[show abstract][hide abstract] ABSTRACT: Serious adverse drug reactions are an important cause of hospitalisation and can result in the withdrawal of licensed drugs. Genetic variation has been shown to influence adverse drug reaction susceptibility, and predictive genetic tests have been developed for a limited number of adverse drug reactions. The identification of people with adverse drug reactions, obtaining samples for genetic analysis and rigorous evaluation of clinical test effectiveness represent significant challenges to predictive genetic test development. Using the example of serious drug-induced liver injury, we illustrate how a database of routinely collected electronic health records could be used to overcome these barriers by (1) facilitating rapid recruitment to genome-wide association studies and (2) supporting efficient randomized controlled trials of predictive genetic test effectiveness.
Drug discovery today 11/2013; · 6.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: Aims: It is widely thought that ST-elevation myocardial infarction (STEMI) is more likely to occur without warning (i.e. an unanticipated event in a previously healthy person) than non-ST-elevation myocardial infarction (NSTEMI), but no large study has evaluated this using prospectively collected data. The aim of this study was to compare the evolution of atherosclerotic disease and cardiovascular risk between people going on to experience STEMI and NSTEMI.
European Heart Journal: Acute Cardiovascular Care. 09/2013; 2(3):235-245.
[show abstract][hide abstract] ABSTRACT: It is widely thought that ST-elevation myocardial infarction (STEMI) is more likely to occur without warning (i.e. an unanticipated event in a previously healthy person) than non-ST-elevation myocardial infarction (NSTEMI), but no large study has evaluated this using prospectively collected data. The aim of this study was to compare the evolution of atherosclerotic disease and cardiovascular risk between people going on to experience STEMI and NSTEMI.
We identified patients experiencing STEMI and NSTEMI in the national registry of myocardial infarction for England and Wales (Myocardial Ischaemia National Audit Project), for whom linked primary care records were available in the General Practice Research Database (as part of the CALIBER collaboration). We compared the prevalence and timing of atherosclerotic disease and major cardiovascular risk factors including smoking, hypertension, diabetes, and dyslipidaemia, between patients later experiencing STEMI to those experiencing NSTEMI.
A total of 8174 myocardial infarction patients were included (3780 STEMI, 4394 NSTEMI). Myocardial infarction without heralding by previously diagnosed atherosclerotic disease occurred in 71% STEMI (95% CI 69-72%) and 50% NSTEMI patients (95% CI 48-51%). The proportions of myocardial infarctions with no prior atherosclerotic disease, major risk factors, or chest pain was 14% (95% CI 13-16%) in STEMI and 9% (95% CI 9-10%) in NSTEMI. The rate of heralding coronary diagnoses was particularly high in the 12 months before infarct; 4.1-times higher (95% CI 3.3-5.0) in STEMI and 3.6-times higher (95% CI 3.1-4.2) in NSTEMI compared to the rate in earlier years.
Acute myocardial infarction occurring without prior diagnosed coronary, cerebrovascular, or peripheral arterial disease was common, especially for STEMI. However, there was a high prevalence of risk factors or symptoms in patients without previously diagnosed disease. Better understanding of the antecedents in the year before myocardial infarction is required.
European heart journal. Acute cardiovascular care. 09/2013; 2(3):235-45.
[show abstract][hide abstract] ABSTRACT: Time series regression studies have been widely used in environmental epidemiology, notably in investigating the short-term associations between exposures such as air pollution, weather variables or pollen, and health outcomes such as mortality, myocardial infarction or disease-specific hospital admissions. Typically, for both exposure and outcome, data are available at regular time intervals (e.g. daily pollution levels and daily mortality counts) and the aim is to explore short-term associations between them. In this article, we describe the general features of time series data, and we outline the analysis process, beginning with descriptive analysis, then focusing on issues in time series regression that differ from other regression methods: modelling short-term fluctuations in the presence of seasonal and long-term patterns, dealing with time varying confounding factors and modelling delayed ('lagged') associations between exposure and outcome. We finish with advice on model checking and sensitivity analysis, and some common extensions to the basic model.
