Identifying unmet clinical need in hypertrophic cardiomyopathy using national electronic health records

Introduction: To evaluate unmet clinical need in unselected hypertrophic cardiomyopathy (HCM) patients to determine the risk of a wide range of subsequent cardiovascular disease endpoints and safety endpoints relevant for trial design. Methods: Population based cohort (CALIBER, linked primary care, hospital and mortality records in England, period 1997–2010), all people diagnosed with HCM were identified and matched by age, sex and general practice with ten randomly selected people without HCM. Random-effects Poisson models were used to assess the associations between HCM and cardiovascular diseases and bleeding. Results: Among 3,290,455 eligible people a diagnosis of hypertrophic cardiomyopathy was found in 4 per 10,000. Forty-one percent of the 1,160 individuals with hypertrophic cardiomyopathy were women and the median age was 57 years. The median follow-up was 4.0 years. Compared to general population controls, people with HCM had higher risk of ventricular arrhythmia (incidence rate ratio = 23.53, [95% confidence interval 12.67–43.72]), cardiac arrest or sudden cardiac death (6.33 [3.69–10.85]), heart failure (4.31, [3.30–5.62]), and atrial fibrillation (3.80 [3.04–4.75]). HCM was also associated with a higher incidence of myocardial infarction ([MI] 1.90 [1.27–2.84]) and coronary revascularisation (2.32 [1.46–3.69]).The absolute Kaplan-Meier risks at 3 years were 8.8% for the composite endpoint of cardiovascular death or heart failure, 8.4% for the composite of cardiovascular death, stroke or myocardial infarction, and 1.5% for major bleeding. Conclusions: Our study identified major unmet need in HCM and highlighted the importance of implementing improved cardiovascular prevention strategies to increase life-expectancy of the contemporary HCM population. They also show that national electronic health records provide an effective method for identifying outcomes and clinically relevant estimates of composite efficacy and safety endpoints essential for trial design in rare diseases

Predictors and temporal trend of flu vaccination in auto-immune rheumatic diseases in the UK: a nationwide prospective cohort study

Objectives: To [1] examine temporal trend in uptake of seasonal influenza vaccine (SIV) in the UK, [2] explore disease and demographic factors associated with vaccination. Methods: 32,751 people with auto-immune rheumatic diseases (AIRDs) prescribed disease modifying anti-rheumatic drugs (DMARDs) between 2006 and 2016 were identified from the Clinical Practice Research Datalink. The proportion vaccinated between 01/September of one year and 31/March of next year was calculated and stratified by age, other indications for vaccination, AIRD type, and number of DMARDs prescribed. Stata and Joinpoint regression programs were used. Results: SIV uptake was high in those aged ≥65 years (82.3% and 80.7% in 2006-07 and 2015-16 respectively). It was significantly lower in other age groups, but improved over time with 51.9% and 61.9% in the 45-64 year age group, and 32.3% and 50.1% in the <45 year age group being vaccinated in 2006-07 and 2015-16 respectively. While 64.9% of the vaccinations in those ≥65 years old occurred by 3rd November, in time to mount a protective immune response before the influenza activity becomes substantial in UK, only 38.9% in the 45-64 year and 26.2% in the <45 year age group without any other reason for vaccination received SIV by this date. Women, those with additional indications for vaccination, on multiple DMARDs and with SLE were more likely to be vaccinated. Conclusion: SIV uptake is low in the under 65s, and the majority of them are not vaccinated in time. Additional effort is required to promote timely uptake of SIV in this population

The use of a bayesian hierarchy to develop and validate a co-morbidity score to predict mortality for linked primary and secondary care data from the NHS in England

Background: We have assessed whether the linkage between routine primary and secondary care records provided an opportunity to develop an improved population based co-morbidity score with the combined information on co-morbidities from both health care settings. Methods: We extracted all people older than 20 years at the start of 2005 within the linkage between the Hospital Episodes Statistics, Clinical Practice Research Datalink, and Office for National Statistics death register in England. A random 50% sample was used to identify relevant diagnostic codes using a Bayesian hierarchy to share information between similar Read and ICD 10 code groupings. Internal validation of the score was performed in the remaining 50% and discrimination was assessed using Harrell’s C statistic. Comparisons were made over time, age, and consultation rate with the Charlson and Elixhauser indexes. Results: 657,264 people were followed up from the 1st January 2005. 98 groupings of codes were derived from the Bayesian hierarchy, and 37 had an adjusted weighting of greater than zero in the Cox proportional hazards model. 11 of these groupings had a different weighting dependent on whether they were coded from hospital or primary care. The C statistic reduced from 0.88 (95% confidence interval 0.88–0.88) in the first year of follow up, to 0.85 (0.85–0.85) including all 5 years. When we stratified the linked score by consultation rate the association with mortality remained consistent, but there was a significant interaction with age, with improved discrimination and fit in those under 50 years old (C=0.85, 0.83–0.87) compared to the Charlson (C=0.79, 0.77–0.82) or Elixhauser index (C=0.81, 0.79–0.83). Conclusions: The use of linked population based primary and secondary care data developed a co-morbidity score that had improved discrimination, particularly in younger age groups, and had a greater effect when adjusting for co-morbidity than existing scores

