Clinical Practice Research Datalink Data Research Articles

Inflammatory marker testing in primary care in the year before Hodgkin lymphoma diagnosis: a UK population-based case-control study in patients aged ≤50 years.

BackgroundProinflammatory conditions are associated with increased risk of Hodgkin lymphoma, although the neoplastic process per se often induces an inflammatory response.AimTo examine pre-diagnostic inflammatory marker test use to identify changes that may define a ‘diagnostic window’ for potential earlier diagnosis.Design and settingThis was a matched case–control study in UK primary care using Clinical Practice Research Datalink data (2002–2016).MethodPrimary care inflammatory marker test use and related findings were analysed in 839 Hodgkin lymphoma patients and 5035 controls in the year pre-diagnosis. Poisson regression models were used to calculate monthly testing rates to examine changes over time in test use. Longitudinal trends in test results and the presence/absence of ‘red-flag’ symptoms were examined.ResultsIn patients with Hodgkin lymphoma, 70.8% (594/839) had an inflammatory marker test in the year pre-diagnosis versus 16.2% (816/5035) of controls (odds ratio 13.7, 95% CI = 11.4 to 16.5, P<0.001). The rate of inflammatory marker testing and mean levels of certain inflammatory marker results increased progressively during the year pre-diagnosis in Hodgkin lymphoma patients while remaining stable in controls. Among patients with Hodgkin lymphoma with a pre-diagnostic test, two-thirds (69.5%, 413/594) had an abnormal result and, among these, 42.6% (176/413) had no other ‘red-flag’ presenting symptom/sign.ConclusionIncreases in inflammatory marker requests and abnormal results occur in many patients with Hodgkin lymphoma several months pre-diagnosis, suggesting this period should be excluded in aetiological studies examining inflammation in Hodgkin lymphoma development, and that a diagnostic time window of appreciable length exists in many patients with Hodgkin lymphoma, many of whom have no other red-flag features.

Are major lower extremity amputations well recorded in primary care electronic health records?: Insights from primary care electronic health records in England.

Major lower extremity amputations (MLEAs) are understood to be well recorded in secondary care in England in the Hospital Episode Statistics (HES) database. It is unclear how well MLEAs are recorded in primary care databases. This study compared MLEA event case ascertainment in Clinical Practice Research Datalink (CPRD) to that in HES. MLEA events were ascertained in CPRD and in HES linkage between 1 January 2010 and 31 December 2019. The number of MLEA events and the number of patients with at least one MLEA in each database were recorded and compared. Individual events were matched between the databases using varying date-matching windows. Reasons for differences in case ascertainment were explored. In total 23262 patients had at least one MLEA record, 8716 (37.5%) had an MLEA record in HES only, 5393 (23.2%) in CPRD only and 9153 (39.4%) in both. Out of a total of 75221 events, 13071 (62.4%) were recorded in HES only and 44151 (81.3%) in CPRD only. 7874 (37.6%) of HES events were recorded in CPRD and 10125 (18.6%) of CPRD events were recorded in HES when using the maximum date matching window of 28 days plus the time between admission and procedure. The main reasons for differences in case ascertainment included, re-recordings and miscoding in CPRD.Compared to HES, MLEAs are poorly recorded in CPRD predominantly due to re-recordings of events and miscoding procedures. CPRD data cannot solely be relied upon to ascertain cases of MLEA; however, HES linkage to CPRD may be useful to obtain medical history of diagnoses, medication and diagnostic tests.

Risk of hospitalization and death associated with sodium glucose cotransporter-2 inhibitors: A comparison with five other classes of antidiabetic drugs

AimWe assessed the risk of all-cause hospitalization and all-cause death associated with the use of Sodium Glucose Cotransporter-2 inhibitors (SGLT2i). MethodsPopulation-based propensity scores-matched cohort study of new users of metformin who subsequently initiated SGLT2i compared to those who initiated dipeptidyl peptidase-4 inhibitors (DPP4i) (primary comparison), sulfonylureas, thiazolidinediones, GLP1-Receptors agonists, and insulin, respectively. Alberta (Canada) health administrative data and United Kingdom Clinical Practice Research Datalink (CPRD) data were used to assess the study outcomes. Conditional Cox regressions were performed to assess the risk of each outcome, separately for each dataset and then results were combined using random-effects meta-analysis. ResultsFor SGLT2i versus DPP4i, 7531 and 1647 SGLT2i-DPP4i matched pairs were analyzed in Alberta and CPRD data respectively. The mean age of patients was 56 and 57 years, and 39% and 43% were females, respectively in Alberta and CPRD cohorts. Compared with DPP-4-i, SGLT2i use was associated with a significant lower risk of all-cause hospitalization (combined hazard ratio (HR): 0.84, 95% confidence interval (95%CI): 0.75–0.95), and all-cause death (0.56, 0.38–0.83). SGLT2i use was also associated with a significant lower risk of all-cause hospitalization and all-cause death when compared to sulfonylureas (HRs: 0.80, 95%CI: 0.71–0.90 and 0.56, 95%CI: 0.38–0.82, respectively) and insulin (HRs: 0.55, 95%CI: 0.41–0.74, and 0.33, 95%CI: 0.24–0.46, respectively). ConclusionsSGLT2i initiation was associated with a decreased risk of all-cause hospitalization and all-cause death when compared to DPP4i, sulfonylureas, and insulin.

