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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 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.

Abstract Background Duchenne muscular dystrophy (DMD) is a rare, muscle‐degenerative disease predominantly affecting males. Natural history models capture the full disease pathway under current care and combine with estimates of new interventions’ effects to assess cost‐effectiveness by health technology decision‐makers. These models require mortality estimates throughout a patient's lifetime, but rare disease datasets typically contain relatively few patients with short follow‐ups. Alternative (published) sources of mortality data may therefore be required. Methods The Clinical Practice Research Datalink (CPRD) was evaluated as a source of mortality and natural history data for future economic evaluations of health technologies for DMD and rare diseases in general in the UK population. This retrospective longitudinal cohort study provides flexible parametric estimates of mortality rates and survival probabilities in the current UK DMD population through primary/secondary records in the CPRD since 1990. It also investigates clinically significant milestones such as corticosteroid use, spinal surgery, and cardiomyopathy in these patients. Results A total of 1121 male patients were included in the study, observed from 0.7 to 48.9 years. Median life expectancy was 25.64 years (95% confidence interval 24.73, 26.47), consistent with previous global estimates. This has improved to 26.47 (25.16, 27.89) years in patients born after 1990. The median ages at corticosteroid initiation, spinal surgery, ventilation, and cardiomyopathy diagnosis were 6.06 years (5.77, 6.29), 14.79 years (14.29, 15.09), 16.97 years (16.50, 18.31), and 15.26 years (14.22, 16.70), respectively. Conclusions Estimates of mortality in UK‐based DMD patients are age‐specific in a uniquely large and nationally representative sample from the CPRD.

Breast cancer is the fifth leading cause of cancer-related deaths worldwide. The randomized controlled trials (RCTs) of targeted therapies in human epidermal receptor 2 (HER2)–positive advanced breast cancer (ABC) have provided an evidence base for regulatory and reimbursement agencies to appraise the use of cancer therapies in clinical practice. However, a subset of these patients harbor additional biomarkers, for example, a positive hormone receptor status that may be more amenable to therapy and improve overall survival (OS). This review seeks to explore the reporting of evidence for treatment effects by the hormone receptor status using the RCT evidence of targeted therapies for HER2-positive ABC patients. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed to identify published RCTs. Extracted data were synthesized using network meta-analysis to obtain the relative effects of HER2-positive-targeted therapies. We identified a gap in the reporting of the effectiveness of therapies by the hormone receptor status as only 15 out of 42 identified RCTs reported hormone receptor subgroup analyses; the majority of which reported progression-free survival but not OS or the overall response rate. In conclusion, we recommend that future trials in ABC should report the effect of cancer therapies in hormone receptor subgroups for all outcomes.

Introduction The COVID-19 pandemic has resulted in significant morbidity and mortality and devastated economies globally. Among groups at increased risk are healthcare workers (HCWs) and ethnic minority groups. Emerging evidence suggests that HCWs from ethnic minority groups are at increased risk of adverse COVID-19-related outcomes. To date, there has been no large-scale analysis of these risks in UK HCWs or ancillary workers in healthcare settings, stratified by ethnicity or occupation, and adjusted for confounders. This paper reports the protocol for a prospective longitudinal questionnaire study of UK HCWs, as part of the UK-REACH programme (The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers).Methods and analysis A baseline questionnaire will be administered to a national cohort of UK HCWs and ancillary workers in healthcare settings, and those registered with UK healthcare regulators, with follow-up questionnaires administered at 4 and 8 months. With consent, questionnaire data will be linked to health records with 25-year follow-up. Univariate associations between ethnicity and clinical COVID-19 outcomes, physical and mental health, and key confounders/explanatory variables will be tested. Multivariable analyses will test for associations between ethnicity and key outcomes adjusted for the confounder/explanatory variables. We will model changes over time by ethnic group, facilitating understanding of absolute and relative risks in different ethnic groups, and generalisability of findings.Ethics and dissemination The study is approved by Health Research Authority (reference 20/HRA/4718), and carries minimal risk. We aim to manage the small risk of participant distress about questions on sensitive topics by clearly participant information that the questionnaire covers sensitive topics and there is no obligation to answer these or any other questions, and by providing support organisation links. Results will be disseminated with reports to Government and papers submitted to pre-print servers and peer reviewed journals.Trial registration number ISRCTN11811602; Pre-results.