International Journal of Epidemiology 06/2013; · 6.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To evaluate targeting of statin prescribing for primary prevention to those with high cardiovascular disease (CVD) risk. DESIGN: Two cohort studies including the general population and initiators of statins aged 35-74 years. SETTING: UK primary care records in the Clinical Practice Research Datalink. PATIENTS: 3.8 million general population patients and 300 914 statin users. INTERVENTION: Statin prescribing. MAIN OUTCOME MEASURES: Statin prescribing by CVD risk; observed 5-year CVD risks; variability between practices. RESULTS: Statin prescribing increased substantially over time to patients with high 10-year CVD risk (≥20%): 7.0% of these received a statin prior to 2007, and 30.4% in 2007 onwards. Prescribing to patients with low risk (<15%) also increased (from 1.9% to 5.0%). Only about half the patients initiating statin treatment were high risk according to CVD risk score. The 5-year CVD risks, as observed during statin treatment, reduced over calendar time (from 17.0% to 7.1%). There was a large variation between general practices in the percentage of high-risk patients prescribed a statin in 2007 onwards, ranging from 8.2% to 61.5%. For low-risk patients, these varied from 2.1% to 29.1%. CONCLUSIONS: There appeared to be substantive overuse in low CVD risk and underuse in high CVD risk (600 000 and 850 000 patients, respectively, in the UK since 2007). There is wide variation between practices in statin prescribing to patients at high CVD risk. There is a clear need for randomised trials for the best strategy to target statin treatment and manage CVD risk for primary prevention.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE:: To determine the awareness, treatment, and control of hypertension and diabetes by migration status. DESIGN:: Cross-sectional study, secondary analyses of the PERU MIGRANT study. PATIENTS:: Rural, rural-to-urban migrants, and urban participants. MAIN OUTCOME MEASURES:: Awareness, treatment, and control of hypertension and diabetes mellitus were calculated using weights to account for participant's group size. RESULTS:: Of 205 of the 987 (weighted prevalence 24.1%, 95% confidence interval: 21.1%-27.1%) participants identified as hypertensive, 48.3% were aware of their diagnosis, 40% of them were receiving treatment, and 30.4% of those receiving treatment were controlled. Diabetes was present in 33 of the 987 (weighted prevalence 4.6%, 95% confidence interval: 3.1%-6%), and diabetes awareness, treatment, and control were 71.1%, 40.6%, and 7.7%, respectively. Suboptimal control rates, defined as those not meeting blood pressure or glycaemia targets among those with the condition, were 95.1% for hypertension and 97% for diabetes. Higher awareness, treatment, and control rates, for both hypertension and diabetes, were observed in rural-to-urban migrants and urban participants compared with rural participants. However, treatment rates were much lower among migrants compared with the urban group. CONCLUSIONS:: These results identify major unmet needs in awareness, treatment, and control of hypertension and diabetes. Particular challenges are lack of awareness of both hypertension and diabetes in rural areas, and poor levels of treatment and control among people who have migrated from rural into urban areas.
