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Background & Objectives Trial Emulation methods can be applied to Population-Scale Linked Electronic Health Records (EHR) to generalise the results of Randomised Controlled Trials (RCTs) to a broader patient population. However, the Data Generating Mechanisms (DGMs) associated with EHR data mean that there is a need to adjust for informative observations, i.e. worse prognosis patients may have more observations. Approach Using the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) as a case study: a RCT of a calcium-channel blocker-based regimen versus a β-blocker-based regimen, an emulated trial was created from population-scale, individual-level, linked anonymized EHR data curated as part of the Wales Multimorbidity e-cohort (WMC) for individuals who would have been eligible for ASCOT-BPLA but who also had Multiple Long-Term Conditions (MLTCs). Outcomes were systolic and diastolic blood pressure estimated/predicted at treatment initiation, 6 weeks, 3 months, and 6 monthly until 4 years. Methods & Results Predictions were made using a fully probabilistic Bayesian joint model which allowed for dropout due to death and which either did or did not also adjust for the frequency of blood pressure observations available. In previous simulation studies such a joint modelling approach has been shown to out-perform other adjustment methods in terms of bias and coverage. Conclusions & Implications Whilst EHR data offer an attractive platform in which to evaluate interventions in people living with MLTCs, the inherent DGMs associated with them need to be taken into account, and the use of a joint modelling approach is an attractive way to achieve this.

Background and Objectives Polypharmacy is increasingly common in people living with multiple long-term conditions (MLTC), but clinical evidence often does not consider medicine interactions beyond two or three treatments at a time. The aim of this research is to develop statistical models to better understand interactions between treatments leading to adverse events for people living with MLTC. Approach We will develop models of risk of adverse events in people with MLTC and polypharmacy using data in the Secure Anonymised Information Linkage (SAIL) Databank - a trusted research environment with linked electronic health record data at the individual-level for the population of Wales, UK. Taking a flexible Bayesian joint modelling approach, where the posterior risk is the product of several sub-models, will enable the characterisation of this complex system in a way that is interpretable for healthcare decision-makers, leading to improved understanding of risk factors for adverse events. Results The Welsh Multimorbidity e-Cohort (WMC) includes 2.9 million people alive and living in Wales on 1st Jan 2000 with follow-up for 20 years. Individuals in the cohort have 932,552,061 medication items prescribed and 277,279 coded adverse events recorded in primary care data. Modelling approaches will focus on feasibility of fitting models to population-level datasets, and the interpretability of the model results for healthcare decision-making. Conclusions and Implications Results have the potential to inform healthcare policy and practice for the management of people living with MLTC and polypharmacy, thus improving patient outcomes and making the best use of limited healthcare resources.

Background and Objectives Healthcare decision-making has previously focused on developing recommendations for single conditions. This research aimed to develop a modeling framework to estimate the effects of multi-indication treatment in people living with multiple long-term conditions. Approach Using a case study in type 2 diabetes mellitus [T2DM], chronic kidney disease [CKD], and heart failure [HF], age-adjusted multistate models were used to estimate the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors as a multi-indication treatment. Baseline hazards were estimated using population-scale, individual-level, linked anonymized electronic health record (EHR) data for 613,195 individuals aged 55 to 85 years in Wales over a 20-year period. Hazard ratios for treatment effects compared to standard of care were obtained from randomized controlled trials for combinations of multiple-long term conditions and incorporated in a patient-level simulation. Results SGLT2 inhibitors increased the estimated mean life expectancy from 0.02 (95% Confidence Interval (CI): -0.02, 0.05) to 1.44 (95% CI: 1.12, 1.74) years in people living with coexisting T2DM, CKD, and HF. The estimated gain in life expectancy was less than 0.5 years for individuals with T2DM, CKD, and HF in different temporally ordered sequences. The estimated mean time to develop HF increased by 3.1 (95% CI: 3.00, 3.24) and 1.34 (95% CI: 1.12, 1.56) years in individuals with CKD, and in those with CKD followed by T2DM. Conclusions and Implications There is an ever increasing need to appraise interventions in people living with multiple long-term conditions to identify optimal treatment strategies and reduce polypharmacy. Multistate models applied to linked EHRs allow for a more rigorous assessment of treatment effects to inform healthcare policy.

