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Depression and Anxiety  2013;30(12):1185-1193.
Depression and anxiety co-occur with substance use and abuse at a high rate. Ascertaining whether substance use plays a causal role in depression and anxiety is difficult or impossible with conventional observational epidemiology. Mendelian randomisation uses genetic variants as a proxy for environmental exposures, such as substance use, which can address problems of reverse causation and residual confounding, providing stronger evidence about causality. Genetic variants can be used instead of directly measuring exposure levels, in order to gain an unbiased estimate of the effect of various exposures on depression and anxiety. The suitability of the genetic variant as a proxy can be ascertained by confirming that there is no relationship between variant and outcome in those who do not use the substance. At present, there are suitable instruments for tobacco use, so we use that as a case study. Proof-of-principle Mendelian randomisation studies using these variants have found evidence for a causal effect of smoking on body mass index. Two studies have investigated tobacco and depression using this method, but neither found strong evidence that smoking causes depression or anxiety; evidence is more consistent with a self-medication hypothesis. Mendelian randomisation represents a technique that can aid understanding of exposures that may or may not be causally related to depression and anxiety. As more suitable instruments emerge (including the use of allelic risk scores rather than individual single nucleotide polymorphisms), the effect of other substances can be investigated. Linkage disequilibrium, pleiotropy, and population stratification, which can distort Mendelian randomisation studies, are also discussed.
PMCID: PMC4235433  PMID: 23847157
instrumental variable; genetics; causal inference; substance use
2.  Errors in reported degrees and respondent driven sampling: Implications for bias☆ 
Drug and Alcohol Dependence  2014;142(100):120-126.
Respondent Driven Sampling (RDS) is a network or chain sampling method designed to access individuals from hard-to-reach populations such as people who inject drugs (PWID). RDS surveys are used to monitor behaviour and infection occurence over time; these estimations require adjusting to account for over-sampling of individuals with many contacts. Adjustment is done based on individuals’ reported total number of contacts, assuming these are correct.
Data on the number of contacts (degrees) of individuals sampled in two RDS surveys in Bristol, UK, show larger numbers of individuals reporting numbers of contacts in multiples of 5 and 10 than would be expected at random. To mimic these patterns we generate contact networks and explore different methods of mis-reporting degrees. We simulate RDS surveys and explore the sensitivity of adjusted estimates to these different methods.
We find that inaccurate reporting of degrees can cause large and variable bias in estimates of prevalence or incidence. Our simulations imply that paired RDS surveys could over- or under-estimate any change in prevalence by as much as 25%. These are particularly sensitive to inaccuracies in the degree estimates of individuals with who have low degree.
There is a substantial risk of bias in estimates from RDS if degrees are not correctly reported. This is particularly important when analysing consecutive RDS samples to assess trends in population prevalence and behaviour. RDS questionnaires should be refined to obtain high resolution degree information, particularly from low-degree individuals. Additionally, larger sample sizes can reduce uncertainty in estimates.
PMCID: PMC4150985  PMID: 24999062
Respondent driven sampling; At-risk populations; Contact network size
3.  Prevalence of Chlamydia in Young Adulthood and Association with Life Course Socioeconomic Position: Birth Cohort Study 
PLoS ONE  2014;9(8):e104943.
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.
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.
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)).
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.
PMCID: PMC4143219  PMID: 25153124
4.  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.
PMCID: PMC4246124  PMID: 25130265
ALSPAC; Adolescence; Depressive symptoms; Alcohol; Longitudinal
5.  Conduct problem trajectories and alcohol use and misuse in mid to late adolescence 
Drug and alcohol dependence  2013;133(1):100-107.
We consider the strength of the relationship between types of conduct problems in early life and pattern of alcohol use during adolescence.
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.
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).
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.
PMCID: PMC3786043  PMID: 23787037
ALSPAC; Conduct problems; Alcohol use; Adolescence; Trajectory
6.  Maternal smoking during pregnancy and offspring smoking initiation: assessing the role of intrauterine exposure 
Addiction (Abingdon, England)  2014;109(6):1013-1021.
