Disagreement concerning atopic dermatitis subtypes between an English prospective cohort (ALSPAC) and linked electronic health records.

BACKGROUND: Subtypes of atopic dermatitis (AD) have been derived from the Avon Longitudinal Study of Parents and Children (ALSPAC) based on presence and severity of symptoms reported in questionnaires (Severe-Frequent, Moderate-Frequent, Moderate-Declining, Mild-Intermittent, Unaffected/Rare). Good agreement between ALSPAC and linked electronic health records (EHRs) would increase trust in the clinical validity of these subtypes and allow inferring subtypes from EHRs alone, which would enable their study in large primary care databases. OBJECTIVES: 1. Explore if presence and number of AD records in EHRs agrees with AD symptom and severity reports from ALSPAC; 2. Explore if EHRs agree with ALSPAC-derived AD subtypes; 3. Construct models to classify ALSPAC-derived AD subtype using EHRs. METHODS: We used data from the ALSPAC prospective cohort study from 11 timepoints until age 14 years (1991-2008), linked to local general practice EHRs. We assessed how far ALSPAC questionnaire responses and derived subtypes agreed with AD as established in EHRs using different AD definitions (e.g., diagnosis and/or prescription) and other AD-related records. We classified AD subtypes using EHRs, fitting multinomial logistic regression models tuning hyperparameters and evaluating performance in the testing set (ROC AUC, accuracy, sensitivity, and specificity). RESULTS: 8,828 individuals out of a total 13,898 had both been assigned an AD subtype and had linked EHRs. The number of AD-related codes in EHRs generally increased with severity of AD subtype, however not all with the Severe-Frequent subtypes had AD in EHRs, and many with the Unaffected/Rare subtype did have AD in EHRs. When predicting ALSPAC AD subtype using EHRs, the best tuned model had ROC AUC of 0.65, sensitivity of 0.29 and specificity of 0.83 (both macro averaged); when different sets of predictors were used, individuals with missing EHR coverage excluded, and subtypes combined, sensitivity was not considerably improved. CONCLUSIONS: ALSPAC and EHRs disagreed not just on AD subtypes, but also on whether children had AD or not. Researchers should be aware that individuals considered as having AD in one source may not be considered as having AD in another.

Association of antenatal or neonatal SARS-COV-2 exposure with developmental and respiratory outcomes, and healthcare usage in early childhood: a national prospective cohort study.

Background: Perinatal exposure to SARS-CoV-2 may affect neurodevelopment before 12 months of age, but longer-term outcomes remain unknown. We examined whether antenatal or neonatal SARS-CoV-2 exposure compared with non-exposure is associated with neurodevelopment, respiratory symptoms, and health care usage in early childhood. Methods: This prospective national population-based cohort study was conducted in England and Wales, United Kingdom. We enrolled term-born children (≥37 weeks' gestation) with and without antenatal or neonatal exposure to SARS-CoV-2 infection by approaching parents of eligible children who were cared for in 87 NHS hospitals. Potential participants were identified through the national active surveillance studies of pregnant women and newborn infants hospitalised with confirmed SARS-CoV-2 infection conducted through the UK Obstetric Surveillance System and the British Paediatric Surveillance Unit. We defined antenatal and neonatal SARS-CoV-2 exposure as infants born to mothers hospitalised with confirmed SARS-CoV-2 infection between 14 + 0 and 36 + 6 weeks gestation and infants admitted to hospital with confirmed SARS-CoV-2 infection within the first 28 days after birth. Children born preterm or with major congenital anomaly or who were not residing in the UK were excluded. We assessed children's development (Ages and Stages Questionnaire 3rd Edition (ASQ-3); Ages and Stages Questionnaire Social-Emotional 2nd Edition (ASQ:SE-2)), respiratory symptoms (Liverpool Respiratory Symptom Questionnaire (LRSQ)) and health care usage (parent-completed questionnaire) at 21-32 months of age. Primary outcome: total ASQ-3 score, converted to z-scores. Secondary outcomes: ASQ:SE-2 z-scores; risk of delay in ASQ-3 domains; total LRSQ scores, converted to z-scores. Analyses were adjusted for children's age, sex, maternal ethnicity, parental education, and index of multiple deprivation. Findings: Between October 20, 2021 and January 27, 2023, we approached 668 and 1877 families out of 712 and 1917 potentially eligible participants in the exposed and comparison cohort. Of the 125 and 306 participants who were enrolled to the exposed and comparison cohort 121 and 301 participants completed the questionnaires and 96 and 243 participants were included in the analysis. In the age adjusted analysis, the mean total ASQ-3 z-score was lower in the exposed than the comparison cohort (-0.3, 95% CI: -0.6 to -0.05), however, when adjusted for sex, parental education, ethnicity and IMD quintile, there was no significant difference (difference in mean z-score = -0.2 95% CI: -0.5 to 0.03). SARS-CoV-2 exposure was associated with increased risk of delayed personal-social skills (odds ratio = 3.81; 95% CI: 1.07-13.66), higher ASQ:SE-2 total z-scores (difference in mean z-score = 0.4; 95% CI: 0.2-0.6) and increased risk of delayed social-emotional development (OR = 3.58, 95% CI: 1.30-9.83), after adjusting for sex, age at assessment, parental education, ethnicity and IMD quintile. The exposed cohort had a higher mean total LRSQ z-score than the comparison cohort (0.3 95% CI: 0-0.6) and higher inpatient (38% vs. 21%, p = 0.0001), outpatient (38% vs. 30%, p = 0.0090), and General Practitioner appointments (60% vs. 50%, p = 0.021) than the comparison cohort, after adjusting for sex, age at assessment, parental education, ethnicity and IMD quintile. No differences in other secondary outcomes between the exposed and comparison cohorts were found. Interpretation: Although the exposed cohort did not differ from the comparison cohort on the primary outcome, total ASQ-3 score, the exposed cohort were at greater risk of delayed social-emotional development, had a greater prevalence of respiratory symptoms and increased health care usage relative to the comparison cohort. The study is limited by the smaller sample size due to the low response rate and lack of clinical developmental assessments. Given the association of poor social-emotional development with antenatal or neonatal SARS-CoV-2 exposure, developmental screening, and follow-up of children with confirmed antenatal or neonatal SARS-CoV-2 infection may be warranted to identify those in need of early intervention. Funding: Action Medical Research for Children.

