Matthew J. Carr

Rare disease studies often rely on small, selected cohorts, are resource-intensive and difficult to scale. UK primary care electronic health record (EHR) databases provide population-based, longitudinal data, but their use for rare genetic disease research has not been systematically examined. Through systematic mapping of publications from five UK primary care EHR databases (CPRD, OPCRD, QResearch, SAIL Databank and THIN), we found that only 0.82% (47 of 5754) of studies reported on rare genetic diseases. Of these, 77% (36 of 47) linked to external datasets. Study designs included case-control, cross-sectional and cohort studies. Cohort designs predominated, often with individual-level matched comparators. Case ascertainment was primarily based on routinely recorded diagnostic codes. Most studies examined a single disease, collectively encompassing 23 conditions. There was a skew towards multisystem, neurological, autosomal dominant and single-gene disorders, with relatively higher population frequencies and therapeutic tractability. Rare disease sample sizes ranged from 21 to 5059 (median 392). Important insights were revealed into phenotypic variation, phenotype expansion, complications and management outcomes, including findings not readily identifiable in traditional studies. Examples include higher prevalence of hereditary haemorrhagic telangiectasia in females, consistent with sex-modified phenotypic expression; non-skeletal complications and premature mortality in X-linked hypophosphataemia; and elevated malignancy risk in myotonic dystrophy type 1 with type 2 diabetes, potentially attenuated by metformin. In conclusion, UK primary care EHR databases are markedly underutilised for rare genetic diseases. For many conditions, limited availability of diagnostic codes is a constraint. However, their demonstrated capacity, scale, scope and population representativeness support wider use.

Aims/hypothesis: Suboptimal sleep health is linked to higher risks for incident type 2 diabetes. We aimed to assess the clinical utility of adding self-reported sleep traits to a type 2 diabetes prediction model. Methods: In this cohort study, we used UK Biobank data and Cox proportional hazards models to examine how self-reported sleep duration and insomnia symptoms were associated with incident type 2 diabetes risk. Harrell’s C statistic and net reclassification improvement (NRI) were used to assess whether sleep traits improved the incident type 2 diabetes discrimination and predictive utility achieved using QDiabetes variables, with and without including a type 2 diabetes polygenic risk score (PGS). Independent replication was explored in the Nurses’ Health Study, the Nurses’ Health Study II and the Health Professionals Follow-up Study. Results: Extremes of sleep duration and occasional or frequent insomnia symptoms were associated with higher risks for incident type 2 diabetes. In the UK Biobank and replication cohorts, adding sleep traits to the QDiabetes risk score did not improve type 2 diabetes prediction (C statistic: QDiabetes alone 0.8933; QDiabetes + sleep duration 0.8939; QDiabetes + insomnia 0.8931; QDiabetes + sleep traits 0.8935). The corresponding total NRI values were: 0.08 (95% CI −0.18, 0.33), 0.04 (95% CI −0.08, 0.16) and 0.04 (95% CI −0.10, 0.18). Inclusion of PGS data marginally improved the type 2 diabetes risk prediction achieved using The QDiabetes calculator, with or without the inclusion of sleep traits in the model (QDiabetes + PGS: C statistic 0.8945; total NRI 0.20 [95% CI 0.12, 0.28]; QDiabetes + PGS + sleep traits: C statistic 0.8946; total NRI 0.18 [95% CI 0.09, 0.27]). Conclusions/interpretation: While sleep duration and insomnia symptoms were associated with type 2 diabetes risk, they are not useful for improving type 2 diabetes prediction beyond QDiabetes model performance. Inclusion of a type 2 diabetes PGS marginally improved prediction but lacked clear clinical utility. Graphical

Background: Despite growing concerns about young people’s mental health, it remains unclear how rates of psychiatric diagnoses and psychotropic medication prescribing have changed. Aim: To investigate temporal trends in UK primary care-recorded incidence of (1) psychiatric diagnoses: attention deficit hyperactivity disorders (ADHD), autism spectrum conditions, anxiety disorders, depression, substance misuse, and personality disorders, and (2) psychotropic medication prescribing, in individuals aged 1–24 years. Design and setting: This was a population-based study using primary care data from the Clinical Practice Research Datalink. Method: The monthly incidence of each outcome from January 2010 to March 2022 were calculated. Negative binomial regression was used to predict expected incidence rates when the COVID-19 pandemic began in March 2020, based on antecedent trends. Observed and predicted (that is, expected) rates were compared. Results: In the 2 years following March 2020, the incidence of ADHD diagnoses in females was 24.7% (95% confidence interval = 11.9 to 38.9%) greater than the expected incidence rate predicted from the trends before the pandemic. The increase in ADHD diagnoses occurred more commonly for females aged 20–24 years, followed by those aged 17–19 years, as well as among females from less deprived areas. Similar trends were observed for ADHD medications. Observed rates of other outcomes, including common mental illnesses, were below or close to the expected levels, with the differentials between observed and expected rates being greater for males than females. Conclusion: Increased ADHD awareness may partly explain the study's findings. However, the fall in other diagnoses may reflect barriers to accessing health services at the height of the pandemic. Early identification and timely treatment of mental health difficulties and neurodevelopmental conditions are crucial.

