Predicting type 1 diabetes in children using electronic health records in primary care in the UK: development and validation of a machine-learning algorithm.

BACKGROUND: Children presenting to primary care with suspected type 1 diabetes should be referred immediately to secondary care to avoid life-threatening diabetic ketoacidosis. However, early recognition of children with type 1 diabetes is challenging. Children might not present with classic symptoms, or symptoms might be attributed to more common conditions. A quarter of children present with diabetic ketoacidosis, a proportion unchanged over 25 years. Our aim was to investigate whether a machine-learning algorithm could lead to earlier detection of type 1 diabetes in primary care. METHODS: We developed the predictive algorithm using Welsh primary care electronic health records (EHRs) linked to the Brecon Dataset, a register of children newly diagnosed with type 1 diabetes. Children were included from their first primary care record within the study period of Jan 1, 2000, to Dec 31, 2016, until either type 1 diabetes diagnosis, they turned 15 years of age, or study end. We developed an ensemble learner (SuperLearner) using 26 potential predictors. Validation of the algorithm was done in English EHRs from the Clinical Practice Research Datalink (primary care) and Hospital Episode Statistics, focusing on the ability of the algorithm to identify children who went on to develop type 1 diabetes and the time by which diagnosis could be anticipated. FINDINGS: The development dataset comprised 34 754 400 primary care contacts, relating to 952 402 children, and the validation dataset comprised 43 089 103 primary care contacts, relating to 1 493 328 children. Of these, 1829 (0·19%) children younger than 15 years in the development dataset, and 1516 (0·10%) in the validation dataset had a reliable date of type 1 diabetes diagnosis. If set to give an alert in 10% of contacts, an estimated 71·6% (95% CI 68·8-74·4) of the children with type 1 diabetes would receive an alert by the algorithm in the 90 days before diagnosis, with diagnosis anticipated, on average, by an estimated 9·34 days (95% CI 7·77-10·9). INTERPRETATION: If implemented into primary care settings, this predictive algorithm could substantially reduce the proportion of patients with new-onset type 1 diabetes presenting in diabetic ketoacidosis. Acceptability of alert thresholds should be explored in primary care. FUNDING: Diabetes UK.

Childhood Outcomes in Children with and without Cardiac Echogenic Foci: An Electronic Birth Cohort Study in Wales, UK.

There is uncertainty about outcomes associated with cardiac echogenic foci (CEF) seen at the midtrimester ultrasound scan because of limited population-based follow-up data. This can lead to unnecessary invasive testing and significant parental anxiety. We analysed data from a cohort study, The Welsh Study of Mothers and Babies, to examine whether children with CEF had more adverse outcomes during childhood compared with children without CEF. Children born between 1 January 2009 and 31 December 2011 were followed until 31 January 2018, migration out of Wales, or death. The primary outcome was cardiac hospital admissions, defined a priori by an expert steering group. Secondary outcomes included congenital cardiac anomalies, and hospital admissions for other causes. There was no evidence of an association between isolated CEF and cardiac hospital admissions (hazard ratio 0.87, 95% confidence interval [CI] 0.33-2.25, p value 0.768), or with congenital cardiac anomalies. There was a small increased risk of a respiratory admission with isolated CEF (hazard ratio 1.27, 95% CI 1.04-1.54, p value 0.020). Further research is needed on features of CEF, such as location or number, to fully understand the clinical significance of these findings.

Hypothetical Estimands in Clinical Trials: A Unification of Causal Inference and Missing Data Methods.

The ICH E9 addendum introduces the term intercurrent event to refer to events that happen after treatment initiation and that can either preclude observation of the outcome of interest or affect its interpretation. It proposes five strategies for handling intercurrent events to form an estimand but does not suggest statistical methods for estimation. In this article we focus on the hypothetical strategy, where the treatment effect is defined under the hypothetical scenario in which the intercurrent event is prevented. For its estimation, we consider causal inference and missing data methods. We establish that certain "causal inference estimators" are identical to certain "missing data estimators." These links may help those familiar with one set of methods but not the other. Moreover, using potential outcome notation allows us to state more clearly the assumptions on which missing data methods rely to estimate hypothetical estimands. This helps to indicate whether estimating a hypothetical estimand is reasonable, and what data should be used in the analysis. We show that hypothetical estimands can be estimated by exploiting data after intercurrent event occurrence, which is typically not used. Supplementary materials for this article are available online.