Antenatal and neonatal exposure to SARS-CoV-2 and children's development: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review of the impact of antenatal and neonatal exposure to SARS-CoV-2 on developmental outcomes in preterm and term-born infants. METHODS: We searched Embase, Emcare, MEDLINE, PsycINFO, Web of Science and grey literature on May 27, 2022 and updated on May 8, 2023. Studies defining exposure with a positive SARS-CoV-2 protein or genetic material, used a contemporaneous non-exposed cohort, and reported developmental outcomes up to 2 years of age were included. RESULTS: Four out of 828 screened studies were included. Meta-analysis included 815 infants screened for developmental delay (n = 306 exposed; n = 509 non-exposed) between 3- and 11-months of age. Among term-born infants, we did not find an increased risk of delay in communication (odd's ratio: 0.73 (95% CI: 0.24-2.24)), gross motor (1.50 (0.62, 3.62)), fine motor (2.90 (0.58, 14.43)), problem-solving (1.19 (0.54, 2.66)) or personal-social development (1.93 (0.78, 4.75)) in exposed infants. The number of preterm-born infants in the exposed (n = 37) and comparison cohorts (n = 41) were too few to report meaningful comparisons. CONCLUSION: Evidence regarding the potential impact of antenatal or neonatal exposure to SARS-CoV-2 infection on developmental outcomes in early infancy is limited and inconsistent. Larger cohorts with outcomes beyond the first year of life are needed. IMPACT: The current evidence examining associations between SARS-CoV-2 exposure during the neonatal period and developmental outcomes in infancy is limited by there being few studies with extremely small sample sizes. Based on sparse data there was no consistent association between antenatal or neonatal exposure to SARS-CoV-2 infection and an adverse impact on developmental outcomes below 12 months of age for babies born preterm or at term. This study highlights that larger cohorts with outcomes assessed beyond the first year are needed to determine the potential longer-term impact of SARS-CoV-2 infection exposure on child development.

Non-linear associations of maternal pre-pregnancy body mass index with risk of stillbirth, infant, and neonatal mortality in over 28 million births in the USA: a retrospective cohort study.

Background: Higher maternal pre-pregnancy body mass index (BMI) has been associated with higher risk of stillbirth, infant and neonatal mortality. Studies exploring underweight have varied in their conclusions. Our aim was to examine the risk of stillbirth, infant and neonatal mortality across the BMI distribution and establish a likely healthy BMI range. Methods: In this retrospective cohort study, we used publicly available datasets (covering 1st January 2014 to 31st December 2021) from the US National Center for Health Statistics National Vital Statistics System. All births were eligible; analyses included those with non-missing data. Fractional polynomial multivariable logistic regression was used to examine the associations of maternal pre-pregnant BMI with stillbirth (birth with no signs of life at ≥24 weeks), infant mortality (death of a live born baby aged <365 days) and neonatal mortality (death of a live born baby aged <28 days). Findings: There were 77,896/28,310,154 (2.8 per 1000 births) stillbirths, 143,620/28,231,807 (5.1 per 1000 live births) infant deaths and 94,246/28,231,807 (3.3 per 1000 live births) neonatal deaths among complete cases. Mean (SD) BMI was 27.1 kg/m2 (6.7 kg/m2). We found non-linear associations between BMI and all three outcomes; risk was elevated at both low and high BMIs although, for stillbirth, the increased risk at low BMI was less marked than for infant/neonatal mortality. The lowest risk was at a BMI of 21 kg/m2 for infant and neonatal mortality and 19 kg/m2 for stillbirth. Interpretation: Public health messaging for preconception and postnatal care should focus on healthy weight to maximise maternal and child health, and not focus solely on maternal overweight or obesity. Funding: European Research Council, US National Institute of Health, UK Medical Research Council and National Institute for Health and Care Research.