Critical pathways in cardiology 06/2013; 12(2):53-58.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: The role of antibiotics in treating mild or moderate exacerbations in patients with acute chronic obstructive pulmonary disease (COPD) is unclear. The aims were to: (i) describe patient characteristics associated with acute exacerbations amongst a representative COPD population, (ii) explore the relationship between COPD severity and outcomes amongst patients with exacerbations, and (iii) quantify variability by general practice in prescribing of antibiotics for COPD exacerbations. METHOD: A cohort of 62,747 patients with COPD was identified from primary care general practices (GP) in England, and linked to hospital admission and death certificate data. Exacerbation cases were matched to three controls and characteristics compared using conditional logistic regression. Outcomes were compared using incidence rates and Cox regression, stratified by disease severity. Variability of prescribing at the GP level was evaluated graphically and by using multilevel models. RESULTS: COPD severity was found to be associated with exacerbation and subsequent mortality (very severe vs. mild, odds ratio for exacerbation 2.12 [95%CI 19.5--2.32]), hazard ratio for mortality 2.14 [95%CI 1.59--2.88]). Whilst 61% of exacerbation cases were prescribed antibiotics, this proportion varied considerably between GP practices (interquartile range, 48--73%). This variation is greater than can be explained by patient characteristics alone. CONCLUSIONS: There is significant variability between GP practices in the prescribing of antibiotics to COPD patients experiencing exacerbations. Combined with a lack of evidence on the effects of treatment, this supports the need and opportunity for a large scale pragmatic randomised trial of the prescribing of antibiotics for COPD patients with exacerbations, in order to clarify their effectiveness and long term outcomes whilst ensuring the representativeness of subjects.
BMC Pulmonary Medicine 05/2013; 13(1):32. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Herpes zoster is common and has serious consequences, notably post-herpetic neuralgia (PHN). Vaccine efficacy against incident zoster and PHN has been demonstrated in clinical trials, but effectiveness has not been studied in unselected general populations unrestricted by region, full health insurance coverage, or immune status. Our objective was to assess zoster vaccine effectiveness (VE) against incident zoster and PHN in a general population-based setting.
A cohort study of 766,330 fully eligible individuals aged ≥65 years was undertaken in a 5% random sample of Medicare who received and did not receive zoster vaccination between 1st January 2007 and 31st December 2009. Incidence rates and hazard ratios for zoster and PHN were determined in vaccinated and unvaccinated individuals. Analyses were adjusted for age, gender, race, low income, immunosuppression, and important comorbidities associated with zoster, and then stratified by immunosuppression status. Adjusted hazard ratios were estimated using time-updated Cox proportional hazards models. Vaccine uptake was low (3.9%) particularly among black people (0.3%) and those with evidence of low income (0.6%). 13,112 US Medicare beneficiaries developed incident zoster; the overall zoster incidence rate was 10.0 (9.8-10.2) per 1,000 person-years in the unvaccinated group and 5.4 (95% CI 4.6-6.4) per 1,000 person-years in vaccinees, giving an adjusted VE against incident zoster of 0.48 (95% CI 0.39-0.56). In immunosuppressed individuals, VE against zoster was 0.37 (95% CI 0.06-0.58). VE against PHN was 0.59 (95% CI 0.21-0.79).
Vaccine uptake was low with variation in specific patient groups. In a general population cohort of older individuals, zoster vaccination was associated with reduction in incident zoster, including among those with immunosuppression. Importantly, this study demonstrates that zoster vaccination is associated with a reduction in PHN. Please see later in the article for the Editors' Summary.
PLoS Medicine 04/2013; 10(4):e1001420. · 15.25 Impact Factor
[show abstract][hide abstract] ABSTRACT: Shah Ebrahim and colleagues argue that more research on non-communicable diseases (NCDs) in both high-income countries and low- and middle-income countries can result in mutual benefits and will help better address the growing burden of NCDs.
PLoS Medicine 01/2013; 10(1):e1001377. · 15.25 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate recent respiratory and influenza-like illnesses (ILIs) in acute myocardial infarction patients compared with patients hospitalised for acute non-vascular surgical conditions during the second wave of the 2009 influenza A H1N1 pandemic.
Coronary care unit, acute cardiology and acute surgical admission wards in a major teaching hospital in London, UK.
134 participants (70 cases and 64 controls) aged ≥40 years hospitalised for acute myocardial infarction and acute surgical conditions between 21 September 2009 and 28 February 2010, frequency-matched for gender, 5-year age-band and admission week. PRIMARY EXPOSURE: ILI (defined as feeling feverish with either a cough or sore throat) within the last month. SECONDARY EXPOSURES: Acute respiratory illness within the last month not meeting ILI criteria; nasopharyngeal and throat swab positive for influenza virus.
