English Clinical Practice Research Datalink Research Articles

5613022 SOCIETAL BURDEN OF SICKLE CELL DISEASE IN THE UK: EMPIRICAL ESTIMATES OF PRODUCTIVITY LOSS AND LOSS OF FUTURE INCOME USING REAL-WORLD EVIDENCE

Background: Sickle cell disease (SCD) is associated with high healthcare resource utilization (HCRU), lowered life expectancy, and unemployment. The combination of routine healthcare appointments, acute crises, and organ damage causes productivity loss (PL). Early death and long-term unemployment also lead to loss of future income (LFI). Both PL and LFI are important aspects of the burden of SCD on society, as lost income due to a genetic disease can have intergenerational impacts. Aims: To empirically quantify the societal cost of SCD using observed PL and estimated LFI. Methods: We identified 9272 patients aged ≥12 years with SCD using the English Clinical Practice Research Datalink (CPRD) linked with Hospital Episode Statistics between January 1, 2007 and March 31, 2019. We obtained mortality data from the Office of National Statistics (ONS) death register. To quantify PL, we assigned time to HCRU events based on Choi et al, 2019.1 We assessed PL due to sickness at home using doctors’ sick notes in the CPRD, assuming 10 days’ PL for each note. Patients could self-certify sickness without a doctor’s note for 7 days. We assumed a 5-day work week, with 1 day of 7.5 h based on the average 37.5 h UK work week. We estimated costs of PL by multiplying the mean hourly adult wage for the year the resource was used by the time lost. For patients aged 12 to 18 years, PL was attributed to a main caregiver using adult wages. We inflated the cost of PL to 2021 pounds sterling using the Consumer Price Index (CPI). Unemployment, medical retirement, and death were LFI events. Once patients were recorded as unemployed or medically retired, we assumed they never returned to work. We also assumed those who did not die lived past state retirement age, which is currently 68 years. Only observed events were used to calculate the discounted present value of LFI based on years from the earliest LFI event to age 68. The discount rate was 3.5%. We used the 2021 age-specific mean income from the ONS to estimate future income at each decade. Results: A total of 62.5% of patients were female; 73.5% were Black; mean (standard deviation) age was 36.3 (15.7) years. Median follow-up was 7.1 years (interquartile range 3.6-10.1). Mean cost of PL was £1821 per patient-year (PPY), equivalent to >3 weeks’ average 2021 UK weekly earnings (£586). Patients lost a mean of 5.5 days PPY in hospital stays, 2.7 days PPY in outpatient clinics, 3.6 days PPY for primary care visits, 1.1 days PPY in emergency care, and 2.2 days PPY for sickness at home. We estimated £510,315 LFI for each patient with an LFI event, equivalent to £30,546 per patient in the cohort. Of the 555 LFI events, 425 (76.6%) were deaths, occurring at a median age of 61 years. Unemployment accounted for 129 (23.2%) events occurring at a median age of 39 years. One person (0.2%) was medically retired at age 61. Summary/Conclusion: To our knowledge, this is the first study presenting empirical estimates of PL and LFI for patients with SCD from a large, nationally representative UK data set.Societal costs of SCD in the UK are substantial; PL due to healthcare appointments or to sickness at home is equivalent to >3 weeks’ lost earnings PPY. Those who cannot work or die of their disease lose over £500,000 in a lifetime. Our results are consistent with Lubeck et al, 2019, who estimated an LFI of $695,000 (£489,800, purchasing power parity inflated to 2021 using the CPI) from a simulated SCD cohort in the US.2

BLOod Test Trend for cancEr Detection (BLOTTED): protocol for an observational and prediction model development study using English primary care electronic health record data

BackgroundSimple blood tests can play an important role in identifying patients for cancer investigation. The current evidence base is limited almost entirely to tests used in isolation. However, recent evidence suggests combining multiple types of blood tests and investigating trends in blood test results over time could be more useful to select patients for further cancer investigation. Such trends could increase cancer yield and reduce unnecessary referrals. We aim to explore whether trends in blood test results are more useful than symptoms or single blood test results in selecting primary care patients for cancer investigation. We aim to develop clinical prediction models that incorporate trends in blood tests to identify the risk of cancer.MethodsPrimary care electronic health record data from the English Clinical Practice Research Datalink Aurum primary care database will be accessed and linked to cancer registrations and secondary care datasets. Using a cohort study design, we will describe patterns in blood testing (aim 1) and explore associations between covariates and trends in blood tests with cancer using mixed-effects, Cox, and dynamic models (aim 2). To build the predictive models for the risk of cancer, we will use dynamic risk modelling (such as multivariate joint modelling) and machine learning, incorporating simultaneous trends in multiple blood tests, together with other covariates (aim 3). Model performance will be assessed using various performance measures, including c-statistic and calibration plots.DiscussionThese models will form decision rules to help general practitioners find patients who need a referral for further investigation of cancer. This could increase cancer yield, reduce unnecessary referrals, and give more patients the opportunity for treatment and improved outcomes.