Perspectives of Statistician, Microbiologist, and Clinician Stakeholders on the Use of Microbiological Outcomes in Randomised Trials of Antimicrobial Stewardship Interventions.

Microbiological data are used as indicators of infection, for diagnosis, and the identification of antimicrobial resistance in trials of antimicrobial stewardship interventions. However, several problems have been identified in a recently conducted systematic review (e.g., inconsistency in reporting and oversimplified outcomes), which motivates the need to understand and improve the use of these data including analysis and reporting. We engaged key stakeholders including statisticians, clinicians from both primary and secondary care, and microbiologists. Discussions included issues identified in the systematic review and questions about the value of using microbiological data in clinical trials, perspectives on current microbiological outcomes reported in trials, and alternative statistical approaches to analyse these data. Various factors (such as unclear sample collection process, dichotomising or categorising complex microbiological data, and unclear methods of handling missing data) were identified that contributed to the low quality of the microbiological outcomes and the analysis of these outcomes in trials. Whilst not all of these factors would be easy to overcome, there is room for improvement and a need to encourage researchers to understand the impact of misusing these data. This paper discusses the experience and challenges of using microbiological outcomes in clinical trials.

Non-thermal disruption of ß-adrenergic receptor-activated Ca2+ signalling and apoptosis in human ES-derived cardiomyocytes by microwave electric fields at 2.4 GHz.

The ubiquity of wireless electronic-device connectivity has seen microwaves emerge as one of the fastest growing forms of electromagnetic exposure. A growing evidence-base refutes the claim that wireless technologies pose no risk to human health at current safety levels designed to limit thermal (heating) effects. The potential impact of non-thermal effects of microwave exposure, especially in electrically-excitable tissues (e.g., heart), remains controversial. We exposed human embryonic stem-cell derived cardiomyocytes (CM), under baseline and beta-adrenergic receptor (ß-AR)-stimulated conditions, to microwaves at 2.4 GHz, a frequency used extensively in wireless communication (e.g., 4G, Bluetooth™ and WiFi). To control for any effect of sample heating, experiments were done in CM subjected to matched rates of direct heating or CM maintained at 37 °C. Detailed profiling of the temporal and amplitude features of Ca2+ signalling in CM under these experimental conditions was reconciled with the extent and spatial clustering of apoptosis. The data show that exposure of CM to 2.4 GHz EMF eliminated the normal Ca2+ signalling response to ß-AR stimulation and provoked spatially-clustered apoptosis. This is first evidence that non-thermal effects of 2.4 GHz microwaves might have profound effects on human CM function, responsiveness to activation, and survival.

Right needle, right patient, right time? A national flash-mob audit of thromboprophylaxis in palliative care.

