnitude of this association for children whose mothers were heavy smokers was comparable with the quantity of half the levels of cotinine observed among children who were irregular (i.e., nonweekly) active smokers, and it was greater than five times higher than that seen in nonsmoking children whose mothers didn’t smoke. This provides further evidence for the importance of public health interventions to reduce smoking exposure in the home.
doi:10.1093/ntr/ntt094
PMCID: PMC3819976  PMID: 23880896
16.  Which Behavioral, Emotional and School Problems in Middle-Childhood Predict Early Sexual Behavior? 
Journal of Youth and Adolescence  2013;43(4):507-527.
Mental health and school adjustment problems are thought to distinguish early sexual behavior from normative timing (16–18 years), but little is known about how early sexual behavior originates from these problems in middle-childhood. Existing studies do not allow for co-occurring problems, differences in onset and persistence, and there is no information on middle-childhood school adjustment in relationship to early sexual activity. This study examined associations between several middle-childhood problems and early sexual behavior, using a subsample (N = 4,739, 53 % female, 98 % white, mean age 15 years 6 months) from a birth cohort study, the Avon Longitudinal Study of Parents and Children. Adolescents provided information at age 15 on early sexual behavior (oral sex and/or intercourse) and sexual risk-taking, and at age 13 on prior risk involvement (sexual behavior, antisocial behavior and substance use). Information on hyperactivity/inattention, conduct problems, depressive symptoms, peer relationship problems, school dislike and school performance was collected in middle-childhood at Time 1 (6–8 years) and Time 2 (10–11 years). In agreement with previous research, conduct problems predicted early sexual behavior, although this was found only for persistent early problems. In addition, Time 2 school dislike predicted early sexual behavior, while peer relationship problems were protective. Persistent early school dislike further characterized higher-risk groups (early sexual behavior preceded by age 13 risk, or accompanied by higher sexual risk-taking). The study establishes middle-childhood school dislike as a novel risk factor for early sexual behavior and higher-risk groups, and the importance of persistent conduct problems. Implications for the identification of children at risk and targeted intervention are discussed, as well as suggestions for further research.
Electronic supplementary material
The online version of this article (doi:10.1007/s10964-013-9973-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s10964-013-9973-x
PMCID: PMC3949009  PMID: 23824981
Sexual behavior; Adolescent; Conduct problems; School engagement; ALSPAC
17.  Risk of Pelvic Inflammatory Disease Following Chlamydia trachomatis Infection: Analysis of Prospective Studies With a Multistate Model 
American Journal of Epidemiology  2013;178(3):484-492.
Our objective in this study was to estimate the probability that a Chlamydia trachomatis (CT) infection will cause an episode of clinical pelvic inflammatory disease (PID) and the reduction in such episodes among women with CT that could be achieved by annual screening. We reappraised evidence from randomized controlled trials of screening and controlled observational studies that followed untreated CT-infected and -uninfected women to measure the development of PID. Data from these studies were synthesized using a continuous-time Markov model which takes into account the competing risk of spontaneous clearance of CT. Using a 2-step piecewise homogenous Markov model that accounts for the distinction between prevalent and incident infections, we investigated the possibility that the rate of PID due to CT is greater during the period immediately following infection. The available data were compatible with both the homogenous and piecewise homogenous models. Given a homogenous model, the probability that a CT episode will cause clinical PID was 0.16 (95% credible interval (CrI): 0.06, 0.25), and annual screening would prevent 61% (95% CrI: 55, 67) of CT-related PID in women who became infected with CT. Assuming a piecewise homogenous model with a higher rate during the first 60 days, corresponding results were 0.16 (95% CrI: 0.07, 0.26) and 55% (95% CrI: 32, 72), respectively.
doi:10.1093/aje/kws583
PMCID: PMC3727337  PMID: 23813703
Bayesian analysis; causal effect; Chlamydia trachomatis; Markov model; mass screening; meta-analysis; pelvic inflammatory disease; prospective studies
18.  Prenatal alcohol exposure and childhood balance ability: findings from a UK birth cohort study 
BMJ Open  2013;3(6):e002718.