Persistence of health inequalities in childhood injury in the UK: a population-based cohort study of children under 5

BACKGROUND: Injury is a significant cause of childhood death and can result in substantial long-term disability. Injuries are more common in children from socio-economically deprived families, contributing to health inequalities between the most and least affluent. However, little is known about how the relationship between injuries and deprivation has changed over time in the UK. METHODS: We conducted a cohort study of all children under 5 registered in one of 495 UK general practices that contributed medical data to The Health Improvement Network database between 1990–2009. We estimated the incidence of fractures, burns and poisonings by age, sex, socio-economic group and calendar period and adjusted incidence rate ratios (IRR) comparing the least and most socio-economically deprived areas over time. Estimates of the UK annual burden of injuries and the excess burden attributable to deprivation were derived from incidence rates. RESULTS: The cohort of 979,383 children experienced 20,804 fractures, 15,880 burns and 10,155 poisonings, equating to an incidence of 75.8/10,000 person-years (95% confidence interval 74.8–76.9) for fractures, 57.9 (57.0–58.9) for burns and 37.3 (35.6–38.0) for poisonings. Incidence rates decreased over time for burns and poisonings and increased for fractures (p<0.001 test for trend for each injury). They were significantly higher in more deprived households (IRR test for trend p<0.001 for each injury type) and these gradients persisted over time. We estimate that 865 fractures, 3,763 burns and 3,043 poisonings could be prevented each year in the UK if incidence rates could be reduced to those of the most affluent areas. CONCLUSIONS: The incidence of burns and poisonings declined between 1990 and 2009 but increased for fractures. Despite these changes, strong socio-economic inequalities persisted resulting in an estimated 9,000 additional medically-attended injuries per year in under-5s

Sensitivity of the UK clinical practice research datalink to detect neurodevelopmental effects of medicine exposure in utero:comparative analysis of an antiepileptic drug-exposed cohort

Introduction: Electronic healthcare data have several advantages over prospective observational studies, but the sensitivity of data on neurodevelopmental outcomes and its comparability with data generated through other methodologies is unknown. Objectives: The objectives of this study were to determine whether data from the UK Clinical Practice Research Datalink (CPRD) produces similar risk estimates to a prospective cohort study in relation to the risk of neurodevelopmental disorders (NDDs) following prenatal antiepileptic drug (AED) exposure. Methods: A cohort of mother–child pairs of women with epilepsy (WWE) was identified in the CPRD and matched to a cohort without epilepsy. The study period ran from 1 January 2000 to 31 March 2007 and children were required to be in the CPRD at age 6 years. AED exposure during pregnancy was determined from prescription data and children with an NDD diagnosis by 6 years were identified from Read clinical codes. The prevalence and risk of NDDs was calculated for mother–child pairs in WWE stratified by AED regimen and for those without epilepsy. Comparisons were made with the results of the prospective Liverpool and Manchester Neurodevelopment Group study which completed assessment on 201 WWE and 214 without epilepsy at age 6 years. Results: In the CPRD, 1018 mother–child pairs to WWE and 6048 to women without epilepsy were identified. The CPRD identified a lower prevalence of NDDs than the prospective study. In both studies, NDDs were more frequently reported in children of WWE than women without epilepsy, although the CPRD risk estimate was lower (2.16 vs. 0.96%, p < 0.001 and 7.46 vs. 1.87%, p = 0.0128). NDD prevalence differed across AED regimens but the CPRD data did not replicate the significantly higher risk of NDDs following in utero monotherapy valproate exposure (adjusted odds ratio [ORadj] 2.02, 95% confidence interval [CI] 0.52–7.86) observed in the prospective study (ORadj 6.05, 95% CI 1.65–24.53). Conclusion: It was possible to identify NDDs in the CPRD; however, the CPRD appears to under-record these outcomes. Larger studies are required to investigate further