BACKGROUND: The prevention of hospital associated thrombosis in palliative care remains controversial yet many countries recommend the documented risk assessment and where appropriate pharmacological prophylaxis of inpatients with advanced cancer. AIM: To audit adherence to national guidelines which require hospitalised patients to be risk assessed and receive appropriate thromboprophylaxis. DESIGN: A one day "flash-mob" audit across multiple clinical inpatient sites across the United Kingdom. SETTING/PARTICIPANTS: Inpatients receiving palliative care within hospitals, hospices and specialist palliative care units across the United Kingdom. RESULTS: Data were collected from 1125 patients (514 hospital and 611 hospice/specialist palliative care units). Appropriate thromboprophylaxis was observed in 90 % of hospital and 90 % hospice/specialist palliative care units. Documented risk assessment was only found in 79 % and 71 % of patient notes respectively. Pharmacological thromboprophylaxis was contraindicated in 88 % of hospice/specialist palliative care unit patients due to bleeding risk or receiving end-of-life care. Twenty-four percent of patients in hospital had contraindications due to receiving end of life care, bleeding risk and thrombocytopenia. Patients in hospice/specialist palliative care units were of poorer performance status prior to admission with a history of gradual deterioration. Hospitalised patients were more likely to have been admitted following an acute deterioration of previous good performance status. CONCLUSION: Thromboprophylaxis guidelines were followed correctly for the majority of patients. There were considerable differences in the demographics of patients according to place of admission. Patients admitted to hospice/specialist palliative care units were sicker and had more contraindications to prophylaxis than those admitted to hospital. Thromboprophylaxis focused research data conducted in hospices is unlikely to be applicable to the care of palliative care patients admitted acutely to hospital.

Adversity profiles of children receiving care and support from social services: A latent-class analysis of school-aged children in Wales.

BACKGROUND: Children receive care and support from social services due to the risk of harm or impeded development or because of disability. This study aimed to identify typologies of adversity experienced by children receiving care and support from social services and to explore how typologies differ by sociodemographic characteristics. METHODS: This is a cross-sectional study of 'Children Receiving Care and Support' (N = 12 792) during 2017/2018 in Wales, UK. We sought to (1) examine the prevalence of household adversities experienced by children in receipt of care and support from social services; (2) identify typologies of household adversities; and (3) explore how typologies of household adversities differ by family characteristics (demographics, measures of social disadvantage, perinatal and care factors). RESULTS: We found evidence for multiple risk factor constellations. The four-class solution suggested four distinct classes of adversities: child disability (50.0%), low adversities (20.3%), family poor health (6.7%) and multiple risks (23.0%). Children in the 'multiple risk' class were significantly more likely to be younger, more deprived and 'looked after' by the local authority compared with those in the 'low adversities' class. CONCLUSIONS: Given the presence of different constellations of household adversities, policies and interventions that address multiple risk factors simultaneously may be more effective and have longer-lasting benefits.

Mediation of the total effect of cystic fibrosis-related diabetes on mortality: A UK Cystic Fibrosis Registry cohort study.

AIM: To investigate whether the effect of cystic fibrosis-related diabetes (CFRD) on the composite outcome of mortality or transplant could act through lung function, pulmonary exacerbations and/or nutritional status. METHODS: A retrospective cohort of adult cystic fibrosis (CF) patients who had not been diagnosed with CFRD were identified from the UK Cystic Fibrosis Registry (n = 2750). Rate of death or transplant was compared between patients who did and did not develop CFRD (with insulin use) during follow-up using Poisson regression, separately by sex. Causal mediation methods were used to investigate whether lung function, pulmonary exacerbations and nutritional status lie on the causal pathway between insulin-treated CFRD and mortality/transplant. RESULTS: At all ages, the mortality/transplant rate was higher in both men and women diagnosed with CFRD. Pulmonary exacerbations were the strongest mediator of the effect of CFRD on mortality/transplant, with an estimated 15% [95% CI: 7%, 28%] of the effect at 2 years post-CFRD diagnosis attributed to exacerbations, growing to 24% [95% CI: 9%, 46%] at 4 years post-diagnosis. Neither lung function nor nutritional status were found to be significant mediators of this effect. Estimates were similar but with wider confidence intervals in a cohort that additionally included people with CFRD but not using insulin. CONCLUSION: There is evidence that pulmonary exacerbations mediate the effect of CFRD on mortality but, as they are estimated to mediate less than one-quarter of the total effect, the mechanism through which CFRD influences survival may involve other factors.

Methods of analysis for survival outcomes with time-updated mediators, with application to longitudinal disease registry data.