Introduction As the world continues to grapple with the COVID-19 pandemic, emerging evidence suggests that individuals from ethnic minority backgrounds may be disproportionately affected. The United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) project has been initiated to generate rapid evidence on whether and why ethnicity affects COVID-19 diagnosis and clinical outcomes in healthcare workers (HCWs) in the UK, through five interlinked work packages/work streams, three of which form the basis of this protocol. The ethico-legal work (Work Package 3) aims to understand and address legal, ethical and acceptability issues around big data research; the HCWs experiences study (Work Package 4) explores their work and personal experiences, perceptions of risk, support and coping mechanisms; the stakeholder engagement work (Work Package 5) aims to provide feedback and support with the formulation and dissemination of the project recommendations.Methods and analysis Work Package 3 has two different research strands: (A) desk-based doctrinal research; and (B) empirical qualitative research with key opinion leaders. For the empirical research, in-depth interviews will be conducted digitally and recorded with participants permission. Recordings will be transcribed, coded and analysed using thematic analysis. In Work Package 4, online in-depth interviews and focus groups will be conducted with approximately 150 HCWs, from across the UK, and these will be recorded with participants consent. The recordings will be transcribed and coded and data will be analysed using thematic analysis. Work Package 5 will achieve its objectives through regular group meetings and in-group discussions.Ethics and dissemination Ethical approval has been received from the London-Brighton & Sussex Research Ethics Committee of the Health Research Authority (Ref No 20/HRA/4718). Results of the study will be published in open-access journals, and disseminated through conference presentations, project website, stakeholder organisations, media and scientific advisory groups.Trial registration number ISRCTN11811602.

Introduction COVID-19 has spread rapidly worldwide, causing significant morbidity and mortality. People from ethnic minorities, particularly those working in healthcare settings, have been disproportionately affected. Current evidence of the association between ethnicity and COVID-19 outcomes in people working in healthcare settings is insufficient to inform plans to address health inequalities.Methods and analysis This study combines anonymised human resource databases with professional registration and National Health Service data sets to assess associations between ethnicity and COVID-19 diagnosis, hospitalisation and death in healthcare workers in the UK. Adverse COVID-19 outcomes will be assessed between 1 February 2020 (date following first confirmed COVID-19 case in UK) and study end date (31 January 2021), allowing 1-year of follow-up. Planned analyses include multivariable Poisson, logistic and flexible parametric time-to-event regression within each country, adjusting for core predictors, followed by meta-analysis of country-specific results to produce combined effect estimates for the UK. Mediation analysis methods will be explored to examine the direct, indirect and mediated interactive effects between ethnicity, occupational group and COVID-19 outcomes.Ethics and dissemination Ethical approval for the UK-REACH programme has been obtained via the expedited HRA COVID-19 processes (REC ref: 20/HRA/4718, IRAS ID: 288316). Research information will be anonymised via the Secure Anonymised Information Linkage Databank before release to researchers. Study results will be submitted for publication in an open access peer-reviewed journal and made available on our dedicated website (https://uk-reach.org/).Trial registration number ISRCTN11811602.

Abstract Background When designing studies it is common to search the literature to investigate variability estimates to use in sample size calculations. Proprietary data of previously designed trials in a particular indication are also used to obtain estimates of variability. Estimates of treatment effects are typically obtained from randomised controlled clinical trials (RCTs). Based on the observed estimates of treatment effect, variability and the minimum clinical relevant difference to detect, the sample size for a subsequent trial is estimated. However, data from real world evidence (RWE) studies, such as observational studies and other interventional studies in patients in routine clinical practice, are not widely used in a systematic manner when designing studies. In this paper, we propose a framework for inclusion of RWE in planning of a clinical development programme. Methods In our proposed approach, all evidence, from both RCTs and RWE (i.e. from studies in routine clinical practice), available at the time of designing of a new clinical trial is combined in a Bayesian network meta-analysis (NMA). The results can be used to inform the design of the next clinical trial in the programme. The NMA was performed at key milestones, such as at the end of the phase II trial and prior to the design of key phase III studies. To illustrate the methods, we designed an alternative clinical development programme in multiple sclerosis using RWE through clinical trial simulations. Results Inclusion of RWE in the NMA and the resulting trial simulations demonstrated that 284 patients per arm were needed to achieve 90% power to detect effects of predetermined size in the TRANSFORMS study. For the FREEDOMS and FREEDOMS II clinical trials, 189 patients per arm were required. Overall there was a reduction in sample size of at least 40% across the three phase III studies, which translated to a time savings of at least 6 months for the undertaking of the fingolimod phase III programme. Conclusion The use of RWE resulted in a reduced sample size of the pivotal phase III studies, which led to substantial time savings compared to the approach of sample size calculations without RWE.

