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1.  Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people 
The contemporary associations of type 2 diabetes with a wide range of incident cardiovascular diseases have not been compared. We aimed to study associations between type 2 diabetes and 12 initial manifestations of cardiovascular disease.
We used linked primary care, hospital admission, disease registry, and death certificate records from the CALIBER programme, which links data for people in England recorded in four electronic health data sources. We included people who were (or turned) 30 years or older between Jan 1, 1998, to March 25, 2010, who were free from cardiovascular disease at baseline. The primary endpoint was the first record of one of 12 cardiovascular presentations in any of the data sources. We compared cumulative incidence curves for the initial presentation of cardiovascular disease and used Cox models to estimate cause-specific hazard ratios (HRs). This study is registered at (NCT01804439).
Our cohort consisted of 1 921 260 individuals, of whom 1 887 062 (98·2%) did not have diabetes and 34 198 (1·8%) had type 2 diabetes. We observed 113 638 first presentations of cardiovascular disease during a median follow-up of 5·5 years (IQR 2·1–10·1). Of people with type 2 diabetes, 6137 (17·9%) had a first cardiovascular presentation, the most common of which were peripheral arterial disease (reported in 992 [16·2%] of 6137 patients) and heart failure (866 [14·1%] of 6137 patients). Type 2 diabetes was positively associated with peripheral arterial disease (adjusted HR 2·98 [95% CI 2·76–3·22]), ischaemic stroke (1·72 [1·52–1·95]), stable angina (1·62 [1·49–1·77]), heart failure (1·56 [1·45–1·69]), and non-fatal myocardial infarction (1·54 [1·42–1·67]), but was inversely associated with abdominal aortic aneurysm (0·46 [0·35–0·59]) and subarachnoid haemorrhage (0·48 [0·26–0.89]), and not associated with arrhythmia or sudden cardiac death (0·95 [0·76–1·19]).
Heart failure and peripheral arterial disease are the most common initial manifestations of cardiovascular disease in type 2 diabetes. The differences between relative risks of different cardiovascular diseases in patients with type 2 diabetes have implications for clinical risk assessment and trial design.
Wellcome Trust, National Institute for Health Research, and Medical Research Council.
PMCID: PMC4303913  PMID: 25466521
2.  Prediction of Cardiovascular Risk Using Framingham, ASSIGN and QRISK2: How Well Do They Predict Individual Rather than Population Risk? 
PLoS ONE  2014;9(10):e106455.
The objective of this study was to evaluate the performance of risk scores (Framingham, Assign and QRISK2) in predicting high cardiovascular disease (CVD) risk in individuals rather than populations.
Methods and findings
This study included 1.8 million persons without CVD and prior statin prescribing using the Clinical Practice Research Datalink. This contains electronic medical records of the general population registered with a UK general practice. Individual CVD risks were estimated using competing risk regression models. Individual differences in the 10-year CVD risks as predicted by risk scores and competing risk models were estimated; the population was divided into 20 subgroups based on predicted risk. CVD outcomes occurred in 69,870 persons. In the subgroup with lowest risks, risk predictions by QRISK2 were similar to individual risks predicted using our competing risk model (99.9% of people had differences of less than 2%); in the subgroup with highest risks, risk predictions varied greatly (only 13.3% of people had differences of less than 2%). Larger deviations between QRISK2 and our individual predicted risks occurred with calendar year, different ethnicities, diabetes mellitus and number of records for medical events in the electronic health records in the year before the index date. A QRISK2 estimate of low 10-year CVD risk (<15%) was confirmed by Framingham, ASSIGN and our individual predicted risks in 89.8% while an estimate of high 10-year CVD risk (≥20%) was confirmed in only 48.6% of people. The majority of cases occurred in people who had predicted 10-year CVD risk of less than 20%.
Application of existing CVD risk scores may result in considerable misclassification of high risk status. Current practice to use a constant threshold level for intervention for all patients, together with the use of different scoring methods, may inadvertently create an arbitrary classification of high CVD risk.
PMCID: PMC4182667  PMID: 25271417
3.  Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults 
Lancet  2014;384(9945):755-765.
High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers.
With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects.
5·24 million individuals were included; 166 955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m2 increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56–1·69; p<0·0001), gallbladder (1·31, 1·12–1·52; p<0·0001), kidney (1·25, 1·17–1·33; p<0·0001), cervix (1·10, 1·03–1·17; p=0·00035), thyroid (1·09, 1·00–1·19; p=0·0088), and leukaemia (1·09, 1·05–1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12–1·27), colon (1·10, 1·07–1·13), ovarian (1·09, 1.04–1.14), and postmenopausal breast cancers (1·05, 1·03–1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95–1·00; premenopausal breast cancer 0·89, 0·86–0·92) and in never-smokers (prostate 0·96, 0·93–0·99; premenopausal breast cancer 0·89, 0·85–0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93–1·05; oral cavity 1·07, 0·91–1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m2 population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI.
BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups.
National Institute for Health Research, Wellcome Trust, and Medical Research Council.
PMCID: PMC4151483  PMID: 25129328
4.  Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD) 
BMJ Open  2014;4(7):e005540.
The optimal method of identifying people with chronic obstructive pulmonary disease (COPD) from electronic primary care records is not known. We assessed the accuracy of different approaches using the Clinical Practice Research Datalink, a UK electronic health record database.
951 participants registered with a CPRD practice in the UK between 1 January 2004 and 31 December 2012. Individuals were selected for ≥1 of 8 algorithms to identify people with COPD. General practitioners were sent a brief questionnaire and additional evidence to support a COPD diagnosis was requested. All information received was reviewed independently by two respiratory physicians whose opinion was taken as the gold standard.
Primary outcome measure
The primary measure of accuracy was the positive predictive value (PPV), the proportion of people identified by each algorithm for whom COPD was confirmed.
951 questionnaires were sent and 738 (78%) returned. After quality control, 696 (73.2%) patients were included in the final analysis. All four algorithms including a specific COPD diagnostic code performed well. Using a diagnostic code alone, the PPV was 86.5% (77.5–92.3%) while requiring a diagnosis plus spirometry plus specific medication; the PPV was slightly higher at 89.4% (80.7–94.5%) but reduced case numbers by 10%. Algorithms without specific diagnostic codes had low PPVs (range 12.2–44.4%).
Patients with COPD can be accurately identified from UK primary care records using specific diagnostic codes. Requiring spirometry or COPD medications only marginally improved accuracy. The high accuracy applies since the introduction of an incentivised disease register for COPD as part of Quality and Outcomes Framework in 2004.
PMCID: PMC4120321  PMID: 25056980
5.  Association between clinical presentations before myocardial infarction and coronary mortality: a prospective population-based study using linked electronic records 
European Heart Journal  2014;35(35):2363-2371.
Ischaemia in different arterial territories before acute myocardial infarction (AMI) may influence post-AMI outcomes. No studies have evaluated prospectively collected information on ischaemia and its effect on short- and long-term coronary mortality. The objective of this study was to compare patients with and without prospectively measured ischaemic presentations before AMI in terms of infarct characteristics and coronary mortality.
Methods and results
As part of the CALIBER programme, we linked data from primary care, hospital admissions, the national acute coronary syndrome registry and cause-specific mortality to identify patients with first AMI (n = 16,439). We analysed time from AMI to coronary mortality (n = 5283 deaths) using Cox regression (median 2.6 years follow-up), comparing patients with and without recent ischaemic presentations. Patients with ischaemic presentations in the 90 days before AMI experienced lower coronary mortality in the first 7 days after AMI compared with those with no prior ischaemic presentations, after adjusting for age, sex, smoking, diabetes, blood pressure and cardiovascular medications [HR: 0.64 (95% CI: 0.57–0.73) P < 0.001], but subsequent mortality was higher [HR: 1.42 (1.13–1.77) P = 0.001]. Patients with ischaemic presentations closer in time to AMI had the lowest seven day mortality (P-trend = 0.001).
In the first large prospective study of ischaemic presentations prior to AMI, we have shown that those occurring closest to AMI are associated with lower short-term coronary mortality following AMI, which could represent a natural ischaemic preconditioning effect, observed in a clinical setting.
Clinical trials registration identifier NCT01604486.
PMCID: PMC4163194  PMID: 25038774
Myocardial infarction; Epidemiology; Ischaemia
6.  Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice pesearch datalink 
There is strong evidence of reductions in major vascular events from statins across all cardiovascular risk categories. However, trials of statin therapy have provided conflicting results regarding statin use and type 2 diabetes (T2DM). We aimed to assess the effect of statins on T2DM development.
We carried out a population-based cohort study using the Clinical Practice Research Datalink (CPRD), a database of computerized clinical records. Every patient aged 30–85 years old starting a statin between 1989 and 2009 was matched with up to five non-statin users. The observation period in CPRD ended in 31 December 2011. Cox proportional hazard regression was used to compare rates of T2DM between statin users and non-users, using propensity score method to adjust for systematic differences between groups.
The study basis comprised 2,016,094 individuals, including 430,890 people who received a statin, matched to 1,585,204 people not prescribed a statin. Mean follow-up time was 5.43 years for statin users and 3.89 years for nonusers. During follow-up 130,395 individuals developed T2DM. Statin use was associated with an increased risk of T2DM (HR 1.57; 95% CI 1.54-1.59), which increases with longer duration of use. The increased risk was smaller among people with hypertension or cardiovascular disease and was only apparent after 5 or more years treatment with statins in these groups. Conversely, age-specific risk ratios decreased in older people.
Statin use is associated with an increased risk of T2DM. Our results suggest that the relative risk is higher among people without diagnosed hypertension or cardiovascular disease. These findings should be considered in the context of the observational nature of the data which is prone to bias and unmeasured confounding.
