Emily Herrett

Validation and validity of diagnoses in the General Practice Research Database: a systematic review

AIMS To investigate the range of methods used to validate diagnoses in the General Practice Research Database (GPRD), to summarize findings and to assess the quality of these validations. METHODS A systematic literature review was performed by searching PubMed and Embase for publications using GPRD data published between 1987 and April 2008. Additional publications were identified from conference proceedings, back issues of relevant journals, bibliographies of retrieved publications and relevant websites. Publications that reported attempts to validate disease diagnoses recorded in the GPRD were included. RESULTS We identified 212 publications, often validating more than one diagnosis. In total, 357 validations investigating 183 different diagnoses met our inclusion criteria. Of these, 303 (85%) utilized data from outside the GPRD to validate diagnoses. The remainder utilized only data recorded in the database. The median proportion of cases with a confirmed diagnosis was 89% (range 24–100%). Details of validation methods and results were often incomplete. CONCLUSIONS A number of methods have been used to assess validity. Overall, estimates of validity were high. However, the quality of reporting of the validations was often inadequate to permit a clear interpretation. Not all methods provided a quantitative estimate of validity and most methods considered only the positive predictive value of a set of diagnostic codes in a highly selected group of cases. We make recommendations for methodology and reporting to strengthen further the use of the GPRD in research.

Data Resource Profile: Clinical Practice Research Datalink (CPRD)

The Clinical Practice Research Datalink (CPRD) is an ongoing primary care database of anonymised medical records from general practitioners, with coverage of over 11.3 million patients from 674 practices in the UK. With 4.4 million active (alive, currently registered) patients meeting quality criteria, approximately 6.9% of the UK population are included and patients are broadly representative of the UK general population in terms of age, sex and ethnicity. General practitioners are the gatekeepers of primary care and specialist referrals in the UK. The CPRD primary care database is therefore a rich source of health data for research, including data on demographics, symptoms, tests, diagnoses, therapies, health-related behaviours and referrals to secondary care. For over half of patients, linkage with datasets from secondary care, disease-specific cohorts and mortality records enhance the range of data available for research. The CPRD is very widely used internationally for epidemiological research and has been used to produce over 1000 research studies, published in peer-reviewed journals across a broad range of health outcomes. However, researchers must be aware of the complexity of routinely collected electronic health records, including ways to manage variable completeness, misclassification and development of disease definitions for research.

Effects of ambient temperature on the incidence of myocardial infarction

Context: While the effects of weather and, in particular, ambient temperature on overall mortality are well documented, the strength of the evidence base for the effects on acute myocardial infarction (MI) are less clear. Objective: To systematically review studies specifically focusing on the effects of temperature on MI. Data sources: Medline, Embase, and GeoBase publication databases, as well as reference lists, and the websites of a number of relevant public organisations. Study selection: Studies of original data in which ambient temperature was an exposure of interest and MI a specific outcome were selected. Data extraction: The reported effects of ambient temperature on the risk of MI, including effect sizes and confidence intervals, where possible, were recorded. Methodological details were also extracted, including study population, location and setting, ascertainment of MI events, adjustment for potential confounders and consideration of lagged effects. Results: 19 studies were identified, of which 14 considered the short-term effects of temperature on a daily timescale, the remainder looking at longer-term effects. Overall, 8 of the 12 studies which included relevant data from the winter season reported a statistically significant short-term increased risk of MI at lower temperatures, while increases in risk at higher temperatures were reported in 7 of the 13 studies with relevant data. A number of differences were identified between studies in the population included demographics, location, local climate, study design and statistical methodology. Conclusion: A number of studies, including some that were large and relatively well controlled, suggested that both hot and cold weather had detrimental effects on the short-term risk of MI. However, further research with consistent methodology is needed to clarify the magnitude of these effects and to show which populations and individuals are vulnerable.

Completeness and diagnostic validity of recording acute myocardial infarction events in primary care, hospital care, disease registry, and national mortality records: cohort study

Objective 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. Design Cohort study. Participants 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). Setting One country (England) with one health system (the National Health Service). Main outcome measures 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). Results 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%). Conclusion 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.

The Myocardial Ischaemia National Audit Project (MINAP)

Aims of MINAP To audit the quality of care of patients with acute coronary syndrome and provide a resource for academic research. Quality of care interventions Feedback to hospitals, ambulance services and cardiac networks regarding benchmarking of performance against national standards and targets. Setting All 230 acute hospitals in England and Wales. Years: 2000-present. Population Consecutive patients, unconsented. Current number of records: 735 000. Startpoints Any acute coronary syndrome, including non-ST-elevation myocardial infarction, ST-elevation myocardial infarction and unstable angina. Baseline data 123 fields covering demographic factors, co-morbid conditions and treatment in hospital. No blood resource. Data capture Manual entry by clerks, nurses or doctors onto Lotus Notes; non-financial incentives at hospital level. Data quality Hospitals perform an annual data validation study, where data are re-entered from the case notes in 20 randomly selected records that are held on the server. In 2008 data were >90% complete for 20 key fields, with >80% completeness for all but four of the remaining fields. Endpoints and linkages to other data All-cause mortality is obtained through linkage with Office for National Statistics. No other linkages exist at present. Access to data Available for research and audit by application to the MINAP Academic Group. http://www.rcplondon.ac.uk/CLINICAL-STANDARDS/ORGANISATION/PARTNERSHIP/Pages/MINAP-.aspx.