To assess whether associations between maternal smoking during pregnancy and offspring smoking initiation are due to intrauterine mechanisms.
Comparison of associations of maternal and partner smoking behaviour during pregnancy with offspring smoking initiation using partner smoking as a negative control (n = 6484) and a Mendelian randomization analysis (n = 1020), using a genetic variant in the mothers as a proxy for smoking cessation during pregnancy.
A longitudinal birth cohort in South West England.
Participants of the Avon Longitudinal Study of Parents and Children (ALSPAC).
Smoking status during pregnancy was self-reported by mother and partner in questionnaires administered at pregnancy. Latent classes of offspring smoking initiation (non-smokers, experimenters, late-onset regular smokers and early-onset regular smokers) were previously developed from questionnaires administered at 14–16 years. A genetic variant, rs1051730, was genotyped in the mothers.
Both mother and partner smoking were similarly positively associated with offspring smoking initiation classes, even after adjustment for confounders. Odds ratios (OR) [95% confidence interval (CI)] for class membership compared with non-smokers were: experimenters: mother OR = 1.33 (95% CI = 1.06, 1.67), partner OR = 1.28 (95% CI = 1.06, 1.55), late-onset regular smokers: mother OR = 1.80 (95% CI = 1.43, 2.26), partner OR = 1.86 (95% CI = 1.52, 2.28) and early-onset regular smokers: mother OR = 2.89 (95% CI = 2.12, 3.94), partner OR = 2.50 (95% CI = 1.85, 3.37). There was no clear evidence for a dose–response effect of either mother or partner smoking heaviness on class membership. Maternal rs1051730 genotype was not clearly associated with offspring smoking initiation class in pre-pregnancy smokers (P = 0.35).
The association between smoking during pregnancy and offspring smoking initiation does not appear to operate through intrauterine mechanisms.
PMCID: PMC4114534  PMID: 24521169
ALSPAC; intrauterine; maternal smoking; Mendelian randomization; negative control; offspring smoking; pregnancy; tobacco
7.  Illicit and pharmaceutical drug consumption estimated via wastewater analysis. Part B: Placing back-calculations in a formal statistical framework 
The Science of the Total Environment  2014;487(100):642-650.
Concentrations of metabolites of illicit drugs in sewage water can be measured with great accuracy and precision, thanks to the development of sensitive and robust analytical methods. Based on assumptions about factors including the excretion profile of the parent drug, routes of administration and the number of individuals using the wastewater system, the level of consumption of a drug can be estimated from such measured concentrations. When presenting results from these ‘back-calculations’, the multiple sources of uncertainty are often discussed, but are not usually explicitly taken into account in the estimation process. In this paper we demonstrate how these calculations can be placed in a more formal statistical framework by assuming a distribution for each parameter involved, based on a review of the evidence underpinning it. Using a Monte Carlo simulations approach, it is then straightforward to propagate uncertainty in each parameter through the back-calculations, producing a distribution for instead of a single estimate of daily or average consumption. This can be summarised for example by a median and credible interval. To demonstrate this approach, we estimate cocaine consumption in a large urban UK population, using measured concentrations of two of its metabolites, benzoylecgonine and norbenzoylecgonine. We also demonstrate a more sophisticated analysis, implemented within a Bayesian statistical framework using Markov chain Monte Carlo simulation. Our model allows the two metabolites to simultaneously inform estimates of daily cocaine consumption and explicitly allows for variability between days. After accounting for this variability, the resulting credible interval for average daily consumption is appropriately wider, representing additional uncertainty. We discuss possibilities for extensions to the model, and whether analysis of wastewater samples has potential to contribute to a prevalence model for illicit drug use.
•Analysis of wastewater allows estimation of illicit drug consumption.•However, it is crucial to formally acknowledge the many sources of uncertainty.•The simple and flexible Monte Carlo simulation approach allows this.•There are many software options: we provide an Excel spreadsheet and R code.•Bayesian modelling using Markov chain Monte Carlo allows interesting extensions.