Multiple imputation of missing data under missing at random: including a collider as an auxiliary variable in the imputation model can induce bias.

Epidemiological studies often have missing data, which are commonly handled by multiple imputation (MI). In MI, in addition to those required for the substantive analysis, imputation models often include other variables ("auxiliary variables"). Auxiliary variables that predict the partially observed variables can reduce the standard error (SE) of the MI estimator and, if they also predict the probability that data are missing, reduce bias due to data being missing not at random. However, guidance for choosing auxiliary variables is lacking. We examine the consequences of a poorly chosen auxiliary variable: if it shares a common cause with the partially observed variable and the probability that it is missing (i.e., it is a "collider"), its inclusion can induce bias in the MI estimator and may increase the SE. We quantify, both algebraically and by simulation, the magnitude of bias and SE when either the exposure or outcome is incomplete. When the substantive analysis outcome is partially observed, the bias can be substantial, relative to the magnitude of the exposure coefficient. In settings in which a complete records analysis is valid, the bias is smaller when the exposure is partially observed. However, bias can be larger if the outcome also causes missingness in the exposure. When using MI, it is important to examine, through a combination of data exploration and considering plausible casual diagrams and missingness mechanisms, whether potential auxiliary variables are colliders.

Linkage of the Avon Longitudinal Study of Parents and Children (ALSPAC) to Avon & Somerset Police regional police records.

This data note describes a new resource for crime-related research: the Avon Longitudinal Study of Parents and Children (ALSPAC) linked to regional police records. The police data were provided by Avon & Somerset Police (A&SP), whose area of responsibility contains the ALSPAC recruitment area. In total, ALSPAC had permission to link to crime records for 12,662 of the 'study children' (now adults, who were born in the early 1990s).  The linkage took place in two stages: Stage 1 involved the ALSPAC Data Linkage Team establishing the linkage using personal identifiers common to both the ALSPAC participant database and A&SP records using deterministic and probabilistic methods. Stage 2 involved A&SP extracting attribute data on the matched individuals, removing personal identifiers and securely sharing the de-identified records with ALSPAC. The police data extraction took place in July 2021, when the participants were in their late 20s/early 30s. This data note contains details on the resulting linked police records available. In brief, electronic police records were available from 2007 onwards. In total, 1757 participants (14%) linked to at least one police record for a charge, offence 'taken into consideration', caution, or another out of court disposal. Linked participants had a total of 6413 records relating to 6283 offences. Almost three quarters of the linked participants were male. The most common offence types were violence against the person (22% of records), drug offences (19%), theft (17%) and public order offences (11%). This data note also details important issues that researchers using the local police data should be aware of, including the importance of defining an appropriate denominator, completeness, and biases affecting police records.

Multiple imputation of missing data under missing at random: compatible imputation models are not sufficient to avoid bias if they are mis-specified.

OBJECTIVES: Epidemiological studies often have missing data, which are commonly handled by multiple imputation (MI). Standard (default) MI procedures use simple linear covariate functions in the imputation model. We examine the bias that may be caused by acceptance of this default option and evaluate methods to identify problematic imputation models, providing practical guidance for researchers. STUDY DESIGN AND SETTING: Using simulation and real data analysis, we investigated how imputation model mis-specification affected MI performance, comparing results with complete records analysis (CRA). We considered scenarios in which imputation model mis-specification occurred because (i) the analysis model was mis-specified or (ii) the relationship between exposure and confounder was mis-specified. RESULTS: Mis-specification of the relationship between outcome and exposure, or between exposure and confounder, can cause biased CRA and MI estimates (in addition to any bias in the full-data estimate due to analysis model mis-specification). MI by predictive mean matching can mitigate model mis-specification. Methods for examining model mis-specification were effective in identifying mis-specified relationships. CONCLUSION: When using MI methods that assume data are MAR, compatibility between the analysis and imputation models is necessary, but not sufficient to avoid bias. We propose a step-by-step procedure for identifying and correcting mis-specification of imputation models.

Looked after children in prison as adults: life adversity and neurodisability.