Medications for chronic obstructive pulmonary disease: a historical non-interventional cohort study with validation against RCT results.

Chronic obstructive pulmonary disease treatment is informed by randomised controlled trial results, but it is unclear if these findings apply to people excluded from these trials. We used data from the TORCH (TOwards a Revolution in COPD Health) randomised controlled trial to validate non-interventional methods for assessing the clinical effectiveness of chronic obstructive pulmonary disease treatment in the UK Clinical Practice Research Datalink, before applying these methods to the analysis of people who would have been excluded from TORCH. To validate the use of non-interventional Clinical Practice Research Datalink data and methods for estimating chronic obstructive pulmonary disease treatment effects against trial results, and, using validated methods, to determine treatment effects in people who would have been excluded from the TORCH trial. A historical non-interventional cohort design, including validation against randomised controlled trial results. The UK Clinical Practice Research Datalink. People aged ≥ 18 years with chronic obstructive pulmonary disease registered in Clinical Practice Research Datalink GOLD between January 2000 and January 2017. For objective 1, we prepared a cohort that was analogous to the TORCH trial cohort by applying TORCH trial inclusion/exclusion criteria followed by individual matching to TORCH trial participants. For objectives 2 and 3, we prepared cohorts that were analogous to the TORCH trial that, nevertheless, would not have been eligible for the TORCH trial because of age, asthma, comorbidity or mild disease. The long-acting beta-2 agonist and inhaled corticosteroid combination product Seretide (GlaxoSmithKline plc) [i.e. fluticasone propionate plus salmeterol (FP-SAL)] compared with (1) no FP-SAL exposure or (2) exposure to salmeterol (i.e. the long-acting beta-2 agonist) only. Exacerbations, mortality, pneumonia and time to treatment change. For objective 1, the exacerbation rate ratio was comparable to that in the TORCH trial for FP-SAL compared with salmeterol (0.85, 95% confidence interval 0.74 to 0.97, vs. TORCH trial 0.88, 95% confidence interval 0.81 to 0.95), but not for FP-SAL compared with no FP-SAL (1.30, 95% confidence interval 1.19 to 1.42, vs. TORCH trial 0.75, 95% confidence interval 0.69 to 0.81). Active comparator results were also consistent with the TORCH trial for mortality (hazard ratio 0.93, 95% confidence interval 0.65 to 1.32, vs. TORCH trial hazard ratio 0.93, 95% confidence interval 0.77 to 1.13) and pneumonia (risk ratio 1.39, 95% confidence interval 1.04 to 1.87, vs. TORCH trial risk ratio 1.47, 95% confidence interval 1.25 to 1.73). For objectives 2 and 3, active comparator results were consistent with the TORCH trial for exacerbations, with the exception of people with milder chronic obstructive pulmonary disease, in whom we observed a stronger protective association (risk ratio 0.56, 95% confidence interval 0.46 to 0.70, vs. TORCH trial risk ratio 0.85, 95% confidence interval 0.74 to 0.97). For the analysis of mortality, we saw a lack of association with being prescribed FP-SAL (vs. being prescribed salmeterol), with the exception of those with prior asthma, for whom we observed an increase in mortality (hazard ratio 1.49, 95% confidence interval 1.21 to 1.85, vs. TORCH trial-analogous HR 0.93, 95% confidence interval 0.64 to 1.32). Routinely collected electronic health record data can be used to successfully measure chronic obstructive pulmonary disease treatment effects when comparing two treatments, but not for comparisons between active treatment and no treatment. Analyses involving patients who would have been excluded from trials mostly suggests that treatment effects for FP-SAL are similar to trial effects, although further work is needed to characterise a small increased risk of death in those with concomitant asthma. Some of our analyses had small numbers. The differences in treatment effects that we found should be investigated further in other data sets. Currently recommended chronic obstructive pulmonary disease inhaled combination therapy (other than FP-SAL) should also be investigated using these methods. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 51. See the NIHR Journals Library website for further project information.