Objectives Mental wellbeing can deteriorate throughout adolescence; females and children from low-income families more likely to experience mental health conditions. Views of greenspace from home positively impact cognition, but links with wellbeing has not been explored in children. We linked environment and survey data for 14 year olds in Wales, UK. Approach Our cross-sectional study examined the relationship between views of greenspace and wellbeing for >1000 children aged 14 years living in Wales between 2015-2016. We linked data on views of greenspace from the home location with individual-level wellbeing and socio-demographic data in the SAIL Databank; a secure research environment. Our health outcome was derived from self-reported wellbeing measures in the Millennium Cohort Study. Views of greenspace were derived from LiDAR data and quantified on a continuous scale (0-1). We used Generalised Additive Models to investigate associations between views of greenspace and wellbeing; adjusting for factors such as parent wellbeing and deprivation. Results Homes in coastal areas had larger views of greenspace than non-coastal residences. Individuals living in the most deprived areas had smaller views of greenspace (mean = 0.03) than least deprived (mean = 0.12). Overall, individuals living in detached homes had the greatest views of greenspace (0.4) and flats had the poorest views of greenspace (mean = 0.02). We will report our final regression analyses at the conference investigating the association between views of greenspace and adolescent wellbeing. Our models will be fully adjusted and sub-analyses will be stratified by gender and urban/rural status. We will also report findings on whether deprivation mediates for any relationships. Conclusion Our study is the first to link objectively measured views of greenspace with wellbeing data for a national cohort. Our results can be used to develop interventions to support good wellbeing in adolescents. Further longitudinal research is required to investigate the causal pathways between views of greenspace and adolescent wellbeing.

Objectives Having multiple long term health conditions (MLTCs), also known as multimorbidity, is becoming increasingly common as populations age. Understanding how clusters of diseases are likely to lead to other diseases and the effect of multimorbidity on healthcare resource use (HRU) will be of great importance as this trend continues. Approach Graph-based approaches, also called network analysis in the literature, have been used previously to study multimorbidity. The use of hypergraphs, which are generalisations of graphs where edges can connect to any number of nodes, and their application to the problem of understanding multimorbidity will be discussed. Analysis using hypergraphs was carried out using a population-scale cohort of people in the Secure Anonymised Information Linkage (SAIL) Databank to find the diseases and disease sets which are most important based on a measure of prevalence and measures of healthcare resource utilisation in secondary care. Results The most important sets of diseases based on the centrality of a hypergraph weighted by a measure of prevalence featured hypertension, and the most important was hypertension and diabetes. The most important sets of diseases based on the centrality of a hypergraph weighted by a measure of unplanned inpatient HRU were arrhythmia, heart failure and hypertension while for a measure of outpatient HRU the most important set of diseases was diabetes and hypertension. Conclusion Hypergraphs are very flexible and general mathematical objects and there is still a great deal of development that can be done to make them more useful in epidemiological settings and beyond.

Objectives In Wales almost a quarter of adults and 1 in 8 reception age children are obese. Linked data is a key tool to understanding the role of the built environment on obesity rates and is an important part of developing strategies to combat the obesity epidemic in Wales. Approach We set out to develop an analytical platform for generating evidence on key aspects of the built environment which impact child and adult obesity including; walkability, fast food availability, green space size and qualities, active transport routes and school environments. Utilising the Secure Anonymised Information Linkage (SAIL) Databank We linked multi-sectoral data including routine health data, cohort data, administrative data and linked Geographic Information Systems generated metrics at household and school level. The platform will inform policy makers with and facilitate a better understanding of associations between a range of social, health and built environment factors. Results We have created a range of built environment variables including temporally and age varying walkability indices, viewable greenspace, garden and house size, access to services and parks for 1.5 million households. In the first instance, as part of the BEACHES project, this data has been linked to several health datasets including the Child Measurement Programme (CMP, n=188,800) where initial results have shown that associations between garden size and Body Mass Index in children displays a non-linear negative correlation. We have also created follow-up measures for the CMP using routinely collected general practice data which further enables linking 28,389 height and weight measurements. However, potential bias in these follow-up measures is poorly understood with further work being undertaken to assess usability. Conclusion The integrated multi-sectoral data platform approach to linking environmental, administrative, health and cohort data aims to develop insights on a range of public health issues. We are working with a range of stakeholders to develop evidence-based policy initiatives to reduce obesity in Wales.