PURPOSE: Looked after children (LAC) are criminalised at five times the rate of children in the general population. Children in contact with both child welfare and child justice systems have higher rates of neurodisability and substance use problems, and LAC in general have high rates of school exclusion, homelessness and unemployment. This study aims to understand whether these factors persist in LAC who are in prison as adults. DESIGN/METHODOLOGY/APPROACH: Administrative data collected by the Do-IT profiler screening tool in a prison in Wales, UK, were analysed to compare sentenced prisoners who were LAC (n = 631) to sentenced prisoners who were not LAC (n = 2,201). The sample comprised all prisoners who were screened on entry to prison in a two-year period. FINDINGS: Prisoners who were LAC scored more poorly on a functional screener for neurodisability (effect size = 0.24), and on four self-report measures capturing traits of dyslexia (0.22), attention-deficit hyperactivity disorder (0.40), autism spectrum disorders (0.34) and developmental co-ordination disorder (0.33). Prisoners who were LAC were more likely to have been to a pupil referral unit (0.24), have substance use problems (0.16), be homeless or marginally housed (0.18) and be unemployed or unable to work due to disability (0.13). ORIGINALITY/VALUE: This study uniquely contributes to our understanding of prisoners who were LAC as a target group for intervention and support with re-integration into the community upon release. LAC in prison as adults may require additional interventions to help with employment, housing and substance use. Education programmes in prison should screen for neurodisability, to develop strategies to support engagement.

Health and Well-Being in Surviving Congenital Heart Disease Patients: An Umbrella Review With Synthesis of Best Evidence.

Background: Advances in the management of congenital heart disease (CHD) patients have enabled improvement in long-term survival even for those with serious defects. Research priorities (for patients, families and clinicians) have shifted from a focus on how to improve survival to exploring long-term outcomes in patients with CHD. A comprehensive appraisal of available evidence could inform best practice to maximize health and well-being, and identify research gaps to direct further research toward patient and clinical need. We aimed to critically appraise all available published systematic reviews of health and well-being outcomes in adult patients with CHD. Methods: We conducted an umbrella review, including any systematic reviews that assessed the association of having vs. not having CHD with any long-term health (physical or mental), social (e.g., education, occupation) or well-being [e.g., quality of life (QoL)] outcome in adulthood (≥18-years). Results: Out of 1330 articles screened, we identified five systematic reviews of associations of CHD with adult outcomes. All but one (which studied QoL) explored health outcomes: one cardiovascular, two mental, and one mortality after transplant. CHD patients had a higher risk of stroke, coronary heart disease and heart failure, with the pooled relative risk (RR) for any outcome of 3.12 (95% CI: 3.01 to 3.24), with substantial heterogeneity (I2 = 99%) explained by the outcome being studied (stronger association for heart failure) and geography (stronger in Europe compared with other regions). CHD patients had a higher risk of anxiety (OR = 2.58 (1.45 to 4.59)], and higher mean scores for depression/anxiety symptoms (difference in means = -0.11 SD (-0.28 to 0.06), I2 = 94%)]. Compared with patients having a cardiac transplant for other (non-CHD) diseases, CHD patients had higher short-term mortality (RR at 30-days post-transplant = 2.18 [1.62 to 2.93)], with moderate heterogeneity (I2 = 41%) explained by previous surgery (higher mortality with prior Fontan/Glenn operation). All domains of QoL were lower in patients with Fontan's circulation than non-CHD adults. Conclusion: Adults with CHD have poorer cardiovascular, mental health and QoL outcomes, and higher short-term mortality after transplant. The paucity of systematic reviews, in particular for outcomes such as education, occupation and lifestyles, highlights the need for this to be made a priority by funders and researchers. Systematic Review Registration: [www.crd.york.ac.uk/prospero], identifier [CRD42020175034].

Effect of SARS-CoV-2 infection in neonates or in pregnancy on developmental outcomes at 21-24 months (SINEPOST): study protocol for a prospective cohort study.

INTRODUCTION: Exposure to SARS-CoV-2 during pregnancy or in the neonatal period may impact fetal or neonatal brain development either through direct central nervous system infection or indirectly through the adverse effects of viral infection-related inflammation in the mother or newborn infant. This study aims to determine whether there are early neurodevelopmental effects of SARS-CoV-2 infection. METHODS AND ANALYSIS: We will conduct a prospective national population-based cohort study of children aged 21-24 months who were born at term (≥37 weeks' gestation) between 1 March 2020 and 28 February 2021 and were either antenatally exposed, neonatally exposed or unexposed (comparison cohort) to SARS-CoV-2. Nationally, hospitals will identify and approach parents of children eligible for inclusion in the antenatally and neonatally exposed cohorts using information from the UK Obstetric Surveillance System (UKOSS) and British Paediatric Surveillance Unit (BPSU) national surveillance studies and will identify and approach eligible children for the comparison cohort through routine birth records. Parents will be asked to complete questionnaires to assess their child's development at 21-24 months of age. Outcome measures comprise the Ages and Stages Questionnaire, Third Edition (ASQ-3), Ages and Stages Questionnaire Social-Emotional, Second Edition (ASQ-SE-2), Liverpool respiratory symptoms questionnaire and questionnaire items to elicit information about healthcare usage. With parental consent, study data will be linked to routine health and education records for future follow-up. Regression models will compare ASQ-3 and ASQ-SE-2 scores and proportions, frequency of respiratory symptoms and healthcare usage between the exposed and comparison cohorts, adjusting for potential confounders. ETHICS AND DISSEMINATION: Ethics approval was obtained from the London-Westminster Research Ethics Committee. Findings will be disseminated in scientific conference presentations and peer-reviewed publications. ISRCTN REGISTRATION NUMBER: ISRCTN99910769.