Prevalence, healthcare resource utilization and mortality of Lennox-Gastaut syndrome: retrospective linkage cohort study

PurposeTo retrospectively investigate the prevalence, demography, antiseizure medication (ASM) usage, healthcare resource utilization (HCRU), and mortality of patients with Lennox-Gastaut syndrome (LGS) in primary and secondary care in the UK. MethodsPatients with confirmed LGS were anonymously identified from the UK Clinical Practice Research Datalink (CPRD) GOLD database (01/01/1987–31/1b0/2018) using the LGS Read Code (F250500). Probable LGS was identified using the International Classification of Diseases-10/Read Code for epilepsy (Hospital Episode Statistics [HES]/CPRD) plus rufinamide prescription. Period prevalence was calculated based on patients enrolled in CPRD GOLD and alive in 2017. CPRD data were linked to HES to calculate HCRU, and to the Office for National Statistics mortality registry. ResultsPeriod prevalence of LGS was 0.578/10,000 (n = 180), with 74 and 106 patients identified with confirmed (0.289/10,000) and probable LGS (0.420/10,000). Mean (max) ASM usage was ~1 (3) per year. In confirmed LGS, valproate (72%), lamotrigine (69%), and clobazam (66%) were the most commonly prescribed ASMs. HCRU (per patient-year) was similar in confirmed and probable LGS and mostly consisted of primary care general practitioner consultations (4–6), outpatient visits (5–10), inpatient admissions (1–4), and A&E visits (1). During the follow-up period, 18 patients died with crude mortality rates of 6.12 (confirmed LGS) and 4.17 (probable LGS) deaths per 1000 person-years. ConclusionPrevalence of LGS appears low in the UK. The similarly high HCRU and mortality rates in confirmed and probable LGS support the validity and specificity of the probable LGS algorithm and high burden of LGS.

Feasibility of using Clinical Practice Research Datalink data to identify patients with chronic obstructive pulmonary disease to enrol into real-world trials.

PurposeTo assess the feasibility of using Clinical Practice Research Datalink (CPRD) data for identifying populations of patients with chronic obstructive pulmonary disease (COPD) eligible for a hypothetical pragmatic trial.MethodsA retrospective multidatabase cohort study using CPRD primary care and linked secondary care data to describe the characteristics of populations of patients with COPD. Patients' demographic and lifestyle factors, comorbidity profile, spirometry measurements and treatment changes were evaluated, as was the distribution of follow‐up time and types of losses during follow‐up. Characteristics were evaluated using descriptive statistics.ResultsA total of 322 991 patients from 1148 primary care practices in the United Kingdom across two CPRD primary care databases, CPRD GOLD and CPRD Aurum, were potentially eligible to participate in a hypothetical trial using CPRD, starting on 31 December 2017. Patients with COPD in CPRD GOLD and CPRD Aurum were comparable in terms of age (median age 70 vs. 68 years), gender (50% vs. 52% male), disease severity (e.g., 25% vs. 24% Medical Research Council [MRC] dyspnoea score grades 3–5) and history of respiratory conditions (e.g., 43% vs. 38% asthma). High proportions of patients with COPD in CPRD GOLD and CPRD Aurum were available on 31 December 2012 for follow‐up at 1, 2, and 5 years (92%, 85% and 67%, respectively).ConclusionsPatients and data from CPRD GOLD and CPRD Aurum were comparable across key aspects relevant to COPD trials. A pragmatic trial using CPRD to recruit patients with COPD is scientifically feasible.

Concordance in the recording of stroke across UK primary and secondary care datasets: a population-based cohort study.