Elevated triglycerides and reduced high-density lipoprotein cholesterol are independently associated with the onset of advanced chronic kidney disease: a cohort study of 911,360 individuals from the United Kingdom

BackgroundIncreased total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C) concentrations, are established risk factors for cardiovascular morbidity and mortality; but their impact on the risk of advanced chronic kidney disease (CKD) is unclear. This study evaluates the association between the different lipid profiles and the onset of advanced CKD using a general population sample.MethodsThis observational study used records of 911,360 individuals from the English Clinical Practice Research Datalink (from 2000 to 2014), linked to coded hospital discharges and mortality registrations. Cox models were used to examine the independent association between the equal quarters of TC, TG, LDL-C, and HDL-C and the risk of advanced CKD, after adjustment for sex and age, and potential effect mediators.ResultsDuring a median follow-up of 7.5 years, 11,825 individuals developed CKD stages 4–5. After adjustment for sex and age, the hazard ratios (HRs) and confidence intervals (CIs) for CKD stages 4–5 comparing the 4th vs. 1st quarters of TG and 1st vs. 4th quarters of HDL-C were 2.69 (95% CI, 2.49–2.90) and 2.61 (95% CI, 2.42–2.80), respectively. Additional adjustment for potential effect mediators reduced the HRs to 1.28 (95% CI, 1.15–1.43), and 1.27 (95% CI, 1.14–1.41), respectively. There was no evidence of fully adjusted associations with CKD stages 4–5 for levels of either TC or LDL-C.ConclusionsElevated TG and reduced HDL-C levels are independently associated with the onset of advanced CKD. Future studies, such as in basic science and randomized trials, are needed to understand whether associations between TG and HDL-C and the development of CKD are causal.

Factors associated with potentially missed acute deterioration in primary care: cohort study of UK general practices

BackgroundIn the UK, while most primary care contacts are uncomplicated, safety incidents do occur and result in patient harm, for example, failure to recognise a patient’s deterioration in health.AimTo determine the patient and healthcare factors associated with potentially missed acute deterioration in health.Design and settingCohort of patients registered with English Clinical Practice Research Datalink general practices between 1 April 2014 and 31 December 2017 with linked hospital data.MethodA potentially missed acute deterioration was defined as a patient having a self-referred admission to hospital having been seen in primary care by a GP in the 3 days beforehand. All diagnoses and subsets of commonly-reported missed conditions were analysed..ResultsA total of 116 097 patients contacted a GP 3 days before an emergency admission. Patients with sepsis (adjusted odds ratio [aOR] 1.09, 95% confidence interval [CI] = 1.01 to 1.18) or urinary tract infections (aOR 1.09, 95% CI = 1.04 to 1.14) were more likely to self-refer. The duration of GP appointments was associated with self-referral. On average, a 5-minute increase in appointment time resulted in a 10% decrease in the odds of self-referred admissions (aOR 0.90, 95% CI = 0.89 to 0.91). Patients having a telephone consultation (compared with face-to-face consultation) (aOR 1.14, 95% CI = 1.11 to 1.18) previous health service use, and presence of comorbidities were also associated with self-referred admission.ConclusionDifferentiating acute deterioration from self-limiting conditions can be difficult for clinicians, particularly in patients with sepsis, urinary tract infections, or long-term conditions. The findings of this study support the call for longer GP consultations and caution against reliance on telephone consultations in primary care; however, more research is needed to understand the underlying mechanisms.

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.

What are the implications of using individual and combined sources of routinely collected data to identify and characterise incident site-specific cancers? a concordance and validation study using linked English electronic health records data

ObjectivesTo describe the benefits and limitations of using individual and combinations of linked English electronic health data to identify incident cancers.Design and settingOur descriptive study uses linked English Clinical Practice...

Do Systemic Antibiotics Prior to Cancer Diagnosis Impact on All-Cause Mortality for Malignant Cancers? Findings from Two UK Population-Based Cohort Studies