Educational attainment in patients with congenital heart disease: a comprehensive systematic review and meta-analysis.

BACKGROUND: Our aim was to comprehensively review published evidence on the association between having a congenital heart disease (CHD) compared with not, on educational attainment (i.e. not obtaining a university degree, completing secondary education, or completing any vocational training vs. obtaining/completing) in adults. METHOD: Studies were eligible if they reported the rate, odds, or proportion of level of educational attainment in adults by whether or not they had a CHD. RESULT: Out of 1537 articles screened, we identified 11 (N = 104,585 participants, 10,487 with CHD), 10 (N = 167,470 participants, 11,820 with CHD), and 8 (N = 150,813 participants, 9817 with CHD) studies reporting information on university education, secondary education, and vocational training, respectively in both CHD and non-CHD participants. Compared to their non-CHD peers, CHD patients were more likely not to obtain a university degree (OR = 1.38, 95% CI [1.16, 1.65]), complete secondary education (OR = 1.33, 95% CI [1.09, 1.61]) or vocational training (OR = 1.11, 95% CI [0.98, 1.26]). For all three outcomes there was evidence of between study heterogeneity, with geographical area contributing to this heterogeneity. CONCLUSION: This systematic review identified all available published data on educational attainment in CHD patients. Despite broad inclusion criteria we identified relatively few studies that included a comparison group from the same population, and amongst those that did, few adjusted for key confounders. Pooled analyses suggest evidence of lower levels of educational attainment in patients with CHD when compared to non-CHD peers. The extent to which this may be explained by confounding factors, such as parental education, or mediated by treatments is not possible to discern from the current research literature.

Assessing and predicting adolescent and early adulthood common mental disorders using electronic primary care data: analysis of a prospective cohort study (ALSPAC) in Southwest England.

OBJECTIVES: We aimed to examine agreement between common mental disorders (CMDs) from primary care records and repeated CMD questionnaire data from ALSPAC (the Avon Longitudinal Study of Parents and Children) over adolescence and young adulthood, explore factors affecting CMD identification in primary care records, and construct models predicting ALSPAC-derived CMDs using only primary care data. DESIGN AND SETTING: Prospective cohort study (ALSPAC) in Southwest England with linkage to electronic primary care records. PARTICIPANTS: Primary care records were extracted for 11 807 participants (80% of 14 731 eligible). Between 31% (3633; age 15/16) and 11% (1298; age 21/22) of participants had both primary care and ALSPAC CMD data. OUTCOME MEASURES: ALSPAC outcome measures were diagnoses of suspected depression and/or CMDs. Primary care outcome measure were Read codes for diagnosis, symptoms and treatment of depression/CMDs. For each time point, sensitivities and specificities for primary care CMD diagnoses were calculated for predicting ALSPAC-derived measures of CMDs, and the factors associated with identification of primary care-based CMDs in those with suspected ALSPAC-derived CMDs explored. Lasso (least absolute selection and shrinkage operator) models were used at each time point to predict ALSPAC-derived CMDs using only primary care data, with internal validation by randomly splitting data into 60% training and 40% validation samples. RESULTS: Sensitivities for primary care diagnoses were low for CMDs (range: 3.5%-19.1%) and depression (range: 1.6%-34.0%), while specificities were high (nearly all >95%). The strongest predictors of identification in the primary care data for those with ALSPAC-derived CMDs were symptom severity indices. The lasso models had relatively low prediction rates, especially in the validation sample (deviance ratio range: -1.3 to 12.6%), but improved with age. CONCLUSIONS: Primary care data underestimate CMDs compared to population-based studies. Improving general practitioner identification, and using free-text or secondary care data, is needed to improve the accuracy of models using clinical data.

Framework for the treatment and reporting of missing data in observational studies: The Treatment And Reporting of Missing data in Observational Studies framework.

Missing data are ubiquitous in medical research. Although there is increasing guidance on how to handle missing data, practice is changing slowly and misapprehensions abound, particularly in observational research. Importantly, the lack of transparency around methodological decisions is threatening the validity and reproducibility of modern research. We present a practical framework for handling and reporting the analysis of incomplete data in observational studies, which we illustrate using a case study from the Avon Longitudinal Study of Parents and Children. The framework consists of three steps: 1) Develop an analysis plan specifying the analysis model and how missing data are going to be addressed. An important consideration is whether a complete records' analysis is likely to be valid, whether multiple imputation or an alternative approach is likely to offer benefits and whether a sensitivity analysis regarding the missingness mechanism is required; 2) Examine the data, checking the methods outlined in the analysis plan are appropriate, and conduct the preplanned analysis; and 3) Report the results, including a description of the missing data, details on how the missing data were addressed, and the results from all analyses, interpreted in light of the missing data and the clinical relevance. This framework seeks to support researchers in thinking systematically about missing data and transparently reporting the potential effect on the study results, therefore increasing the confidence in and reproducibility of research findings.