BackgroundPrevious work has demonstrated that the recording of acute health outcomes, such as myocardial infarction (MI), may be suboptimal in primary healthcare databases.AimTo assess the completeness and accuracy of the recording of stroke in UK primary care.Design & settingA population-based longitudinal cohort study.MethodCases of stroke were identified separately in Clinical Practice Research Datalink (CPRD) primary care records and linked Hospital Episode Statistics (HES). The recording of events in the same patient across the two datasets was compared. The reliability of strategies to identify fatal strokes in primary care and hospital records was also assessed.ResultsOf the 75 674 stroke events that were identified in either CPRD or HES data during the period of the study, 54 929 (72.6%) were recorded in CPRD and 51 013 (67.4%) were recorded in HES. Two-fifths (n = 30 268) of all recorded strokes were found in both datasets (allowing for a time window of 120 days). Among these 'matched' strokes the subtype was recorded accurately in approximately 75% of CPRD records (compared with coding in HES); however, 43.5% of ischaemic strokes in HES were coded as 'non-specific' strokes in CPRD data. Furthermore, 48.2% had same-day recordings, and 56.2% were date-matched within ±1 day.ConclusionThe completeness and accuracy of stroke recording is improved by the use of linked hospital and primary care records. For studies that have a time-sensitive research question, the use of linked, as opposed to stand-alone, CPRD data is strongly recommended.

Association of non-malignant diseases with thrombocytosis: a prospective cohort study in general practice.

BackgroundThrombocytosis is an excess of platelets, which is diagnosed as a platelet count >400 × 109/l. An association of thrombocytosis with undiagnosed cancer has recently been established, but the association with non-malignant disease has not been studied in primary care.AimTo examine, in English primary care, the 1-year incidence of non-malignant diseases in patients with new thrombocytosis and the incidence of pre-existing non-malignant diseases in patients who develop new thrombocytosis.Design and settingProspective cohort study using English Clinical Practice Research Datalink data from 2000 to 2013.MethodNewly incident and pre-existing rates of non-malignant diseases associated with thrombocytosis were compared between patients with thrombocytosis and age- and sex-matched patients with a normal platelet count. Fifteen candidate non-malignant diseases were identified from literature searches.ResultsIn the thrombocytosis cohort of 39 850 patients, 4579 (11.5%) were newly diagnosed with any one of the candidate diseases, compared with 443 out of 9684 patients (4.6%) in the normal platelet count cohort (relative risk [RR] 2.5, 95% confidence intervals [CI] = 2.3 to 2.8); iron-deficiency anaemia was the most common new diagnosis (4.5% of patients with thrombocytosis, RR 4.9, 95% CI = 4.0 to 6.1). A total of 22 612 (57.0%) patients with thrombocytosis had a pre-existing non-malignant diagnosis compared with 4846 patients (50%) in the normal platelet count cohort (odds ratio 1.3, 95% CI = 1.2 to 1.4). There was no statistically significant difference in cancer diagnoses between patients with and without pre-existing disease in the thrombocytosis cohort.ConclusionThrombocytosis is associated with several non-malignant diseases. Clinicians can use these findings as part of their holistic diagnostic approach to help guide further investigations and management of patients with thrombocytosis.

Characteristics, service use, and mortality of clusters of multimorbid patients in England: a population-based study

BackgroundMultimorbidity is a major challenge facing health systems. To help understand the changes to services and policies that are required, we investigated which diseases co-occur and which combinations lead to the highest mortality and service use. MethodsFor this population-based study, we used linked primary and secondary care electronic health records contributed by general practices in England to the Clinical Practice Research Datalink (CPRD). The study includes all multimorbid adults (aged ≥18 years) with two or more predefined long-term health conditions. For the primary objective, latent class analysis, stratified by age groups, was used to identify multimorbidity clusters using a random set of 80% of the multimorbid patients, with consistency of results checked in the remaining 20%. Associations between multimorbidity clusters, demographics and primary outcomes (hospitalisation, polypharmacy and mortality) were quantified using generalised linear models as the secondary objective. This study was approved by the CPRD Independent Scientific Advisory Committee and is covered by their ethical approval. FindingsWe included all adult patients with multimorbidity (n=113 211) from a random sample of the CPRD data (n=391 669). Physical–mental health co-morbidity and respiratory disease and multimorbidity clusters were common across all age strata. In people younger than 65 years, the substance misuse and mental illness co-morbidity cluster (<7% prevalence; consisted mostly of male, current smokers and patients from deprived areas) had the highest demographic-adjusted 5-year mortality rate (in the age 45–64 years strata, the adjusted odds ratio was 1·08 [95% CI 1·07–1·10]) despite low health service use. Cardiovascular-related clusters were prevalent in people aged 65 years or older, in whom the cluster chronic pain, cardiovascular disease, and mental illness (age 65–84 years strata) had the highest number of primary care consultations in 1 year (median 23 [IQR 14–35]) and 5-year mortality (39%). In the 85 years and older age strata, patients in the low service use multimorbidity cluster had the lowest number of morbidities (median 3 [2–4]), service use, and mortality. Across identification and validation data, results showed consistency between obtained disease profiles, similar classification quality, and similar relationships between patient clusters, demographic characteristics, and primary outcomes. InterpretationInterventions and policies to improve the care of patients with multimorbidity might be more effective when targeted at the distinct clusters of multimorbidity that we have highlighted. Results may be further strengthened by validation in external databases. FundingMRC Career Development Award (MR/P021573/1).

