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1.  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
2.  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
3.  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
4.  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
5.  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
6.  Which Behavioral, Emotional and School Problems in Middle-Childhood Predict Early Sexual Behavior? 
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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Does consideration of either psychological or material disadvantage improve coronary risk prediction? Prospective observational study of Scottish men 
Objective
To assess the value of psychosocial risk factors in discriminating between individuals at higher and lower risk of coronary heart disease, using risk prediction equations.
Design
Prospective observational study.
Setting
Scotland.
Participants
5191 employed men aged 35 to 64 years and free of coronary heart disease at study enrolment
Main outcome measures
Area under receiver operating characteristic (ROC) curves for risk prediction equations including different risk factors for coronary heart disease.
Results
During the first 10 years of follow up, 203 men died of coronary heart disease and a further 200 were admitted to hospital with this diagnosis. Area under the ROC curve for the standard Framingham coronary risk factors was 74.5%. Addition of “vital exhaustion” and psychological stress led to areas under the ROC curve of 74.5% and 74.6%, respectively. Addition of current social class and lifetime social class to the standard Framingham equation gave areas under the ROC curve of 74.6% and 74.9%, respectively. In no case was there strong evidence for improved discrimination of the model containing the novel risk factor over the standard model.
Conclusions
Consideration of psychosocial risk factors, including those that are strong independent predictors of heart disease, does not substantially influence the ability of risk prediction tools to discriminate between individuals at higher and lower risk of coronary heart disease.
doi:10.1136/jech.2006.055921
PMCID: PMC2660009  PMID: 17699540
cardiovascular disease; risk assessment; Framingham risk score; primary prevention; psychosocial factors
17.  DataSHIELD: resolving a conflict in contemporary bioscience—performing a pooled analysis of individual-level data without sharing the data 
Background Contemporary bioscience sometimes demands vast sample sizes and there is often then no choice but to synthesize data across several studies and to undertake an appropriate pooled analysis. This same need is also faced in health-services and socio-economic research. When a pooled analysis is required, analytic efficiency and flexibility are often best served by combining the individual-level data from all sources and analysing them as a single large data set. But ethico-legal constraints, including the wording of consent forms and privacy legislation, often prohibit or discourage the sharing of individual-level data, particularly across national or other jurisdictional boundaries. This leads to a fundamental conflict in competing public goods: individual-level analysis is desirable from a scientific perspective, but is prevented by ethico-legal considerations that are entirely valid.
Methods Data aggregation through anonymous summary-statistics from harmonized individual-level databases (DataSHIELD), provides a simple approach to analysing pooled data that circumvents this conflict. This is achieved via parallelized analysis and modern distributed computing and, in one key setting, takes advantage of the properties of the updating algorithm for generalized linear models (GLMs).
Results The conceptual use of DataSHIELD is illustrated in two different settings.
Conclusions As the study of the aetiological architecture of chronic diseases advances to encompass more complex causal pathways—e.g. to include the joint effects of genes, lifestyle and environment—sample size requirements will increase further and the analysis of pooled individual-level data will become ever more important. An aim of this conceptual article is to encourage others to address the challenges and opportunities that DataSHIELD presents, and to explore potential extensions, for example to its use when different data sources hold different data on the same individuals.
doi:10.1093/ije/dyq111
PMCID: PMC2972441  PMID: 20630989
Pooling; analysis; meta-analysis; individual-level; study-level; generalized linear model; GLM; ethico-legal; ELSI; identification; disclosure; distributed computing; bioinformatics; information technology; IT
18.  Healthcare and patient costs of a proactive chlamydia screening programme: the Chlamydia Screening Studies project 
Sexually Transmitted Infections  2007;83(4):276-281.
Background and objective
Most economic evaluations of chlamydia screening do not include costs incurred by patients. The objective of this study was to estimate both the health service and private costs of patients who participated in proactive chlamydia screening, using mailed home‐collected specimens as part of the Chlamydia Screening Studies project.
Methods
Data were collected on the administrative costs of the screening study, laboratory time and motion studies and patient‐cost questionnaire surveys were conducted. The cost for each screening invitation and for each accepted offer was estimated. One‐way sensitivity analysis was conducted to explore the effects of variations in patient costs and the number of patients accepting the screening offer.