Factors associated with participation over time in the Avon Longitudinal Study of Parents and Children: a study using linked education and primary care data.

BACKGROUND: In observational research, choosing an optimal analysis strategy when variables are incomplete requires an understanding of the factors associated with ongoing participation and non-response, but this cannot be fully examined with incomplete data. Linkage to external datasets provides additional information on those with incomplete data, allowing examination of factors related to missingness. METHODS: We examined the association between baseline sociodemographic factors and ongoing participation in the Avon Longitudinal Study of Parents and Children. We investigated whether child and adolescent outcomes measured in linked education and primary care data were associated with participation, after accounting for baseline factors. To demonstrate the potential for bias, we examined whether the association between maternal smoking and these outcomes differed in the subsample who completed the 19-year questionnaire. RESULTS: Lower levels of school attainment, lower general practitioner (GP) consultation and prescription rates, higher body mass index (BMI), special educational needs (SEN) status, not having an asthma diagnosis, depression and being a smoker were associated with lower participation after adjustment for baseline factors. For example, the adjusted odds ratio (OR) for participation comparing ever smokers (by 18 years) with non-smokers was: 0.65, 95% CI (0.56, 0.75). The associations with maternal smoking differed between the subsample of participants at 19 years and the entire sample, although differences were small and confidence intervals overlapped. For example: for SEN status, OR = 1.19 (1.06, 1.33) (all participants); OR = 1.03 (0.79, 1.45) (subsample). CONCLUSIONS: A range of health-related and educational factors are associated with ongoing participation in ALSPAC; this is likely to be the case in other cohort studies. Researchers need to be aware of this when planning their analysis. Cohort studies can use linkage to routine data to explore predictors of ongoing participation and conduct sensitivity analyses to assess potential bias.

External validation of the improving partial risk adjustment in surgery (PRAIS-2) model for 30-day mortality after paediatric cardiac surgery.

OBJECTIVE: Independent temporal external validation of the improving partial risk adjustment in surgery model (PRAIS-2) to predict 30-day mortality in patients undergoing paediatric cardiac surgery. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Paediatric cardiac surgery. INTERVENTION: PRAIS-2 validation was carried out using a two temporally different single centre (Bristol, UK) cohorts: Cohort 1 surgery undertaken from April 2004 to March 2009 and Cohort 2 from April 2015 to July 2019. For each subject PRAIS-2 score was calculated according to the original formula. PARTICIPANTS: A total of 1352 (2004-2009) and 1197 (2015-2019) paediatric cardiac surgical procedures were included in the Cohort 1 and Cohort 2, respectively (median age at the procedure 6.3 and 7.1 months). PRIMARY AND SECONDARY OUTCOME MEASURES: PRAIS-2 performance was assessed in terms of discrimination by means of ROC (receiver operating characteristic) curve analysis and calibration by using the calibration belt method. RESULTS: PRAIS-2 score showed excellent discrimination for both cohorts (AUC 0.72 (95%CI: 0.65 to 0.80) and 0.88 (95%CI: 0.82 to 0.93), respectively). While PRAIS-2 was only marginally calibrated in Cohort 1, with a tendency to underestimate risk in lowrisk and overestimate risk in high risk procedures (P-value = 0.033), validation in Cohort 2 showed good calibration with the 95% confidence belt containing the bisector for predicted mortality (P-value = 0.143). We also observed good prediction accuracy in the non-elective procedures (N = 483;AUC 0.78 (95%CI 0.68 to 0.87); Calibration belt containing the bisector (P-value=0.589). CONCLUSIONS: In a single centre UK-based cohort, PRAIS-2 showed excellent discrimination and calibration in predicting 30-day mortality in paediatric cardiac surgery including in those undergoing non-elective procedures. Our results support a wider adoption of PRAIS-2 score in the clinical practice.

The potential for linking cohort participants to official criminal records: a pilot study using the Avon Longitudinal Study of Parents and Children (ALSPAC).

