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1.  Childhood body mass index growth trajectories and endometrial cancer risk 
International Journal of Cancer  2016;140(2):310-315.
Previously, we found that excess weight already in childhood has positive associations with endometrial cancer; however, associations with changes in body mass index (BMI) during childhood are not well understood. Therefore, we examined whether growth in childhood BMI is associated with endometrial cancer and its sub‐types. A cohort of 155,505 girls from the Copenhagen School Health Records Register with measured weights and heights at the ages of 6–14 years and born 1930–1989 formed the analytical population. BMI was transformed to age‐specific z scores. Using linear spline multilevel models, each girl's BMI growth trajectory was estimated as the deviance from the average trajectory for three different growth periods (6.25–7.99, 8.0–10.99, 11.0–14.0 years). Via a link to health registers, 1,020 endometrial cancer cases were identified, and Cox regressions were performed. A greater gain in BMI during childhood was positively associated with endometrial cancer but no differences between the different growth periods were detected in models adjusted for baseline BMI. The hazard ratios for the associations with overall growth during childhood per 0.1 z score increase were 1.15 (95% confidence interval [CI]: 1.07–1.24) for all endometrial cancers, 1.12 (95% CI: 1.04–1.21) for estrogen‐dependent cancers, 1.16 (95% CI: 1.06–1.26) for endometrioid adenocarcinomas and 1.46 (95% CI: 1.16–1.84) for non‐estrogen‐dependent cancers. Growth in BMI in early life is positively linked to later endometrial cancer risk. We did not identify any sensitive childhood growth period, which suggests that excess gain in BMI during the entire childhood period should be avoided.
What's new?
High body mass index (BMI) early in life is linked to an increased risk of endometrial cancer in adulthood. Potentially influencing that association are the amount by which BMI increases in childhood, as well as the timing of BMI increase. Here, analyses of data from the Copenhagen School Health Records Register for girls ages 6 to 14 shows that endometrial cancer risk is increased by greater BMI gain across ages, while the specific age at which BMI increases occurs has little impact. Excess BMI gain at any time during childhood could set the stage for endometrial carcinogenesis.
doi:10.1002/ijc.30464
PMCID: PMC5132154  PMID: 27718528
body weights and measures; child; endometrial neoplasms; growth and development; obesity
2.  Defining adolescent common mental disorders using electronic primary care data: a comparison with outcomes measured using the CIS-R 
BMJ Open  2016;6(12):e013167.
Objective
To compare the prevalence of common mental disorders (CMDs) derived from data held in primary care records with that measured using the revised Clinical Interview Schedule (CIS-R) in order to assess the potential robustness of findings based only on routinely collected data.
Design and setting
Comparison study using linkage between the Avon Longitudinal Study of Parents and Children (ALSPAC) and electronic primary care records.
Participants
We studied 1562 adolescents who had completed the CIS-R in ALSPAC at age 17–18 years and had linkage established to their primary care records.
Outcome measures
Outcome measures from ALSPAC were whether or not an individual met International Classification of Diseases-10 criteria for a diagnosis of (1) a CMD or, specifically, (2) depression. Lists of Read codes corresponding to diagnoses, symptoms and treatments were used to create 12 definitions of CMD and depression alone using the primary care data. We calculated sensitivities and specificities of these, using CIS-R definitions as the reference standard.
Results
Sensitivities ranged from 5.2% to 24.3% for depression and from 3.8% to 19.2% for CMD. The specificities of all definitions were above 98% for depression and above 96% for CMD.
For both outcomes, the definition that included current diagnosis, treatment or symptoms identified the highest proportion of CIS-R cases.
Conclusions
Most individuals meeting case definitions for CMD based on primary care data also met CIS-R case definitions. Conversely many individuals identified as cases using the CIS-R had no evidence of CMD in their clinical records. This suggests that clinical databases are likely to yield underestimates of the burden of CMD in the population. However, clinical records appear to yield valid diagnoses which may be useful for studying risk factors and consequences of CMD. The greatest epidemiological value may be obtained when information is available from survey and clinical records.
doi:10.1136/bmjopen-2016-013167
PMCID: PMC5168670  PMID: 27909036
depression; common mental disorders; ALSPAC; data linkage; electronic patient records; CIS-R
3.  Appropriate inclusion of interactions was needed to avoid bias in multiple imputation 
Objective
Missing data are a pervasive problem, often leading to bias in complete records analysis (CRA). Multiple imputation (MI) via chained equations is one solution, but its use in the presence of interactions is not straightforward.