Purpose: To examine variation in oral, injectable, and inhaled corticosteroid (CS) prescribing in primary care, exploring treatment persistence and coverage.Methods: We examined patient‐level electronic health records from English general practices in the Clinical Practice Research Datalink Aurum database. We delineated a cohort of new users of oral, injectable, or inhaled CS with prescriptions issued between January 1, 2000, and June 30, 2021. Lorenz curves assessed potential prescribing skewness, and Kaplan–Meier (KM) plots estimated treatment persistence. The Proportion of Patients Covered (PPC) method estimated the proportion of patients still covered by treatment 1 year after initiation.Results: We observed 1 942 571 CS users across 1471 general practices, with 20% of oral and inhaled CS users accounting for almost 80% of total CS use. Older patients with comorbidities including respiratory diseases (13.5%), skin conditions (5.8%), or inflammatory bowel diseases (1.6%) were more likely to be prescribed higher doses. The KM plots showed that 20% of oral and 50% of inhaled CS users were persistent after one and 2 months, respectively. The PPC method indicated that 30% of oral and 60% of inhaled CS users were covered by treatment 6 months post‐initiation. Some variation was observed when different grace periods were applied. Combined use of oral and inhaled CS was observed for 6.9% of patients.Conclusion: A fifth of patients receiving CS accounted for over 80% of oral and inhaled CS prescribing in primary care. Identifying these patients is crucial for targeting future interventions to promote patient safety and cost‐effective CS use.

Primary endocrine therapy (PET) offers non-surgical treatment for older women with early-stage breast cancer who are unsuitable for surgery due to frailty or comorbidity. This research assessed all-cause and breast cancer-specific mortality of PET vs. surgery in older women (≥70 years) with oestrogen-receptor-positive early-stage breast cancer by frailty and comorbidity levels. This study used UK secondary data to analyse older female patients from 2000 to 2016. Patients were censored until 31 May 2019 and grouped by the Charlson comorbidity index (CCI) and hospital frailty risk score (HFRS). Cox regression models compared all-cause and breast cancer-specific mortality between PET and surgery within each group, adjusting for patient preferences and covariates. Sensitivity analyses accounted for competing risks. There were 23,109 patients included. The hazard ratio (HR) comparing PET to surgery for overall survival decreased significantly from 2.1 (95%CI: 2.0, 2.2) to 1.2 (95%CI: 1.1, 1.5) with increasing HFRS and from 2.1 (95%CI: 2.0, 2.2) to 1.4 (95%CI 1.2, 1.7) with rising CCI. However, there was no difference in BCSM for frail older women (HR: 1.2; 0.9, 1.9). There were no differences in competing risk profiles between other causes of death and breast cancer-specific mortality with PET versus surgery, with a subdistribution hazard ratio of 1.1 (0.9, 1.4) for high-level HFRS (p = 0.261) and CCI (p = 0.093). Given limited survival gains from surgery for older patients, PET shows potential as an effective option for frail older women with early-stage breast cancer. Despite surgery outperforming PET, surgery loses its edge as frailty increases, with negligible differences in the very frail.

Objective To determine the magnitude of any excess risk of mortality and hospitalisation due to COVID-19 infection in patients with congenital heart disease (CHD) in the UK healthcare system. Methods Matched case–control study within the Clinical Practice Research Datalink study of anonymised general practice records in the National Health Service in England. Patients with CHD were stratified for disease severity according to the European Society of Cardiology guidelines. Presence of a positive COVID-19 test, hospitalisation with a diagnosis of COVID-19 and COVID-19-related mortality were compared in case and control groups. Results 86 441 patients with CHD and 335 839 controls were studied. Of patients with a positive COVID-19 test, patients with CHD were more likely than controls to be hospitalised (22.4% vs 14.5%; OR=1.77 (95% CI 1.60 to 1.96); p=2.11e−28) and suffer COVID-19-related death (6.1% vs 3.8%; OR=1.60 (95% CI 1.35 to 1.89); p=7.00e−08). The excess risk of COVID-19 hospitalisation and death rose with increasing physiological severity of CHD (presence of pulmonary vascular disease and/or cyanosis), rather than anatomical complexity. Conclusions In this study of the COVID-19 pandemic experience, using population health records in over 86000 patients with CHD in England, patients with CHD with COVID-19 were at around 50–75% higher risk of hospitalisation and mortality compared with matched controls with COVID-19. We provide the first primary care-derived estimates for COVID-19 hospitalisation and case-fatality rates in patients with CHD. Some factors predictive of worse COVID-19 outcome in general populations (such as non-white ethnic group), and other CHD-specific comorbidities (such as pulmonary hypertension), influenced outcomes among patients with CHD.