PMCID: PMC4118294  PMID: 25022519
Statins; Type 2 diabetes; Cardiovascular; Safety; Observational
7.  First Trimester Exposure to Anxiolytic and Hypnotic Drugs and the Risks of Major Congenital Anomalies: A United Kingdom Population-Based Cohort Study 
PLoS ONE  2014;9(6):e100996.
Despite their widespread use the effects of taking benzodiazepines and non-benzodiazepine hypnotics during pregnancy on the risk of major congenital anomaly (MCA) are uncertain. The objectives were to estimate absolute and relative risks of MCAs in children exposed to specific anxiolytic and hypnotic drugs taken in the first trimester of pregnancy, compared with children of mothers with depression and/or anxiety but not treated with medication and children of mothers without diagnosed mental illness during pregnancy.
We identified singleton children born to women aged 15–45 years between 1990 and 2010 from a large United Kingdom primary care database. We calculated absolute risks of MCAs for children with first trimester exposures of different anxiolytic and hypnotic drugs and used logistic regression with a generalised estimating equation to compare risks adjusted for year of childbirth, maternal age, smoking, body mass index, and socioeconomic status.
Overall MCA prevalence was 2.7% in 1,159 children of mothers prescribed diazepam, 2.9% in 379 children with temazepam, 2.5% in 406 children with zopiclone, and 2.7% in 19,193 children whose mothers had diagnosed depression and/or anxiety but no first trimester drug exposures. When compared with 2.7% in 351,785 children with no diagnosed depression/anxiety nor medication use, the adjusted odds ratios were 1.02 (99% confidence interval 0.63–1.64) for diazepam, 1.07 (0.49–2.37) for temazepam, 0.96 (0.42–2.20) for zopiclone and 1.27 (0.43–3.75) for other anxiolytic/hypnotic drugs and 1.01 (0.90–1.14) for un-medicated depression/anxiety. Risks of system-specific MCAs were generally similar in children exposed and not exposed to such medications.
We found no evidence for an increase in MCAs in children exposed to benzodiazepines and non-benzodiazepine hypnotics in the first trimester of pregnancy. These findings suggest that prescription of these drugs during early pregnancy may be safe in terms of MCA risk, but findings from other studies are required before safety can be confirmed.
PMCID: PMC4071000  PMID: 24963627
8.  Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people 
Lancet  2014;383(9932):1899-1911.
The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared. In this study, we aimed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease.
We used linked electronic health records from 1997 to 2010 in the CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic health Records) programme to assemble a cohort of 1·25 million patients, 30 years of age or older and initially free from cardiovascular disease, a fifth of whom received blood pressure-lowering treatments. We studied the heterogeneity in the age-specific associations of clinically measured blood pressure with 12 acute and chronic cardiovascular diseases, and estimated the lifetime risks (up to 95 years of age) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30, 60, and 80 years. This study is registered at, number NCT01164371.
During 5·2 years median follow-up, we recorded 83 098 initial cardiovascular disease presentations. In each age group, the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90–114 mm Hg and diastolic blood pressure of 60–74 mm Hg, with no evidence of a J-shaped increased risk at lower blood pressures. The effect of high blood pressure varied by cardiovascular disease endpoint, from strongly positive to no effect. Associations with high systolic blood pressure were strongest for intracerebral haemorrhage (hazard ratio 1·44 [95% CI 1·32–1·58]), subarachnoid haemorrhage (1·43 [1·25–1·63]), and stable angina (1·41 [1·36–1·46]), and weakest for abdominal aortic aneurysm (1·08 [1·00–1·17]). Compared with diastolic blood pressure, raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease, whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure. Pulse pressure associations were inverse for abdominal aortic aneurysm (HR per 10 mm Hg 0·91 [95% CI 0·86–0·98]) and strongest for peripheral arterial disease (1·23 [1·20–1·27]). People with hypertension (blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3% (95% CI 62·9–63·8) compared with 46·1% (45·5–46·8) for those with normal blood pressure, and developed cardiovascular disease 5·0 years earlier (95% CI 4·8–5·2). Stable and unstable angina accounted for most (43%) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years, whereas heart failure and stable angina accounted for the largest proportion (19% each) of years of life lost from index age 80 years.
The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study. Despite modern treatments, the lifetime burden of hypertension is substantial. These findings emphasise the need for new blood pressure-lowering strategies, and will help to inform the design of randomised trials to assess them.
Medical Research Council, National Institute for Health Research, and Wellcome Trust.
PMCID: PMC4042017  PMID: 24881994
9.  Quantification of risk factors for herpes zoster: population based case-control study 
Objectives To quantify the effects of possible risk factors for herpes zoster at different ages.
Design Case-control study.
Setting UK Clinical Practice Research Datalink primary care data.
Participants 144 959 adults diagnosed with zoster between 2000 and 2011; 549 336 age, sex, and practice matched controls.