Study Design and Setting
We simulated data with outcome Y dependent on binary explanatory variables X and Z and their interaction XZ. Six scenarios were simulated (Y continuous and binary, each with no interaction, a weak and a strong interaction), under five missing data mechanisms. We use directed acyclic graphs to identify when CRA and MI would each be unbiased. We evaluate the performance of CRA, MI without interactions, MI including all interactions, and stratified imputation. We also illustrated these methods using a simple example from the National Child Development Study (NCDS).
Results
MI excluding interactions is invalid and resulted in biased estimates and low coverage. When XZ was zero, MI excluding interactions gave unbiased estimates but overcoverage. MI including interactions and stratified MI gave equivalent, valid inference in all cases. In the NCDS example, MI excluding interactions incorrectly concluded there was no evidence for an important interaction.
Conclusions
Epidemiologists carrying out MI should ensure that their imputation model(s) are compatible with their analysis model.
doi:10.1016/j.jclinepi.2016.07.004
PMCID: PMC5176003  PMID: 27445178
Multiple imputation; Missing data; Interaction; Complete case analysis; Bias; Simulation
4.  Loss to Follow-up in Cohort Studies 
Background
Although cohort members tend to be healthy and affluent compared with the whole population, some studies indicate this does not bias certain exposure-outcome associations. It is less clear whether this holds when socioeconomic position (SEP) is the exposure of interest.
Methods
As an illustrative example, we use data from the Avon Longitudinal Study of Parents and Children. We calculate estimates of maternal education inequalities in outcomes for which data are available on almost the whole cohort (birth weight and length, breastfeeding, preterm birth, maternal obesity, smoking during pregnancy, educational attainment). These are calculated for the full cohort (n~12,000) and in restricted subsamples defined by continued participation at age 10 years (n~7,000) and age 15 years (n~5,000).
Results
Loss to follow-up was related both to SEP and outcomes. For each outcome, loss to follow-up was associated with underestimation of inequality, which increased as participation rates decreased (eg, mean birth-weight difference between highest and lowest SEP was 116 g [95% confidence interval = 78 to 153] in the full sample and 93 g [45 to 141] and 62 g [5 to 119] in those attending at ages 10 and 15 years, respectively).
Conclusions
Considerable attrition from cohort studies may result in biased estimates of socioeconomic inequalities, and the degree of bias may worsen as participation rates decrease. However, even with considerable attrition (>50%), qualitative conclusions about the direction and approximate magnitude of inequalities did not change among most of our examples. The appropriate analysis approaches to alleviate bias depend on the missingness mechanism.
doi:10.1097/EDE.0b013e31827623b1
PMCID: PMC5102324  PMID: 23211345
5.  Socioeconomic disparities in trajectories of adiposity across childhood 
Background
Socioeconomic inequalities in obesity are consistently observed in high-income countries. The development of such inequalities across childhood; however, has not been studied using longitudinal data.
Methods
Using data from the Avon Longitudinal Study of Parents and Children (participants were born 1991/2 in South-West England), we modelled trajectories of ponderal index (PI) (N=12 246) from birth to 2 years and body mass index (BMI) (N=11 380) from 2 to 10 years. Individual trajectories were estimated using mixed-effects models, and differences in trajectories by socioeconomic position (measured by maternal education) were investigated.
Results
There was little socioeconomic patterning of PI from birth to 2 years. Socioeconomic differences in BMI began to emerge by 4 years old, and widened with increasing age. Amongst girls there was a clear gradient across all categories of maternal education by age 8, with daughters of more educated women being less adipose. Amongst boys, sons of degree-educated women had lower BMI but there was little difference between the lower maternal education categories. By 10 years old the mean BMI difference between the highest and lowest maternal education category was 0.38 kg/m2 for boys and 0.89 kg/m2 for girls. The results imply that interventions to prevent inequalities in childhood obesity should begin in pre-school years.
doi:10.3109/17477166.2010.500387
PMCID: PMC5102325  PMID: 20860432
Child; longitudinal studies; obesity; socioeconomic factors; ALSPAC
6.  Investigating the prostate specific antigen, body mass index and age relationship: is an age–BMI-adjusted PSA model clinically useful? 
Cancer Causes & Control  2016;27(12):1465-1474.
Purpose
Previous studies indicate a possible inverse relationship between prostate-specific antigen (PSA) and body mass index (BMI), and a positive relationship between PSA and age. We investigated the associations between age, BMI, PSA, and screen-detected prostate cancer to determine whether an age–BMI-adjusted PSA model would be clinically useful for detecting prostate cancer.
Methods
Cross-sectional analysis nested within the UK ProtecT trial of treatments for localized cancer. Of 18,238 men aged 50–69 years, 9,457 men without screen-detected prostate cancer (controls) and 1,836 men with prostate cancer (cases) met inclusion criteria: no history of prostate cancer or diabetes; PSA < 10 ng/ml; BMI between 15 and 50 kg/m2. Multivariable linear regression models were used to investigate the relationship between log-PSA, age, and BMI in all men, controlling for prostate cancer status.
