Russell Steele

Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis.

OBJECTIVES This study was designed to determine whether statins reduce all-cause mortality in elderly patients with coronary heart disease. BACKGROUND Statins continue to be underutilized in elderly patients because evidence has not consistently shown that they reduce mortality. METHODS We searched 5 electronic databases, the Internet, and conference proceedings to identify relevant trials. In addition, we obtained unpublished data for the elderly patient subgroups from 4 trials and for the secondary prevention subgroup from the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) trial. Inclusion criteria were randomized allocation to statin or placebo, documented coronary heart disease, > or =50 elderly patients (defined as age > or =65 years), and > or =6 months of follow-up. Data were analyzed with hierarchical Bayesian modeling. RESULTS We included 9 trials encompassing 19,569 patients with an age range of 65 to 82 years. Pooled rates of all-cause mortality were 15.6% with statins and 18.7% with placebo. We estimated a relative risk reduction of 22% over 5 years (relative risk [RR] 0.78; 95% credible interval [CI] 0.65 to 0.89). Furthermore, statins reduced coronary heart disease mortality by 30% (RR 0.70; 95% CI 0.53 to 0.83), nonfatal myocardial infarction by 26% (RR 0.74; 95% CI 0.60 to 0.89), need for revascularization by 30% (RR 0.70; 95% CI 0.53 to 0.83), and stroke by 25% (RR 0.75; 95% CI 0.56 to 0.94). The posterior median estimate of the number needed to treat to save 1 life was 28 (95% CI 15 to 56). CONCLUSIONS Statins reduce all-cause mortality in elderly patients and the magnitude of this effect is substantially larger than had been previously estimated.

Should Meta-Analyses of Interventions Include Observational Studies in Addition to Randomized Controlled Trials? A Critical Examination of Underlying Principles

In their recent article, Shrier et al. (l) considered a 95% confidence interval as being one with a 95% probability that a population parameter is included in the interval and a 5% probability that it will lie outside the interval. We wish to clarify some aspects of confidence intervals’ interpretation. A simple example illustrates our points. Let us consider a group of 20 patients who receive a new treatment. Only 6 fail to respond to the treatment. Let p be the population proportion of possible patients who would not respond to the treatment. p is the parameter of interest; its true unknown value is the quantity to be estimated. Considering the Bernoulli process, the likelihood is p(1 p) for 0 < p < 1. We calculate an exact interval with 90% confidence (2) that happens to be nonsymmetric around 6/20: (0.175, 0.505). This may be the smallest (most precise) 90% confidence interval for the observation ‘‘6 out of 20.’’ The correct interpretation of the information that p is in this interval with 90% confidence is as follows: If we could repeat this procedure over a large number of samples of size 20, the true unknown value of p would be contained in 90% of the intervals; hence, we are confident that our particular interval, (0.175, 0.505), contains the true value of p. Note that we never use the term probability, since this interpretation is actually a frequentist one. The evaluation is based on samples that could have been observed but were not. Note also that since p is not a random quantity in the frequentist environment, p belongs (or not) to the interval without any probability attached to the statement. This is the reason to speak about confidence, not probability. Alternatively, to build Bayesian credible intervals (2, 3), consider a uniform prior in (0;1). This corresponds to normalizing the likelihood function, producing a beta posterior with, for example, a1⁄4 7 and b1⁄4 15. The 90% credible interval, the smallest interval with a posterior probability of 0.9, is (0.165, 0.483). This interval contains pwith a posterior probability of 0.9. In fact, this is the smallest interval that has 90%of the area under the likelihood function. This interval is a bit narrower than the confidence interval presented previously. We have shown that if one decides to use probabilities to replace confidences, the construction of the intervals is completely different than the usual method. In other words, Shrier et al.’s interpretation of the 95% confidence interval given on page 1204 of their article (1) and in their Appendix was technically incorrect. Rather than providing 95% confidence that the true value of the population parameter lies within the interval, the correct interpretation is that with the performance of equivalent studies, 95%of the observed confidence intervals would cover the true value of the parameter—a subtle but important difference, since population parameters are not random quantities and therefore probability statements should not be attached to them. Only in the Bayesian framework, which was not considered by Shrier et al., are parameters treated as random variables.

Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer

Background: Cut-off scores for determining positivity of biomarkers detected by immunohistochemistry are often set arbitrarily and vary between reports. Aims: To evaluate the performance of receiver operating characteristic (ROC) curve analysis in determining clinically important cut-off scores for a novel tumour marker, the receptor for hyaluronic acid mediated motility (RHAMM), and show the reproducibility of the selected cut-off scores in 1197 mismatch-repair (MMR) proficient colorectal cancers (CRC). Methods: Immunohistochemistry for RHAMM was performed using a tissue microarray of 1197 MMR-proficient CRC. Immunoreactivity was scored using a semi-quantitative scoring method by evaluating the percentage of positive tumour cells. ROC curve analysis was performed for T stage, N stage, tumour grade, vascular invasion and survival. The score with the shortest distance from the curve to the point with both maximum sensitivity and specificity, i.e. the point (0.0, 1.0), was selected as the cut-off score leading to the greatest number of tumours correctly classified as having or not having the clinical outcome. In order to determine the reliability of the selected cut-off scores, 100 bootstrapped replications were performed to resample the data. Results: The cut-off score for T stage, N stage, tumour grade and vascular invasion was 100% and that for survival 90%. The most frequently selected cut-off score from the 100 resamples was also 100% for T stage, N stage, tumour grade, and vascular invasion and 90% for survival. Conclusions: ROC curve analysis can be used as an alternative method in the selection and validation of cut-off scores for determining the clinically relevant threshold for immunohistochemical tumour positivity.

The Scleroderma Patient-centered Intervention Network (SPIN) Cohort: protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context

Introduction Psychosocial and rehabilitation interventions are increasingly used to attenuate disability and improve health-related quality of life (HRQL) in chronic diseases, but are typically not available for patients with rare diseases. Conducting rigorous, adequately powered trials of these interventions for patients with rare diseases is difficult. The Scleroderma Patient-centered Intervention Network (SPIN) is an international collaboration of patient organisations, clinicians and researchers. The aim of SPIN is to develop a research infrastructure to test accessible, low-cost self-guided online interventions to reduce disability and improve HRQL for people living with the rare disease systemic sclerosis (SSc or scleroderma). Once tested, effective interventions will be made accessible through patient organisations partnering with SPIN. Methods and analysis SPIN will employ the cohort multiple randomised controlled trial (cmRCT) design, in which patients consent to participate in a cohort for ongoing data collection. The aim is to recruit 1500–2000 patients from centres across the world within a period of 5 years (2013–2018). Eligible participants are persons ≥18 years of age with a diagnosis of SSc. In addition to baseline medical data, participants will complete patient-reported outcome measures every 3 months. Upon enrolment in the cohort, patients will consent to be contacted in the future to participate in intervention research and to allow their data to be used for comparison purposes for interventions tested with other cohort participants. Once interventions are developed, patients from the cohort will be randomly selected and offered interventions as part of pragmatic RCTs. Outcomes from patients offered interventions will be compared with outcomes from trial-eligible patients who are not offered the interventions. Ethics and dissemination The use of the cmRCT design, the development of self-guided online interventions and partnerships with patient organisations will allow SPIN to develop, rigourously test and effectively disseminate psychosocial and rehabilitation interventions for people with SSc.

Health-related quality of life in systemic sclerosis: A systematic review

OBJECTIVE A number of studies (all n <200) have assessed health-related quality of life (HRQOL) in patients with systemic sclerosis (SSc), but no systematic review of the effect of SSc on HRQOL has been done. The objective of this study was to systematically review the literature on HRQOL in SSc measured using the Medical Outcomes Trust Short Form 36 (SF-36). METHODS A comprehensive search was conducted in August 2007 using Medline, CINAHL, and EMBase to identify original research studies reporting SF-36 scores of SSc patients. Selected studies were reviewed and characteristics of the study samples and SF-36 data were extracted. Bayesian meta-analysis and meta-regression were performed to obtain pooled estimates of SF-36 physical component summary (PCS) and mental component summary (MCS) scores for all patients as well as by limited and diffuse disease status. RESULTS Twelve data sets with a total of 1,127 SSc patients were included in the systematic review. HRQOL was impaired in patients with SSc, with pooled SF-36 PCS scores being more than 1 SD below the general population (38.3; 95% credible interval [95% CI] 35.2, 41.5) and pooled SF-36 MCS scores being approximately 0.5 SDs below the general population (46.6; 95% CI 44.2, 49.1). SF-36 PCS scores were 3.5 points (95% CI -1.0, 8.0) lower in patients with diffuse compared with limited disease. CONCLUSION This study provides robust evidence of the presence and magnitude of impairment in HRQOL in patients with SSc. Although the impairment appears greater in physical health, mental health impairment is also reported.

Malnutrition is common in systemic sclerosis: results from the Canadian Scleroderma Research Group database.