Objective
To investigate the association of prenatal alcohol exposure with balance in10-year-old children.
Design
Population-based prospective longitudinal study.
Setting
Former Avon region of UK (Southwest England).
Participants
6915 children from the Avon Longitudinal Study of Parents and Children who had a balance assessment at age 10 and had data on maternal alcohol consumption.
Outcome measures
3 composite balance scores: dynamic balance (beam-walking), static balance eyes open, static balance eyes closed (heel-to-toe balance on a beam and standing on one leg, eyes open or closed).
Results
Most mothers (95.5%) consumed no-to-moderate amounts (3–7 glasses/week) of alcohol during pregnancy. Higher total-alcohol consumption was associated with maternal-social advantage, whereas binge drinking (≥4 units/day) and abstinence were associated with maternal social disadvantage. No evidence was found of an adverse effect of maternal-alcohol consumption on childhood balance. Higher maternal-alcohol use during pregnancy was generally associated with better offspring outcomes, with some specific effects appearing strong (static balance eyes open and moderate total alcohol exposure at 18 weeks, adjusted OR 1.23 (95% CI 1.01 to 1.49); static balance eyes closed and moderate total alcohol exposure at 18 weeks, adjusted OR 1.25 (95% CI 1.06 to 1.48). Similar results were found for both paternal and postnatal maternal alcohol exposure. A Mendelian-randomization approach was used to estimate the association between maternal genotype and offspring balance using the non-synonymous variant rs1229984*A (ADH1B) to proxy for lower maternal alcohol consumption; no strong associations were found between this genotype/proxy and offspring balance.
Conclusions
No evidence was found to indicate that moderate maternal alcohol consumption in this population sample had an adverse effect on offspring balance at age 10. An apparent beneficial effect of higher total maternal alcohol consumption on offspring balance appeared likely to reflect residual confounding.
doi:10.1136/bmjopen-2013-002718
PMCID: PMC3686236  PMID: 23794556
Epidemiology; Genetics
19.  Characterizing Patterns of Smoking Initiation in Adolescence: Comparison of Methods for Dealing With Missing Data 
Nicotine & Tobacco Research  2011;13(12):1266-1275.
Introduction:
Tobacco use is common and remains one of the leading causes of preventable death in developed countries. Smoking commonly begins in adolescence, and hence, it is important to understand how smoking behavior develops during this period.
Methods:
In a U.K.-based birth cohort, we analyzed repeated measures of smoking frequency in a sample of 7,322 young adolescents. Latent class analysis was used to summarize the data, and the resulting classes of behavior were related to a range of smoking risk factors. Results from a complete case analysis were compared with estimation using full-information maximum likelihood (FIML) and estimation using multiple imputation (MI).
Results:
Fifty-three percent of the sample reported having smoked a whole cigarette by age 16 years. The longitudinal data were summarized by 4 distinct patterns of smoking initiation: nonsmokers (79.7%), experimenters (10.3%), late-onset regular smokers (5.5%), and early-onset regular smokers (4.5%). Social disadvantage, other substance use, conduct problems, and female sex were strongly related to being a regular smoker; however, no risk factors studied showed any strong or consistent association with experimentation. In the complete case sample, smoking prevalence was lower, and in addition, the association between different smoking patterns and covariates was often inconsistent with those obtained through FIML/MI.
Conclusions:
Most young people have experimented with tobacco smoking by age 16 years, and regular smoking is established in a substantial minority characterized by social disadvantage, other substance, use and conduct disorder. Prevention strategies should focus on this subgroup as most children who experiment with tobacco do not progress to regular smoking.
doi:10.1093/ntr/ntr161
PMCID: PMC3223580  PMID: 21994336
20.  Fetal Alcohol Exposure and IQ at Age 8: Evidence from a Population-Based Birth-Cohort Study 
PLoS ONE  2012;7(11):e49407.