Mediation analysis is a useful tool to illuminate the mechanisms through which an exposure affects an outcome but statistical challenges exist with time-to-event outcomes and longitudinal observational data. Natural direct and indirect effects cannot be identified when there are exposure-induced confounders of the mediator-outcome relationship. Previous measurements of a repeatedly-measured mediator may themselves confound the relationship between the mediator and the outcome. To overcome these obstacles, two recent methods have been proposed, one based on path-specific effects and one based on an additive hazards model and the concept of exposure splitting. We investigate these techniques, focusing on their application to observational datasets. We apply both methods to an analysis of the UK Cystic Fibrosis Registry dataset to identify how much of the relationship between onset of cystic fibrosis-related diabetes and subsequent survival acts through pulmonary function. Statistical properties of the methods are investigated using simulation. Both methods produce unbiased estimates of indirect and direct effects in scenarios consistent with their stated assumptions but, if the data are measured infrequently, estimates may be biased. Findings are used to highlight considerations in the interpretation of the observational data analysis.

A systematic review investigating the use of microbiology outcome measures in randomized controlled trials evaluating antimicrobial stewardship interventions published between 2011 and 2021.

INTRODUCTION: Antimicrobial stewardship interventions (ASIs) aim to reduce the emergence of antimicrobial resistance. We sought to systematically evaluate how microbiological outcomes have been handled and analysed in randomized controlled trials (RCTs) evaluating ASIs. METHODS: We searched PubMed and Embase from 2011-21. Studies were selected if they were RCTs evaluating ASIs. A narrative synthesis approach was taken, identifying whether the study reported any microbiological data (bacterial genus/species; bacterial colony counts; prevalence of bacterial, microbiologically defined infections; and antibiotic susceptibility, measured pre-randomization or post-randomization in one arm only) or outcomes (post-randomization data compared between arms). Studies with or without microbiological data/outcomes were summarized in terms of study characteristics, methods of reporting and analysis of these outcomes. RESULTS: We identified 117 studies, with 34 (29.1%) collecting microbiological data and 18 (15.4%) reporting microbiological outcomes. Most studies with microbiological outcomes were conducted in secondary care (12/18, 66.7%) and targeted adult populations (14/18, 77.8%), and the intervention involved biomarker-guided rapid diagnostic testing (7/18, 38.9%). The overall quality of reporting and analysing microbiological outcomes was low and inconsistent. The selected study population in analyses and methods of handling missing data were unclear. CONCLUSIONS: This review demonstrates that the quality of handling and reporting microbiological outcomes in RCTs of ASIs was low. The lack of consistency and clarity made it difficult to compare the findings across studies, limiting policy- and clinical decision-making. Therefore, there is a clear need for the development of guidance for handling microbiological outcomes in RCTs and adopting appropriate methods to evaluate these data carefully.

Online survey comparing coping responses to SARS-CoV-2 by people with and without existing health conditions in the UK.

OBJECTIVES: To investigate the impact of SARS-CoV-2 on self-reported mood, coping and health behaviours of people living with existing health conditions in the UK to understand how to improve coping responses to the threat of SARS-CoV-2. DESIGN: Quantitative design using a cross-sectional survey. SETTING: Online survey in the UK. PARTICIPANTS: UK adults (18+ years) were eligible to participate. A total of 9110 people participated. Of these, 4377 (48%) reported at least one existing health condition, 874 (10%) reported having two or more existing conditions, and 715 (8%) reported having an existing mental health condition. PRIMARY AND SECONDARY OUTCOME MEASURES: Multivariable linear regression and sequential multiple mediation analysis were used to estimate differences in average scores for active and avoidant coping response scores due to pre-existing health conditions, and to investigate the extent to which these differences are explained by differences in perceptions, beliefs, concerns and mood. RESULTS: People with pre-existing physical (+1.11 higher; 95% CI 0.88 to 1.34) and especially mental health conditions (3.06 higher; 95% CI 2.65 to 3.48) reported poorer health and used more avoidant coping compared with healthy participants. Under some strong untestable assumptions, we estimate that experiencing low mood or concern related to SARS-CoV-2 mostly explained the relationship between existing health conditions and avoidant coping. CONCLUSION: Psychological support and interventions including behaviour change are required to mitigate the psychological burden of the SARS-CoV-2 pandemic and increase autonomy in people with and without pre-existing conditions during this highly uncertain time. Psychologists are well placed to support clinicians and people with existing health conditions to minimise the psychological impact of SARS-CoV-2, in order to alleviate the subsequent strain on healthcare services.