Results
In the 11,293 included men, the median PSA was 1.2 ng/ml (IQR: 0.7–2.6); mean age 61.7 years (SD 4.9); and mean BMI 26.8 kg/m2 (SD 3.7). There were a 5.1% decrease in PSA per 5 kg/m2 increase in BMI (95% CI 3.4–6.8) and a 13.6% increase in PSA per 5-year increase in age (95% CI 12.0–15.1). Interaction tests showed no evidence for different associations between age, BMI, and PSA in men above and below 3.0 ng/ml (all p for interaction >0.2). The age–BMI-adjusted PSA model performed as well as an age-adjusted model based on National Institute for Health and Care Excellence (NICE) guidelines at detecting prostate cancer.
Conclusions
Age and BMI were associated with small changes in PSA. An age–BMI-adjusted PSA model is no more clinically useful for detecting prostate cancer than current NICE guidelines. Future studies looking at the effect of different variables on PSA, independent of their effect on prostate cancer, may improve the discrimination of PSA for prostate cancer.
doi:10.1007/s10552-016-0827-1
PMCID: PMC5108825  PMID: 27830401
Prostate cancer; PSA; BMI; Age; Prostate cancer screening; PSA–BMI equation
7.  Protocol for a cluster randomised controlled trial of an intervention to improve the mental health support and training available to secondary school teachers – the WISE (Wellbeing in Secondary Education) study 
BMC Public Health  2016;16:1089.
Background
Teachers are reported to be at increased risk of common mental health disorders compared to other occupations. Failure to support teachers adequately may lead to serious long-term mental disorders, poor performance at work (presenteeism), sickness absence and health-related exit from the profession. It also jeopardises student mental health, as distressed staff struggle to develop supportive relationships with students, and such relationships are protective against student depression. A number of school-based trials have attempted to improve student mental health, but these have mostly focused on classroom based approaches and have failed to establish effectiveness. Only a few studies have introduced training for teachers in supporting students, and none to date have included a focus on improving teacher mental health. This paper sets out the protocol (version 4.4 20/07/16) for a study aiming to address this gap.
Methods
Cluster randomised controlled trial with secondary schools as the unit of randomisation. Intervention schools will receive: i) Mental Health First Aid (MHFA) training for a group of staff nominated by their colleagues, after which they will set up a confidential peer support service for colleagues ii) training in MHFA for schools and colleges for a further group of teachers, which will equip them to more effectively support student mental health iii) a short mental health awareness raising session and promotion of the peer support service for all teachers. Comparison schools will continue with usual practice. The primary outcome is teacher wellbeing measured using the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS). Secondary outcomes are teacher depression, absence and presenteeism, and student wellbeing, mental health difficulties, attendance and attainment. Measures will be taken at baseline, one year follow up (teachers only) and two year follow up. Economic and process evaluations will be embedded within the study.
Discussion
This study will establish the effectiveness and cost-effectiveness of an intervention that supports secondary school teachers’ wellbeing and mental health, and improves their skills in supporting students. It will also provide information regarding intervention implementation and sustainability.
Trial registration
International Standard Randomised Controlled Trial Number: ISRCTN95909211 registered 24/03/16
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-3756-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-016-3756-8
PMCID: PMC5070146  PMID: 27756268
Cluster randomised controlled trial; Secondary school; Mental health; Wellbeing; Teacher; Adolescence
8.  A pilot cluster randomised controlled trial of a support and training intervention to improve the mental health of secondary school teachers and students – the WISE (Wellbeing in Secondary Education) study 
BMC Public Health  2016;16:1060.
Background
Secondary school teachers are at heightened risk of psychological distress, which can lead to poor work performance, poor quality teacher-student relationships and mental illness. A pilot cluster randomised controlled trial (RCT) – the WISE study – evaluated the feasibility of a full-scale RCT of an intervention to support school staff’s own mental health, and train them in supporting student mental health.
Methods
Six schools were randomised to an intervention or control group. In the intervention schools i) 8–9 staff received Mental Health First Aid (MHFA) training and became staff peer supporters, and ii) youth MHFA training was offered to the wider staff body. Control schools continued with usual practice. We used thematic qualitative data analysis and regression modelling to ascertain the feasibility, acceptability and potential usefulness of the intervention.