BACKGROUND:Patients with atrial fibrillation are at a greater risk of stroke and therefore the main goal for treatment of patients with atrial fibrillation is to prevent stroke from occurring. There are a number of different stroke prevention treatments available to include warfarin and novel oral anticoagulants. Previous network meta-analyses of novel oral anticoagulants for stroke prevention in atrial fibrillation acknowledge the limitation of heterogeneity across the included trials but have not explored the impact of potentially important treatment modifying covariates. OBJECTIVES:To explore potentially important treatment modifying covariates using network meta-regression analyses for stroke prevention in atrial fibrillation. METHODS:We performed a network meta-analysis for the outcome of ischaemic stroke and conducted an exploratory regression analysis considering potentially important treatment modifying covariates. These covariates included the proportion of patients with a previous stroke, proportion of males, mean age, the duration of study follow-up and the patients underlying risk of ischaemic stroke. RESULTS:None of the covariates explored impacted relative treatment effects relative to placebo. Notably, the exploration of 'study follow-up' as a covariate supported the assumption that difference in trial durations is unimportant in this indication despite the variation across trials in the network. CONCLUSION:This study is limited by the quantity of data available. Further investigation is warranted, and, as justifying further trials may be difficult, it would be desirable to obtain individual patient level data (IPD) to facilitate an effort to relate treatment effects to IPD covariates in order to investigate heterogeneity. Observational data could also be examined to establish if there are potential trends elsewhere. The approach and methods presented have potentially wide applications within any indication as to highlight the potential benefit of extending decision problems to include additional comparators outside of those of primary interest to allow for the exploration of heterogeneity.

Objectives - Arrowroot is an old-fashioned remedy for diarrhoea, but no clinical studies have been done to evaluate its effectiveness. The aim of this pilot study was to assess its efficacy as a treatment for diarrhoea in 11 patients, all of whom had irritable bowel syndrome with diarrhoea as a feature. Methods - The patients were interviewed and a questionnaire completed on entry into the trial. They then took 10 mL arrowroot powder three times a day for one month and discontinued the treatment for the subsequent month. Questionnaires were completed after one month on treatment and at the end of the trial after one month off treatment. Results - Arrowroot reduced diarrhoea and had a long-term effect on constipation. It also eased abdominal pain. Conclusion - Arrowroot is an effective treatment for diarrhoea. Its action could be explained by several theories which relate to an increase in faecal bulk and thus a more efficient bowel action. The number of patients was small, and further studies are needed to substantiate preliminary results.Objetivos - Araruta é um antigo (absoleto) remédio usado para a diarréia, porém estudos clínicos não têm sido realizados para avaliar sua efetividade. O objetivo deste estudo piloto foi avaliar sua eficácia como um tratamento para diarréia em 11 pacientes, todos eles portadores de síndrome do intestino irritável, com diarréia, como uma manifestação clínica. Métodos - Os pacientes foram entrevistados e um questionário foi preenchido à admissão no estudo (protocolo). Em seguida, receberam 10 mL de araruta em pó, três vezes ao dia durante um mês e descontinuaram este tratamento no mês subseqüente. Os questionários foram preenchidos após o mês de tratamento e ao fim do estudo após o mês de abstinência. Resultados - Araruta reduziu a diarréia e manteve um efeito de constipação por longo prazo. Ela também aliviou a dor abdominal. Conclusão - Araruta é um efetivo tratamento para diarréia. Seu mecanismo de ação poderia ser explicado por várias teorias relacionadas a um aumento do bolo fecal e, conseqüentemente, uma ação intestinal mais eficiente. O número de pacientes foi pequeno, assim estudos adicionais são necessários para substanciar os resultados preliminares.

Prognostic factor research aims to identify factors associated with subsequent clinical outcome in people with a particular disease or health condition. In this article, the second in the PROGRESS series, the authors discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.

Abstract  We set out to determine the incidence of symptomatic postpartum urinary retention (PUR) after vaginal delivery and to establish any associated risk factors. We carried out a retrospective case-control study of women having PUR after vaginal delivery from 2001 to 2005. Four controls, matched for date of delivery, were selected for each case in univariate and multivariate conditional logistic regression analyses. There were 15,757 deliveries and 30 cases of PUR (incidence 0.2%). Median duration of PUR was 19 days (range 3–85). Eighty percent were managed with intermittent self-catheterization. The use of regional analgesia increased the risk of PUR [odds ratio (OR) 6.33, 95% confidence interval (CI) 2.01–19.96], while ethnicity (Caucasian vs Asian) reduced the risk (OR 0.27, CI 0.08–0.85) (p<0.05). PUR is uncommon but carries significant morbidity. Epidural analgesia and Asian ethnic origin increase the risk. We recommend routine catheterization for up to 24 h after delivery after epidural analgesia. [ABSTRACT FROM AUTHOR]