Covid-19 Coping Survey: an In-depth Qualitative Analysis of Free-Text Responses from People With and Without Existing Health Conditions in the UK.

BACKGROUND: There is currently a lack of qualitative research exploring how cognitive and emotional reactions to the threat of SARS-CoV-2 affected the health behaviours of people living with and without pre-existing mental and physical health conditions. We aimed to investigate how the threat of SARS-CoV-2 influenced the thoughts, feelings and health behaviours of people with and without pre-existing health conditions in the UK. METHODS: A cross-sectional online survey of UK adults (aged 18 and over). Free-text responses were analysed using a qualitative framework approach guided by the Common-Sense Model of Self-Regulation. RESULTS: Of the 9110 respondents, 2763 participants provided at least one free-text response. Three main themes were derived from the data. Theme one, locus of control, reports on the extent to which people felt in control during the first wave of the pandemic. Theme two, emotional impact, conveys how individuals felt and how people's personal circumstances made them more vulnerable to experiencing negative emotions during the pandemic. Theme three, coping strategies, describes common health-protective and health-threatening behaviours performed by individuals, as well as the importance of social connectedness, the social context and the need for collective action during the first national lockdown. CONCLUSION: Complex psychological interventions including behaviour change are required to mitigate the psychological burden of the SARS-CoV-2 pandemic and increase autonomy in people with and without pre-existing conditions during this highly uncertain time. Behavioural scientists can support governments and public health agencies to develop evidence-based communication and behaviour change strategies that support people to address unhelpful beliefs and emotions and strengthen coping abilities as the UK moves through and beyond the SARS-CoV-2 pandemic.

SARS-CoV-2 sero-prevalence in the workforces of three large workplaces in South Wales: a sero-epidemiological study.

BACKGROUND: Sero-prevalence studies quantify the proportion of a population that has antibodies against SARS-CoV-2, and can be used to identify the extent of the COVID-19 pandemic at a population level. The aim of the study was to assess the sero-prevalence of SARS-CoV-2 antibodies in the workforce at three workplaces: a food factory, non-food factory and call-centre. METHODS: Nine hundred ninety-three participants were recruited from three workplaces in South Wales. Participants completed a questionnaire and had a lateral flow point-of-care SARS-CoV-2 antibody test administered by a healthcare professional. The data were analysed using multivariable logistic regression, both using complete records only and following multiple imputation. RESULTS: The sero-prevalence of SARS-CoV-2 antibodies ranged from 4% (n = 17/402) in the non-food factory to 10% (n = 28/281) in the food factory (OR 2.93; 95% CI 1.26 to 6.81). After taking account of confounding factors evidence of a difference remained (cOR comparing food factory to call centre (2.93; 95% CI 1.26 to 6.81) and non-food factory (3.99; 95% CI 1.97 to 8.08) respectively). The SARS-CoV-2 antibody prevalence also varied between roles within workplaces. People working in office based roles had a 2.23 times greater conditional odds (95% CI 1.02 to 4.87) of being positive for SARS-CoV-2 antibodies than those working on the factory floor. CONCLUSION: The sero-prevalence of SARS-CoV-2 antibodies varied by workplace and work role. Whilst it is not possible to state whether these differences are due to COVID-19 transmission within the workplaces, it highlights the importance of considering COVID-19 transmission in a range of workplaces and work roles.

Using Negative Control Outcomes and Difference-in-Differences Analysis to Estimate Treatment Effects in an Entirely Treated Cohort: The Effect of Ivacaftor in Cystic Fibrosis.

