Application of propensity scores and marginal structural models evaluating the effect of allopurinol in gout using primary care medical records

Background Primary care electronic health records (EHR) capture real life patterns of healthcare utilisation over time. This provides the opportunity to estimate the effect of allopurinol on long term outcomes in people with gout. However, use of such data gives rise to confounding by indication which may change over time, a major impediment in treatment effect estimation. Methods A cohort of patients consulting for gout between 1997 2002 and not previously prescribed urate-lowering drugs were identified from the Clinical Practice Research Datalink GOLD and were followed up until the end of 2014. Effect of allopurinol vs. non-use was evaluated on reaching target serum urate (SU) level ≤360μmol/L, mortality, healthcare utilisation, vascular and renal diseases. Three statistical approaches with differing complexities and assumptions imposed were considered: (1) baseline measurement of allopurinol and covariates with confounding controlled for using propensity score (PS) subclassification; (2) extending the methods in (1) to repeated measures where allopurinol and covariates were measured yearly; (3) using marginal structural models (MSM) within the repeated measures set-up. Survival models estimated hazard ratios with 95% confidence intervals. Robustness of estimated treatment effects to unmeasured confounding was evaluated. Results 16,876 patients were eligible for analysis (mean age (standard deviation) 62 (14.1) years, 77% male). Baseline analysis found allopurinol was associated with higher chance of reaching target SU level (2.32 (1.97, 2.74)) and fewer gout consultations (0.70 (0.65, 0.75)), and with increased risk of mortality (1.10 (1.03, 1.17)), gout hospitalisation (1.82 (1.64, 2.02)), coronary heart disease (1.11 (1.02, 1.21)), and renal disease (1.19 (1.10, 1.28)). In the repeated measures setting, issues with poor performance of PS estimation were identified in both time-varying PS subclassification and MSM. These were resolved by allowing associations between covariates and initiation and continuation of allopurinol to differ in MSM; larger treatment effect estimates were obtained for most outcomes compared with baseline analysis and statistical significance was lost for mortality. The treatment effect estimates for target SU level and gout hospitalisation were likely to be robust to unmeasured confounding however, unmeasured confounding may explain away the treatment effects for coronary heart disease and renal disease. Conclusion Fitting complex models to EHR is challenging and consideration needs to be given to both clinical and statistical assumptions made during data preparation and analysis. Associations of allopurinol with adverse outcomes persisted, regardless of statistical approach used. This may be due to remaining residual confounding and/or because allopurinol dosage and adherence is suboptimal in primary care. Nevertheless, the treatment effect estimates obtain are relevant to UK primary care and provide evidence that managing gout in the long term needs to be improved

Incidence and Progression of Hallux Valgus: A Prospective Cohort Study

OBJECTIVE: Hallux valgus is a common and disabling condition. The objective of this study was to identify factors associated with hallux valgus incidence and progression. METHODS: Participants were from a population-based prospective cohort study, the Clinical Assessment Study of the Foot. All adults aged =50 years registered with four general practices in North Staffordshire, UK were invited to take part in a postal survey at baseline and at 7-year follow-up which included health questionnaires and self-assessment of hallux valgus using line drawings. RESULTS: Complete baseline and follow-up data were available for 1,482 participants (739 women and 743 men, mean [standard deviation] age 62.9 [8.1] years), of whom 450 (30.4%) had hallux valgus in at least one foot at baseline. Incident hallux valgus was identified in 207 (20.1%) participants (349 [15.4%] feet) and was associated with baseline age, poorer physical health, foot pain and wearing shoes with a very narrow toe-box shape between the age of 20 and 29 years. Hallux valgus progression was identified in 497 (33.6%) participants (719 [24.3%] feet) but was not associated with any baseline factors. CONCLUSION: Incident hallux valgus develops in one in five adults aged =50 years over a 7-year period and is related to age, poorer physical health, foot pain and previous use of constrictive footwear. Progression occurs in one in three adults. These findings suggest that changes in first metatarsophalangeal joint alignment may still occur beyond the age of 50 years

Identification of Patterns of Foot and Ankle Pain in the Community: Cross-sectional Findings from the Clinical Assessment Study of the Foot

Objectives: To investigate patterns of foot and ankle pain locations and symptoms, socio-demographic and comorbid characteristics to examine whether there are distinct foot and ankle pain phenotypes. Methods: Adults aged =50 years registered with four general practices in North Staffordshire were mailed a Health Survey questionnaire. Participants reporting foot pain in the last month indicated foot pain location on a foot manikin. Foot and ankle pain patterns were investigated by latent class analysis. Associations between the classes with foot pain symptoms, socio-demographic and comorbid characteristics were assessed. Results: 4455 participants with complete foot pain and manikin data were included in this analysis (mean age 65 years (SD 9.8), 49% male). Of those with foot and ankle pain (n=1356), 90% had pain in more than one region. Six distinct classes of foot and ankle pain were identified: no pain (71%); bilateral forefoot/midfoot pain (4%), bilateral hindfoot pain (5%), left forefoot/midfoot pain (8%), right forefoot/midfoot pain (5%) and bilateral widespread foot and ankle pain (6%). People with bilateral widespread foot and ankle pain were more likely to be female, obese, depressed, anxious, have/had a manual occupation, have comorbidities, lower SF-12 scores and greater foot-specific disability. Age did not differ between classes. Conclusions: Six distinct classes of foot and ankle pain locations were identified, and those with bilateral widespread foot and ankle pain had distinct characteristics. Further investigation of these individuals is required to determine if they have poorer outcomes over time and whether they would benefit from earlier identification and treatment

Identifying Long-Term Trajectories of Foot Pain Severity and Potential Prognostic Factors: A Population-Based Cohort Study.

ObjectivesTo identify distinct foot pain trajectories over 7 years and examine their associations with potential prognostic factors.MethodsAdults ages ≥50 years and registered with 4 general practices in North Staffordshire, UK were mailed a baseline health survey. Those reporting current or recent foot pain were invited to attend a research assessment clinic. Follow-up was by repeated postal surveys at 18, 36, 54, and 84 months. Distinct trajectories of foot pain were explored using latent class growth analysis (LCGA). Subsequently, identified trajectories were combined into most and least progressive groups, and covariate-adjusted associations with a range of prognostic factors were examined.ResultsOf 560 adults with foot pain attending baseline research clinics, 425 (76%) provided data at baseline and 2 or more follow-up time points. LCGA for foot pain severity (0-10 numerical rating scale) identified a 4-trajectory model: "mild, improving" (37%); "moderate, improving" (33%); "moderate-severe, persistent" (24%); and "severe, persistent" (6%). Compared with individuals in more favorable (improving) pain trajectories, those in less favorable (persistent) pain trajectories were more likely to be obese, have routine/manual and intermediate occupations, have poorer physical and mental health, have catastrophizing beliefs, have greater foot-specific functional limitation, and have self-assessed hallux valgus at baseline.ConclusionsFour distinct trajectories of foot pain were identified over a 7-year period, with one-third of individuals classified as having pain that is persistently moderate-severe and severe in intensity. The effect of intervening to target modifiable prognostic factors such as obesity and hallux valgus on long-term outcomes in people with foot pain requires investigation

Determining cardiovascular risk in patients with unattributed chest pain in UK primary care: an electronic health record study

BACKGROUND: Most adults presenting in primary care with chest pain symptoms will not receive a diagnosis ("unattributed" chest pain) but are at increased risk of cardiovascular events. AIM: To assess within patients with unattributed chest pain, risk factors for cardiovascular events and whether those at greatest risk of cardiovascular disease can be ascertained by an existing general population risk prediction model or by development of a new model. METHODS: The study used UK primary care electronic health records from the Clinical Practice Research Datalink (CPRD) linked to admitted hospitalisations. Study population was patients aged 18 plus with recorded unattributed chest pain 2002-2018. Cardiovascular risk prediction models were developed with external validation and comparison of performance to QRISK3, a general population risk prediction model. RESULTS: There were 374,917 patients with unattributed chest pain in the development dataset. Strongest risk factors for cardiovascular disease included diabetes, atrial fibrillation, and hypertension. Risk was increased in males, patients of Asian ethnicity, those in more deprived areas, obese patients, and smokers. The final developed model had good predictive performance (external validation c-statistic 0.81, calibration slope 1.02). A model using a subset of key risk factors for cardiovascular disease gave nearly identical performance. QRISK3 underestimated cardiovascular risk. CONCLUSION: Patients presenting with unattributed chest pain are at increased risk of cardiovascular events. It is feasible to accurately estimate individual risk using routinely recorded information in the primary care record, focusing on a small number of risk factors. Patients at highest risk could be targeted for preventative measures