Results
Thirteen training observations, 14 staff focus groups and 6 staff interviews were completed, and 438 staff (43.5 %) and 1,862 (56.3 %) students (years 8 and 9) completed questionnaires at baseline and one year later. MHFA training was considered relevant for schools, and trainees gained in knowledge, confidence in helping others, and awareness regarding their own mental health. Suggestions for reducing the length of the training and focusing on helping strategies were made. A peer support service was established in all intervention schools and was perceived to be helpful in supporting individuals in difficulty – for example through listening, and signposting to other services - and raising the profile of mental health at a whole school level. Barriers to use included lack of knowledge about the service, concerns about confidentiality and a preference for accessing support from pre-existing networks.
Conclusions
The WISE intervention is feasible and acceptable to schools. Results support the development of a full-scale cluster RCT, if steps are taken to improve response rates and implement the suggested improvements to the intervention.
Trial registration
International Standard Randomised Controlled Trial Number: ISRCTN13255300 retrospectively registered 28/09/16.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-3737-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-016-3737-y
PMCID: PMC5053067  PMID: 27716226
Teacher mental health; Mental health in schools; Adolescence; Wellbeing; Pilot randomised controlled trial
9.  Linear spline multilevel models for summarising childhood growth trajectories: A guide to their application using examples from five birth cohorts 
Childhood growth is of interest in medical research concerned with determinants and consequences of variation from healthy growth and development. Linear spline multilevel modelling is a useful approach for deriving individual summary measures of growth, which overcomes several data issues (co-linearity of repeat measures, the requirement for all individuals to be measured at the same ages and bias due to missing data). Here, we outline the application of this methodology to model individual trajectories of length/height and weight, drawing on examples from five cohorts from different generations and different geographical regions with varying levels of economic development. We describe the unique features of the data within each cohort that have implications for the application of linear spline multilevel models, for example, differences in the density and inter-individual variation in measurement occasions, and multiple sources of measurement with varying measurement error. After providing example Stata syntax and a suggested workflow for the implementation of linear spline multilevel models, we conclude with a discussion of the advantages and disadvantages of the linear spline approach compared with other growth modelling methods such as fractional polynomials, more complex spline functions and other non-linear models.
doi:10.1177/0962280213503925
PMCID: PMC4074455  PMID: 24108269
child; growth; height; longitudinal; multilevel models; spline; weight; ALSPAC; Born in Bradford; Generation XXI; Pelotas; PROBIT
10.  The range of peripapillary retinal nerve fibre layer and optic disc parameters, in children aged up to but not including 18 years of age who were born prematurely: protocol for a systematic review 
Systematic Reviews  2016;5(1):144.
Background
The parameters of the optic disc and peripapillary retinal nerve fibre layer (pRNFL) in premature children may vary with disease processes that contribute to visual impairment and blindness and so could be useful as an objective measure in at-risk children.
Methods
A systematic review of current literature on the range of pRNFL and optic disc parameters in children aged less than 18 years, who were born before 37 weeks gestation, will be performed. The bibliographic databases MEDLINE, CINAHL, EMBASE, Scopus and Web of Science will be systematically searched. Where possible and appropriate, study-specific estimates will be combined using meta-analysis to obtain an overall summary estimate of pRNFL thickness and cup-disc ratio across studies, and results will be presented by age of population.
Discussion
This review aims to improve understanding of what might be considered within/outside the range of normality for this high-risk group.
Systematic review registration
The review is registered on PROSPERO: CRD42016037933
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0319-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13643-016-0319-0
PMCID: PMC5006449  PMID: 27577553
Optic nerve; Retinal nerve fibre layer/retinal nerve fiber layer; Paediatrics/pediatrics; Ophthalmology; Premature/prematurity; Optical coherence tomography (OCT)
11.  Live-birth rate associated with repeat in vitro fertilisation treatment cycles 
JAMA  2015;314(24):2654-2662.
Importance
The likelihood of achieving a live-birth with repeat in-vitro fertilisation (IVF) is unclear, yet treatment is commonly limited to three or four embryo transfers.
Objective
To determine the live-birth rate per initiated IVF cycle and with repeated cycles.
Design, Setting and Participants
Prospective study of 156,947 UK women who received 257,398 IVF ovarian stimulation cycles between 2003 and 2010 and were followed until June 2012.
Main exposure
IVF, with a cycle defined as an episode of ovarian stimulation and all subsequent separate fresh and frozen embryo transfers.
Main Outcome(s)
Live-birth rate per IVF cycle and the cumulative live-birth rates across all cycles in all women and by age and treatment type. Optimal, prognosis-adjusted and conservative cumulative live-birth rates were estimated, reflecting 0%, 30% and 100% of women discontinuing due to poor prognosis and having a live-birth rate of zero had they continued.