When an entire cohort of patients receives a treatment, it is difficult to estimate the treatment effect in the treated because there are no directly comparable untreated patients. Attempts can be made to find a suitable control group (e.g., historical controls), but underlying differences between the treated and untreated can result in bias. Here we show how negative control outcomes combined with difference-in-differences analysis can be used to assess bias in treatment effect estimates and obtain unbiased estimates under certain assumptions. Causal diagrams and potential outcomes are used to explain the methods and assumptions. We apply the methods to UK Cystic Fibrosis Registry data to investigate the effect of ivacaftor, introduced in 2012 for a subset of the cystic fibrosis population with a particular genotype, on lung function and annual rate (days/year) of receiving intravenous (IV) antibiotics (i.e., IV days). We consider 2 negative control outcomes: outcomes measured in the pre-ivacaftor period and outcomes among persons ineligible for ivacaftor because of their genotype. Ivacaftor was found to improve lung function in year 1 (an approximately 6.5-percentage-point increase in ppFEV1), was associated with reduced lung function decline (an approximately 0.5-percentage-point decrease in annual ppFEV1 decline, though confidence intervals included 0), and reduced the annual rate of IV days (approximately 60% over 3 years).

Adverse childhood experiences and child mental health: an electronic birth cohort study.

BACKGROUND: Adverse childhood experiences (ACEs) are negatively associated with a range of child health outcomes. In this study, we explored associations between five individual ACEs and child mental health diagnoses or symptoms. ACEs included living with someone who had an alcohol-related problem, common mental health disorder or serious mental illness, or experienced victimisation or death of a household member. METHODS: We analysed data from a population-level electronic cohort of children in Wales, UK, (N = 191,035) between the years of 1998 and 2012. We used Cox regression with discrete time-varying exposure variables to model time to child mental health diagnosis during the first 15 years of life. Child mental health diagnoses include five categories: (i) externalising symptoms (anti-social behaviour), (ii) internalising symptoms (stress, anxiety, depression), (iii) developmental delay (e.g. learning disability), (iv) other (e.g. eating disorder, personality disorders), and (v) any mental health diagnosis, which was created by combining externalising symptoms, internalising symptoms and other. Our analyses were adjusted for social deprivation and perinatal risk factors. RESULTS: There were strong univariable associations between the five individual ACEs, sociodemographic and perinatal factors (e.g. gestational weight at birth) and an increased risk of child mental health diagnoses. After adjusting for sociodemographic and perinatal aspects, there was a remaining conditional increased risk of any child mental health diagnosis, associated with victimisation (conditional hazard ratio (cHR) 1.90, CI 95% 1.34-2.69), and living with an adult with a common mental health diagnosis (cHR 1.63, CI 95% 1.52-1.75). Coefficients of product terms between ACEs and deprivation were not statistically significant. CONCLUSION: The increased risk of child mental health diagnosis associated with victimisation, or exposure to common mental health diagnoses, and alcohol problems in the household supports the need for policy measures and intervention strategies for children and their families.

Psychosocial determinants of quit motivation in older smokers from deprived backgrounds: a cross-sectional survey.

OBJECTIVES: To identify psychosocial determinants of quit motivation in older deprived smokers. The evidence may be used to optimise smoking cessation interventions for the target population. DESIGN: Cross-sectional survey using online recruitment methods including Facebook-targeted advertising. SETTING: UK, 2019. PARTICIPANTS: Current smokers aged 50 years or older and from a socioeconomically deprived background. MAIN OUTCOME MEASURES: Measures included motivation to stop smoking, smoking history, perceived social support, self-efficacy for quitting, self-exempting beliefs and lung cancer risk perception. Multivariable regression was used to analyse factors associated with quit motivation. RESULTS: Of a total 578 individuals who consented to take part, 278 (48.1%) did not meet the inclusion criteria. Of the 300 eligible participants, most were recruited using Facebook (94.0%), were aged 50-64 years (83.7%) and women (85.7%). Most participants were renting from a housing association (72.0%) and had low education (61.0%). Higher motivation to quit was statistically significantly associated with a higher intensity of previous quit attempts (p=0.03), higher quit confidence (p=0.01), higher smoking self-efficacy (p=0.01), a lower risk-minimising beliefs score (p=0.01) and using traditional nicotine replacement therapy (NRT) when trying to stop smoking or cut down (p<0.001). CONCLUSION: Older smokers from deprived backgrounds face complex barriers to quitting smoking. Interventions are needed to increase self-efficacy for quitting, modify risk-minimising beliefs and target elements of previous quit attempts (ie, the use of NRT) that are associated with motivation to stop smoking.