Encounters for foot and ankle pain in UK primary care: a population-based cohort study of CPRD data.

BackgroundOlder patients who have foot pain report variation in access to services to manage their foot health. To plan services it is essential to understand the scale and burden of foot pain that exists for GPs.AimTo provide UK-wide population-level data of the frequency of foot and/or ankle pain encounters recorded in general practice.Design and settingPopulation-based cohort design study using data drawn from the UK Clinical Practice Research Datalink (CPRD) from January 2010 to December 2013.MethodAll CPRD data were collected prospectively by participating GPs. The primary outcome was prevalence of GP encounters for foot and/or ankle pain, stratified by age, sex, and different subgroups of causes.ResultsA foot and/or ankle pain encounter was recorded for 346 067 patients, and there was a total of 567 095 recorded encounters (mean per person 1.6, standard deviation [SD] 1.3). The prevalence of recorded encounters of foot and/or ankle pain was 2980 per 100 000 (3%). The number of patients with a recorded encounter of foot and/or ankle pain was 1820 per 100 000 (1.8%). Foot and/or ankle pain encounters were reported across all age groups (54.4% females), with those aged 71–80 years placing the greatest burden on GPs. The most common specified referrals were to orthopaedics (n = 36 881) and physiotherapy (n = 33 987), followed by podiatry (n = 25 980).ConclusionThe burden of foot and/or ankle pain encounters recorded by GPs is not insubstantial, and spans all ages, with a high proportion of referrals to orthopaedics. The authors recommend further exploration of ‘first-contact practitioners’ for foot and/or ankle pain in general practice to alleviate the burden on GPs.

Treatment of first-time traumatic anterior shoulder dislocation: the UK TASH-D cohort study.

Shoulder dislocations are the most common joint dislocations seen in emergency departments. Most traumatic cases are anterior and cause recurrent dislocations. Management options include surgical and conservative treatments. There is a lack of evidence about which method is most effective after the first traumatic anterior shoulder dislocation (TASD). To produce UK age- and sex-specific incidence rates for TASD. To assess whether or not surgery within 6 months of a first-time TASD decreases re-dislocation rates compared with no surgery. To identify clinical predictors of recurrent dislocation. A population-based cohort study of first-time TASD patients in the UK. An initial validation study and subsequent propensity-score-matched analysis to compare re-dislocation rates between surgery and no surgery after a first-time TASD. Prediction modelling was used to identify potential predictors of recurrent dislocation. UK primary and secondary care data. Patients with a first-time TASD between 1997 and 2015. Stabilisation surgery within 6 months of a first-time TASD (compared with no surgery). Stabilisation surgery within 12 months of a first-time TASD was also carried out as a sensitivity analysis. Re-dislocation rate up to 2 years after the first TASD. Eligible patients were identified from the Clinical Practice Research Datalink (CPRD) (1997-2015). Accuracy of shoulder dislocation coding was internally validated using the CPRD General Practitioner questionnaire service. UK age- and sex-specific incidence rates for TASD were externally validated against rates from the USA and Canada. A propensity-score-matched analysis using linked CPRD and Hospital Episode Statistics (HES) data compared re-dislocation rates for patients aged 16-35 years, comparing surgery with no surgery. Multivariable Cox regression models for predicting re-dislocation were developed for the surgical and non-surgical cohorts. Shoulder dislocation was coded correctly for 89% of cases in the CPRD [95% confidence interval (CI) 83% to 95%], with a 'primary' dislocation confirmed for 76% of cases (95% CI 67% to 85%). Far fewer patients than expected received stabilisation surgery within 6 months of a first TASD, leading to an underpowered study. Around 20% of re-dislocation rates were observed for both surgical and non-surgical patients. The sensitivity analysis at 12 months also showed little difference in re-dislocation rates. Missing data on risk factors limited the value of the prediction modelling; however, younger age, epilepsy and sex (male) were identified as statistically significant predictors of re-dislocation. Far fewer than the expected number of patients had surgery after a first-time TASD, resulting in an underpowered study. This and residual confounding from missing risk factors mean that it is not possible to draw valid conclusions. This study provides, for the first time, UK data on the age- and sex-specific incidence rates for TASD. Most TASD occurs in men, but an unexpected increased incidence was observed in women aged > 50 years. Surgery after a first-time TASD is uncommon in the NHS. Re-dislocation rates for patients receiving surgery after their first TASD are higher than previously expected; however, important residual confounding risk factors were not recorded in NHS primary and secondary care databases, thus preventing useful recommendations. The high incidence of TASD justifies investigation into preventative measures for young men participating in contact sports, as well as investigating the risk factors in women aged > 50 years. A randomised controlled trial would account for key confounders missing from CPRD and HES data. A national TASD registry would allow for a more relevant data capture for this patient group. Independent Scientific Advisory Committee (ISAC) for the Medicines and Healthcare Products Regulatory Agency (ISAC protocol 15_0260). The National Institute for Health Research Health Technology Assessment programme.