Background
Observational studies have generated conflicting evidence on the effects of moderate maternal alcohol consumption during pregnancy on offspring cognition mainly reflecting problems of confounding. Among mothers who drink during pregnancy fetal alcohol exposure is influenced not only by mother’s intake but also by genetic variants carried by both the mother and the fetus. Associations between children’s cognitive function and both maternal and child genotype at these loci can shed light on the effects of maternal alcohol consumption on offspring cognitive development.
Methods
We used a large population based study of women recruited during pregnancy to determine whether genetic variants in alcohol metabolising genes in this cohort of women and their children were related to the child’s cognitive score (measured by the Weschler Intelligence Scale) at age 8.
Findings
We found that four genetic variants in alcohol metabolising genes in 4167 children were strongly related to lower IQ at age 8, as was a risk allele score based on these 4 variants. This effect was only seen amongst the offspring of mothers who were moderate drinkers (1–6 units alcohol per week during pregnancy (per allele effect estimates were −1.80 (95% CI = −2.63 to −0.97) p = 0.00002, with no effect among children whose mothers abstained during pregnancy (0.16 (95%CI = −1.05 to 1.36) p = 0.80), p-value for interaction  = 0.009). A further genetic variant associated with alcohol metabolism in mothers was associated with their child’s IQ, but again only among mothers who drank during pregnancy.
doi:10.1371/journal.pone.0049407
PMCID: PMC3498109  PMID: 23166662
21.  TESTING A LEVEL OF RESPONSE TO ALCOHOL-BASED MODEL OF HEAVY DRINKING AND ALCOHOL PROBLEMS IN 1,905 17-YEAR-OLDS 
Background
The low level of response (LR) to alcohol is one of several genetically-influenced characteristics that increase the risk for heavy drinking and alcohol problems. Efforts to understand how LR operates through additional life influences have been carried out primarily in modest sized U.S.-based samples with limited statistical power, raising questions about generalizability and about the importance of components with smaller effects. This study evaluates a full LR-based model of risk in a large sample of adolescents from the U.K.
Methods
Cross-sectional structural equation models (SEM) were used for the approximate first half of the age 17 subjects assessed by the Avon Longitudinal Study of Parents and Children (ALSPAC), generating data on 1,905 adolescents (0 age 17.8 years, 44.2% males). LR was measured with the Self-Rating of the Effects of Alcohol (SRE) Questionnaire, outcomes were based on drinking quantities and problems, and standardized questionnaires were used to evaluate peer substance use, alcohol expectancies, and using alcohol to cope with stress.
Results
In this young and large U.K. sample, a low LR related to more adverse alcohol outcomes both directly and through partial mediation by all three additional key variables (peer substance use, expectancies, and coping). The models were similar in males and females.
Conclusions
These results confirm key elements of the hypothesized LR-based model in a large U.K. sample, supporting some generalizability beyond U.S. groups. They also indicate that with enough statistical power multiple elements contribute to how LR relates to alcohol outcomes, and reinforce the applicability of the model to both genders.
doi:10.1111/j.1530-0277.2011.01536.x
PMCID: PMC3183150  PMID: 21762180
ALSPAC; alcohol; level of response; structural equation models; adolescents
22.  Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children 
The Avon Longitudinal Study of Parents and Children (ALSPAC) is a transgenerational prospective observational study investigating influences on health and development across the life course. It considers multiple genetic, epigenetic, biological, psychological, social and other environmental exposures in relation to a similarly diverse range of health, social and developmental outcomes. Recruitment sought to enrol pregnant women in the Bristol area of the UK during 1990–92; this was extended to include additional children eligible using the original enrolment definition up to the age of 18 years. The children from 14 541 pregnancies were recruited in 1990–92, increasing to 15 247 pregnancies by the age of 18 years. This cohort profile describes the index children of these pregnancies. Follow-up includes 59 questionnaires (4 weeks–18 years of age) and 9 clinical assessment visits (7–17 years of age). The resource comprises a wide range of phenotypic and environmental measures in addition to biological samples, genetic (DNA on 11 343 children, genome-wide data on 8365 children, complete genome sequencing on 2000 children) and epigenetic (methylation sampling on 1000 children) information and linkage to health and administrative records. Data access is described in this article and is currently set up as a supported access resource. To date, over 700 peer-reviewed articles have been published using ALSPAC data.