PMCID: PMC4039139  PMID: 24636801
Sewage epidemiology; Monte Carlo simulation; Uncertainty propagation; Bayesian modelling; Illicit drugs
8.  Barriers and facilitators to HPV vaccination of young women in high-income countries: a qualitative systematic review and evidence synthesis 
BMC Public Health  2014;14:700.
Vaccination against Human Papillomavirus (HPV) is recommended for adolescent young women prior to sexual debut to reduce cervical cancer related mortality and morbidity. Understanding factors affecting decision-making of HPV vaccination of young women is important so that effective interventions can be developed which address barriers to uptake in population groups less likely to receive the HPV vaccine.
We undertook a qualitative systematic review and evidence synthesis to examine decision-making relating to the HPV vaccination of young women in high-income countries. A comprehensive search of databases from inception to March 2012 was undertaken to identify eligible studies reporting the perspectives of key stakeholders including policy makers, professionals involved in programme, parents, and young women. Factors affecting uptake of the vaccine were examined at different levels of the socio-ecological model (policy, community, organisational, interpersonal and intrapersonal).
Forty-one studies were included. Whether young women receive the HPV vaccine is strongly governed by the decisions of policy makers, healthcare professionals, and parents. These decisions are shaped by: financial considerations; social norms and values relating to sexual activity, and; trust in vaccination programmes and healthcare providers. Financial constraints may be overcome through universal healthcare systems offering the HPV vaccine free at the point of delivery. In the healthcare setting, judgements by healthcare professionals about whether to recommend the vaccine may restrict a young woman’s access to the vaccine irrespective of her own beliefs and preferences. Parents may decide not to allow their daughters to be vaccinated, based on cultural or religious perceptions about sexual activity.
Barriers to the uptake of the HPV vaccine have implications for young women’s future sexual, physical and reproductive health. Interventions to address barriers to uptake of the vaccine should target appropriate, and multiple, levels of the socio-ecological model. Issues of trust require clear, accessible, and sometimes culturally appropriate, information about the HPV vaccination programme. Although young women are central to the HPV vaccination programme, their views are underrepresented in the qualitative literature. Future research should consider young women’s perceptions of, and involvement in, consent and decision-making.
PMCID: PMC4100058  PMID: 25004868
Adolescents; Decision-making; HPV vaccine; Health inequalities; Ethnicity
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.
PMCID: PMC4094936  PMID: 24727307
alcohol problems; adolescence; gene-by-environment; ALSPAC; FinnTwin12
10.  Recapture or Precapture? Fallibility of Standard Capture-Recapture Methods in the Presence of Referrals Between Sources 
American Journal of Epidemiology  2014;179(11):1383-1393.
Capture-recapture methods, largely developed in ecology, are now commonly used in epidemiology to adjust for incomplete registries and to estimate the size of difficult-to-reach populations such as problem drug users. Overlapping lists of individuals in the target population, taken from administrative data sources, are considered analogous to overlapping “captures” of animals. Log-linear models, incorporating interaction terms to account for dependencies between sources, are used to predict the number of unobserved individuals and, hence, the total population size. A standard assumption to ensure parameter identifiability is that the highest-order interaction term is 0. We demonstrate that, when individuals are referred directly between sources, this assumption will often be violated, and the standard modeling approach may lead to seriously biased estimates. We refer to such individuals as having been “precaptured,” rather than truly recaptured. Although sometimes an alternative identifiable log-linear model could accommodate the referral structure, this will not always be the case. Further, multiple plausible models may fit the data equally well but provide widely varying estimates of the population size. We demonstrate an alternative modeling approach, based on an interpretable parameterization and driven by careful consideration of the relationships between the sources, and we make recommendations for capture-recapture in practice.
PMCID: PMC4036210  PMID: 24727806
bias; log-linear models; model selection; parameter identifiability; problem drug use; prevalence estimation
11.  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.
PMCID: PMC4172989  PMID: 24197169
Conduct problems; ALSPAC; Trajectory outcomes
12.  The health, social and educational needs of children who have survived meningitis and septicaemia: the parents’ perspective 
BMC Public Health  2013;13:954.