Main outcome measures Conditional logistic regression was used to generate adjusted odds ratios to estimate the strength of association of each potential risk factor with zoster and assess effect modification by age.
Results The median age of the cases and controls was 62 years. Factors associated with increased risk of zoster included rheumatoid arthritis (3111 (2.1%) v 8029 (1.5%); adjusted odds ratio 1.46, 99% confidence interval 1.38 to 1.55), inflammatory bowel disease (1851 (1.3%) v 5118 (0.9%); 1.36, 1.26 to 1.46), chronic obstructive pulmonary disease (6815 (4.7%) v 20 201 (3.7%); 1.32, 1.27 to 1.37), asthma (10 243 (7.1%) v 31 865 (5.8%); 1.21, 1.17 to 1.25), chronic kidney disease (8724 (6.0%) v 29 437 (5.4%); 1.14, 1.09 to 1.18), and depression (6830 (4.7%) v 22 052 (4.0%); 1.15, 1.10 to 1.20). Type 1, but not type 2, diabetes showed some association with zoster (adjusted odds ratio 1.27, 1.07 to 1.50). The relative effects of many assessed risk factors were larger in younger patients. Patients with severely immunosuppressive conditions were at greatest risk of zoster—for example, patients with lymphoma (adjusted odds ratio 3.90, 3.21 to 4.74) and myeloma (2.16, 1.84 to 2.53), who are not eligible for zoster vaccination.
Conclusions A range of conditions were associated with increased risk of zoster. In general, the increased risk was proportionally greater in younger age groups. Current vaccines are contraindicated in people at the greatest risk of zoster, highlighting the need for alternative risk reduction strategies in these groups.
PMCID: PMC4019782  PMID: 25134101
10.  Preparedness of Tanzanian health facilities for outpatient primary care of hypertension and diabetes: a cross-sectional survey 
The Lancet Global Health  2014;2(5):e285-e292.
Historically, health facilities in sub-Saharan Africa have mainly managed acute, infectious diseases. Few data exist for the preparedness of African health facilities to handle the growing epidemic of chronic, non-communicable diseases (NCDs). We assessed the burden of NCDs in health facilities in northwestern Tanzania and investigated the strengths of the health system and areas for improvement with regard to primary care management of selected NCDs.
Between November, 2012, and May, 2013, we undertook a cross-sectional survey of a representative sample of 24 public and not-for-profit health facilities in urban and rural Tanzania (four hospitals, eight health centres, and 12 dispensaries). We did structured interviews of facility managers, inspected resources, and administered self-completed questionnaires to 335 health-care workers. We focused on hypertension, diabetes, and HIV (for comparison). Our key study outcomes related to service provision, availability of guidelines and supplies, management and training systems, and preparedness of human resources.
Of adult outpatient visits to hospitals, 58% were for chronic diseases compared with 20% at health centres, and 13% at dispensaries. In many facilities, guidelines, diagnostic equipment, and first-line drug therapy for the primary care of NCDs were inadequate, and management, training, and reporting systems were weak. Services for HIV accounted for most chronic disease visits and seemed stronger than did services for NCDs. Ten (42%) facilities had guidelines for HIV whereas three (13%) facilities did for NCDs. 261 (78%) health workers showed fair knowledge of HIV, whereas 198 (59%) did for hypertension and 187 (56%) did for diabetes. Generally, health systems were weaker in lower-level facilities. Front-line health-care workers (such as non-medical-doctor clinicians and nurses) did not have knowledge and experience of NCDs. For example, only 74 (49%) of 150 nurses had at least fair knowledge of diabetes care compared with 85 (57%) of 150 for hyptertension and 119 (79%) of 150 for HIV, and only 31 (21%) of 150 had seen more than five patients with diabetes in the past 3 months compared with 50 (33%) of 150 for hypertension and 111 (74%) of 150 for HIV.
Most outpatient services for NCDs in Tanzania are provided at hospitals, despite present policies stating that health centres and dispensaries should provide such services. We identified crucial weaknesses (and strengths) in health systems that should be considered to improve primary care for NCDs in Africa and identified ways that HIV programmes could serve as a model and structural platform for these improvements.
UK Medical Research Council.
PMCID: PMC4013553  PMID: 24818084
11.  Text messaging reminders for influenza vaccine in primary care: protocol for a cluster randomised controlled trial (TXT4FLUJAB) 
BMJ Open  2014;4(5):e004633.
The UK government recommends that at least 75% of people aged under 64 with certain conditions receive an annual influenza vaccination. Primary care practices often fall short of this target and strategies to increase vaccine uptake are required. Text messaging reminders are already used in 30% of practices to remind patients about vaccination, but there has been no trial addressing their effectiveness in increasing influenza vaccine uptake in the UK.
The aims of the study are (1) to develop the methodology for conducting cluster randomised trials of text messaging interventions utilising routine electronic health records and (2) to assess the effectiveness of using a text messaging influenza vaccine reminder in achieving an increase in influenza vaccine uptake in patients aged 18–64 with chronic conditions, compared with standard care.
