Applying quantitative bias analysis to estimate the plausible effects of selection bias in a cluster randomised controlled trial: secondary analysis of the Primary care Osteoarthritis Screening Trial (POST).

BACKGROUND: Selection bias is a concern when designing cluster randomised controlled trials (c-RCT). Despite addressing potential issues at the design stage, bias cannot always be eradicated from a trial design. The application of bias analysis presents an important step forward in evaluating whether trial findings are credible. The aim of this paper is to give an example of the technique to quantify potential selection bias in c-RCTs. METHODS: This analysis uses data from the Primary care Osteoarthritis Screening Trial (POST). The primary aim of this trial was to test whether screening for anxiety and depression, and providing appropriate care for patients consulting their GP with osteoarthritis would improve clinical outcomes. Quantitative bias analysis is a seldom-used technique that can quantify types of bias present in studies. Due to lack of information on the selection probability, probabilistic bias analysis with a range of triangular distributions was also used, applied at all three follow-up time points; 3, 6, and 12 months post consultation. A simple bias analysis was also applied to the study. RESULTS: Worse pain outcomes were observed among intervention participants than control participants (crude odds ratio at 3, 6, and 12 months: 1.30 (95% CI 1.01, 1.67), 1.39 (1.07, 1.80), and 1.17 (95% CI 0.90, 1.53), respectively). Probabilistic bias analysis suggested that the observed effect became statistically non-significant if the selection probability ratio was between 1.2 and 1.4. Selection probability ratios of > 1.8 were needed to mask a statistically significant benefit of the intervention. CONCLUSIONS: The use of probabilistic bias analysis in this c-RCT suggested that worse outcomes observed in the intervention arm could plausibly be attributed to selection bias. A very large degree of selection of bias was needed to mask a beneficial effect of intervention making this interpretation less plausible

Comparison of clinical burden between patients with erosive hand osteoarthritis and inflammatory arthritis in symptomatic community-dwelling adults: the Keele clinical assessment studies.

OBJECTIVE: To investigate in the general population the clinical impact of erosive OA in interphalangeal joints (IPJs) compared with symptomatic radiographic hand OA and inflammatory arthritis. METHODS: Standardized assessments with hand radiographs were performed in participants of two population-based cohorts in North Staffordshire with hand symptoms lasting ≥1 day in the past month. Erosive OA was defined as the presence of an eroded or remodelled phase in ≥1 IPJ using the Verbruggen-Veys method. Radiographic hand OA was defined as the presence of ≥1 IPJ/first carpometacarpal joint with a Kellgren-Lawrence score of ≥2. Diagnoses of inflammatory arthritis were based on medical records. Hand pain and disability were assessed with the Australian/Canadian Hand Osteoarthritis Index (AUSCAN). Linear regression analyses were used to compare clinical determinants between groups and calculate mean differences with 95% CIs, adjusted for age and sex. RESULTS: Of 1076 participants with hand symptoms [60% women, mean age 64.8 years (s.d. 8.3 years)]; 80 persons (7.4%) had erosive OA. The population prevalence of erosive OA in ≥1 IPJ was 2.4% (95% CI 1.8, 3.0). Persons with erosive OA reported more pain and disability than persons with symptomatic radiographic hand OA [adjusted mean difference 1.3 (95% CI 0.3, 2.3) and 2.3 (95% CI 0.4, 4.2), respectively]. Individuals with inflammatory arthritis (n = 44) reported more pain and disability than those with erosive OA [adjusted mean difference 1.7 (95% CI 0.05, 3.4) and 6.3 (95% CI 2.8, 9.9), respectively]. CONCLUSION: While erosive OA has a greater impact than symptomatic radiographic hand OA in the general population, it is not as severe in terms of hand pain and disability as inflammatory RA

Rotation and activity of pre-main-sequence stars

We present a study of rotation (vsini) and chromospheric activity (Halpha EW) based on an extensive set of high-resolution optical spectra obtained with MIKE on the 6.5m Magellan Clay telescope. Our targets are 74 F-M dwarfs in the young stellar associations Eta Cha, TW Hydrae, Beta Pic, and Tuc-Hor, spanning ages from 6 to 30 Myr. While the Halpha EW for most F and G stars are consistent with pure photospheric absorption, most K and M stars show chromospheric emission. By comparing Halpha EW in our sample to results in the literature, we see a clear evolutionary sequence: Chromospheric activity declines steadily from the T Tauri phase to the main sequence. Using activity as an age indicator, we find a plausible age range for the Tuc-Hor association of 10-40 Myr. Between 5 and 30 Myr, we do not see evidence for rotational braking in the total sample, thus angular momentum is conserved, in contrast to younger stars. This difference indicates a change in the rotational regulation at 5-10 Myr, possibly because disk braking cannot operate longer than typical disk lifetimes, allowing the objects to spin up. The rotation-activity relation is flat in our sample; in contrast to main-sequence stars, there is no linear correlation for slow rotators. We argue that this is because young stars generate their magnetic fields in a fundamentally different way from main-sequence stars, and not just the result of a saturated solar-type dynamo. By comparing our rotational velocities with published rotation periods for a subset of stars, we determine ages of 13 (7-20) Myr and 9 (7-17} Myr for the Eta Cha and TWA associations, respectively, consistent with previous estimates. Thus we conclude that stellar radii from evolutionary models by Baraffe et al. (1998) are in agreement with the observed radii within +-15%. (abridged)Comment: 40 pages, 8 figures, ApJ, in pres

Impact of co-morbid burden on mortality in patients with coronary heart disease, heart failure, and cerebrovascular accident: a systematic review and meta-analysis.

Aims: We sought to investigate the prognostic impact of co-morbid burden as defined by the Charlson Co-morbidity Index (CCI) in patients with a range of prevalent cardiovascular diseases. Methods and results: We searched MEDLINE and EMBASE to identify studies that evaluated the impact of CCI on mortality in patients with cardiovascular disease. A random-effects meta-analysis was undertaken to evaluate the impact of CCI on mortality in patients with coronary heart disease (CHD), heart failure (HF), and cerebrovascular accident (CVA). A total of 11 studies of acute coronary syndrome (ACS), 2 stable coronary disease, 5 percutaneous coronary intervention (PCI), 13 HF, and 4 CVA met the inclusion criteria. An increase in CCI score per point was significantly associated with a greater risk of mortality in patients with ACS [pooled relative risk ratio (RR) 1.33; 95% CI 1.15-1.54], PCI (RR 1.21; 95% CI 1.12-1.31), stable coronary artery disease (RR 1.38; 95% CI 1.29-1.48), and HF (RR 1.21; 95% CI 1.13-1.29), but not CVA. A CCI score of >2 significantly increased the risk of mortality in ACS (RR 2.52; 95% CI 1.58-4.04), PCI (RR 3.36; 95% CI 2.14-5.29), HF (RR 1.76; 95% CI 1.65-1.87), and CVA (RR 3.80; 95% CI 1.20-12.01). Conclusion: Increasing co-morbid burden as defined by CCI is associated with a significant increase in risk of mortality in patients with underlying CHD, HF, and CVA. CCI provides a simple way of predicting adverse outcomes in patients with cardiovascular disease and should be incorporated into decision-making processes when counselling patients

Erosive osteoarthritis: a more severe form of radiographic hand osteoarthritis rather than a distinct entity?

OBJECTIVES: To determine whether erosive osteoarthritis shares the same pattern of joint involvement and risk profile as increasing grades of non-erosive hand osteoarthritis. METHODS: Participants were from two population-based cohorts, aged ≥50 years, reporting hand symptoms in the previous month. Interphalangeal joints were assessed for erosive osteoarthritis (Verbruggen-Veys erosive or remodelled phase) and radiographic osteoarthritis (sliding cut-offs of K&L≥2, K&L≥3 and K&L=4). At the joint level, similarities in the frequency and pattern of erosive and non-erosive osteoarthritis were assessed by Spearman's rank correlation coefficients and generalised estimating equations. At the person level, individuals with erosive osteoarthritis were compared to those with non-erosive osteoarthritis using logistic regression, adjusted for age and gender (aOR), for the following exposures: family history, previous injury, overuse and metabolic factors (BMI, dyslipidaemia, hypertension, diabetes). RESULTS: In 1076 symptomatic participants the ranked frequency of involvement for erosive joints was comparable to joints with K&L≥3 and K&L=4 (r>0.95). Patterns of joint involvement in erosive osteoarthritis were strongest for symmetry (aOR=6.5; 95% CI 3.0 to 14.1), followed by row (2.0; 0.8 to 5.0) and ray (0.3; 0.0 to 2.5), which was similar to joints with K&L≥3 and K&L=4. Individuals with erosive osteoarthritis (n=80) had an increased risk of metabolic syndrome (2.7; 1.0 to 7.1), notably dyslipidaemia (4.7; 2.1 to 10.6) compared with non-erosive osteoarthritis classed K&L≥3 (n=193). CONCLUSIONS: The similar frequency of radiographic joint involvement and patterning in erosive osteoarthritis and more severe non-erosive osteoarthritis is consistent with prevalent erosive osteoarthritis being a severe form of hand osteoarthritis rather than a distinct entity. Metabolic exposures, dyslipidaemia in particular, may be implicated in erosive osteoarthritis

The clinical assessment study of the foot (CASF): study protocol for a prospective observational study of foot pain and foot osteoarthritis in the general population.

BACKGROUND: Symptomatic osteoarthritis (OA) affects approximately 10% of adults aged over 60 years. The foot joint complex is commonly affected by OA, yet there is relatively little research into OA of the foot, compared with other frequently affected sites such as the knee and hand. Existing epidemiological studies of foot OA have focussed predominantly on the first metatarsophalangeal joint at the expense of other joints. This three-year prospective population-based observational cohort study will describe the prevalence of symptomatic radiographic foot OA, relate its occurrence to symptoms, examination findings and life-style-factors, describe the natural history of foot OA, and examine how it presents to, and is diagnosed and managed in primary care. METHODS: All adults aged 50 years and over registered with four general practices in North Staffordshire, UK, will be invited to participate in a postal Health Survey questionnaire. Respondents to the questionnaire who indicate that they have experienced foot pain in the preceding twelve months will be invited to attend a research clinic for a detailed clinical assessment. This assessment will consist of: clinical interview; physical examination; digital photography of both feet and ankles; plain x-rays of both feet, ankles and hands; ultrasound examination of the plantar fascia; anthropometric measurement; and a further self-complete questionnaire. Follow-up will be undertaken in consenting participants by postal questionnaire at 18 months (clinic attenders only) and three years (clinic attenders and survey participants), and also by review of medical records. DISCUSSION: This three-year prospective epidemiological study will combine survey data, comprehensive clinical, x-ray and ultrasound assessment, and review of primary care records to identify radiographic phenotypes of foot OA in a population of community-dwelling older adults, and describe their impact on symptoms, function and clinical examination findings, and their presentation, diagnosis and management in primary care

Investigating outcome inequalities in osteoarthritis management programmes: an analysis of registry data from the good life with osteoarthritis in Denmark (GLA:D®) programme using tapered balancing

Purpose: The burden of osteoarthritis (OA) is often greater among disadvantaged people and communities, prompting calls for more attention to equity-focussed research and policy. A specific concern is whether healthcare interventions may inadvertently widen health inequalities. OA management programmes (OAMP) have emerged in the past decade in a major international effort to improve provision of core non-surgical care for people with OA. Recent studies have focussed on equity of access. We address a complementary issue: having gained access, do people from socially disadvantaged groups have poorer outcomes than their advantaged counterparts, and if so, what might determine this? Methods: The study population was consecutive adults with knee OA attending the 8-week GLA:D® supervised exercise and education programme in Denmark between Oct 2014-Feb 2018. We defined a ‘multiple social disadvantage’ group based on primary/secondary school education and being either born outside Denmark or not having Danish citizenship. Their outcomes were compared with those of native Danish citizens with higher education. Outcomes of interest were pain intensity (0-100 VAS), KOOS Quality of Life subscale (QOL 0-100), EQ-5D-5L health utility (-0.624-1.0) at 3 and 12 months. Missing data were imputed using multiple imputation with chained equations. We used Coarsened Exact Matching (CEM) to restrict group comparisons to areas of common support, i.e. sufficient overlap on key prognostic factors (age, sex, body mass index, baseline value of the outcome measure of interest). We then used Entropy Balancing to sequentially control for differences between disadvantaged and advantaged groups in: (1) baseline value of the outcomes of interest (2) type of treatment centre, enrollment year (3) age, sex (4) BMI, previous knee injury, previous knee surgery (5) no. of selected comorbidities, no. of other non-knee pain sites (6) self-efficacy score, self-reported presence of depression (7) previous/current tailored exercise advice, weight loss counselling, analgesia/natural remedies (8) attendance at GLA:D® education and exercise sessions. Mean differences in outcomes between disadvantaged and advantaged groups were then estimated by weighted linear regression without balancing and then with entropy balancing weights from steps 1-8. Results: Of 18,448 eligible participants, 250 (1.4%) were classed as disadvantaged. Compared with advantaged participants, they were younger, less likely to have attended GLA:D® in a private physiotherapy clinic, reported more comorbidity, pain sites, depression, lower self-efficacy, and lower attendance on GLA:D® sessions. Both groups showed overall improvements over baseline in mean pain VAS, KOOS QOL and EQ5D scores at 3 months, typically maintained at 12 months. Before covariate balancing, disadvantaged participants had substantially worse scores than advantaged participants on each measure at both follow-up points (e.g. crude between-group mean differences (95%CI) in pain VAS at 12 months: 8.6 (4.5, 12.6) respectively: Table 1). Balancing for differences on baseline score, comorbidity, self-efficacy, and depression had the greatest effect on reducing differences in outcomes. Conclusions: Both disadvantaged and advantaged adults with knee OA reported improvements in key outcomes up to 12 months after OAMP attendance. However, compared with more advantaged adults, disadvantaged adults typically began the OAMP with more severe pain and poorer quality of life. This gap in outcomes was not reduced following OAMP attendance: for generic health-related quality of life in particular the gap widened slightly. Low self-efficacy, depression and other comorbidities may be potential determinants. Our analysis is of observed outcomes in a relatively small group with multiple disadvantage attending one OAMP. We encourage further work in other settings and groups. If confirmed, our findings suggest that while improving access to OAMPs for socially disadvantaged people with OA is important, additional actions may be needed to reduce outcome inequalities