Results
In all women the live-birth rate for the first cycle was 29.5% (95%CI: 29.3, 29.7). This remained above 20% up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate across all cycles continued to increase up to the ninth, with 65.3% (64.8, 65.8) of women achieving a live-birth by the sixth cycle. In women younger than 40 using their own oocytes, the live-birth rate for the first cycle was 32.3% (32.0, 32.5), and remained above 20% up to and including the fourth cycle. Six cycles achieved a cumulative prognosis-adjusted live-birth rate of 68.4% (67.8, 68.9). For women aged 40-42, the live-birth rate for the first cycle was 12.3% (95%CI: 11.8, 12.8), with six cycles achieving a cumulative prognosis-adjusted live-birth rate of 31.5% (29.7, 33.3). For women older than 42 years all rates within each cycle were less than 4%. No age differential was observed among women using donor oocytes. Rates were lower in those with untreated male factor infertility compared to those with any other cause, but treatment with either intra-cytoplasmic sperm injection or sperm donation removed this difference.
Conclusions and relevance
Among women in the UK undergoing IVF, the cumulative prognosis-adjusted live-birth rate after six cycles was 65.3%, with variations by age and treatment type. These findings support the efficacy of extending the number of IVF cycles beyond three or four.
doi:10.1001/jama.2015.17296
PMCID: PMC4934614  PMID: 26717030
12.  Low level lead exposure and pregnancy outcomes in an observational birth cohort study: dose–response relationships 
BMC Research Notes  2016;9:291.
Background
National and international guidelines on safe levels for blood Pb in pregnancy focus on a threshold above which exposure is of concern. However, it has recently been suggested that the decrease in birth weight per unit increase in blood Pb is actually greater at lower than at higher concentrations of Pb without evidence of a lower threshold of effect. Our aim was to investigate whether there was evidence for a differential effect of maternal Pb levels on birth outcomes and/or a threshold value for effects.
Methods
Blood samples from pregnant women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) were analysed. Data collected on the infants included anthropometric variables. We fitted adjusted multivariable fractional polynomial models for birth outcomes.
Results
Adjusted models that assumed a linear relationship between untransformed blood Pb and the outcomes provided the best fit: an increase of 1 µg/dl was associated with changes in birth weight of −9.93 (95 % CI −20.27, 0.41) g, head circumference −0.03 (95 % CI −0.06, 0.00) cm and crown–heel length −0.05 (95 % CI −0.10, 0.00) cm.
Conclusion
There was no evidence in this study to suggest a supralinear dose–response relationship or a lower threshold for the effect of maternal blood Pb on birth outcomes. This has implications for consideration of national and international guidelines on levels of concern in pregnancy. Exposure to Pb should be kept as low as possible during pregnancy to minimise adverse outcomes.
doi:10.1186/s13104-016-2092-5
PMCID: PMC4893212  PMID: 27260491
ALSPAC; Lead; Pregnancy; Birth outcomes; Dose–response
13.  Studying the Life Course Health Consequences of Childhood Adversity: Challenges and Opportunities 
Circulation  2015;131(19):1645-1647.
doi:10.1161/CIRCULATIONAHA.115.016251
PMCID: PMC4457277  PMID: 25858195
Inequalities; Adversity; Life course; Editorial
14.  Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study 
American Journal of Epidemiology  2016;183(12):1149-1158.
Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991–2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1–15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness.
doi:10.1093/aje/kww009
PMCID: PMC4908211  PMID: 27188935
Avon Longitudinal Study of Parents and Children; attrition bias; cohort studies; genetic risk; longitudinal studies; schizophrenia; study nonparticipation
15.  The range of peripapillary retinal nerve fibre layer and optic disc parameters in children aged up to but not including 18 years of age, as measured by optical coherence tomography: protocol for a systematic review 
Systematic Reviews  2016;5:71.
Background
The parameters of the optic disc and peripapillary retinal nerve fibre layer (pRNFL) in children may vary with disease processes that contribute to visual impairment and blindness and so could be useful as an objective measure in at-risk children. There is no standardised reference for the normal parameters of the optic disc and pRNFL in children; however, there are a large number of small individual studies that have been undertaken to look at these measures.
Methods
A systematic review of current literature on the range of pRNFL and optic disc parameters in children aged less than 18 years will be performed. Studies will be considered for review if they report numerical data on optic disc and pRNFL parameters, measured using optical coherence tomography. Outcome measures will include mean pRNFL thickness and cup-disc ratio. The bibliographic databases Medline, CINAHL, EMBASE, Scopus and Web of Science will be systematically searched from 1991. Screening of search results will be conducted by two authors working independently, as will extraction of primary and secondary outcome data. Ten per cent of all other data extraction will be checked by a second author. Results will be compiled and presented in evidence tables. Where possible and appropriate, study-specific estimates will be combined to obtain an overall summary estimate of pRNFL thickness and cup-disc ratio across studies and results will be presented by age of population. Subgroup analyses will be undertaken for children of different ethnicities.