The effectiveness of COVID-19 vaccines to prevent long COVID symptoms:staggered cohort study of data from the UK, Spain, and Estonia

Background: Although vaccines have proved effective to prevent severe COVID-19, their effect on preventing long-term symptoms is not yet fully understood. We aimed to evaluate the overall effect of vaccination to prevent long COVID symptoms and assess comparative effectiveness of the most used vaccines (ChAdOx1 and BNT162b2). Methods: We conducted a staggered cohort study using primary care records from the UK (Clinical Practice Research Datalink [CPRD] GOLD and AURUM), Catalonia, Spain (Information System for Research in Primary Care [SIDIAP]), and national health insurance claims from Estonia (CORIVA database). All adults who were registered for at least 180 days as of Jan 4, 2021 (the UK), Feb 20, 2021 (Spain), and Jan 28, 2021 (Estonia) comprised the source population. Vaccination status was used as a time-varying exposure, staggered by vaccine rollout period. Vaccinated people were further classified by vaccine brand according to their first dose received. The primary outcome definition of long COVID was defined as having at least one of 25 WHO-listed symptoms between 90 and 365 days after the date of a PCR-positive test or clinical diagnosis of COVID-19, with no history of that symptom 180 days before SARS-Cov-2 infection. Propensity score overlap weighting was applied separately for each cohort to minimise confounding. Sub-distribution hazard ratios (sHRs) were calculated to estimate vaccine effectiveness against long COVID, and empirically calibrated using negative control outcomes. Random effects meta-analyses across staggered cohorts were conducted to pool overall effect estimates. Findings: A total of 1 618 395 (CPRD GOLD), 5 729 800 (CPRD AURUM), 2 744 821 (SIDIAP), and 77 603 (CORIVA) vaccinated people and 1 640 371 (CPRD GOLD), 5 860 564 (CPRD AURUM), 2 588 518 (SIDIAP), and 302 267 (CORIVA) unvaccinated people were included. Compared with unvaccinated people, overall HRs for long COVID symptoms in people vaccinated with a first dose of any COVID-19 vaccine were 0·54 (95% CI 0·44–0·67) in CPRD GOLD, 0·48 (0·34–0·68) in CPRD AURUM, 0·71 (0·55–0·91) in SIDIAP, and 0·59 (0·40–0·87) in CORIVA. A slightly stronger preventative effect was seen for the first dose of BNT162b2 than for ChAdOx1 (sHR 0·85 [0·60–1·20] in CPRD GOLD and 0·84 [0·74–0·94] in CPRD AURUM). Interpretation: Vaccination against COVID-19 consistently reduced the risk of long COVID symptoms, which highlights the importance of vaccination to prevent persistent COVID-19 symptoms, particularly in adults. Funding: National Institute for Health and Care Research.</p

An Evaluation of Different Strategies for Sampling Controls in an Online Case-Crossover Study of Acute Flares in Knee Osteoarthritis.