Methods and analysis
This cluster randomised trial will recruit general practices across three settings in English primary care (Clinical Practice Research Datalink, ResearchOne and London iPLATO text messaging software users) and randomise them to either standard care or a text messaging campaign to eligible patients. Flu vaccine uptake will be ascertained using routinely collected, anonymised electronic patient records. This protocol outlines the proposed study design and analysis methods.
Ethics and dissemination
This study will determine the effectiveness of text messaging vaccine reminders in primary care in increasing influenza vaccine uptake, and will strengthen the methodology for using electronic health records in cluster randomised trials of text messaging interventions. This trial was approved by the Surrey Borders Ethics Committee (13/LO/0872). The trial results will be disseminated at national conferences and published in a peer-reviewed medical journal. The results will also be distributed to the Primary Care Research Network and to all participating general practices.
Trial registration number
This study is registered at ISRCTN48840025, July 2013.
PMCID: PMC4025454  PMID: 24793252
Primary Care; Epidemiology; Preventive Medicine
12.  Burden of disease in adults admitted to hospital in a rural region of coastal Kenya: an analysis of data from linked clinical and demographic surveillance systems 
The Lancet Global Health  2014;2(4):e216-e224.
Estimates of the burden of disease in adults in sub-Saharan Africa largely rely on models of sparse data. We aimed to measure the burden of disease in adults living in a rural area of coastal Kenya with use of linked clinical and demographic surveillance data.
We used data from 18 712 adults admitted to Kilifi District Hospital (Kilifi, Kenya) between Jan 1, 2007, and Dec 31, 2012, linked to 790 635 person-years of observation within the Kilifi Health and Demographic Surveillance System, to establish the rates and major causes of admission to hospital. These data were also used to model disease-specific disability-adjusted life-years lost in the population. We used geographical mapping software to calculate admission rates stratified by distance from the hospital.
The main causes of admission to hospital in women living within 5 km of the hospital were infectious and parasitic diseases (303 per 100 000 person-years of observation), pregnancy-related disorders (239 per 100 000 person-years of observation), and circulatory illnesses (105 per 100 000 person-years of observation). Leading causes of hospital admission in men living within 5 km of the hospital were infectious and parasitic diseases (169 per 100 000 person-years of observation), injuries (135 per 100 000 person-years of observation), and digestive system disorders (112 per 100 000 person-years of observation). HIV-related diseases were the leading cause of disability-adjusted life-years lost (2050 per 100 000 person-years of observation), followed by non-communicable diseases (741 per 100 000 person-years of observation). For every 5 km increase in distance from the hospital, all-cause admission rates decreased by 11% (95% CI 7–14) in men and 20% (17–23) in women. The magnitude of this decline was highest for endocrine disorders in women (35%; 95% CI 22–46) and neoplasms in men (30%; 9–45).
Adults in rural Kenya face a combined burden of infectious diseases, pregnancy-related disorders, cardiovascular illnesses, and injuries. Disease burden estimates based on hospital data are affected by distance from the hospital, and the amount of underestimation of disease burden differs by both disease and sex.
The Wellcome Trust, GAVI Alliance.
PMCID: PMC3986034  PMID: 24782954
13.  What is the difference between missing completely at random and missing at random? 
The terminology describing missingness mechanisms is confusing. In particular the meaning of ‘missing at random’ is often misunderstood, leading researchers faced with missing data problems away from multiple imputation, a method with considerable advantages. The purpose of this article is to clarify how ‘missing at random’ differs from ‘missing completely at random’ via an imagined dialogue between a clinical researcher and statistician.
PMCID: PMC4121561  PMID: 24706730
missing data; missing at random; multiple imputation
14.  Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients 
European heart journal  2013;35(13):844-852.
The population with stable coronary artery disease (SCAD) is growing but validated models to guide their clinical management are lacking. We developed and validated prognostic models for all-cause mortality and non-fatal myocardial infarction (MI) or coronary death in SCAD.
Methods and results
Models were developed in a linked electronic health records cohort of 102 023 SCAD patients from the CALIBER programme, with mean follow-up of 4.4 (SD 2.8) years during which 20 817 deaths and 8856 coronary outcomes were observed. The Kaplan–Meier 5-year risk was 20.6% (95% CI, 20.3, 20.9) for mortality and 9.7% (95% CI, 9.4, 9.9) for non-fatal MI or coronary death. The predictors in the models were age, sex, CAD diagnosis, deprivation, smoking, hypertension, diabetes, lipids, heart failure, peripheral arterial disease, atrial fibrillation, stroke, chronic kidney disease, chronic pulmonary disease, liver disease, cancer, depression, anxiety, heart rate, creatinine, white cell count, and haemoglobin. The models had good calibration and discrimination in internal (external) validation with C-index 0.811 (0.735) for all-cause mortality and 0.778 (0.718) for non-fatal MI or coronary death. Using these models to identify patients at high risk (defined by guidelines as 3% annual mortality) and support a management decision associated with hazard ratio 0.8 could save an additional 13-16 life years or 15-18 coronary event-free years per 1000 patients screened, compared with models with just age, sex, and deprivation.