Introduction: Linking longitudinal cohort resources with police-recorded records of criminal activity has the potential to inform public health style approaches and may reduce potential sources of bias from self-reported criminal data collected by cohort studies. A pilot linkage to police records in the Avon Longitudinal Study of Parents and Children (ALSPAC) allows us to consider the acceptability of this linkage, its utility as a data resource, differences in self-reported crime according to consent status for data linkage, and the appropriate governance mechanism to support such a linkage. Methods: We carried out a pilot study that linked data from the ALSPAC birth cohort to Ministry of Justice (MoJ) records on criminal cautions and convictions. This pilot was conducted on a fully anonymous basis, meaning we cannot link the identified records to any participant or the wider information within the dataset. Using ALSPAC data, we used summary statistics to investigate differences in self-reported criminal activity according to socio-economic background and consent status. We used MoJ records to identify the geographic and temporal concentration of criminality in the ALSPAC cohort. Results: We found that the linkage appears acceptable to participants (4% of the sample opted out), levels of criminality are high enough to support research and that the majority of crimes occurred in Avon & Somerset (the policing area local to ALSPAC). Both those who opted out of linkage or did not respond to consent requests had higher levels of self-reported criminal behaviour compared to participants who provided explicit consent. Conclusions: These findings suggest that data linkage in ALSPAC provides opportunities to study criminal behaviour and that linked individual-level records can provide robust research in the area. Our findings also suggest the potential for bias when only using samples that have explicitly consented to data linkage, highlighting the limitations of opt-in consent strategies.

Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records.

BACKGROUND: Patients with opioid dependency prescribed opioid agonist treatment (OAT) may also be prescribed sedative drugs. This may increase mortality risk but may also increase treatment duration, with overall benefit. We hypothesised that prescription of benzodiazepines in patients receiving OAT would increase risk of mortality overall, irrespective of any increased treatment duration. METHODS AND FINDINGS: Data on 12,118 patients aged 15-64 years prescribed OAT between 1998 and 2014 were extracted from the Clinical Practice Research Datalink. Data from the Office for National Statistics on whether patients had died and, if so, their cause of death were available for 7,016 of these patients. We identified episodes of prescription of benzodiazepines, z-drugs, and gabapentinoids and used linear regression and Cox proportional hazards models to assess the associations of co-prescription (prescribed during OAT and up to 12 months post-treatment) and concurrent prescription (prescribed during OAT) with treatment duration and mortality. We examined all-cause mortality (ACM), drug-related poisoning (DRP) mortality, and mortality not attributable to DRP (non-DRP). Models included potential confounding factors. In 36,126 person-years of follow-up there were 657 deaths and 29,540 OAT episodes, of which 42% involved benzodiazepine co-prescription and 29% concurrent prescription (for z-drugs these respective proportions were 20% and 11%, and for gabapentinoids 8% and 5%). Concurrent prescription of benzodiazepines was associated with increased duration of methadone treatment (adjusted mean duration of treatment episode 466 days [95% CI 450 to 483] compared to 286 days [95% CI 275 to 297]). Benzodiazepine co-prescription was associated with increased risk of DRP (adjusted HR 2.96 [95% CI 1.97 to 4.43], p < 0.001), with evidence of a dose-response effect, but showed little evidence of an association with non-DRP (adjusted HR 0.91 [95% CI 0.66 to 1.25], p = 0.549). Co-prescription of z-drugs showed evidence of an association with increased risk of DRP (adjusted HR 2.75 [95% CI 1.57 to 4.83], p < 0.001) but little evidence of an association with non-DRP (adjusted HR 0.79 [95% CI 0.49 to 1.28], p = 0.342). There was no evidence of an association of gabapentinoid co-prescription with DRP (HR 1.54 [95% CI 0.60 to 3.98], p = 0.373) but evidence of an association with increased non-DRP (HR 1.83 [95% CI 1.28 to 2.62], p = 0.001). Concurrent benzodiazepine prescription also increased mortality risk after consideration of duration of OAT (adjusted HR for DRP with benzodiazepine concurrent prescription 3.34 [95% CI 2.14 to 5.20], p < 0.001). The main limitation of this study is the possibility that unmeasured confounding factors led to an association between benzodiazepine prescription and DRP that is not causal. CONCLUSIONS: In this study, co-prescription of benzodiazepine was specifically associated with increased risk of DRP in opioid-dependent individuals. Co-prescription of z-drugs and gabapentinoids was also associated with increased mortality risk; however, for z-drugs there was no evidence for a dose-response effect on DRP, and for gabapentinoids the increased mortality risk was not specific to DRP. Concurrent prescription of benzodiazepine was associated with longer treatment but still increased risk of death overall. Clinicians should be cautious about prescribing benzodiazepines to opioid-dependent individuals.

Socio-demographic patterns in hospital admissions and accident and emergency attendances among young people using linkage to NHS Hospital Episode Statistics: results from the Avon Longitudinal Study of Parents and Children.