Short term effects of temperature on risk of myocardial infarction in England and Wales: time series regression analysis of the Myocardial Ischaemia National Audit Project (MINAP) registry

Objective To examine the short term relation between ambient temperature and risk of myocardial infarction. Design Daily time series regression analysis. Setting 15 conurbations in England and Wales. Participants 84 010 hospital admissions for myocardial infarction recorded in the Myocardial Ischaemia National Audit Project during 2003-6 (median 57 events a day). Main outcome measures Change in risk of myocardial infarction associated with a 1°C difference in temperature, including effects delayed by up to 28 days. Results Smoothed graphs revealed a broadly linear relation between temperature and myocardial infarction, which was well characterised by log-linear models without a temperature threshold: each 1°C reduction in daily mean temperature was associated with a 2.0% (95% confidence interval 1.1% to 2.9%) cumulative increase in risk of myocardial infarction over the current and following 28 days, the strongest effects being estimated at intermediate lags of 2-7 and 8-14 days: increase per 1°C reduction 0.6% (95% confidence interval 0.2% to 1.1%) and 0.7% (0.3% to 1.1%), respectively. Heat had no detrimental effect. Adults aged 75-84 and those with previous coronary heart disease seemed more vulnerable to the effects of cold than other age groups (P for interaction 0.001 or less in each case), whereas those taking aspirin were less vulnerable (P for interaction 0.007). Conclusions Increases in risk of myocardial infarction at colder ambient temperatures may be one driver of cold related increases in overall mortality, but an increased risk of myocardial infarction at higher temperatures was not detected. The risk of myocardial infarction in vulnerable people might be reduced by the provision of targeted advice or other interventions, triggered by forecasts of lower temperature.

Effects of air pollution on the incidence of myocardial infarction

Context: Short-term fluctuations in air pollution have been associated with changes in both overall and cardiovascular mortality. Objective: To consider the effects of air pollution on myocardial infarction (MI) risk by systematically reviewing studies looking at this specific outcome. Data sources: Medline, Embase and TOXNET publication databases, as well as reference lists and the websites of relevant public organisations. Study selection: Studies presenting original data with MI as a specific outcome and one or more of the following as an exposure of interest were included: particulate matter (PM), black carbon/black smoke, ozone, carbon monoxide, nitrogen oxides, sulphur dioxide and traffic exposure. Data extraction: The effects of each pollutant on risk of MI, including effect sizes and confidence intervals, were recorded where possible. Methodological details were also extracted including study population, location and setting, ascertainment of MI events, adjustment for potential confounders and consideration of lagged effects. Results: 26 studies were identified: 19 looked at the short-term effects of pollution on a daily timescale; the remaining 7 at longer-term effects. A proportion of studies reported statistically significant detrimental effects of PM with diameter <2.5 µm (3/5 studies, risk increase estimates ranging from 5 to 17% per 10 µg/m3 increase), PM <10 µm (3/10, 0.7–11% per 10 µg/m3), CO (6/14, 2–4% per ppm), SO2 (6/13, effect estimates on varied scales) and NO2 (6/13, 1–9% per 10 ppb). Increasing ozone levels were associated with a reduction in MI risk in 3/12 studies. A number of differences in location, population and demographics and study methodology between studies were identified that might have affected results. Conclusion: There is some evidence that short-term fluctuations in air pollution affect the risk of MI. However, further studies are needed to clarify the nature of these effects and identify vulnerable populations and individuals.

Data Resource Profile: Cardiovascular disease research using linked bespoke studies and electronic health records (CALIBER)

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 ∼105 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 s.denaxas@ucl.ac.uk

The effects of hourly differences in air pollution on the risk of myocardial infarction: case crossover analysis of the MINAP database

Objectives To investigate associations between air pollution levels and myocardial infarction (MI) on short timescales, with data at an hourly temporal resolution. Design Time stratified case crossover study linking clinical data from the Myocardial Ischaemia National Audit Project (MINAP) with PM10, ozone, CO, NO2, and SO2 data from the UK National Air Quality Archive. Pollution effects were investigated with delays (lags) of 1–6, 7–12, 13–18, 19–24, and 25–72 hours in both single and multi-pollutant models, adjusted for ambient temperature, relative humidity, circulating levels of influenza and respiratory syncytial virus, day of week, holidays, and residual seasonality within calendar month strata. Setting Population based study in 15 conurbations in England and Wales. Subjects 79 288 diagnoses of myocardial infarction recorded over the period 2003–6. Main outcome measures Excess risk of myocardial infarction per 10 µg/m3 increase in pollutant level. Results In single pollutant models, PM10 and NO2 levels were associated with a very short term increase in risk of myocardial infarction 1–6 hours later (excess risks 1.2% (95% confidence interval 0.3 to 2.1) and 1.1% (0.3 to 1.8) respectively per 10 μg/m3 increase); the effects persisted in multi-pollutant models, though with only weak evidence of an independent PM10 effect (P=0.05). The immediate risk increases were followed by reductions in risk at longer lags: we found no evidence of any net excess risk associated with the five pollutants studied over a 72 hour period after exposure. Conclusions Higher levels of PM10 and NO2, which are typically markers of traffic related pollution, seem to be associated with transiently increased risk of myocardial infarction 1–6 hours after exposure, but later reductions in risk suggest that air pollution may be associated with bringing events forward in time (“short-term displacement”) rather than increasing overall risk. The well established effect of air pollution on cardiorespiratory mortality may not be mediated through increasing the acute risk of myocardial infarction, but through another mechanism.

Effect of β blockers on mortality after myocardial infarction in adults with COPD: population based cohort study of UK electronic healthcare records

Objectives 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. Design Population based cohort study in England. Setting UK national registry of myocardial infarction (Myocardial Ischaemia National Audit Project (MINAP)) linked to the General Practice Research Database (GPRD), 2003-11. Participants 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. Main outcome measure 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. Results 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). Conclusions 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. Registration NCT01335672.