These validated prognostic models could be used in clinical practice to support risk stratification as recommended in clinical guidelines.
PMCID: PMC3971383  PMID: 24353280
Stable coronary artery disease; Stable angina; Prognosis; Myocardial infarction; Electronic health records; CALIBER
15.  Risk of Stroke Following Herpes Zoster: A Self-Controlled Case-Series Study 
Adults developing zoster are at increased risk of stroke for 6 months with a >3-fold increased risk following zoster ophthalmicus. Incidence ratios of stroke were lower among those receiving antiviral drugs compared with untreated individuals, suggesting a possible protective effect.
Background. Herpes zoster is common and vaccine preventable. Stroke risk may be increased following zoster, but evidence is sparse and could be explained by differences between people with and without zoster. Our objective was to determine if stroke risk is increased following zoster.
Methods. Within-person comparisons were undertaken using the self-controlled case-series method and data from the UK Clinical Practice Research Datalink (1987–2012). Participants had a first-ever diagnosis of zoster and stroke within the study period. Stroke incidence in periods following zoster was compared with incidence in other time periods. Age-adjusted incidence ratios (IRs) and 95% confidence intervals (CIs) were calculated.
Results. A total of 6584 individuals were included. Stroke rate was increased following zoster compared with the baseline unexposed period, then gradually reduced over 6 months: weeks 1–4 (age-adjusted IR, 1.63; 95% CI, 1.32–2.02), weeks 5–12 (IR, 1.42; 95% CI, 1.21–1.68), and weeks 13–26 (IR, 1.23; 95% CI, 1.07–1.42), with no increase thereafter. A stronger effect was observed for individuals with zoster ophthalmicus, rising to a >3-fold rate 5–12 weeks after zoster. Oral antivirals were given to 55% of individuals: IRs for stroke were lower among those receiving antivirals compared with those not treated, suggesting a protective effect.
Conclusions. We have established an increased stroke rate within 6 months following zoster. Findings have implications for zoster vaccination programs, which may reduce stroke risk following zoster. The low antiviral prescribing rate needs to be improved; our data suggest that antiviral therapy may lead to a reduced stroke risk following zoster.
PMCID: PMC4017889  PMID: 24700656
herpes zoster; stroke; self-controlled case-series study
16.  Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals 
Background At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.
Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT).
Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84–1.43) for ε2/ε2; 0.85 (95% CrI: 0.78–0.92) for ε2/ε3; 1.05 (95% CrI: 0.89–1.24) for ε2/ε4; 1.05 (95% CrI: 0.99–1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94–1.33) for ε4/ε4 using the ε3/ε3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10−152), apolipoprotein B (P-trend: 8.7 × 10−06) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10−26) and HDL-C (P-trend: 1.6 × 10−12). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.
Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
PMCID: PMC3619955  PMID: 23569189
Stroke; lipids; apolipoprotein E; cardiovascular disease; systematic review; meta-analysis; biomarkers
17.  Rationale and cross-sectional study design of the Research on Obesity and type 2 Diabetes among African Migrants: the RODAM study 
BMJ Open  2014;4(3):e004877.
Obesity and type 2 diabetes (T2D) are highly prevalent among African migrants compared with European descent populations. The underlying reasons still remain a puzzle. Gene–environmental interaction is now seen as a potential plausible factor contributing to the high prevalence of obesity and T2D, but has not yet been investigated. The overall aim of the Research on Obesity and Diabetes among African Migrants (RODAM) project is to understand the reasons for the high prevalence of obesity and T2D among sub-Saharan Africans in diaspora by (1) studying the complex interplay between environment (eg, lifestyle), healthcare, biochemical and (epi)genetic factors, and their relative contributions to the high prevalence of obesity and T2D; (2) to identify specific risk factors within these broad categories to guide intervention programmes and (3) to provide a basic knowledge for improving diagnosis and treatment.
Methods and analysis
RODAM is a multicentre cross-sectional study among homogenous sub-Saharan African participants (ie, Ghanaians) aged >25 years living in rural and urban Ghana, the Netherlands, Germany and the UK ( Standardised data on the main outcomes, genetic and non-genetic factors are collected in all locations. The aim is to recruit 6250 individuals comprising five subgroups of 1250 individuals from each site. In Ghana, Kumasi and Obuasi (urban stratum) and villages in the Ashanti region (rural stratum) are served as recruitment sites. In Europe, Ghanaian migrants are selected through the municipality or Ghanaian organisations registers.
Ethics and dissemination
Ethical approval has been obtained in all sites. This paper gives an overview of the rationale, conceptual framework and methods of the study. The differences across locations will allow us to gain insight into genetic and non-genetic factors contributing to the occurrence of obesity and T2D and will inform targeted intervention and prevention programmes, and provide the basis for improving diagnosis and treatment in these populations and beyond.