Discussion
This review aims to provide an overview of the parameters of the optic disc and pRNFL in children of different ages in order to identify gaps in knowledge and to improve understanding of what might be considered within/outside the range of normality. The findings will be presented in peer-reviewed journals and will be presented at conferences.
Systematic review registration
PROSPERO CRD42016033068
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0247-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13643-016-0247-z
PMCID: PMC4853851  PMID: 27138009
Optic nerve; Retinal nerve fibre layer/retinal nerve fiber layer; Paediatrics / paediatrics; Ophthalmology; Normal range; Population; Optical coherence tomography (OCT)
16.  Using Data Linkage to Investigate Inconsistent Reporting of Self-Harm and Questionnaire Non-Response 
Archives of Suicide Research  2016;20(2):113-141.
The objective of this study was to examine agreement between self-reported and medically recorded self-harm, and investigate whether the prevalence of self-harm differs in questionnaire responders vs. non-responders. A total of 4,810 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) completed a self-harm questionnaire at age 16 years. Data from consenting participants were linked to medical records (number available for analyses ranges from 205–3,027). The prevalence of self-harm leading to hospital admission was somewhat higher in questionnaire non-responders than responders (2.0 vs. 1.2%). Hospital attendance with self-harm was under-reported on the questionnaire. One third reported self-harm inconsistently over time; inconsistent reporters were less likely to have depression and fewer had self-harmed with suicidal intent. Self-harm prevalence estimates derived from self-report may be underestimated; more accurate figures may come from combining data from multiple sources.
doi:10.1080/13811118.2015.1033121
PMCID: PMC4841016  PMID: 26789257
agreement; ALSPAC; consistency; data linkage; self-harm; suicide attempt
17.  Early Life Factors and Inter-Country Heterogeneity in BMI Growth Trajectories of European Children: The IDEFICS Study 
PLoS ONE  2016;11(2):e0149268.
Background
Starting from birth, this explorative study aimed to investigate between-country differences in body mass index (BMI) trajectories and whether early life factors explain these differences.
Methods
The sample included 7,644 children from seven European countries (Belgium, Cyprus, Germany, Hungary, Italy, Spain, Sweden) participating in the multi-centre IDEFICS study. Information on early life factors and in total 53,409 repeated measurements of height and weight from 0 to <12 years of age were collected during the baseline (2007/2008) and follow-up examination (2009/2010) supplemented by records of routine child health visits. Country-specific BMI growth curves were estimated using fractional polynomial mixed effects models. Several covariates focussing on early life factors were added to the models to investigate their role in the between-countries differences.
Results
Large between-country differences were observed with Italian children showing significantly higher mean BMI values at all ages ≥ 3 years compared to the other countries. For instance, at age 11 years mean BMI values in Italian boys and girls were 22.3 [21.9;22.8; 99% confidence interval] and 22.0 [21.5;22.4], respectively, compared to a range of 18.4 [18.1;18.8] to 20.3 [19.8;20.7] in boys and 18.2 [17.8;18.6] to 20.3 [19.8;20.7] in girls in the other countries. After adjustment for early life factors, differences between country-specific BMI curves became smaller. Maternal BMI was the factor being most strongly associated with BMI growth (p<0.01 in all countries) with associations increasing during childhood. Gestational weight gain (GWG) was weakly associated with BMI at birth in all countries. In some countries, positive associations between BMI growth and children not being breastfed, mothers’ smoking during pregnancy and low educational level of parents were found.
Conclusion
Early life factors seem to explain only some of the inter-country variation in growth. Maternal BMI showed the strongest association with children’s BMI growth.
doi:10.1371/journal.pone.0149268
PMCID: PMC4762899  PMID: 26901773
18.  Genetic Influences on Trajectories of Systolic Blood Pressure Across Childhood and Adolescence 
Background
Blood pressure (BP) tends to increase across childhood and adolescence, but the genetic influences on rates of BP change are not known. Potentially important genetic influences could include genetic variants identified in genome-wide association studies of adults as being associated with BP, height, and body mass index. Understanding the contribution of these genetic variants to changes in BP across childhood and adolescence could yield understanding into the life course development of cardiovascular risk.
Methods and Results
Pooling data from 2 cohorts (the Avon Longitudinal Study of Parents and Children [n=7013] and the Western Australian Pregnancy Cohort [n=1459]), we examined the associations of allelic scores of 29 single-nucleotide polymorphisms (SNPs) for adult BP, 180 height SNPs, and 32 body mass index SNPs, with trajectories of systolic BP (SBP) from 6 to 17 years of age, using linear spline multilevel models. The allelic scores of BP and body mass index SNPs were associated with SBP at 6 years of age (per-allele effect sizes, 0.097 mm Hg [SE, 0.039 mm Hg] and 0.107 mm Hg [SE, 0.037 mm Hg]); associations with age-related changes in SBP between 6 and 17 years of age were of small magnitude and imprecisely estimated. The allelic score of height SNPs was only weakly associated with SBP changes. No sex or cohort differences in genetic effects were observed.