Results
The time and costs of processing urine specimens and vulvo‐vaginal swabs from women using two nucleic acid amplification tests were similar. The total cost per screening invitation was £20.37 (95% CI £18.94 to 24.83). This included the National Health Service cost per individual screening invitation £13.55 (95% CI £13.15 to 14.33) and average patient costs of £6.82 (95% CI £5.48 to 10.22). Administrative costs accounted for 50% of the overall cost.
Conclusions
The cost of proactive chlamydia screening is comparable to those of opportunistic screening. Results from this study, which is the first to collect private patient costs associated with a chlamydia screening programme, could be used to inform future policy recommendations and provide unique primary cost data for economic evaluations.
doi:10.1136/sti.2006.023374
PMCID: PMC2598691  PMID: 17229792
19.  Survival and cessation in injecting drug users: prospective observational study of outcomes and effect of opiate substitution treatment 
Objectives To examine survival and long term cessation of injecting in a cohort of drug users and to assess the influence of opiate substitution treatment on these outcomes.
Design Prospective open cohort study.
Setting A single primary care facility in Edinburgh.
Participants 794 patients with a history of injecting drug use presenting between 1980 and 2007; 655 (82%) were followed up by interview or linkage to primary care records and mortality register, or both, and contributed 10 390 person years at risk; 557 (85%) had received opiate substitution treatment.
Main outcome measures Duration of injecting: years from first injection to long term cessation, defined as last injection before period of five years of non-injecting; mortality before cessation; overall survival.
Results In the entire cohort 277 participants achieved long term cessation of injecting, and 228 died. Half of the survivors had poor health related quality of life. Median duration from first injection to death was 24 years for participants with HIV and 41 years for those without HIV. For each additional year of opiate substitution treatment the hazard of death before long term cessation fell 13% (95% confidence interval 17% to 9%) after adjustment for HIV, sex, calendar period, age at first injection, and history of prison and overdose. Conversely exposure to opiate substitution treatment was inversely related to the chances of achieving long term cessation.
Conclusions Opiate substitution treatment in injecting drug users in primary care reduces this risk of mortality, with survival benefits increasing with cumulative exposure to treatment. Treatment does not reduce the overall duration of injecting.
doi:10.1136/bmj.c3172
PMCID: PMC2895695  PMID: 20595255
20.  The Edinburgh Addiction Cohort: recruitment and follow-up of a primary care based sample of injection drug users and non drug-injecting controls 
BMC Public Health  2010;10:101.
Background
Injection drug use is an important public health problem. Epidemiological understanding of this problem is incomplete as longitudinal studies in the general population are difficult to undertake. In particular little is known about early life risk factors for later drug injection or about the life course of injection once established including the influence of medical and social interventions.
Methods
Individuals thought to be drug injectors were identified through a single primary medical care facility in Edinburgh between 1980 and 2006 and flagged with the General Registry Office. From October 2005 - October 2007, these cases were traced and invited to undergo interview assessment covering early life experience, substance use, health and social histories. Age and sex matched controls for confirmed cases (alive and dead) were later recruited through the same health facility. Controls for living cases completed the same structured interview schedule. Data were also collected on cases and controls through linkage to routine primary care records, death registrations, hospital contact statistics and police and prison records. All interviews were conducted with the knowledge and permission of the current GP.
Results
The initial cohort size was 814. At start of follow up 227 had died. Of the remaining 587: 20 had no contact details and 5 had embarked from the UK; 40 declined participation; 38 did not respond to invitations; 14 were excluded by their GP on health or social grounds and 22 had their contact details withheld by administrative authorities. 448 were interviewed of whom 16 denied injection and were excluded. Of 191 dead cases with medical records 4 were excluded as their records contained no evidence of injection. 5 interviewed cases died before follow up was concluded though these individuals were counted as "live" cases. 1 control per case (dead and alive) was recruited. Linkage to Scottish Morbidity Records data (available from 1981 onwards) on general acute inpatient and day cases, mental health inpatient and day cases and cancer was provided by Information Services, NHS Scotland, for all cases interviewed and all dead cases. The Scottish Prison Service provided records for 198 (46%) of cases interviewed, 48 cases not interviewed and 34 (18%) of dead cases. For a sub-sample of 100 interviewees a search of the Lothian and Borders police database was made for official criminal records and 94 had criminal records. Data linkage for controls is ongoing.