Depression as a Risk Factor for the Initial Presentation of Twelve Cardiac, Cerebrovascular, and Peripheral Arterial Diseases: Data Linkage Study of 1.9 Million Women and Men

BACKGROUND: Depression is associated with coronary heart disease and stroke, but associations with a range of pathologically diverse cardiovascular diseases are not well understood. We examine the risk of 12 cardiovascular diseases according to depression status (history or new onset). METHODS: Cohort study of 1,937,360 adult men and women, free from cardiovascular disease at baseline, using linked UK electronic health records between 1997 and 2010. The exposures were new-onset depression (a new GP diagnosis of depression and/or prescription for antidepressants during a one-year baseline), and history of GP-diagnosed depression before baseline. The primary endpoint was initial presentation of 12 cardiovascular diseases after baseline. We used disease-specific Cox proportional hazards models with multiple imputation adjusting for cardiovascular risk factors (age, sex, socioeconomic status, smoking, blood pressure, diabetes, cholesterol). RESULTS: Over a median [IQR] 6.9 [2.1-10.5] years of follow-up, 18.9% had a history of depression and 94,432 incident cardiovascular events occurred. After adjustment for cardiovascular risk factors, history of depression was associated with: stable angina (Hazard Ratio = 1.38, 95%CI 1.32-1.45), unstable angina (1.70, 1.60-1.82), myocardial infarction (1.21, 1.16-1.27), unheralded coronary death (1.23, 1.14-1.32), heart failure (1.18, 1.13-1.24), cardiac arrest (1.14, 1.03-1.26), transient ischemic attack (1.31, 1.25-1.38), ischemic stroke (1.26, 1.18-1.34), subarachnoid haemorrhage (1.17, 1.01-1.35), intracerebral haemorrhage (1.30, 1.17-1.45), peripheral arterial disease (1.24, 1.18-1.30), and abdominal aortic aneurysm (1.12,1.01-1.24). New onset depression developed in 2.9% of people, among whom 63,761 cardiovascular events occurred. New onset depression was similarly associated with each of the 12 diseases, with no evidence of stronger associations compared to history of depression. The strength of association between depression and these cardiovascular diseases did not differ between women and men. CONCLUSION: Depression was prospectively associated with cardiac, cerebrovascular, and peripheral diseases, with no evidence of disease specificity. Further research is needed in understanding the specific pathophysiology of heart and vascular disease triggered by depression in healthy populations

The risk of oesophago-gastric cancer in symptomatic patients in primary care: A large case-control study using electronic records

BACKGROUND: Over 15 000 new oesophago-gastric cancers are diagnosed annually in the United Kingdom, with most being advanced disease. We identified and quantified features of this cancer in primary care. METHODS: Case-control study using electronic primary-care records of the UK patients aged ≥40 years was performed. Cases with primary oesophago-gastric cancer were matched to controls on age, sex and practice. Putative features of cancer were identified in the year before diagnosis. Odds ratios (ORs) were calculated for these features using conditional logistic regression, and positive predictive values (PPVs) were calculated. RESULTS: A total of 7471 cases and 32 877 controls were studied. Sixteen features were independently associated with oesophago-gastric cancer (all P5% in patients ≥55 years was for dysphagia. In patients <55 years, all PPVs were <1%. CONCLUSION: Symptoms of oesophago-gastric cancer reported in secondary care were also important in primary care. The results should inform guidance and commissioning policy for upper GI endoscopy

rEHR: An R package for manipulating and analysing Electronic Health Record data

Research with structured Electronic Health Records (EHRs) is expanding as data becomes more accessible; analytic methods advance; and the scientific validity of such studies is increasingly accepted. However, data science methodology to enable the rapid searching/extraction, cleaning and analysis of these large, often complex, datasets is less well developed. In addition, commonly used software is inadequate, resulting in bottlenecks in research workflows and in obstacles to increased transparency and reproducibility of the research. Preparing a research-ready dataset from EHRs is a complex and time consuming task requiring substantial data science skills, even for simple designs. In addition, certain aspects of the workflow are computationally intensive, for example extraction of longitudinal data and matching controls to a large cohort, which may take days or even weeks to run using standard software. The rEHR package simplifies and accelerates the process of extracting ready-for-analysis datasets from EHR databases. It has a simple import function to a database backend that greatly accelerates data access times. A set of generic query functions allow users to extract data efficiently without needing detailed knowledge of SQL queries. Longitudinal data extractions can also be made in a single command, making use of parallel processing. The package also contains functions for cutting data by time-varying covariates, matching controls to cases, unit conversion and construction of clinical code lists. There are also functions to synthesise dummy EHR. The package has been tested with one for the largest primary care EHRs, the Clinical Practice Research Datalink (CPRD), but allows for a common interface to other EHRs. This simplified and accelerated work flow for EHR data extraction results in simpler, cleaner scripts that are more easily debugged, shared and reproduced

Acute maternal infection and risk of pre-eclampsia: a population-based case-control study.