29 of 134 (21.6%) participants reported respiratory illness within the last month, of whom 13 (9.7%) had illnesses meeting ILI criteria. The most frequently reported category for timing of respiratory symptom onset was 8-14 days before admission (31% of illnesses). Cases were more likely than controls to report ILI-adjusted OR 3.17 (95% CI 0.61 to 16.47)-as well as other key respiratory symptoms, and were less likely to have received influenza vaccination-adjusted OR 0.46 (95% CI 0.19 to 1.12)-although the differences were not statistically significant. No swabs were positive for influenza virus.
Point estimates suggested that recent ILI was more common in patients hospitalised with acute myocardial infarction than with acute surgical conditions during the second wave of the influenza A H1N1 pandemic, and influenza vaccination was associated with cardioprotection, although the findings were not statistically significant. The study was underpowered, partly because the age groups typically affected by acute myocardial infarction had low rates of infection with the pandemic influenza strain compared with seasonal influenza.
[show abstract][hide abstract] ABSTRACT: Community-acquired lower respiratory tract infections (LRTI) and pneumonia (CAP) are common causes of morbidity and mortality among those aged ≥65 years; a growing population in many countries. Detailed incidence estimates for these infections among older adults in the United Kingdom (UK) are lacking. We used electronic general practice records from the Clinical Practice Research Data link, linked to Hospital Episode Statistics inpatient data, to estimate incidence of community-acquired LRTI and CAP among UK older adults between April 1997-March 2011, by age, sex, region and deprivation quintile. Levels of antibiotic prescribing were also assessed. LRTI incidence increased with fluctuations over time, was higher in men than women aged ≥70 and increased with age from 92.21 episodes/1000 person-years (65-69 years) to 187.91/1000 (85-89 years). CAP incidence increased more markedly with age, from 2.81 to 21.81 episodes/1000 person-years respectively, and was higher among men. For both infection groups, increases over time were attenuated after age-standardisation, indicating that these rises were largely due to population aging. Rates among those in the most deprived quintile were around 70% higher than the least deprived and were generally higher in the North of England. GP antibiotic prescribing rates were high for LRTI but lower for CAP (mostly due to immediate hospitalisation). This is the first study to provide long-term detailed incidence estimates of community-acquired LRTI and CAP in UK older individuals, taking person-time at risk into account. The summary incidence commonly presented for the ≥65 age group considerably underestimates LRTI/CAP rates, particularly among older individuals within this group. Our methodology and findings are likely to be highly relevant to health planners and researchers in other countries with aging populations.
PLoS ONE 01/2013; 8(9):e75131. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate whether the use and timing of prescription of β blockers in patients with chronic obstructive pulmonary disease (COPD) having a first myocardial infarction was associated with survival and to identify factors related to their use.
Population based cohort study in England.
UK national registry of myocardial infarction (Myocardial Ischaemia National Audit Project (MINAP)) linked to the General Practice Research Database (GPRD), 2003-11.
Patients with COPD with a first myocardial infarction in 1 January 2003 to 31 December 2008 as recorded in MINAP, who had no previous evidence of myocardial infarction in their GPRD or MINAP record. Data were provided by the Cardiovascular Disease Research using Linked Bespoke studies and Electronic Health Records (CALIBER) group at University College London.
Cox proportional hazards ratio for mortality after myocardial infarction in patients with COPD in those prescribed β blockers or not, corrected for covariates including age, sex, smoking status, drugs, comorbidities, type of myocardial infarction, and severity of infarct.