Conclusions
Injecting drug users recruited from a community setting can be successfully followed-up through interviews and record linkage. Information from injecting cases is being analysed in terms of injecting patterns and possible influences on these. Comparisons between cases and controls will allow identification of possibly modifiable early life risk factors for drug injection and will also clarify the burden of disease associated with injection and the influence on this of different health and social interventions.
doi:10.1186/1471-2458-10-101
PMCID: PMC2841670  PMID: 20187928
21.  Variation in NHS utilisation of vault smear tests in women post-hysterectomy: A study, using routinely collected datasets 
BMC Women's Health  2008;8:6.
Background
20% of women living in the UK have a hysterectomy during their lifetime, levels are higher in the USA, making it one of the most commonly performed major surgical procedures. Understanding of the indications for hysterectomy and of the rationale for follow-up of women post hysterectomy is currently limited. Guidelines concerning follow-up by means of vaginal vault cytology tests exist but these are not based on 'gold standard' evidence. Furthermore, the extent to which current practice reflects these guidelines is unclear. This study aims to determine the factors associated with variability in hysterectomy rates and subsequent follow-up after surgery by use of the vaginal vault smear cytology test.
Methods/Design
All women resident in the West Midlands region, of the United Kingdom, who had a hysterectomy operation between 1st April 2002 and 30th March 2003 will be identified from the Hospital Episodes Statistics database which also contains proxy data on deprivation status, derived from postcode and self declared ethnicity. These data will be linked to regional cervical screening records for each woman and histopathology laboratory records from the relevant hospitals. Study objectives are to describe: Indications for the hysterectomy operation, histology at hysterectomy, subsequent follow-up by use or non-use of vaginal vault cytology tests and variation between histological groups. Additionally the data will be categorised according to a woman's cytology screening history prior to surgery (i.e. always normal, borderline, resolved abnormalities, CIN etc) and these different groups compared. Variations in these outcomes according to age, deprivation and ethnic group will also be examined. Analysis will be undertaken using SPSS.
Discussion
This study will clarify patterns of current practice in one large English region and determine whether this practice reflects existing guidelines. The study will also strengthen the evidence base for future guidelines.
Study registration
National Research Register N0138173331
doi:10.1186/1472-6874-8-6
PMCID: PMC2329610  PMID: 18373859
22.  Confirmatory Real-Time PCR Assay for Human Papillomavirus (HPV) Type 52 Infection in Anogenital Specimens Screened for HPV Infection with the Linear Array HPV Genotyping Test▿  
Journal of Clinical Microbiology  2007;45(11):3821-3823.
A novel real-time PCR assay for detection of human papillomavirus type 52 (HPV-52) DNA (RT-52) was evaluated on 265 anogenital samples. RT-52 had a sensitivity of 98.4% and a specificity of 100% compared to conventional HPV-52 typing assays, including hybridization of PGMY products with an HPV-52-specific probe and PCR sequencing of HPV-52 E6.
doi:10.1128/JCM.01145-07
PMCID: PMC2168527  PMID: 17898159
23.  Cost effectiveness of home based population screening for Chlamydia trachomatis in the UK: economic evaluation of chlamydia screening studies (ClaSS) project 
BMJ : British Medical Journal  2007;335(7614):291.
Objective To investigate the cost effectiveness of screening for Chlamydia trachomatis compared with a policy of no organised screening in the United Kingdom.
Design Economic evaluation using a transmission dynamic mathematical model.
Setting Central and southwest England.
Participants Hypothetical population of 50 000 men and women, in which all those aged 16-24 years were invited to be screened each year.
Main outcome measures Cost effectiveness based on major outcomes averted, defined as pelvic inflammatory disease, ectopic pregnancy, infertility, or neonatal complications.