Background: Persons discharged from inpatient psychiatric services are at greatly elevated risk of harming themselves or inflicting violence on others, but no studies have reported gender-specific absolute risks for these two outcomes across the spectrum of psychiatric diagnoses. We aimed to estimate absolute risks for self-harm and interpersonal violence post-discharge according to gender and diagnostic category. Methods: Danish national registry data were utilized to investigate 62,922 discharged inpatients, born 1967–2000. An age and gender matched cohort study was conducted to examine risks for self-harm and interpersonal violence at 1 year and at 10 years post-discharge. Absolute risks were estimated as cumulative incidence percentage values. Results: Patients diagnosed with substance misuse disorders were at especially elevated risk, with the absolute risks for either self-harm or interpersonal violence being 15.6% (95% CI 14.9, 16.3%) of males and 16.8% (15.6, 18.1%) of females at 1 year post-discharge, rising to 45.7% (44.5, 46.8%) and 39.0% (37.1, 40.8%), respectively, within 10 years. Diagnoses of personality disorders and early onset behavioral and emotional disorders were also associated with particularly high absolute risks, whilst risks linked with schizophrenia and related disorders, mood disorders, and anxiety/somatoform disorders, were considerably lower. Conclusions: Patients diagnosed with substance misuse disorders, personality disorders and early onset behavioral and emotional disorders are at especially high risk for internally and externally directed violence. It is crucial, however, that these already marginalized individuals are not further stigmatized. Enhanced care at discharge and during the challenging transition back to life in the community is needed.

Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999–2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13–0.77) for metaxalone to 3.44 (95% confidence interval: 1.53–7.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.

Background: Atrial fibrillation (AF) is an important risk factor for ischaemic stroke, and AF incidence is expected to increase. Guidelines recommend using oral anticoagulants (OACs) to prevent the development of stroke. However, studies have reported the frequent underuse of OACs in AF patients. The objective of this study is to describe nonvalvular atrial fibrillation (NVAF) incidence in England and assess the clinical and socioeconomic factors associated with the underprescribing of OACs. Methods and findings: We conducted a population-based retrospective cohort study using the UK Clinical Practice Research Datalink (CPRD) database to identify patients with NVAF aged ≥18 years and registered in English general practices between 2009 and 2019. Annual incidence rate of NVAF by age, deprivation quintile, and region was estimated. OAC prescribing status was explored for patients at risk for stroke and classified into the following: OAC, aspirin only, or no treatment. We used a multivariable multinomial logistic regression model to estimate relative risk ratios (RRRs) and 95% confidence intervals (CIs) of the factors associated with OAC or aspirin-only prescribing compared to no treatment in patients with NVAF who are recommended to take OAC. The multivariable regression was adjusted for age, sex, comorbidities, socioeconomic status, baseline treatment, frailty, bleeding risk factors, and takes into account clustering by general practice. Between 2009 and 2019, 12,517,191 patients met the criteria for being at risk of developing NVAF. After a median follow-up of 4.6 years, 192,265 patients had an incident NVAF contributing a total of 647,876 person-years (PYR) of follow-up. The overall age-adjusted incidence of NVAF per 10,000 PYR increased from 20.8 (95% CI: 20.4; 21.1) in 2009 to 25.5 (25.1; 25.9) in 2019. Higher incidence rates were observed for older ages and males. Among NVAF patients eligible for anticoagulation, OAC prescribing rose from 59.8% (95% CI: 59.0; 60.6) in 2009 to 83.2% (95% CI: 83.0; 83.4) in 2019. Several conditions were associated with lower risk of OAC prescribing: dementia [RRR 0.52 (0.47; 0.59)], liver disease 0.58 (0.50; 0.67), malignancy 0.74 (0.72; 0.77), and history of falls 0.82 (0.78; 0.85). Compared to white ethnicity, patients from black and other ethnic minorities were less likely to receive OAC; 0.78 (0.65; 0.94) and 0.76 (0.64; 0.91), respectively. Patients living in the most deprived areas were less likely to receive OAC 0.85 (0.79; 0.91) than patients living in the least deprived areas. Practices located in the East of England were associated with higher risk of prescribing aspirin only over no treatment than practices in London (RRR 1.22; 95% CI 1.02 to 1.45). The main limitation of this study is that these findings depends on accurate recording of conditions by health professionals and the inevitable residual confounding due to lack of data on certain factors that could be associated with under-prescribing of OACs. Conclusions: The incidence of NVAF increased between 2009 and 2015, before plateauing. Underprescribing of OACs in NVAF is associated with a range of comorbidities, ethnicity, and socioeconomic factors, demonstrating the need for initiatives to reduce inequalities in the care for AF patients.