Among 1063 patients with COPD, treatment with β blockers started during the hospital admission for myocardial infarction was associated with substantial survival benefits (fully adjusted hazard ratio 0.50, 95% confidence interval 0.36 to 0.69; P<0.001; median follow-up time 2.9 years). Patients already taking a β blocker before their myocardial infarction also had a survival benefit (0.59, 0.44 to 0.79; P<0.001). Similar results were obtained with propensity scores as an alternative method to adjust for differences between those prescribed and not prescribed β blockers. With follow-up started from date of discharge from hospital, the effect size was slightly attenuated but there was a similar protective effect of treatment with β blockers started during hospital admission for myocardial infarction (0.64, 0.44 to 0.94; P=0.02).
The use of β blockers started either at the time of hospital admission for myocardial infarction or before a myocardial infarction is associated with improved survival after myocardial infarction in patients with COPD.
[show abstract][hide abstract] ABSTRACT: To determine the completeness and diagnostic validity of myocardial infarction recording across four national health record sources in primary care, hospital care, a disease registry, and mortality register.
21 482 patients with acute myocardial infarction in England between January 2003 and March 2009, identified in four prospectively collected, linked electronic health record sources: Clinical Practice Research Datalink (primary care data), Hospital Episode Statistics (hospital admissions), the disease registry MINAP (Myocardial Ischaemia National Audit Project), and the Office for National Statistics mortality register (cause specific mortality data).
One country (England) with one health system (the National Health Service).
Recording of acute myocardial infarction, incidence, all cause mortality within one year of acute myocardial infarction, and diagnostic validity of acute myocardial infarction compared with electrocardiographic and troponin findings in the disease registry (gold standard).
Risk factors and non-cardiovascular coexisting conditions were similar across patients identified in primary care, hospital admission, and registry sources. Immediate all cause mortality was highest among patients with acute myocardial infarction recorded in primary care, which (unlike hospital admission and disease registry sources) included patients who did not reach hospital, but at one year mortality rates in cohorts from each source were similar. 5561 (31.0%) patients with non-fatal acute myocardial infarction were recorded in all three sources and 11 482 (63.9%) in at least two sources. The crude incidence of acute myocardial infarction was underestimated by 25-50% using one source compared with using all three sources. Compared with acute myocardial infarction defined in the disease registry, the positive predictive value of acute myocardial infarction recorded in primary care was 92.2% (95% confidence interval 91.6% to 92.8%) and in hospital admissions was 91.5% (90.8% to 92.1%).
Each data source missed a substantial proportion (25-50%) of myocardial infarction events. Failure to use linked electronic health records from primary care, hospital care, disease registry, and death certificates may lead to biased estimates of the incidence and outcome of myocardial infarction. TRIAL REGISTRATION : NCT01569139 clinicaltrials.gov.
[show abstract][hide abstract] ABSTRACT: To measure the association between orlistat and acute liver injury.
Self controlled case series study.
Population based primary care setting, United Kingdom.
94 695 patients receiving orlistat and registered in the UK Clinical Practice Research Datalink and linked with Hospital Episode Statistics data between 1999 and 2011.
Relative incidence of acute liver injury comparing periods when patients were receiving orlistat with periods of non-usage.
Among 94 695 patients who received orlistat, 988 cases of acute liver injury were identified, with 335 confirmed as definite cases and 653 as probable cases. For all cases an increased incidence of liver injury was detected during the 90 day period before orlistat was first started, with an incidence rate ratio of 1.50 (95% confidence interval 1.10 to 2.06). The incidence remained raised during the first 30 days of treatment (2.21, 1.43 to 3.42), before returning to baseline levels with prolonged treatment. When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of liver injury was not increased (1.02, 0.67 to 1.56). An analysis restricted to definite cases showed no evidence of an increased risk of liver injury during treatment.
The incidence of acute liver injury was higher in the periods both immediately before and immediately after the start of orlistat treatment. This suggests that the observed increased risks of liver injury linked to the start of treatment may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug.