Making apples from oranges: Comparing noncollapsible effect estimators and their standard errors after adjustment for different covariate sets.

We revisit the well-known but often misunderstood issue of (non)collapsibility of effect measures in regression models for binary and time-to-event outcomes. We describe an existing simple but largely ignored procedure for marginalizing estimates of conditional odds ratios and propose a similar procedure for marginalizing estimates of conditional hazard ratios (allowing for right censoring), demonstrating its performance in simulation studies and in a reanalysis of data from a small randomized trial in primary biliary cirrhosis patients. In addition, we aim to provide an educational summary of issues surrounding (non)collapsibility from a causal inference perspective and to promote the idea that the words conditional and adjusted (likewise marginal and unadjusted) should not be used interchangeably.

Demographic and socioeconomic patterns in the risk of alcohol-related hospital admission in children and young adults with childhood onset type-1 diabetes from a record-linked longitudinal population cohort study in Wales.

BACKGROUND: Little is known about alcohol-related harm in children and young adults with type 1 diabetes (T1D). Education on managing alcohol intake is provided to teenagers with T1D in paediatric clinics in Wales, but its effectiveness is unknown. We compared the patterns in risk of alcohol-related hospital admissions (ARHA) between individuals with and without childhood-onset T1D. METHODS: We extracted data for 1 791 577 individuals born during 1979 to 2014 with a general practitioner registration in Wales, and record-linked the demographic data to ARHA between 1998 and June 2016 within the Secure Anonymised Information Linkage Databank (SAIL). Linkage to a national T1D register (Brecon Cohort) identified 3575 children diagnosed aged <15 years since 1995. We estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the risk of ARHA using recurrent-event models, including interaction terms. RESULTS: Individuals with T1D had a higher riskof ARHA (HR: 1.78; 95% CI: 1.60-1.98), adjusted for age group, sex, and deprivation. The risk in people with diabetes was highest aged 14 to 17 years, around three times higher than the peak in non-T1D aged 18 to 22. Females with diabetes had a lower risk generally. The association between deprivation and ARHA was weaker in the T1D group. CONCLUSION: Young people with T1D had increased risks of ARHA, particularly at school age, and smaller socioeconomic inequalities in ARHA. A review of interventions to reduce alcohol-related harm in T1D is needed, perhaps including modification of current education and guidance for teenagers on managing alcohol consumption and reviewing criteria for hospital admission.

Marginal structural models for repeated measures where intercept and slope are correlated: An application exploring the benefit of nutritional supplements on weight gain in HIV-infected children initiating antiretroviral therapy.

BACKGROUND: The impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear. METHODS: In the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications. RESULTS: In simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction. DISCUSSION: This study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures.

CATS II Long-term Anthropometric and Metabolic Effects of Maternal Sub-optimal Thyroid Function in Offspring and Mothers.

CONTEXT AND OBJECTIVES: The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF). DESIGN & PARTICIPANTS: 332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression. RESULTS: Offspring's measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median [interquartile ratio] 28.3 [24.6-32.6] kg/m2) compared with NGTF (25.8 [22.9-30.0] kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 [1.43-3.50] mU/L) than NGTF (1.54 [1.12-2.07] mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 [23.1-29.8] kg/m2, P = 0.672) and TSH (1.68 [0.89-2.96] mU/L; P = 0.474) values similar to NGTF mothers. CONCLUSIONS: Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF.