Analysis of multicenter clinical trials with very low event rates

INTRODUCTION: In a five-arm randomized clinical trial (RCT) with stratified randomization across 54 sites, we encountered low primary outcome event proportions, resulting in multiple sites with zero events either overall or in one or more study arms. In this paper, we systematically evaluated different statistical methods of accounting for center in settings with low outcome event proportions. METHODS: We conducted a simulation study and a reanalysis of a completed RCT to compare five popular methods of estimating an odds ratio for multicenter trials with stratified randomization by center: (i) no center adjustment, (ii) random intercept model, (iii) Mantel-Haenszel model, (iv) generalized estimating equation (GEE) with an exchangeable correlation structure, and (v) GEE with small sample correction (GEE-small sample correction). We varied the number of total participants (200, 500, 1000, 5000), number of centers (5, 50, 100), control group outcome percentage (2%, 5%, 10%), true odds ratio (1, > 1), intra-class correlation coefficient (ICC) (0.025, 0.075), and distribution of participants across the centers (balanced, skewed). RESULTS: Mantel-Haenszel methods generally performed poorly in terms of power and bias and led to the exclusion of participants from the analysis because some centers had no events. Failure to account for center in the analysis generally led to lower power and type I error rates than other methods, particularly with ICC = 0.075. GEE had an inflated type I error rate except in some settings with a large number of centers. GEE-small sample correction maintained the type I error rate at the nominal level but suffered from reduced power and convergence issues in some settings when the number of centers was small. Random intercept models generally performed well in most scenarios, except with a low event rate (i.e., 2% scenario) and small total sample size (n ≤ 500), when all methods had issues. DISCUSSION: Random intercept models generally performed best across most scenarios. GEE-small sample correction performed well when the number of centers was large. We do not recommend the use of Mantel-Haenszel, GEE, or models that do not account for center. When the expected event rate is low, we suggest that the statistical analysis plan specify an alternative method in the case of non-convergence of the primary method

Improving Ethical Review of Research Involving Incentives for Health Promotion

Alex London and colleagues propose new ethical frameworks for evaluating the risks associated with research in which financial or other incentives are used to promote healthy behavior

Relationships of the Location and Content of Rounds to Specialty, Institution, Patient-Census, and Team Size

OBJECTIVE: Existing observational data describing rounds in teaching hospitals are 15 years old, predate duty-hour regulations, are limited to one institution, and do not include pediatrics. We sought to evaluate the effect of medical specialty, institution, patient-census, and team participants upon time at the bedside and education occurring on rounds. METHODS AND PARTICIPANTS: Between December of 2007 and October of 2008 we performed 51 observations at Lucile Packard Children's Hospital, Seattle Children's Hospital, Stanford University Hospital, and the University of Washington Medical Center of 35 attending physicians. We recorded minutes spent on rounds in three location and seven activity categories, members of the care team, and patient-census. RESULTS: Results presented are means. Pediatric rounds had more participants (8.2 vs. 4.1 physicians, p<.001; 11.9 vs. 2.4 non-physicians, p<.001) who spent more minutes in hallways (96.9 min vs. 35.2 min, p<.001), fewer minutes at the bedside (14.6 vs. 38.2 min, p = .01) than internal medicine rounds. Multivariate regression modeling revealed that minutes at the bedside per patient was negatively associated with pediatrics (-2.77 adjusted bedside minutes; 95% CI -4.61 to -0.93; p<.001) but positively associated with the number of non-physician participants (0.12 adjusted bedside minutes per non physician participant; 95% CI 0.07 to 0.17; p = <.001). Education minutes on rounds was positively associated with the presence of an attending physician (2.70 adjusted education minutes; 95% CI 1.27 to 4.12; p<.001) and with one institution (1.39 adjusted education minutes; 95% CI 0.26 to 2.53; p = .02). CONCLUSIONS: Pediatricians spent less time at the bedside on rounds than internal medicine physicians due to reasons other than patient-census or the number of participants in rounds. Compared to historical data, internal medicine rounds were spent more at the bedside engaged in patient care and communication, and less upon educational activities