Survivors of bacterial meningitis and septicaemia can experience a range of after-effects. There is little published research on the needs and provision of aftercare for children surviving bacterial meningitis and septicaemia.
Mixed methods study employing a survey and follow-up interviews with a sample of survey participants recruited from Meningitis Research Foundation’s member database and social media.
Of 194 eligible survey respondents, 77% reported at least moderate short-term after-effects, and 57% a need for aftercare or support. Most parents reported that their child received a hearing test (98%) and follow-up appointment with a paediatrician (66%). Psychosocial after-effects were most common and the greatest need was for educational support. About half of participants felt their children’s needs for aftercare were met. We conducted interviews with 18 parents. Findings suggest access could be limited by: parents’ inability to navigate systems in place, child’s age, and delayed identification of sequelae. Parents felt a comprehensive explanation of possible after-effects on discharge from hospital was required, and found uncertain prognoses difficult. Good communication between professionals enabled a service tailored to the child’s needs.
Our study supports the NICE and SIGN guidelines and highlights areas for improvement in the aftercare of these children.
PMCID: PMC3852620  PMID: 24112360
Meningitis; Septicaemia; Sequelae; Aftercare; Survey; Qualitative
13.  Combination Interventions to Prevent HCV Transmission Among People Who Inject Drugs: Modeling the Impact of Antiviral Treatment, Needle and Syringe Programs, and Opiate Substitution Therapy 
Background. Interventions such as opiate substitution therapy (OST) and high-coverage needle and syringe programs (HCNSP) cannot substantially reduce hepatitis C virus (HCV) prevalence among people who inject drugs (PWID). HCV antiviral treatment may prevent onward transmission. We project the impact of combining OST, HCNSP, and antiviral treatment on HCV prevalence/incidence among PWID.
Methods. An HCV transmission model among PWID was used to project the combinations of OST, HCNSP, and antiviral treatment required to achieve different prevalence and incidence reductions within 10 years for 3 chronic prevalence scenarios and the impact of HCV treatment if only delivered through OST programs. Multivariate and univariate sensitivity analyses were performed.
Results. Large reductions (>45%) in HCV chronic prevalence over 10 years require HCV antiviral treatment. Scaling up OST and HCNSP substantially reduces the treatment rate required to achieve specific HCV prevalence reductions. If OST and HCNSP coverage were increased to 40% each (no coverage at baseline), then annually treating 10, 23, or 42 per 1000 PWID over 10 years would halve prevalence for 20%, 40%, or 60% baseline chronic HCV prevalences, respectively. Approximately 30% fewer treatments are necessary with new direct-acting antivirals. If coverage of OST and HCNSP is 50% at baseline, similar prevalence reductions require higher treatment rates for the same OST and HCNSP coverage.
Conclusions. Combining antiviral treatment with OST with HCNSP is critical for achieving substantial reductions (>50%) in HCV chronic prevalence over 10 years. Empirical studies are required on how best to scale up antiviral treatment and combine treatment with other interventions.
PMCID: PMC3722076  PMID: 23884064
14.  Cost-effectiveness of HCV case-finding for people who inject drugs via dried blood spot testing in specialist addiction services and prisons 
BMJ Open  2013;3(8):e003153.
People who inject drugs (PWID) are at high risk for acquiring hepatitis C virus (HCV), but many are unaware of their infection. HCV dried blood spot (DBS) testing increases case-finding in addiction services and prisons. We determine the cost-effectiveness of increasing HCV case-finding among PWID by offering DBS testing in specialist addiction services or prisons as compared to using venepuncture.
Cost-utility analysis using a dynamic HCV transmission model among PWID, including: disease progression, diagnosis, treatment, injecting status, incarceration and addition services contact.
DBS testing in specialist addiction services or prisons. Intervention impact was determined by a meta-analysis of primary data.
Primary and secondary outcome measures
Costs (in UK £, £1=US$1.60) and utilities (quality-adjusted life years, QALYs) were attached to each state and the incremental cost effectiveness ratio (ICER) determined. Multivariate uncertainty and one-way sensitivity analyses were performed.