BACKGROUND: In England emergency hospital admissions among children are increasing and the under 25s are the most frequent attenders of A&E departments. Children of lower socio-economic status (SES) have poorer health outcomes and higher hospital admission rates. NHS Hospital Episode Statistics (HES) are increasingly being used for research but lack detailed data on individual characteristics such as SES. We report the results of an Avon Longitudinal Study of Parents and Children (ALSPAC) study that linked the data of 3,189 consenting participants to HES. We describe rates of hospital admission, emergency readmissions, and A&E attendances and examine socio-demographic correlates of these. METHODS: Subjects were singletons and twins enrolled in ALSPAC who had provided consent for linkage to their health records by the study cut-off date (31.02.12). Linkage was carried out by the Health and Social Care Information Centre (now NHS Digital). We examined rates of admissions between birth and age 20 and A&E attendances between 14 and 20 years. Socio-demographic information collected in ALSPAC questionnaires during pregnancy were used to examine factors associated with admissions, emergency readmissions (an emergency admission within 30 days of discharge) and A&E attendances. RESULTS: Excluding birth records, we found at least one admission for 1,792/3,189 (56.2%) participants and 4,305 admissions in total. Admission rates were highest in the first year of life. Among males, admissions declined until about age 5 and then remained relatively stable; conversely, among females, they increased sharply from the age of 15. ICD 10 chapters for diseases of the digestive system and injury and poisoning accounted for the largest proportions of admissions (15.8 and 14.5%, respectively). Tooth decay was the highest single cause of admission for those aged 5-9 years. Overall, 1,518/3,189 (47.6%) of participants attended A&E at least once, with a total of 3,613 attendances between age 14 and 20 years. Individuals from more deprived backgrounds had higher rates of admissions, readmissions and A&E attendances. CONCLUSIONS: Linkage between cohort studies such as ALSPAC and HES data provides unique opportunities for detailed insights into socio-demographic and other determinants of hospital activity, which can inform secondary care demand management in the NHS.

Is screen time associated with anxiety or depression in young people? Results from a UK birth cohort.

BACKGROUND: There is limited and conflicting evidence for associations between use of screen-based technology and anxiety and depression in young people. We examined associations between screen time measured at 16 years and anxiety and depression at 18. METHODS: Participants (n = 14,665; complete cases n = 1869) were from the Avon Longitudinal Study of Parents and Children, a UK-based prospective cohort study. We assessed associations between various types of screen time (watching television, using a computer, and texting, all measured via questionnaire at 16y), both on weekdays and at weekends, and anxiety and depression (measured via the Revised Clinical Interview Schedule at 18y). Using ordinal logistic regression, we adjusted for multiple confounders, particularly focussing on activities that might have been replaced by screen time (for example exercising or playing outdoors). RESULTS: More time spent using a computer on weekdays was associated with a small increased risk of anxiety (OR for 1-2 h = 1.17, 95% CI: 1.01 to 1.35; OR for 3+ hours = 1.30, 95% CI: 1.10 to 1.55, both compared to < 1 h, p for linear trend = 0.003). We found a similar association between computer use at weekends and anxiety (OR for 1-2 h = 1.17, 95% CI: 0.94 to 1.46; OR for 3+ hours = 1.28, 95% CI: 1.03 to 1.48, p for linear trend = 0.03). Greater time spent using a computer on weekend days only was associated with a small increased risk in depression (OR for 1-2 h = 1.12, 95% CI: 0.93 to 1.35; OR for 3+ hours = 1.35, 95% CI: 1.10 to 1.65, p for linear trend = 0.003). Adjusting for time spent alone attenuated effects for anxiety but not depression. There was little evidence for associations with texting or watching television. CONCLUSIONS: We found associations between increased screen time, particularly computer use, and a small increased risk of anxiety and depression. Time spent alone was found to attenuate some associations, and further research should explore this.

Maternal reproductive hormones and angiogenic factors in pregnancy and subsequent breast cancer risk.

PURPOSE: Breast cancer risk associated with pregnancy characteristics may be mediated by maternal hormones or angiogenic factors. METHODS: We conducted a prospective breast cancer case-control study among women in the Avon Longitudinal Study of Parents and Children (ALSPAC) and Norwegian Mother and Child Cohort Study (MoBa) related to maternal pregnancy prolactin (n = 254 cases and 374 controls), placental growth factor (PlGF, n = 252 and 371), soluble fms-like tyrosine kinase-1 (sFlt-1, n = 118 and 240) and steroid hormone concentrations (ALSPAC only, n = 173 and 171). Odds ratios (OR) and 95% confidence intervals (CI) for a 1 SD change in analytes were estimated using unconditional logistic regression with matching factors (cohort, mother's birth year, serum/plasma, blood collection timing) and gestational age. RESULTS: Breast cancer ORs (95% CI) were 0.85 (0.51-1.43) for estradiol, 0.86 (0.67-1.09) for testosterone, 0.89 (0.71-1.13) for androstenedione, 0.97 (0.71-1.34) for hCG, 0.93 (0.75, 1.15) for prolactin, 1.00 (0.78-1.27) for PlGF and 1.91 (1.00-3.65 ALSPAC) and 0.94 (0.73-1.21 MoBa) for sFlt-1, and were similar adjusting for potential confounders. Results were similar by blood collection timing, parity, age at first birth or diagnosis, and time between pregnancy and diagnosis. CONCLUSION: These data do not provide strong evidence of associations between maternal hormones or angiogenic factors with subsequent maternal breast cancer risk.