Background: In mice models of cancer and human tissues samples, disturbance of the gut microbiota can reduce the effectiveness of chemotherapy and immunotherapy. There is limited evidence in humans whether antibiotics impact on the effectiveness of cancer treatments. We evaluated the associations between antibiotic use before cancer diagnoses and long-term mortality. Methods: Primary care data from general practices contributing to the English Clinical Practice Research Datalink (CPRD) and Welsh Secure Anonymised Information Linkage (SAIL) linked to Cancer Registries (CR) and Office for National Statistics (ONS) mortality records were used. Two cohort studies involving cancer patients (15 types) exposed to antibiotics before cancer diagnosis were identified. Recent, previous and past antibiotic users were compared using Cox regression models. Findings: 129 990 cancer patients from the National Cancer Registration and Analysis Service (NCRAS) linked to CPRD and 131 330 from the Welsh Cancer Intelligence Surveillance Unit (WCISU) were included. In comparison with past antibiotic users, patients who used antibiotics in the recent past before their cancer diagnosis and were mainly treated with chemotherapy or immunotherapy presented increased hazards ratio (HR) for mortality consistently in both cohorts; for leukaemia, the HR in NCRAS was 1·40 (95% CI 1·22-1·60), for lymphoma 1·19 (95% CI 1·06-1·33), for melanoma 1·31 (95% CI 1·12-1·54), and for myeloma 1·19 (95% CI 1·04-1·36). HR for cancer of the uterus, breast, urinary, colorectal, and kidney cancer followed the same trend in both CRs. Sensitivity analyses based on general practice records suggested comparable results to those from CRs. Interpretation: This study supports the hypothesis that prior use of antibiotics may reduce the effectiveness of chemotherapy and immunotherapy, potentially through disruption to the gut microbiota. Although not providing definitive results, the biological plausibility of the findings does support the need for judicious use of antibiotics. Funding: Department of Health and NIHR. Declaration of Interest: We declare no competing interests. Ethical Approval: The protocol was approved by the Independent Scientific Advisory Committee for CPRD research (protocol number 18_198) and SAIL’s Information Governance Protocol Review Panel (protocol number 0855).

Socioeconomic disadvantage and the risk of advanced chronic kidney disease: results from a cohort study with 1.4 million participants.

Several studies have investigated the effect of socioeconomic deprivation on cardiovascular disease (CVD) and diabetes; less is known about its effect on chronic kidney disease (CKD). We aimed to measure the association between deprivation, CKD Stages 4-5 and end-stage renal disease (ESRD) in a general population sample. This observational study examined 1 405 016 participants from the English Clinical Practice Research Datalink (2000-14), linked to hospital discharge data and death certification. Deprivation was assessed according to the participant's postcode. Cox models were used to estimate hazard ratios (HRs) for CKD Stages 4-5 and ESRD, adjusting for age and sex, and additionally for smoking status, body mass index, diabetes, systolic blood pressure, prior CVD and estimated glomerular filtration rate (eGFR) at baseline. During 7.5 years of median follow-up, 11 490 individuals developed CKD Stages 4-5 and 1068 initiated ESRD. After adjustment for age and sex, the HRs and confidence interval (CI) comparing those in the 20% most deprived of the population to the 20% least deprived were 1.76 (95% CI 1.68-1.84) and 1.82 (95% CI 1.56-2.12) for CKD Stages 4-5 and ESRD, respectively. Further adjustment for known risk factors and eGFR substantially attenuated these HRs. Adding our results to all known cohort studies produced a pooled relative risk of 1.61 (95% CI 1.42-1.83) for ESRD, for comparisons between highest to lowest categories of deprivation. Socioeconomic deprivation is independently associated with an increased hazard of CKD Stages 4-5 and ESRD, but in large part may be mediated by known risk factors.

Algorithms for the Capture and Adjudication of Prevalent and Incident Diabetes in UK Biobank.

ObjectivesUK Biobank is a UK-wide cohort of 502,655 people aged 40–69, recruited from National Health Service registrants between 2006–10, with healthcare data linkage. Type 2 diabetes is a key exposure and outcome. We developed algorithms to define prevalent and incident diabetes for UK Biobank. The algorithms will be implemented by UK Biobank and their results made available to researchers on request.MethodsWe used UK Biobank self-reported medical history and medication to assign prevalent diabetes and type, and tested this against linked primary and secondary care data in Welsh UK Biobank participants. Additionally, we derived and tested algorithms for incident diabetes using linked primary and secondary care data in the English Clinical Practice Research Datalink, and ran these on secondary care data in UK Biobank.Results and SignificanceFor prevalent diabetes, 0.001% and 0.002% of people classified as “diabetes unlikely” in UK Biobank had evidence of diabetes in their primary or secondary care record respectively. Of those classified as “probable” type 2 diabetes, 75% and 96% had specific type 2 diabetes codes in their primary and secondary care records. For incidence, 95% of people with the type 2 diabetes-specific C10F Read code in primary care had corroborative evidence of diabetes from medications, blood testing or diabetes specific process of care codes. Only 41% of people identified with type 2 diabetes in primary care had secondary care evidence of type 2 diabetes. In contrast, of incident cases using ICD-10 type 2 diabetes specific codes in secondary care, 77% had corroborative evidence of diabetes in primary care. We suggest our definition of prevalent diabetes from UK Biobank baseline data has external validity, and recommend that specific primary care Read codes should be used for incident diabetes to ensure precision. Secondary care data should be used for incident diabetes with caution, as around half of all cases are missed, and a quarter have no corroborative evidence of diabetes in primary care.

Epidural morphine for outpatients with severe anginal pain.

Seven patients who had chronic coronary artery disease and had undergone coronary artery bypass surgery still suffered from anginal attacks several times daily despite optimal medical treatment. An epidural system of analgesia was implanted subcutaneously and treatment with epidural morphine started. The morphine was administered by the patients themselves or members of their family. During a median observation time of four months (range three to 11) all patients were free of pain while receiving this treatment.