Evaluation of biases present in the cohort multiple randomised controlled trial design: a simulation study

Background The cohort multiple randomised controlled trial (cmRCT) design provides an opportunity to incorporate the benefits of randomisation within clinical practice; thus reducing costs, integrating electronic healthcare records, and improving external validity. This study aims to address a key concern of the cmRCT design: refusal to treatment is only present in the intervention arm, and this may lead to bias and reduce statistical power. Methods We used simulation studies to assess the effect of this refusal, both random and related to event risk, on bias of the effect estimator and statistical power. A series of simulations were undertaken that represent a cmRCT trial with time-to-event endpoint. Intention-to-treat (ITT), per protocol (PP), and instrumental variable (IV) analysis methods, two stage predictor substitution and two stage residual inclusion, were compared for various refusal scenarios. Results We found the IV methods provide a less biased estimator for the causal effect when refusal is present in the intervention arm, with the two stage residual inclusion method performing best with regards to minimum bias and sufficient power. We demonstrate that sample sizes should be adapted based on expected and actual refusal rates in order to be sufficiently powered for IV analysis. Conclusion We recommend running both an IV and ITT analyses in an individually randomised cmRCT as it is expected that the effect size of interest, or the effect we would observe in clinical practice, would lie somewhere between that estimated with ITT and IV analyses. The optimum (in terms of bias and power) instrumental variable method was the two stage residual inclusion method. We recommend using adaptive power calculations, updating them as refusal rates are collected in the trial recruitment phase in order to be sufficiently powered for IV analysis

Calculating total health service utilisation and costs from routinely collected electronic health records using the example of patients with irritable bowel syndrome before and after their first gastroenterology appointment

INTRODUCTION: Health economic models are increasingly important in funding decisions but most are based on data, which may therefore not represent the general population. We sought to establish the potential of real-world data available within the Clinical Practice Research Datalink (CPRD) and linked Hospital Episode Statistics (HES) to determine comprehensive healthcare utilisation and costs as input variables for economic modelling. METHODS: A cohort of patients with irritable bowel syndrome (IBS) who first saw a gastroenterologist in 2008 or 2009, and with 3 years of data before and after their appointment, was created in the CPRD. Primary care, outpatient, inpatient, prescription and colonoscopy data were extracted from the linked CPRD and HES. The appropriate cost to the NHS was attached to each event. Total and stratified annual healthcare utilisation rates and costs were calculated before and after the gastroenterology appointment with distribution parameters. Absolute differences were calculated with 95 % confidence intervals. RESULTS: Total annual healthcare costs over 3 years increase by £935 (95 % CI £928–941) following a gastroenterology appointment for IBS. We derived utilisation and cost data with parameter distributions stratified by demographics and time. Women, older patients, smokers and patients with greater comorbidity utilised more healthcare resources, which generated higher costs. CONCLUSIONS: These linked datasets provide comprehensive primary and secondary care data for large numbers of patients, which allows stratification of outcomes. It is possible to derive input parameters appropriate for economic models and their distributions directly from the population of interest

Potential application of item-response theory to interpretation of medical codes in electronic patient records

Background: electronic patient records are generally coded using extensive sets of codes but the significance of the utilisation of individual codes may be unclear. Item response theory (IRT) models are used to characterise the psychometric properties of items included in tests and questionnaires. This study asked whether the properties of medical codes in electronic patient records may be characterised through the application of item response theory models.Methods: data were provided by a cohort of 47,845 participants from 414 family practices in the UK General Practice Research Database (GPRD) with a first stroke between 1997 and 2006. Each eligible stroke code, out of a set of 202 OXMIS and Read codes, was coded as either recorded or not recorded for each participant. A two parameter IRT model was fitted using marginal maximum likelihood estimation. Estimated parameters from the model were considered to characterise each code with respect to the latent trait of stroke diagnosis. The location parameter is referred to as a calibration parameter, while the slope parameter is referred to as a discrimination parameter.Results: there were 79,874 stroke code occurrences available for analysis. Utilisation of codes varied between family practices with intraclass correlation coefficients of up to 0.25 for the most frequently used codes. IRT analyses were restricted to 110 Read codes. Calibration and discrimination parameters were estimated for 77 (70%) codes that were endorsed for 1,942 stroke patients. Parameters were not estimated for the remaining more frequently used codes. Discrimination parameter values ranged from 0.67 to 2.78, while calibration parameters values ranged from 4.47 to 11.58. The two parameter model gave a better fit to the data than either the one- or three-parameter models. However, high chi-square values for about a fifth of the stroke codes were suggestive of poor item fit.Conclusion: the application of item response theory models to coded electronic patient records might potentially contribute to identifying medical codes that offer poor discrimination or low calibration. This might indicate the need for improved coding sets or a requirement for improved clinical coding practice. However, in this study estimates were only obtained for a small proportion of participants and there was some evidence of poor model fit. There was also evidence of variation in the utilisation of codes between family practices raising the possibility that, in practice, properties of codes may vary for different coder

Long-term exposure to outdoor air pollution and the incidence of chronic obstructive pulmonary disease in a national English cohort.