The accuracy of date of death recording in the Clinical Practice Research Datalink GOLD database in England compared with the Office for National Statistics death registrations.

PurposeIt is not clear whether all deaths are recorded in the Clinical Practice Research Datalink (CPRD) or how accurate a recorded date of death is. Individual‐level linkage with national data from the Office for National Statistics (ONS) and Hospital Episode Statistics (HES) in England offers the opportunity to compare death information across different data sources.MethodsAge‐standardised mortality rates (ASMRs) standardised to the European Standard Population (ESP) 2013 for CPRD were compared with figures published by the ONS, and crude mortality rates were calculated for a sample population with individual linkage between CPRD, ONS, and HES data. Agreement on the fact of death between CPRD and ONS was assessed and presented over time from 1998 to 2013.ResultsThere were 33 997 patients with a record of death in the ONS data; 33 389 (98.2%) of these were also identified in CPRD. Exact agreement on the death date between CPRD and the ONS was 69.7% across the whole study period, increasing from 53.4% in 1998 to 78.0% in 2013. By 2013, 98.8% of deaths were in agreement within ±30 days.ConclusionsFor censoring follow‐up and calculating mortality rates, CPRD data are likely to be sufficient, as a delay in death recording of up to 1 month is unlikely to impact results significantly. Where the exact date of death or the cause is important, it may be advisable to include the individually linked death registration data from the ONS.

How Clinical Practice Research Datalink data are used to support pharmacovigilance.

Pharmacovigilance can be defined as the science of monitoring medicines and vaccines after license for use, the purpose of which is to quantify and characterise the safety profile of a medicine, identify previously unknown adverse reactions, inform risk-benefit assessment, and support the development of actions that can be taken to reduce risks, optimise benefits and monitor their effectiveness. This review discusses the Clinical Practice Research Datalink (CPRD), which is the source of the largest research database in the UK with longitudinal, representative primary care data linked to data from other healthcare settings. CPRD supports international pharmacovigilance by providing a large, anonymised representative general population database with comprehensive capture of patient risk factors and outcomes to researchers within academic, regulatory and pharmaceutical organisations. The specific advantages of CPRD data are discussed in the context of the ‘six Vs of big data’ including volume, velocity, variety, veracity, validity and value. Examples of where CPRD data have been used for pharmacovigilance research and how these have fed into guidelines and policy are discussed.

Doubly robust estimation of the weighted average treatment effect for a target population.

The weighted average treatment effect is a causal measure for the comparison of interventions in a specific target population, which may be different from the population where data are sampled from. For instance, when the goal is to introduce a new treatment to a target population, the question is what efficacy (or effectiveness) can be gained by switching patients from a standard of care (control) to this new treatment, for which the average treatment effect for the control estimand can be applied. In this paper, we propose two estimators based on augmented inverse probability weighting to estimate the weighted average treatment effect for a well-defined target population (ie, there exists a predefined target function of covariates that characterizes the population of interest, for example, a function of age to focus on elderly diabetic patients using samples from the US population). The first proposed estimator is doubly robust if the target function is known or can be correctly specified. The second proposed estimator is doubly robust if the target function has a linear dependence on the propensity score, which can be used to estimate the average treatment effect for the treated and the average treatment effect for the control. We demonstrate the properties of the proposed estimators through theoretical proof and simulation studies. We also apply our proposed methods in a comparison of glucagon-like peptide-1 receptor agonists therapy and insulin therapy among patients with type 2 diabetes, using the UK Clinical Practice Research Datalink data.