A test of financial incentives to improve warfarin adherence

<p>Abstract</p> <p>Background</p> <p>Sub-optimal adherence to warfarin places millions of patients at risk for stroke and bleeding complications each year. Novel methods are needed to improve adherence for warfarin. We conducted two pilot studies to determine whether a lottery-based daily financial incentive is feasible and improves warfarin adherence and anticoagulation control.</p> <p>Methods</p> <p>Volunteers from the University of Pennsylvania Anticoagulation Management Center who had taken warfarin for at least 3 months participated in either a pilot study with a lottery with a daily expected value of $5 (N = 10) or a daily expected value of$3 (N = 10). All subjects received use of an Informedix Med-eMonitor™ System with a daily reminder feature. If subjects opened up their pill compartments appropriately, they were entered into a daily lottery with a 1 in 5 chance of winning $10 and a 1 in 100 chance of winning$100 (pilot 1) or a 1 in 10 chance of winning $10 and a 1 in 100 chance of winning$100 (pilot 2). The primary study outcome was proportion of incorrect warfarin doses. The secondary outcome was proportion of INR measurements not within therapeutic range. Within-subject pre-post comparisons were done of INR measurements with comparisons with either historic means or within-subject comparisons of incorrect warfarin doses.</p> <p>Results</p> <p>In the first pilot, the percent of out-of-range INRs decreased from 35.0% to 12.2% during the intervention, before increasing to 42% post-intervention. The mean proportion of incorrect pills taken during the intervention was 2.3% incorrect pills, compared with a historic mean of 22% incorrect pill taking in this clinic population. Among the five subjects who also had MEMS cap adherence data from warfarin use in our prior study, mean incorrect pill taking decreased from 26% pre-pilot to 2.8% in the pilot. In the second pilot, the time out of INR range decreased from 65.0% to 40.4%, with the proportion of mean incorrect pill taking dropping to 1.6%.</p> <p>Conclusion</p> <p>A daily lottery-based financial incentive demonstrated the potential for significant improvements in missed doses of warfarin and time out of INR range. Further testing should be done of this approach to determine its effectiveness and potential application to both warfarin and other chronic medications.</p

Effects on incident reporting after educating residents in patient safety: a controlled study

<p>Abstract</p> <p>Background</p> <p>Medical residents are key figures in delivering health care and an important target group for patient safety education. Reporting incidents is an important patient safety domain, as awareness of vulnerabilities could be a starting point for improvements. This study examined effects of patient safety education for residents on knowledge, skills, attitudes, intentions and behavior concerning incident reporting.</p> <p>Methods</p> <p>A controlled study with follow-up measurements was conducted. In 2007 and 2008 two patient safety courses for residents were organized. Residents from a comparable hospital acted as external controls. Data were collected in three ways: 1] questionnaires distributed before, immediately after and three months after the course, 2] incident reporting cards filled out by course participants during the course, and 3] residents' reporting data gathered from hospital incident reporting systems.</p> <p>Results</p> <p>Forty-four residents attended the course and 32 were external controls. Positive changes in knowledge, skills and attitudes were found after the course. Residents' intentions to report incidents were positive at all measurements. Participants filled out 165 incident reporting cards, demonstrating the skills to notice incidents. Residents who had reported incidents before, reported more incidents after the course. However, the number of residents reporting incidents did not increase. An increase in reported incidents was registered by the reporting system of the intervention hospital.</p> <p>Conclusions</p> <p>Patient safety education can have immediate and long-term positive effects on knowledge, skills and attitudes, and modestly influence the reporting behavior of residents.</p

High workload and job stress are associated with lower practice performance in general practice: an observational study in 239 general practices in the Netherlands

Contains fulltext : 80493.pdf (publisher's version ) (Open Access)BACKGROUND: The impact of high physician workload and job stress on quality and outcomes of healthcare delivery is not clear. Our study explored whether high workload and job stress were associated with lower performance in general practices in the Netherlands. METHODS: Secondary analysis of data from 239 general practices, collected in practice visits between 2003 to 2006 in the Netherlands using a comprehensive set of measures of practice management. Data were collected by a practice visitor, a trained non-physician observer using patients questionnaires, doctors and staff. For this study we selected five measures of practice performance as outcomes and six measures of GP workload and job stress as predictors. A total of 79 indicators were used out of the 303 available indicators. Random coefficient regression models were applied to examine associations. RESULTS AND DISCUSSION: Workload and job stress are associated with practice performance.Workload: Working more hours as a GP was associated with more positive patient experiences of accessibility and availability (b = 0.16). After list size adjustment, practices with more GP-time per patient scored higher on GP care (b = 0.45). When GPs provided more than 20 hours per week per 1000 patients, patients scored over 80% on the Europep questionnaire for quality of GP care.Job stress: High GP job stress was associated with lower accessibility and availability (b = 0.21) and insufficient practice management (b = 0.25). Higher GP commitment and more satisfaction with the job was associated with more prevention and disease management (b = 0.35). CONCLUSION: Providing more time in the practice, and more time per patient and experiencing less job stress are all associated with perceptions by patients of better care and better practice performance. Workload and job stress should be assessed by using list size adjusted data in order to realise better quality of care. Organisational development using this kind of data feedback could benefit both patients and GP