[show abstract][hide abstract] ABSTRACT: The goal of cardiovascular disease (CVD) research using linked bespoke studies and electronic health records (CALIBER) is to provide evidence to inform health care and public health policy for CVDs across different stages of translation, from discovery, through evaluation in trials to implementation, where linkages to electronic health records provide new scientific opportunities. The initial approach of the CALIBER programme is characterized as follows: (i) Linkages of multiple electronic heath record sources: examples include linkages between the longitudinal primary care data from the Clinical Practice Research Datalink, the national registry of acute coronary syndromes (Myocardial Ischaemia National Audit Project), hospitalization and procedure data from Hospital Episode Statistics and cause-specific mortality and social deprivation data from the Office of National Statistics. Current cohort analyses involve a million people in initially healthy populations and disease registries with ∼10(5) patients. (ii) Linkages of bespoke investigator-led cohort studies (e.g. UK Biobank) to registry data (e.g. Myocardial Ischaemia National Audit Project), providing new means of ascertaining, validating and phenotyping disease. (iii) A common data model in which routine electronic health record data are made research ready, and sharable, by defining and curating with meta-data >300 variables (categorical, continuous, event) on risk factors, CVDs and non-cardiovascular comorbidities. (iv) Transparency: all CALIBER studies have an analytic protocol registered in the public domain, and data are available (safe haven model) for use subject to approvals. For more information, e-mail firstname.lastname@example.org.
International Journal of Epidemiology 12/2012; · 6.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Antivirals can accelerate rash healing during an acute zoster episode and can limit the severity and duration of pain. Their use within 7 days of rash onset is recommended among specific patient groups.
To describe antiviral prescription patterns and patient characteristics associated with antiviral receipt after zoster diagnosis.
Descriptive study and risk factor analysis using electronic healthcare records from UK general practice.
Incident adult zoster cases occurring between 2000 and 2011 were identified in the General Practice Research Database. Therapy records were searched for antiviral prescriptions of aciclovir, famciclovir, or valaciclovir within 7 days of zoster diagnosis. The proportion of incident zoster cases receiving antivirals was calculated and multivariable logistic regression used to assess associations between patient characteristics and antiviral use.
Of 142 216 incident zoster cases 58.1% received an antiviral prescription. The majority (69.0%) were aciclovir. The proportion receiving antiviral prescriptions increased with age up to 65 years, then declined to 56.8% among patients aged ≥85 years. Being female and of higher socioeconomic status were associated with higher antiviral receipt. Antivirals were more commonly prescribed to immunosuppressed patients with herpes zoster (odds ratio 1.27; 95% CI = 1.22 to 1.33), however they were not given routinely to this patient group.
Antiviral therapies for zoster are under-prescribed in UK general practice even among groups, such as immunosuppressed and older individuals, for whom guidelines recommend treatment. Patients may present too late to receive treatment or physicians may decide that antivirals are not essential treatment. Consideration could be given to reviewing the guidelines.
British Journal of General Practice 12/2012; 62(605):808-14. · 1.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Purpose: Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2) and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case control studies of late stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and over in India. Methods: Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of 4 mutually exclusive stages based on the worse affected eye (0=no AMD, 1-3=early AMD, 4=late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex and study centre. Results: Of 3569 participants, 53.2% had no signs of AMD, 45.6% had features of early AMD, and 1.2% had late AMD. CFH (rs1061170), C2 (rs547154) or CFB (rs438999) were not associated with early or late AMD. In the ARMS2 locus, rs10490924 was associated with both early (adjusted RR 1.22, 95%CI: 1.13-1.33, p<0.0001) and late AMD (adjusted RR 1.81, 95%CI: 1.15-2.86; p=0.01), );whilst rs2672598 was associated only with early AMD (adjusted RR 1.12, 95%CI: 1.02-1.23; p=0.02); . rs10490923 was not associated with early or late AMD. Conclusions: Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India.