PMCID: PMC3963103  PMID: 24657884
18.  Association of HIV and ART with cardiometabolic traits in sub-Saharan Africa: a systematic review and meta-analysis 
Background Sub-Saharan Africa (SSA) has the highest burden of HIV in the world and a rising prevalence of cardiometabolic disease; however, the interrelationship between HIV, antiretroviral therapy (ART) and cardiometabolic traits is not well described in SSA populations.
Methods We conducted a systematic review and meta-analysis through MEDLINE and EMBASE (up to January 2012), as well as direct author contact. Eligible studies provided summary or individual-level data on one or more of the following traits in HIV+ and HIV-, or ART+ and ART- subgroups in SSA: body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TGs) and fasting blood glucose (FBG) or glycated hemoglobin (HbA1c). Information was synthesized under a random-effects model and the primary outcomes were the standardized mean differences (SMD) of the specified traits between subgroups of participants.
Results Data were obtained from 49 published and 3 unpublished studies which reported on 29 755 individuals. HIV infection was associated with higher TGs [SMD, 0.26; 95% confidence interval (CI), 0.08 to 0.44] and lower HDL (SMD, −0.59; 95% CI, −0.86 to −0.31), BMI (SMD, −0.32; 95% CI, −0.45 to −0.18), SBP (SMD, −0.40; 95% CI, −0.55 to −0.25) and DBP (SMD, −0.34; 95% CI, −0.51 to −0.17). Among HIV+ individuals, ART use was associated with higher LDL (SMD, 0.43; 95% CI, 0.14 to 0.72) and HDL (SMD, 0.39; 95% CI, 0.11 to 0.66), and lower HbA1c (SMD, −0.34; 95% CI, −0.62 to −0.06). Fully adjusted estimates from analyses of individual participant data were consistent with meta-analysis of summary estimates for most traits.
Conclusions Broadly consistent with results from populations of European descent, these results suggest differences in cardiometabolic traits between HIV-infected and uninfected individuals in SSA, which might be modified by ART use. In a region with the highest burden of HIV, it will be important to clarify these findings to reliably assess the need for monitoring and managing cardiometabolic risk in HIV-infected populations in SSA.
PMCID: PMC3887568  PMID: 24415610
HIV; ART; cardiometabolic disease; sub-Saharan Africa
19.  Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients 
European Heart Journal  2013;35(13):844-852.
The population with stable coronary artery disease (SCAD) is growing but validated models to guide their clinical management are lacking. We developed and validated prognostic models for all-cause mortality and non-fatal myocardial infarction (MI) or coronary death in SCAD.
Methods and results
Models were developed in a linked electronic health records cohort of 102 023 SCAD patients from the CALIBER programme, with mean follow-up of 4.4 (SD 2.8) years during which 20 817 deaths and 8856 coronary outcomes were observed. The Kaplan–Meier 5-year risk was 20.6% (95% CI, 20.3, 20.9) for mortality and 9.7% (95% CI, 9.4, 9.9) for non-fatal MI or coronary death. The predictors in the models were age, sex, CAD diagnosis, deprivation, smoking, hypertension, diabetes, lipids, heart failure, peripheral arterial disease, atrial fibrillation, stroke, chronic kidney disease, chronic pulmonary disease, liver disease, cancer, depression, anxiety, heart rate, creatinine, white cell count, and haemoglobin. The models had good calibration and discrimination in internal (external) validation with C-index 0.811 (0.735) for all-cause mortality and 0.778 (0.718) for non-fatal MI or coronary death. Using these models to identify patients at high risk (defined by guidelines as 3% annual mortality) and support a management decision associated with hazard ratio 0.8 could save an additional 13–16 life years or 15–18 coronary event-free years per 1000 patients screened, compared with models with just age, sex, and deprivation.
These validated prognostic models could be used in clinical practice to support risk stratification as recommended in clinical guidelines.
PMCID: PMC3971383  PMID: 24353280
Stable coronary artery disease; Stable angina; Prognosis; Myocardial infarction; Electronic health records; CALIBER
20.  Completeness and usability of ethnicity data in UK-based primary care and hospital databases 
Ethnicity recording across the National Health Service (NHS) has improved dramatically over the past decade. This study profiles the completeness, consistency and representativeness of routinely collected ethnicity data in both primary care and hospital settings.
Completeness and consistency of ethnicity recording was examined in the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES), and the ethnic breakdown of the CPRD was compared with that of the 2011 UK censuses.
27.1% of all patients in the CPRD (1990–2012) have ethnicity recorded. This proportion rises to 78.3% for patients registered since April 2006. The ethnic breakdown of the CPRD is comparable to the UK censuses. 79.4% of HES inpatients, 46.8% of outpatients and 26.8% of A&E patients had their ethnicity recorded. Amongst those with ethnicity recorded on >1 occasion, consistency was over 90% in all data sets except for HES inpatients. Combining CPRD and HES increased completeness to 97%, with 85% of patients having the same ethnicity recorded in both databases.