Conclusions
Allelic scores of BP and body mass index SNPs demonstrated associations with SBP at 6 years of age with a similar magnitude but were not strongly associated with changes in SBP with age between 6 and 17 years. Further work is required to identify variants associated with changes with age in BP.
doi:10.1161/CIRCGENETICS.113.000197
PMCID: PMC4759925  PMID: 24200906
adolescent; blood pressure; genetics; humans
19.  Physical Activity Is Prospectively Associated With Adolescent Nonalcoholic Fatty Liver Disease 
ABSTRACT
Objectives:
The aim of the present study was to assess whether objectively measured physical activity at mean ages 12 and 14 years are prospectively associated with ultrasound scan liver fat and stiffness (alanine aminotransferase, aspartate aminotransferase [AST], and γ-glutamyl transferase [GGT]) assessed at mean age 17.8 years.
Methods:
Participants were from the Avon Longitudinal Study of Parents and Children. Total physical activity (counts per minute) and minutes of moderate to vigorous physical activity (MVPA) were measured using ActiGraph accelerometers at mean ages 12 and 14 years.
Results:
Greater total physical activity and MVPA at ages 12 and 14 years were associated with lower odds of liver fat and lower GGT levels at mean age 17.8 years, such as per 15-minute increase in daily MVPA at age 12 years, the confounder adjusted odds ratio of liver fat was 0.47 (95% confidence interval [CI] 0.27–0.84). Associations attenuated after additional adjustment for fat mass as a potential confounder (eg, per 15-minute increase in daily MVPA at age 12 years, the odds ratio of liver fat attenuated to 0.65 [95% CI 0.35–1.21]) or a potential mediator (eg, per 15-minute increase in daily MVPA at age 12 years the odds ratio of liver fat attenuated to 0.59 [95% CI 0.32–1.09]). Results did not further attenuate after additional adjustment for insulin resistance. There was some evidence that greater total physical activity and MVPA at age 12 years were associated with the higher AST levels.
Conclusions:
Adolescents who were more active in childhood have lower odds of fatty liver and lower GGT levels. These findings are likely to be, at least in part, explained by adiposity.
doi:10.1097/MPG.0000000000000904
PMCID: PMC4697952  PMID: 26252921
Avon Longitudinal Study of Parents and Children; childhood; exercise; fatty liver; physical activity
21.  Antenatal blood pressure for prediction of pre-eclampsia, preterm birth, and small for gestational age babies: development and validation in two general population cohorts 
The BMJ  2015;351:h5948.
Study question Can routine antenatal blood pressure measurements between 20 and 36 weeks’ gestation contribute to the prediction of pre-eclampsia and its associated adverse outcomes?
Methods This study used repeated antenatal measurements of blood pressure from 12 996 women in the Avon Longitudinal Study of Parents and Children (ALSPAC) to develop prediction models and validated these in 3005 women from the Southampton Women’s Survey (SWS). A model based on maternal early pregnancy characteristics only (BMI, height, age, parity, smoking, existing and previous gestational hypertension and diabetes, and ethnicity) plus initial mean arterial pressure was compared with a model additionally including current mean arterial pressure, a model including the deviation of current mean arterial pressure from a stratified normogram, and a model including both at different gestational ages from 20-36 weeks.
Study answer and limitations The addition of blood pressure measurements from 28 weeks onwards improved prediction models compared with use of early pregnancy risk factors alone, but they contributed little to the prediction of preterm birth or small for gestational age. Though multiple imputation of missing data was used to increase the sample size and minimise selection bias, the validation sample might have been slightly underpowered as the number of cases of pre-eclampsia was just below the recommended 100. Several risk factors were self reported, potentially introducing measurement error, but this reflects how information would be obtained in clinical practice.
What this study adds The addition of routinely collected blood pressure measurements from 28 weeks onwards improves predictive models for pre-eclampsia based on blood pressure in early pregnancy and other characteristics, facilitating a reduction in scheduled antenatal care.
Funding, competing interests, data sharing UK Wellcome Trust, US National Institutes of Health, and UK Medical Research Council. Other funding sources for authors are detailed in the full online paper. With the exceptions of CM-W, HMI, and KMG there were no competing interests.
doi:10.1136/bmj.h5948
PMCID: PMC4647185  PMID: 26578347
22.  MR-PheWAS: hypothesis prioritization among potential causal effects of body mass index on many outcomes, using Mendelian randomization 
Scientific Reports  2015;5:16645.