OBJECTIVES: The role of outdoor air pollution in the incidence of chronic obstructive pulmonary disease (COPD) remains unclear. We investigated this question using a large, nationally representative cohort based on primary care records linked to hospital admissions. METHODS: A cohort of 812 063 patients aged 40-89 years registered with 205 English general practices in 2002 without a COPD diagnosis was followed from 2003 to 2007. First COPD diagnoses recorded either by a general practitioner (GP) or on admission to hospital were identified. Annual average concentrations in 2002 for particulate matter with an aerodynamic diameter <10 µm (PM10) and <2.5 µm (PM2.5), nitrogen dioxide (NO2), ozone and sulfur dioxide (SO2) at 1 km(2) resolution were estimated from emission-based dispersion models. Hazard ratios (HRs) per interquartile range change were estimated from Cox models adjusting for age, sex, smoking, body mass index and area-level deprivation. RESULTS: 16 034 participants (1.92%) received a COPD diagnosis from their GP and 2910 participants (0.35%) were admitted to hospital for COPD. After adjustment, HRs for GP recorded COPD and PM10, PM2.5 and NO2 were close to unity, positive for SO2 (HR=1.07 (95% CI 1.03 to 1.11) per 2.2 µg/m(3)) and negative for ozone (HR=0.94 (0.89 to 1.00) per 3 µg/m(3)). For admissions HRs for PM2.5 and NO2 remained positive (HRs=1.05 (0.98 to 1.13) and 1.06 (0.98 to 1.15) per 1.9 µg/m(3) and 10.7 µg/m(3), respectively). CONCLUSIONS: This large population-based cohort study found limited, inconclusive evidence for associations between air pollution and COPD incidence. Further work, utilising improved estimates of air pollution over time and enhanced socioeconomic indicators, is required to clarify the association between air pollution and COPD incidence

Advances in Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) is one of the most important side effects of glucocorticoid use, as it leads to an increased risk of fractures. Recently, many published studies have focused on the cellular and molecular mechanisms of bone metabolism, the pathophysiology of GIOP, and the intervention options to prevent GIOP. In this review, recent advances in GIOP are summarized, particularly recent progress in our understanding of the mechanisms of GIOP resulting in improved insight that might result in the development of new treatment options in the near future

Clopidogrel discontinuation after acute coronary syndromes: frequency, predictors and associations with death and myocardial infarction—a hospital registry-primary care linked cohort (MINAP–GPRD)

AIMS: Adherence to evidence-based treatments and its consequences after acute myocardial infarction (MI) are poorly defined. We examined the extent to which clopidogrel treatment initiated in hospital is continued in primary care; the factors predictive of clopidogrel discontinuation and the hazard of death or recurrent MI. METHODS AND RESULTS: We linked the Myocardial Ischaemia National Audit Project registry and the General Practice Research Database to examine adherence to clopidogrel in primary care among patients discharged from hospital after MI (2003-2009). Hospital Episode Statistics and national mortality data were linked, documenting all-cause mortality and non-fatal MI. Of the 7543 linked patients, 4650 were prescribed clopidogrel in primary care within 3 months of discharge. The adjusted odds of still being prescribed clopidogrel at 12 months were similar following non-ST-elevation myocardial infarction (NSTEMI) 53% (95% CI, 51-55) and ST-elevation myocardial infarction (STEMI) 54% (95% CI, 52-56), but contrast with statins: NSTEMI 84% (95% CI, 82-85) and STEMI 89% (95% CI, 87-90). Discontinuation within 12 months was more frequent in older patients [>80 vs. 40-49 years, adjusted hazard ratio (HR) 1.50 (95% CI, 1.15-1.94)] and with bleeding events [HR 1.34 (95% CI, 1.03-1.73)]. 18.15 patients per 100 person-years (95% CI, 16.83-19.58) died or experienced non-fatal MI in the first year following discharge. In patients who discontinued clopidogrel within 12 months, the adjusted HR for death or non-fatal MI was 1.45 (95% CI, 1.22-1.73) compared with untreated patients, and 2.62 (95% CI, 2.17-3.17) compared with patients persisting with clopidogrel treatment. CONCLUSION: This is the first study to use linked registries to determine persistence of clopidogrel treatment after MI in primary care. It demonstrates that discontinuation is common and associated with adverse outcomes