Approach to record linkage of primary care data from Clinical Practice Research Datalink to other health-related patient data: overview and implications

Record linkage is increasingly used to expand the information available for public health research. An understanding of record linkage methods and the relevant strengths and limitations is important for robust analysis and interpretation of linked data. Here, we describe the approach used by Clinical Practice Research Datalink (CPRD) to link primary care data to other patient level datasets, and the potential implications of this approach for CPRD data analysis. General practice electronic health record software providers separately submit de-identified data to CPRD and patient identifiers to NHS Digital, excluding patients who have opted-out from contributing data. Data custodians for external datasets also send patient identifiers to NHS Digital. NHS Digital uses identifiers to link the datasets using an 8-stage deterministic methodology. CPRD subsequently receives a de-identified linked cohort file and provides researchers with anonymised linked data and metadata detailing the linkage process. This methodology has been used to generate routine primary care linked datasets, including data from Hospital Episode Statistics, Office for National Statistics and National Cancer Registration and Analysis Service. 10.6 million (M) patients from 411 English general practices were included in record linkage in June 2018. 9.1M (86%) patients were of research quality, of which 8.0M (88%) had a valid NHS number and were eligible for linkage in the CPRD standard linked dataset release. Linking CPRD data to other sources improves the range and validity of research studies. This manuscript, together with metadata generated on match strength and linkage eligibility, can be used to inform study design and explore potential linkage-related selection and misclassification biases.

Obesity and healthcare resource utilization: results from Clinical Practice Research Database (CPRD).

SummaryBackground/ObjectivesThe economic burden of obesity and type 2 diabetes (T2D) rises with increasing prevalence. This study estimates the association between obesity, healthcare resource utilization (HCRU) and associated costs in individuals with/without T2D.Subjects/MethodsThis observational cohort study used the United Kingdom Clinical Practice Research Datalink data. Between 1 January 2011 and 31 December 2015, total HCRU costs and individual component costs (hospitalizations, general practitioner contacts, prescriptions) were calculated for individuals linked to the Hospital Episodes Statistics database with/without T2D with normal weight, overweight, class I, II, III obesity.ResultsA total of 396,091 individuals were included. Increasing body mass index (BMI) was associated with increased HCRU costs. At each BMI category, costs were greater for individuals with than without T2D. Relative to normal BMI, increasing BMI was positively associated with increased HCRU costs, with similar magnitude regardless of T2D. The total HCRU cost for an individual with class III obesity was 1.4‐fold (£3,695) greater than for normal weight.ConclusionIn the United Kingdom, HCRU costs were positively associated with increasing BMI, irrespective of T2D status. The combination of T2D and obesity was associated with higher HCRU costs compared with individuals of the same BMI, without T2D. These findings suggest that prioritizing weight management programmes focused specifically on individuals with obesity and T2D may be more cost‐effective than for those with obesity alone.

Performing studies using the UK Clinical Practice Research Datalink: to link or not to link?

The Clinical Practice Research Datalink (CPRD) is a repository of electronic medical records collected during routine primary care clinical practice in the UK, and is one of the most widely used sources of real-world data for healthcare research. Although CPRD provides access to comprehensive longitudinal patient records, the data does not fully capture diagnoses or outcomes occurring in secondary care and/or mortality. We provide here an overview of CPRD and the potential bias when using unlinked data in certain situations. Linkage of CPRD to other datasets can help to overcome these limitations. We discuss when to consider linkage to secondary care, disease-specific data sources or the official mortality data when conducting research using CPRD data.

Validation of Cancer Cases Using Primary Care, Cancer Registry, and Hospitalization Data in the United Kingdom.

In the United Kingdom, hospital or cancer registry data can be linked to electronic medical records for a subset of general practices and years. We used Clinical Practice Research Datalink data (2004-2012) from patients treated for overactive bladder. We electronically identified provisional cases of 10 common cancers in General Practitioner Online Database data and validated them by medical profile review. In practices with linkage to Hospital Episodes Statistics and National Cancer Data Repository (2004-2010), we validated provisional cancer cases against these data sources. This linkage also let us identify additional cancer diagnoses in individuals without cancer diagnosis records in the General Practitioner Online Database. Among 50,840 patients, 1,486 provisional cancer cases were identified in the General Practitioner Online Database for 2004-2012. Medical profile review confirmed 93% of 661 cases in nonlinked practices (range, 100% of non-Hodgkin lymphomas and uterine cancer to 77% of skin melanomas) and 96% of 825 cases in linked practices (100% of kidney and uterine cancers to 92% of melanomas). In the subset of linked practices, for 2004-2010, 720 cases were confirmed, of which 68% were identifiable in the General Practitioner Online Database (range, 90% of breast to 36% of kidney cancers). Most cases of cancer identified electronically in the General Practitioner Online Database were confirmed. A substantial proportion of cases, especially of cancer types not typically managed by general practitioners, would be missed without Hospital Episodes Statistics and National Cancer Data Repository data (and are likely missed in nonlinked practices). See video abstract at, http://links.lww.com/EDE/B315. European Union electronic Register of Post-Authorisation Studies (EU PAS Registry) number EUPAS5529, http://www.encepp.eu/encepp/viewResource.htm?id=11107.