For a £20 000 per QALY gained willingness-to-pay threshold, DBS testing in addiction services is cost-effective (ICER of £14 600 per QALY gained). Under the base-case assumption of no continuity of treatment/care when exiting/entering prison, DBS testing in prisons is not cost-effective (ICER of £59 400 per QALY gained). Results are robust to changes in HCV prevalence; increasing PWID treatment rates to those for ex-PWID considerably reduces ICER (£4500 and £30 000 per QALY gained for addiction services and prison, respectively). If continuity of care is >40%, the prison DBS ICER falls below £20 000 per QALY gained.
Despite low PWID treatment rates, increasing case-finding can be cost-effective in specialist addiction services, and in prisons if continuity of treatment/care is ensured.
PMCID: PMC3752052  PMID: 23943776
15.  Association of Maternal Smoking With Child Cotinine Levels 
Nicotine & Tobacco Research  2013;15(12):2029-2036.
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.
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.
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.
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.
PMCID: PMC3819976  PMID: 23880896
16.  Establishing the Melbourne injecting drug user cohort study (MIX): rationale, methods, and baseline and twelve-month follow-up results 
Cohort studies provide an excellent opportunity to monitor changes in behaviour and disease transmission over time. In Australia, cohort studies of people who inject drugs (PWID) have generally focused on older, in-treatment injectors, with only limited outcome measure data collected. In this study we specifically sought to recruit a sample of younger, largely out-of-treatment PWID, in order to study the trajectories of their drug use over time.
Respondent driven sampling, traditional snowball sampling and street outreach methods were used to recruit heroin and amphetamine injectors from one outer-urban and two inner-urban regions of Melbourne, Australia. Information was collected on participants’ demographic and social characteristics, drug use characteristics, drug market access patterns, health and social functioning, and health service utilisation. Participants are followed-up on an annual basis.
688 PWID were recruited into the study. At baseline, the median age of participants was 27.6 years (IQR: 24.4 years – 29.6 years) and two-thirds (67%) were male. Participants reported injecting for a median of 10.2 years (range: 1.5 months – 21.2 years), with 11% having injected for three years or less. Limited education, unemployment and previous incarceration were common. The majority of participants (82%) reported recent heroin injection, and one third reported being enrolled in Opioid Substitution Therapy (OST) at recruitment. At 12 months follow-up 458 participants (71% of eligible participants) were retained in the study. There were few differences in demographic and drug-use characteristics of those lost to follow-up compared with those retained in the study, with attrition significantly associated with recruitment at an inner-urban location, male gender, and providing incomplete contact information at baseline.
Our efforts to recruit a sample of largely out-of-treatment PWID were limited by drug market characteristics at the time, where fluctuating heroin availability has led to large numbers of PWID accessing low-threshold OST. Nevertheless, this study of Australian injectors will provide valuable data on the natural history of drug use, along with risk and protective factors for adverse health outcomes associated with injecting drug use. Comprehensive follow-up procedures have led to good participant retention and limited attrition bias.
PMCID: PMC3691755  PMID: 23786848
Injecting drug use; Cohort; Longitudinal studies; Australia
17.  Introducing vaccination against serogroup B meningococcal disease: An economic and mathematical modelling study of potential impact 
Vaccine  2013;31(23):2638-2646.
•The epidemiological impact and cost-effectiveness of ‘MenB’ vaccination was assessed.•Routine infant vaccination could prevent 27% of cases over the lifetime of a cohort.•This policy could be cost-effective at £9 per vaccine dose.•Substantial disease reductions are predicted if the vaccine also prevents carriage.•In this case infant vaccination and catch-up could reduce disease by 71% in 10 years.
Meningococcal disease remains an important cause of morbidity and mortality worldwide. The first broadly effective vaccine against group B disease (which causes considerable meningococcal disease in Europe, the Americas and Australasia) was licensed in the EU in January 2013; our objective was to estimate the potential impact of introducing such a vaccine in England.