Observational cohort studies can provide rich datasets with a diverse range of phenotypic variables. However, hypothesis-driven epidemiological analyses by definition only test particular hypotheses chosen by researchers. Furthermore, observational analyses may not provide robust evidence of causality, as they are susceptible to confounding, reverse causation and measurement error. Using body mass index (BMI) as an exemplar, we demonstrate a novel extension to the phenome-wide association study (pheWAS) approach, using automated screening with genotypic instruments to screen for causal associations amongst any number of phenotypic outcomes. We used a sample of 8,121 children from the ALSPAC dataset, and tested the linear association of a BMI-associated allele score with 172 phenotypic outcomes (with variable sample sizes). We also performed an instrumental variable analysis to estimate the causal effect of BMI on each phenotype. We found 21 of the 172 outcomes were associated with the allele score at an unadjusted p < 0.05 threshold, and use Bonferroni corrections, permutation testing and estimates of the false discovery rate to consider the strength of results given the number of tests performed. The most strongly associated outcomes included leptin, lipid profile, and blood pressure. We also found novel evidence of effects of BMI on a global self-worth score.
doi:10.1038/srep16645
PMCID: PMC4644974  PMID: 26568383
23.  Prenatal and early life influences on epigenetic age in children: a study of mother–offspring pairs from two cohort studies 
Human Molecular Genetics  2015;25(1):191-201.
DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother–child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging.
doi:10.1093/hmg/ddv456
PMCID: PMC4690495  PMID: 26546615
24.  A longitudinal model for disease progression was developed and applied to multiple sclerosis 
Journal of Clinical Epidemiology  2015;68(11):1355-1365.
Objectives
To develop a model of disease progression using multiple sclerosis (MS) as an exemplar.
Study Design and Settings
Two observational cohorts, the University of Wales MS (UoWMS), UK (1976), and British Columbia MS (BCMS) database, Canada (1980), with longitudinal disability data [the Expanded Disability Status Scale (EDSS)] were used; individuals potentially eligible for MS disease-modifying drugs treatments, but who were unexposed, were selected. Multilevel modeling was used to estimate the EDSS trajectory over time in one data set and validated in the other; challenges addressed included the choice and function of time axis, complex observation-level variation, adjustments for MS relapses, and autocorrelation.
Results
The best-fitting model for the UoWMS cohort (404 individuals, and 2,290 EDSS observations) included a nonlinear function of time since onset. Measurement error decreased over time and ad hoc methods reduced autocorrelation and the effect of relapse. Replication within the BCMS cohort (978 individuals and 7,335 EDSS observations) led to a model with similar time (years) coefficients, time [0.22 (95% confidence interval {CI}: 0.19, 0.26), 0.16 (95% CI: 0.10, 0.22)] and log time [−0.13 (95% CI: −0.39, 0.14), −0.15 (95% CI: −0.70, 0.40)] for BCMS and UoWMS, respectively.
Conclusion
It is possible to develop robust models of disability progression for chronic disease. However, explicit validation is important given the complex methodological challenges faced.
doi:10.1016/j.jclinepi.2015.05.003
PMCID: PMC4643305  PMID: 26071892
Multiple sclerosis; Repeated measures model; Multilevel model; Fractional polynomials; Prognosis; Observational cohorts
25.  Assessment of Offspring DNA Methylation across the Lifecourse Associated with Prenatal Maternal Smoking Using Bayesian Mixture Modelling 
A growing body of research has implicated DNA methylation as a potential mediator of the effects of maternal smoking in pregnancy on offspring ill-health. Data were available from a UK birth cohort of children with DNA methylation measured at birth, age 7 and 17. One issue when analysing genome-wide DNA methylation data is the correlation of methylation levels between CpG sites, though this can be crudely bypassed using a data reduction method. In this manuscript we investigate the effect of sustained maternal smoking in pregnancy on longitudinal DNA methylation in their offspring using a Bayesian hierarchical mixture model. This model avoids the data reduction used in previous analyses. Four of the 28 previously identified, smoking related CpG sites were shown to have offspring methylation related to maternal smoking using this method, replicating findings in well-known smoking related genes MYO1G and GFI1. Further weak associations were found at the AHRR and CYP1A1 loci. In conclusion, we have demonstrated the utility of the Bayesian mixture model method for investigation of longitudinal DNA methylation data and this method should be considered for use in whole genome applications.
doi:10.3390/ijerph121114461
PMCID: PMC4661660  PMID: 26580635
ALSPAC; Bayesian; DNA methylation; epigenetics; longitudinal data; mixture modelling; pregnancy; smoking

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