doi:10.1093/ije/dys064
PMCID: PMC3600618  PMID: 22507743
23.  Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort 
Summary The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile.
doi:10.1093/ije/dys066
PMCID: PMC3600619  PMID: 22507742
24.  Patterns of Alcohol Use in Early Adolescence Predict Problem Use at Age 16 
Aims: Teenagers in the UK report some of the highest rates of alcohol use in Europe. We identify patterns of alcohol use in early adolescence and relate these to hazardous and harmful alcohol use at age 16. Methods: In a UK birth cohort, we analysed repeated measures of alcohol use from age 13 to 15 in a sample of 7100 adolescents. Data on drinking frequency and typical consumption when drinking were modelled separately using a pair of latent class models. Classes of alcohol-use behaviour were contrasted across a range of risk factors and then to hazardous and harmful alcohol use as assessed using the Alcohol Use Disorders Identification Test scale at age 16. Results: Heterogeneity in drinking frequency and consumption could each be captured with three classes corresponding to low, medium and high levels. In total, 14.2% were classified as high-frequency and 8.9% as high consumption alcohol users. Socio-demographic factors, maternal substance use and the young persons' use of tobacco and cannabis were associated with class membership. At age 16, 29% were drinking hazardously and a further 5.6% were assessed as harmful drinkers. Young people in the high drinking frequency or consumption class had a 9-fold increased risk of reporting harmful drinking at age 16. Conclusions: By the age of 16, a substantial proportion of teenagers in this sample were drinking at levels that could be considered hazardous or harmful for an adult. Patterns of alcohol exposure in early adolescence were strongly associated with later alcohol use. Altering drinking patterns in middle adolescence has the potential to reduce harmful use in later adolescence.
doi:10.1093/alcalc/agr156
PMCID: PMC3284685  PMID: 22215001
25.  Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database 
Objective To investigate the effect of opiate substitution treatment at the beginning and end of treatment and according to duration of treatment.
Design Prospective cohort study.
Setting UK General Practice Research Database
Participants Primary care patients with a diagnosis of substance misuse prescribed methadone or buprenorphine during 1990-2005. 5577 patients with 267 003 prescriptions for opiate substitution treatment followed-up (17 732 years) until one year after the expiry of their last prescription, the date of death before this time had elapsed, or the date of transfer away from the practice.
Main outcome measures Mortality rates and rate ratios comparing periods in and out of treatment adjusted for sex, age, calendar year, and comorbidity; standardised mortality ratios comparing opiate users’ mortality with general population mortality rates.
Results Crude mortality rates were 0.7 per 100 person years on opiate substitution treatment and 1.3 per 100 person years off treatment; standardised mortality ratios were 5.3 (95% confidence interval 4.0 to 6.8) on treatment and 10.9 (9.0 to 13.1) off treatment. Men using opiates had approximately twice the risk of death of women (morality rate ratio 2.0, 1.4 to 2.9). In the first two weeks of opiate substitution treatment the crude mortality rate was 1.7 per 100 person years: 3.1 (1.5 to 6.6) times higher (after adjustment for sex, age group, calendar period, and comorbidity) than the rate during the rest of time on treatment. The crude mortality rate was 4.8 per 100 person years in weeks 1-2 after treatment stopped, 4.3 in weeks 3-4, and 0.95 during the rest of time off treatment: 9 (5.4 to 14.9), 8 (4.7 to 13.7), and 1.9 (1.3 to 2.8) times higher than the baseline risk of mortality during treatment. Opiate substitution treatment has a greater than 85% chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months.
Conclusions Clinicians and patients should be aware of the increased mortality risk at the start of opiate substitution treatment and immediately after stopping treatment. Further research is needed to investigate the effect of average duration of opiate substitution treatment on drug related mortality.
doi:10.1136/bmj.c5475
PMCID: PMC2965139  PMID: 20978062

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