Do delays in data availability limit the implementation of near real-time vaccine safety surveillance using the Clinical Practice Research Datalink?

PurposeNear real‐time vaccine safety surveillance (NRTVSS) using electronic health records has been used to detect timely vaccine safety signals. Trial implementation of NRTVSS using the Clinical Practice Research Datalink (CPRD) has shown that there is limited power to detect safety signals for rare events. Delays in recording outcomes and receiving data influence the power and timeliness to identify a signal. Our work aimed to compare how different sources of delays influence power and expected time to signal to implement NRTVSS using CPRD.MethodsWe studied seasonal influenza vaccine/Guillain‐Barré syndrome and performed power and expected time to signal calculations for the 2013‐2014/2014‐2015 seasons. We used the Poisson‐based maximised sequential probability ratio test, which compares observed‐to‐expected events. For each study season, we obtained an average Guillain‐Barré syndrome/seizures age‐sex–adjusted rate from the 5 previous seasons and then used this rate to calculate the expected number of events, assuming a 42‐day risk‐window. Calculations were performed for detecting rate ratios of 1.5 to 10. We compared power and timeliness considering combinations of the presence/absence of delays in recording outcomes and in receiving data. The R‐package Sequential was used.ResultsIn general, there was ≥80% power to detect increases in risk of ≥4 at the end of the season. Assuming absence of delays slightly improved power (a maximum increase of 4%) but did not noticeably reduce time to detect a signal.ConclusionRemoving delays in data availability is insufficient to significantly improve the performance of a NRTVSS system using CPRD. Expansion of CPRD data is required.KEY POINTS The Clinical Practice Research Datalink (CPRD) can be used to implement near real‐time vaccine safety surveillance, but there is limited power to detect signals for rare outcomes.Delays in recording outcomes and in receiving data might limit power and timeliness of a system. We assessed the influence of these sources of delays to inform data providers of the steps required to improve a system using CPRD data.Removing delays in recording outcomes and receiving data is unlikely to significantly improve the performance of a system using CPRD data. Expansion of the data available is needed.

Clinical relevance of thrombocytosis in primary care: a prospective cohort study of cancer incidence using English electronic medical records and cancer registry data.

BackgroundThrombocytosis (raised platelet count) is an emerging risk marker of cancer, but the association has not been fully explored in a primary care context.AimTo examine the incidence of cancer in a cohort of patients with thrombocytosis, to determine how clinically useful this risk marker could be in predicting an underlying malignancy.Design and settingA prospective cohort study using Clinical Practice Research Datalink data from 2000 to 2013.MethodThe 1-year incidence of cancer was compared between two cohorts: 40 000 patients aged ≥40 years with a platelet count of >400 × 109/L (thrombocytosis) and 10 000 matched patients with a normal platelet count. Sub-analyses examined the risk with change in platelet count, sex, age, and different cancer sites.ResultsA total of 1098 out of 9435 males with thrombocytosis were diagnosed with cancer (11.6%; 95% confidence interval [CI] = 11.0 to 12.3), compared with 106 of 2599 males without thrombocytosis (4.1%; 95% CI = 3.4 to 4.9). A total of 1355 out of 21 826 females with thrombocytosis developed cancer (6.2%; 95% CI = 5.9 to 6.5), compared with 119 of 5370 females without (2.2%; 95% CI = 1.8 to 2.6). The risk of cancer increased to 18.1% (95% CI = 15.9 to 20.5) for males and 10.1% (95% CI = 9.0 to 11.3) for females, when a second raised platelet count was recorded within 6 months. Lung and colorectal cancer were more commonly diagnosed with thrombocytosis. One-third of patients with thrombocytosis and lung or colorectal cancer had no other symptoms indicative of malignancy.ConclusionThrombocytosis is a risk marker of cancer in adults; 11.6% and 6.2% cancer incidence in males and females, respectively, is worthy of further investigation for underlying malignancy. These figures well exceed the National Institute for Health and Care Excellence-mandated risk threshold of 3% risk to warrant referral for suspected cancer.