Using CPRD ethnicity from 2006 onwards maximizes completeness and comparability with the UK population. High concordance within and across NHS sources suggests these data are of high value when examining the continuum of care. Poor completeness and consistency of A&E and outpatient data render these sources unreliable.
PMCID: PMC4245896  PMID: 24323951
epidemiology; ethnicity; methods
21.  Prescription of antiviral therapy after herpes zoster in general practice: who receives therapy? 
The British Journal of General Practice  2012;62(605):e808-e814.
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.
Design and setting
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.
PMCID: PMC3505413  PMID: 23211260
antivirals; database; epidemiology; general practice; GPRD; herpes zoster; shingles; United Kingdom
22.  Chickenpox and Risk of Stroke: A Self-controlled Case Series Analysis 
Children who experience chickenpox are at a 4-fold increased risk of ischemic stroke in the subsequent 6 months. The evidence is less strong for adults, possibly due to mechanistic differences in the role of inflammation in adult stroke risk.
Background. There is good evidence that respiratory and other infections that cause systemic inflammation can trigger strokes; however, the role of specific infections is unclear. Case reports have highlighted chickenpox as a possible risk factor for arterial ischemic stroke, particularly in children, but rigorous studies are needed to determine and quantify any increased risk.
Methods. We used anonymized electronic health records totaling >100 million person-years of observation from 4 UK primary care databases to identify individuals who had documented clinical chickenpox and a stroke or transient ischemic attack (TIA). Self-controlled case series methods were used to quantify any increased risk of first stroke or TIA in the 0–6 and 7–12 months following chickenpox compared to other observed time periods. We analyzed data within each database, and performed meta-analyses to obtain summary age-adjusted incidence ratios (IRs) separately for adults and children.
Results. Five hundred sixty eligible individuals (including 60 children) were identified who experienced chickenpox and a stroke or TIA during follow-up. Among children, there was a 4-fold increased risk of stroke in the 0–6 months after chickenpox (summary IR = 4.07; 95% confidence interval [CI], 1.96–8.45; I2 = 0%). Among adults, there was a less marked increased risk with moderate between-database heterogeneity (random-effects summary IR = 2.13; 95% CI, 1.05–4.36; I2 = 51%). There was no significant increased risk of stroke in the 7–12 months after chickenpox in children or adults, nor was there evidence of increased risk of TIA in either time period.
Conclusions. Our study provides new evidence that children who experience chickenpox are at increased risk of stroke in the subsequent 6 months.
PMCID: PMC3864501  PMID: 24092802
chickenpox; stroke; child; adult; risk factors
23.  Representativeness and optimal use of body mass index (BMI) in the UK Clinical Practice Research Datalink (CPRD) 
BMJ Open  2013;3(9):e003389.
To assess the completeness and representativeness of body mass index (BMI) data in the Clinical Practice Research Datalink (CPRD), and determine an optimal strategy for their use.
Descriptive study.
Electronic healthcare records from primary care.
A million patient random sample from the UK CPRD primary care database, aged ≥16 years.
Primary and secondary outcome measures
BMI completeness in CPRD was evaluated by age, sex and calendar period. CPRD-based summary BMI statistics for each calendar year (2003–2010) were age-standardised and sex-standardised and compared with equivalent statistics from the Health Survey for England (HSE).
BMI completeness increased over calendar time from 37% in 1990–1994 to 77% in 2005–2011, was higher among females and increased with age. When BMI at specific time points was assigned based on the most recent record, calendar–year-specific mean BMI statistics underestimated equivalent HSE statistics by 0.75–1.1 kg/m2. Restriction to those with a recent (≤3 years) BMI resulted in mean BMI estimates closer to HSE (≤0.28 kg/m2 underestimation), but excluded up to 47% of patients. An alternative strategy of imputing up-to-date BMI based on modelled changes in BMI over time since the last available record also led to mean BMI estimates that were close to HSE (≤0.37 kg/m2 underestimation).
Completeness of BMI in CPRD increased over time and varied by age and sex. At a given point in time, a large proportion of the most recent BMIs are unlikely to reflect current BMI; consequent BMI misclassification might be reduced by employing model-based imputation of current BMI.
PMCID: PMC3773634  PMID: 24038008
Epidemiology; Primary Care; Statistics & Research Methods
24.  Incidence of Community-Acquired Lower Respiratory Tract Infections and Pneumonia among Older Adults in the United Kingdom: A Population-Based Study 
PLoS ONE  2013;8(9):e75131.
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.
PMCID: PMC3770598  PMID: 24040394
25.  Acute Maternal Infection and Risk of Pre-Eclampsia: A Population-Based Case-Control Study 
PLoS ONE  2013;8(9):e73047.
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.
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.
PMCID: PMC3760871  PMID: 24019891

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