We developed two models to estimate the impact of introducing a new ‘MenB’ vaccine. The cohort model assumes the vaccine protects against disease only; the transmission dynamic model also allows the vaccine to protect against carriage (accounting for herd effects). We used these, and economic models, to estimate the case reduction and cost-effectiveness of a number of different vaccine strategies.
We estimate 27% of meningococcal disease cases could be prevented over the lifetime of an English birth cohort by vaccinating infants at 2,3,4 and 12 months of age with a vaccine that prevents disease only; this strategy could be cost-effective at £9 per vaccine dose. Substantial reductions in disease (71%) can be produced after 10 years by routinely vaccinating infants in combination with a large-scale catch-up campaign, using a vaccine which protects against carriage as well as disease; this could be cost-effective at £17 per vaccine dose.
New ‘MenB’ vaccines could substantially reduce disease in England and be cost-effective if competitively priced, particularly if the vaccines can prevent carriage as well as disease. These results are relevant to other countries, with a similar epidemiology to England, considering the introduction of a new ‘MenB’ vaccine.
PMCID: PMC3743045  PMID: 23566946
MCC, meningococcal serogroup C conjugate; MenB, capsular group B meningococci; QALYs, quality adjusted life years; Meningococcal; Vaccine; Model; Cost-effectiveness
18.  The More You Look, the More You Find: Effects of Hepatitis C Virus Testing Interval on Reinfection Incidence and Clearance and Implications for Future Vaccine Study Design 
The Journal of Infectious Diseases  2012;205(9):1342-1350.
Introduction. Studies have explored whether spontaneous clearance of hepatitis C virus (HCV) infection decreases the likelihood of reinfection or increases the probability of clearance. This analysis investigates whether the conflicting findings from these studies could be due to differences in frequency of HCV RNA testing.
Methods. A model simulated the dynamics of HCV reinfection and clearance among a cohort of injection drug users. For different reinfection incidence and clearance rates, the model evaluated the accuracy of epidemiological studies that used different HCV testing frequencies.
Results. Experimental estimates for the reinfection incidence and clearance probability will be accurate (<20% error) if the testing interval is less than the reinfection clearance duration. Otherwise, experimental estimates can greatly underestimate the real values (≤66% error if reinfection duration is 1 month and the testing interval is 3 months). Uncertainty in experimental estimates also increases at lower reinfection incidences, whereas for lower clearance probabilities the uncertainty in the estimated clearance probability increases but estimated reinfection incidence decreases.
Discussion. Differences in HCV testing interval could account for most between-study variability in the estimated probability of clearing reinfections and is likely to have biased reinfection incidence estimates. Our findings suggest that a high reinfection clearance probability (>75%) is consistent with data.
PMCID: PMC3324399  PMID: 22457292
19.  Inequalities in the uptake of Human Papillomavirus Vaccination: a systematic review and meta-analysis 
Background The human papillomavirus (HPV) vaccine offers an opportunity to reduce health inequalities associated with cervical cancer provided the vaccine is delivered equitably at population level.
Method We reviewed evidence of inequalities in HPV vaccine uptake in young women after undertaking a comprehensive search of databases from inception to March 2012. Studies that compared HPV vaccination initiation and/or completion by at least one ethnicity or socioeconomic-related variable in adolescent young women were included. There were no language restrictions. Data were extracted by two reviewers and pooled in a meta-analysis using a random-effects model; sub-analyses and meta-regression were undertaken to investigate sources of heterogeneity.
Results In all, 29 publications related to 27 studies were included in the review. Black young women were less likely to initiate HPV vaccination compared with White young women (combined OR: 0.89, 95% CI: 0.82–0.97). In the USA, young women without healthcare insurance were less likely to initiate (combined OR: 0.56, 95% CI: 0.40–0.78). There was no strong evidence that lower family income (combined OR: 1.16, 95% CI: 1.00–1.34) or lower parental education (combined OR 1.06, 95% CI: 0.92–1.22) influenced HPV vaccination initiation.