BACKGROUND: Infection in pregnancy may be involved in the aetiology of pre-eclampsia. However, a clear association between acute maternal infection and pre-eclampsia has not been established. We assessed whether acute urinary tract infection, respiratory tract infection, and antibiotic drug prescriptions in pregnancy (a likely proxy for maternal infection) are associated with an increased risk of pre-eclampsia. METHODS AND FINDINGS: We used a matched nested case-control design and data from the UK General Practice Research Database to examine the association between maternal infection and pre-eclampsia. Primiparous women aged at least 13 years and registered with a participating practice between January 1987 and October 2007 were eligible for inclusion. We selected all cases of pre-eclampsia and a random sample of primiparous women without pre-eclampsia (controls). Cases (n=1533) were individually matched with up to ten controls (n=14236) on practice and year of delivery. We calculated odds ratios and 95% confidence intervals for pre-eclampsia comparing women exposed and unexposed to infection using multivariable conditional logistic regression. After adjusting for maternal age, pre-gestational hypertension, diabetes, renal disease and multifetal gestation, the odds of pre-eclampsia were increased in women prescribed antibiotic drugs (adjusted odds ratio 1.28;1.14-1.44) and in women with urinary tract infection (adjusted odds ratio 1.22;1.03-1.45). We found no association with maternal respiratory tract infection (adjusted odds ratio 0.91;0.72-1.16). Further adjustment for maternal smoking and pre-pregnancy body mass index made no difference to our findings. CONCLUSIONS: Women who acquire a urinary infection during pregnancy, but not those who have a respiratory infection, are at an increased risk of pre-eclampsia. Maternal antibiotic prescriptions are also associated with an increased risk. Further research is required to elucidate the underlying mechanism of this association and to determine whether, among women who acquire infections in pregnancy, prompt treatment or prophylaxis against infection might reduce the risk of pre-eclampsia

Ethnicity and the first diagnosis of a wide range of cardiovascular diseases: Associations in a linked electronic health record cohort of 1 million patients

Background: While the association of ethnic group with individual cardiovascular diseases has been studied, little is known about ethnic differences in the initial lifetime presentation of clinical cardiovascular disease in contemporary populations. Methods and results: We studied 1,068,318 people, aged ≥30 years and free from diagnosed CVD at baseline (90.9% White, 3.6% South Asian and 2.9% Black), using English linked electronic health records covering primary care, hospital admissions, acute coronary syndrome registry and mortality registry (CALIBER research platform). During 5.7 years median follow-up between 1997-2010, 95,224 people experienced an incident cardiovascular diagnosis. 80.2% (77.7% -82.5%) of initial presentation in South Asian <60 yrs were coronary heart disease presentations compared to 66.2% (65.7-66.7) in White and 56.7% (52.1%-61.2%) in Black patients. Compared to White patients, Black patients had significantly lower age-sex adjusted hazard ratios (HRs) for initial lifetime presentation of all the coronary disease diagnoses (stable angina HR 0.80 (95% CI 0.68-0.93); unstable angina – 0.75 (0.59-0.97); myocardial infarction 0.49 (0.40-0.62)) while South Asian patients had significantly higher HRs (stable angina – 1.67 (1.52-1.84); unstable angina 1.82 (1.56-2.13); myocardial infarction – 1.67 (1.49-1.87). We found no ethnic differences in initial presentation with heart failure (Black 0.97 (0.79-1.20); S Asian 1.04(0.87-1.26)). Compared to White patients, Black patients were more likely to present with ischaemic stroke (1.24 (0.97-1.58)) and intracerebral haemorrhage (1.44 (0.97-2.12)). Presentation with peripheral arterial disease was less likely for Black (0.63 (0.50-0.80)) and South Asian patients (0.70 (0.57-0.86)) compared with White patients. Discussion: While we found the anticipated substantial predominance of coronary heart disease presentations in South Asian and predominance of stroke presentations in Black patients, we found no ethnic differences in presentation with heart failure. We consider the public health and research implications of our findings