ObjectiveTo evaluate bias and precision of exposure-outcome effect estimates from three control sampling strategies in a case-crossover study.MethodsOnline case-crossover study investigating eight physical activity-related triggers for acute flares in knee osteoarthritis. Exposures were measured in hazard periods (≤24 hours before self-declared flare onset). Control period exposure was measured in three ways: (1) four scheduled questionnaires over 13-weeks, (2) "usual" physical activity levels ascertained at baseline, (3) over three days before flare onset. Derived odds ratios, 95% confidence intervals and standard errors were compared.ResultsOf 744 participants (mean age 62.1 [SD 10.2] years; 61% female), 493 reported 714 flares. Selecting controls from scheduled questionnaires, independent of hazard periods, yielded predominantly odds ratios in the expected direction (exposure "a lot" versus exposure "not at all", range: 0.57-3.22). When controls were sampled at baseline (range: 0.01-1.42) or immediately before a flare (range: 0.30-1.27) most odds ratio estimates were inverted. Standard errors of the log odds ratios were smallest when controls were sampled from scheduled questionnaires (range: 0.264-0.473) compared to controls sampled at baseline (range: 0.267-0.589) or immediately before a flare (range: 0.319-0.621).ConclusionOur findings are sensitive to control sample selection. Under certain conditions, different patterns could be attributed to over reporting and social desirability bias, where people may want to present themselves more positively about their "usual" physical activity levels, at baseline. Exposure measurement at the time of a flare may be less precise and more susceptible to recall bias due to systematically reporting exposures differently during a flare, compared to control measurement independent of flares

The association between comorbidity and physical activity levels in people with osteoarthritis: Secondary analysis from two randomised controlled trials

Objective: To determine whether comorbidity presence, frequency or type is associated with Physical Activity (PA) levels in people with Osteoarthritis (OA). Design: Secondary data analysis of adults aged ≥45, with OA related pain recruited to the BEEP trial (knee pain, n = 514) (ISRCTN93634563) and the MOSAICS trial (peripheral joint pain, n = 525) (ISRCTN06984617). Comorbidities considered were respiratory, cardiovascular diseases (CVD), depression, type 2 diabetes and obesity. Self-report PA was measured using the Physical Activity Scale for the Elderly (PASE). Linear regression models were used to estimate the mean change (β) in PA with comorbidity presence, frequency and type adjusting for potential confounding covariates. Results: In the BEEP trial comorbidity presence was associated with a decrease in PASE score (β = -32.25 [95% confidence interval (95% CI) −48.57, −15.93]). Each additional comorbidity was associated with an incrementally lower PASE score, one comorbidity (β = −24.42 [-42.45, −6.38]), two comorbidities β = −34.76 [-56.05, −13.48]), and three or more comorbidities β = −73.71 [-106.84, −40.58]) compared to those with no comorbidity. This pattern was similar in MOSAICS, but with a plateau in association from two comorbidities onward. In BEEP and MOSAICS, respiratory (β = −40.60 [-60.50, −20.35]; β = −11.82 [-34.95, 11.31]) and CVD (β = −27.15 [-53.25, −1.05]; β = −30.84 [-51.89, −9.80]) comorbidities were associated with the largest reduction in PASE scores respectively. Conclusion: Comorbidity presence and frequency is associated with lower PA levels and respiratory and CVD comorbidities have the greatest impact. Future exploratory work needs to be done to understand how and why comorbidity is associated with PA levels in people with OA

Diabetes, metabolic health, and the development of frozen shoulder: a cohort study in UK electronic health records

Objective Estimate the effect of type 2 diabetes on the development of frozen shoulder and investigate whether the effect is mediated by other metabolic factors. Methods Primary care medical record-based cohort study containing 43,977 patients newly diagnosed with type 2 diabetes and 43,977 without diabetes. Variables were identified using established Read codes. A weighting approach with Cox regression was used to decompose the total effect into the direct effect and indirect effect, mediated by metabolic health (which was defined as the number of metabolic factors developed during follow-up). Estimates were expressed as hazard ratios (HR). Confounders were identified using a DAG. Sensitivity to unmeasured confounding, extreme weights, and missing data were tested. Results The total effect of type 2 diabetes on the development of frozen shoulder was HR = 4.38 (95% CI: 3.70–5.21), the natural indirect effect (mediated through metabolic health) was HR = 0.98 (95% CI: 0.93–1.03) and the natural direct effect was HR = 4.46 (95% CI: 3.68–5.41). Results were robust to unmeasured confounding, extreme weights, and missing data. Conclusions This study suggests that type 2 diabetes may be a cause of frozen shoulder but does not support the hypothesis that the effect is mediated by metabolic health. Clinicians should remain alert that shoulder pain in patients with diabetes could be indicative of a frozen shoulder. This study should raise awareness that, despite often being overlooked, musculoskeletal conditions can be complications of diabetes and should be considered during clinical conversations with patients