Introduction Studies of prevalence and the demographic profile of type 1 diabetes are challenging because of the relative rarity of the condition, however, these outcomes can be determined using routine healthcare data repositories. Understanding the epidemiology of type 1 diabetes allows for targeted interventions and care of this life-affecting condition. Objectives To describe the prevalence, incidence and demographics of persons with type 1 diabetes diagnosed in Wales, UK, using the Secure Anonymised Information Linkage (SAIL) Databank. Methods Data derived from primary and secondary care throughout Wales available in the SAIL Databank were used to identify people with type 1 diabetes to determine the prevalence and incidence of type 1 diabetes over a 10 year period (2008–18) and describe the demographic and clinical characteristics of this population by age, socioeconomic deprivation and settlement type. The seasonal variation in incidence rates was also examined. Results The prevalence of type 1 diabetes in 2018 was 0.32% in the whole population, being greater in men compared to women (0.35% vs 0.28% respectively); highest in those aged 15-29 years (0.52%) and living in the most socioeconomically deprived areas (0.38%). The incidence of type 1 diabetes over 10 years was 14.0 cases/100,000 people/year for the whole population of Wales. It was highest in children aged 0-14 years (33.6 cases/100,000 people/year) and areas of high socioeconomic deprivation (16.8 cases/100,000 people/year) and least in those aged 45-60 years (6.5 cases/100,000 people/year) and in areas of low socioeconomic deprivation (11.63 cases/100,000 people/year). A seasonal trend in the diagnoses of type 1 diabetes was observed with higher incidence in winter months. Conclusion This nation-wide retrospective epidemiological study using routine data revealed that the incidence of type 1 diabetes in Wales was greatest in those aged 0-14 years with a higher incidence and prevalence in the most deprived areas. These findings illustrate the need for health-related policies targeted at high deprivation areas to include type 1 diabetes in their remit.

Introduction Multi-morbidity is a widely recognised but poorly understood global issue that appears to be increasing in prevalence, according to the UK’s Academy of Medical Sciences (AMS) report in 2018. Disease clustering, their determinants and consequences are poorly researched. Better understanding would help drive prevention and improved clinical care, services and patient outcomes. Objectives and Approach Development of two comprehensive population-wide e-cohorts, derived utilising data linkage techniques and including multi-sourced anonymised routine health and demographic data held within the SAIL Databank. The objective is to characterise multi-morbidity and its clustering, determinants and outcomes and compare methods using a) prospective cohort design using multiple data sources in Wales and b) retrospective cohort design to examine household level and environment clustering using GP data in demographically diverse populations (Wales and North East London). The prospective e-cohort focuses on adults living in Wales on 1 st January 2000 and followed up to 2020, including data from the NHS population register, deaths, inpatients, outpatients, Emergency Department, GP, disease registries, laboratory data, and population surveys with QoL measures. This e-cohort will be harmonised with other sites across the UK. The retrospective e-cohort is designed to harmonise with a North East London e-cohort, including all individuals living in Wales on 24 th April 2018 and registered with a GP. Results 2.8 and 2.2 million individuals have been included in the prospective and retrospective cohorts respectively, with 43.6 million person years of follow up. Established comorbidity indices and published phenotypes from libraries are being applied to the data to create initial prevalence and incidence estimates for further analysis. Important clusters will be determined by associations with mortality and excess healthcare utilisation. Conclusion/Implications Building the e-cohorts has involved multiple disciplines across organisations. Multi-morbidity prevalence estimates and study designs will be compared prior to statistical analyses and machine learning methods to evaluate clustering and determinants.

Introduction Type 1 diabetes mellitus (T1DM) is an autoimmune condition characterised by hyperglycaemia, caused by the destruction of insulin producing β-cells in the pancreas. Previous epidemiological population level studies of T1DM and its complications have typically used recorded T1DM diagnoses to determine diabetes status and define cohorts. Objectives and Approach The objective was to identify all persons with T1DM in Wales from Primary (~70\% population coverage) and Secondary Care (100% coverage) data held in the Secure Anonymised Information Linkage (SAIL) databank. People with a coded T1DM diagnosis (using Read codes in Primary Care data and International Classification of Disease (ICD10) codes in Secondary Care data), plus either insulin prescribed shortly after diagnosis or a hospital admission for diabetic ketoacidosis were identified as having T1DM. A sub-group of this SAIL e-cohort were validated using a register of persons diagnosed with T1DM in Wales under 15 years old (Brecon cohort). Results 18,285 people had a T1DM diagnosis and 10,539 had more T1DM than type 2 diabetes mellitus (T2DM) diagnoses. 6,375 persons were identified with T1DM in Primary Care data using our criteria, with a median diagnosis age of 19.2 years (interquartile range 11.0, 35.5). 47.5\% were diagnosed under 18 years of age. 39.6% of people with a T1DM diagnosis did not have T1DM using our criteria. False positive and negative rates of 4.8% and 4.5% respectively were achieved by comparing persons in the SAIL e-cohort against the Brecon cohort. Clinician estimated false positive and negative rates were 1.4% and 3.9% respectively. The prevalence of T1DM in Wales in 2016 was 0.37% or 11,049 people. Conclusion/Implications Our criteria for identifying people with T1DM was more reliable than using diagnosis codes alone, allowing for a more accurate, efficient and reproducible means of identifying individuals with T1DM for researchers utilising the SAIL databank, and other national health repositories.