Conclusions We found strong evidence for differences in HPV vaccination initiation by ethnicity and healthcare coverage, but did not find a strong association with parental education or family income variables. The majority of studies originated from the USA. Population-based studies reporting both initiation and completion of the HPV vaccination programme are required to establish patterns of uptake in different healthcare contexts.
PMCID: PMC3733698  PMID: 23620381
HPV vaccine; socioeconomic factors; ethnic disparity; immunization, adolescents; public health
20.  Stronger evidence is needed before accepting that cannabis plays an important role in the aetiology of schizophrenia in the population 
Schizophrenia is a debilitating but poorly understood condition with very few known modifiable risk factors. Cannabis use can acutely induce psychotic experiences, but its causal relationship to schizophrenia is less well understood. Longitudinal cohort studies suggest that the association between cannabis and psychotic outcomes is not due to chance or reverse causation. However, the association could be due to bias or residual confounding. Methods that can test alternative explanations in greater depth are required. This is especially important as ecological studies have found little association between the increase in cannabis use over recent decades and incidence of psychotic disorders; public health models suggest that cannabis use may need to be treated and prevented in many thousands of users in order to prevent one case of schizophrenia. We believe that, while such uncertainty exists, there is a scientific duty to continue to investigate the role of cannabis in the aetiology of schizophrenia and that the policy case for considering cannabis exposure as a critical target for preventing schizophrenia is yet to be made. However, due to other evidence of the harms of cannabis use, this should not affect the public health message that cannabis can be harmful and that cannabis dependence should be prevented.
PMCID: PMC3544397  PMID: 23361397
21.  Characterizing Patterns of Smoking Initiation in Adolescence: Comparison of Methods for Dealing With Missing Data 
Nicotine & Tobacco Research  2011;13(12):1266-1275.
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.
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).
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.
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.
PMCID: PMC3223580  PMID: 21994336
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.
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.
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.
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.
PMCID: PMC3183150  PMID: 21762180
ALSPAC; alcohol; level of response; structural equation models; adolescents
23.  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.
PMCID: PMC3284685  PMID: 22215001
24.  Optimal Control of Hepatitis C Antiviral Treatment Programme Delivery for Prevention amongst a Population of Injecting Drug Users 
PLoS ONE  2011;6(8):e22309.
In most developed countries, HCV is primarily transmitted by injecting drug users (IDUs). HCV antiviral treatment is effective, and deemed cost-effective for those with no re-infection risk. However, few active IDUs are currently treated. Previous modelling studies have shown antiviral treatment for active IDUs could reduce HCV prevalence, and there is emerging interest in developing targeted IDU treatment programmes. However, the optimal timing and scale-up of treatment is unknown, given the real-world constraints commonly existing for health programmes. We explore how the optimal programme is affected by a variety of policy objectives, budget constraints, and prevalence settings. We develop a model of HCV transmission and treatment amongst active IDUs, determine the optimal treatment programme strategy over 10 years for two baseline chronic HCV prevalence scenarios (30% and 45%), a range of maximum annual budgets (50,000–300,000 per 1,000 IDUs), and a variety of objectives: minimising health service costs and health utility losses; minimising prevalence at 10 years; minimising health service costs and health utility losses with a final time prevalence target; minimising health service costs with a final time prevalence target but neglecting health utility losses. The largest programme allowed for a given budget is the programme which minimises both prevalence at 10 years, and HCV health utility loss and heath service costs, with higher budgets resulting in greater cost-effectiveness (measured by cost per QALY gained compared to no treatment). However, if the objective is to achieve a 20% relative prevalence reduction at 10 years, while minimising both health service costs and losses in health utility, the optimal treatment strategy is an immediate expansion of coverage over 5–8 years, and is less cost-effective. By contrast, if the objective is only to minimise costs to the health service while attaining the 20% prevalence reduction, the programme is deferred until the final years of the decade, and is the least cost-effective of the scenarios.
PMCID: PMC3154900  PMID: 21853030
25.  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.
PMCID: PMC2895695  PMID: 20595255

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