Results The incremental cost per major outcome averted for a programme of screening women only (assuming eight years of screening) was £22 300 (€33 000; $45 000) compared with no organised screening. For a programme screening both men and women, the incremental cost effectiveness ratio was approximately £28 900. Pelvic inflammatory disease leading to hospital admission was the most frequently averted major outcome. The model was highly sensitive to the incidence of major outcomes and to uptake of screening. When both were increased the cost effectiveness ratio fell to £6200 per major outcome averted for screening women only.
Conclusions Proactive register based screening for chlamydia is not cost effective if the uptake of screening and incidence of complications are based on contemporary empirical studies, which show lower rates than commonly assumed. These data are relevant to discussions about the cost effectiveness of the opportunistic model of chlamydia screening being introduced in England.
doi:10.1136/bmj.39262.683345.AE
PMCID: PMC1941857  PMID: 17656504
24.  Vulvovaginal-Swab or First-Catch Urine Specimen To Detect Chlamydia trachomatis in Women in a Community Setting?▿  
Journal of Clinical Microbiology  2006;44(12):4389-4394.
Screening for chlamydia in women is widely recommended. We evaluated the performance of two nucleic acid amplification tests for detecting Chlamydia trachomatis in self-collected vulvovaginal-swab and first-catch urine specimens from women in a community setting and a strategy for optimizing the sensitivity of an amplified enzyme immunoassay on vulvovaginal-swab specimens. We tested 2,745 paired vulvovaginal-swab and urine specimens by PCR (Roche Cobas) or strand displacement amplification (SDA; Becton Dickinson). There were 146 women infected with chlamydia. The assays detected 97.3% (95% confidence interval [CI], 93.1 to 99.2%) of infected patients with vulvovaginal-swab specimens and 91.8% (86.1 to 95.7%) with urine specimens. We tested 2,749 vulvovaginal-swab specimens with both a nucleic acid amplification test and a polymer conjugate-enhanced enzyme immunoassay with negative-gray-zone testing. The relative sensitivities obtained after retesting specimens in the negative gray zone were 74.3% (95% CI, 62.8 to 83.8%) with PCR and 58.3% (95% CI, 46.1 to 69.8%) with SDA. In community settings, both vulvovaginal-swab and first-catch urine specimens from women are suitable substrates for nucleic acid amplification tests, but enzyme immunoassays, even after negative-gray-zone testing, should not be used in screening programs.
doi:10.1128/JCM.01060-06
PMCID: PMC1698412  PMID: 17065268
25.  Opportunistic and systematic screening for chlamydia: a study of consultations by young adults in general practice 
Background
Opportunistic screening for genital chlamydia infection is being introduced in England, but evidence for the effectiveness of this approach is lacking. There are insufficient data about young peoples' use of primary care services to determine the potential coverage of opportunistic screening in comparison with a systematic population-based approach.
Aim
To estimate use of primary care services by young men and women; to compare potential coverage of opportunistic chlamydia screening with a systematic postal approach.
Design of study
Population based cross-sectional study.
Setting
Twenty-seven general practices around Bristol and Birmingham.
Method
A random sample of patients aged 16–24 years were posted a chlamydia screening pack. We collected details of face-to-face consultations from general practice records. Survival and person-time methods were used to estimate the cumulative probability of attending general practice in 1 year and the coverage achieved by opportunistic and systematic postal chlamydia screening.
Results
Of 12 973 eligible patients, an estimated 60.4% (95% confidence interval [CI] = 58.3 to 62.5%) of men and 75.3% (73.7 to 76.9%) of women aged 16–24 years attended their practice at least once in a 1-year period. During this period, an estimated 21.3% of patients would not attend their general practice but would be reached by postal screening, 9.2% would not receive a postal invitation but would attend their practice, and 11.8% would be missed by both methods.
Conclusions
Opportunistic and population-based approaches to chlamydia screening would both fail to contact a substantial minority of the target group, if used alone. A pragmatic approach combining both strategies might achieve higher coverage.
PMCID: PMC1828253  PMID: 16464322
chlamydia trachomatis; family practice; mass screening; primary health care

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