Objective. Systemic sclerosis (SSc) is a multisystem disease associated with significant morbidity and increased mortality. Little is known about nutritional status in SSc. We investigated the prevalence and demographic and clinical correlates of nutritional status in a large cohort of patients with SSc. Methods. This was a cross-sectional multicenter study of patients (n = 586) from the Canadian Scleroderma Research Group Registry. Patients were assessed with detailed clinical histories, medical examinations, and self-administered questionnaires. The primary outcome was risk for malnutrition using the “malnutrition universal screening tool” (MUST). Multiple logistic regression was used to assess the relationship between selected demographic and clinical variables and MUST categories. Results. Of the 586 patients in the study, MUST scores revealed that almost 18% were at high risk for malnutrition. The significant correlates of high malnutrition risk included the number of gastrointestinal (GI) complaints, disease duration, diffuse disease, physician global assessment of disease severity, hemoglobin, oral aperture, abdominal distension on physical examination, and physician-assessed possible malabsorption. Among 14 GI symptoms, only poor appetite and lack of a history of abdominal swelling and bloating predict MUST. These factors accounted for 24% of the variance in MUST scores. Conclusion. The risk for malnutrition in SSc is moderate and is associated with shorter disease duration, markers of GI involvement, and disease severity. Patients with SSc should be screened for malnutrition, and potential underlying causes assessed and treated when possible.

Scoring of p53, VEGF, Bcl-2 and APAF-1 immunohistochemistry and interobserver reliability in colorectal cancer.

Molecular tumor markers are often studied in colorectal cancer using immunohistochemistry to determine their prognostic or predictive value. Protein expression is typically assigned a ‘positive’ score based on a predetermined cutoff. A semiquantitative scoring method that evaluates the percentage of positive tumor cells (0–100%) may provide a better understanding of the prognostic or predictive significance of these markers. The aim of this study was to assess and compare the interobserver agreement of immunohistochemistry scores using a percentage scoring method and three categorical scoring systems. Immunohistochemistry for p53, Bcl-2, vascular endothelial growth factor (VEGF) and apoptotic protease activating factor-1 (APAF-1) was performed on 87 tumor biopsies from patients with rectal carcinoma and scored independently by four pathologists as the percentage of positive tumor cells. Interobserver agreement was assessed by the intraclass correlation coefficient. The intraclass correlation coefficients for p53 and VEGF (>0.6) indicate substantial agreement between observers. The distribution of Bcl-2 and APAF-1 scores in addition to weaker interobserver agreement by percentage scoring suggest that this approach may not be appropriate for these proteins. In conclusion, p53 and VEGF protein expression assessed by immunohistochemistry in colorectal cancer and scored as a percentage of positive tumor cells may be a viable alternative scoring method.

Risk of bias from inclusion of patients who already have diagnosis of or are undergoing treatment for depression in diagnostic accuracy studies of screening tools for depression: systematic review

Objectives To investigate the proportion of original studies included in systematic reviews and meta-analyses on the diagnostic accuracy of screening tools for depression that appropriately exclude patients who already have a diagnosis of or are receiving treatment for depression and to determine whether these systematic reviews and meta-analyses evaluate possible bias from the inclusion of such patients. Design Systematic review. Data sources Medline, PsycINFO, CINAHL, Embase, ISI, SCOPUS, and Cochrane databases were searched from 1 January 2005 to 29 October 2009. Eligibility criteria for selecting studies Systematic reviews and meta-analyses in any language that reported on the diagnostic accuracy of screening tools for depression. Results Only eight of 197 (4%) unique publications from 17 systematic reviews and meta-analyses specifically excluded patients who already had a diagnosis of or were receiving treatment for depression. No systematic reviews or meta-analyses commented on possible bias from the inclusion of such patients, even though 10 reviews used quality assessment tools with items to rate risk of bias from composition of the sample of patients. Conclusions Studies of the accuracy of screening tools for depression rarely exclude patients who already have a diagnosis of or are receiving treatment for depression, a potential bias that is not evaluated in systematic reviews and meta-analyses. This could result in inflated estimates of accuracy on which clinical practice and preventive care guidelines are often based, a problem that takes on greater importance as the rate of diagnosed and treated depression in the population increases.

Quality of life in systemic sclerosis: Psychometric properties of the World Health Organization Disability Assessment Schedule II

OBJECTIVE To determine the validity of the World Health Organization Disability Assessment Schedule II (WHODAS II) in systemic sclerosis (SSc). METHODS Patients enrolled in the Canadian Scleroderma Research Group registry participated in a standardized evaluation and completed the WHODAS II. Criterion validity was assessed by comparing the WHODAS II with the Medical Outcomes Study Short Form 36 (SF-36), construct validity was assessed by examining how it relates to common measures of outcome in SSc, and discriminative validity was assessed by examining how it distinguishes patients with more severe disease from those with less severe disease. RESULTS A total of 402 patients with SSc were included (mean +/- SD age 55 +/- 13 years, 87% women, mean +/- SD disease duration 11 +/- 9 years). The mean +/- SD WHODAS II score was 24.6 +/- 17.4, and the greatest impairments were in life activities and mobility. There were moderate to good correlations between the WHODAS II and the SF-36 Physical Component Summary score (r = -0.44), the SF-36 Mental Component Summary score (r = -0.41), and measures of function (r = 0.54), depression (r = 0.44), pain (r = 0.40), and fatigue (r = -0.49, P < 0.0001 for all). The WHODAS II was able to consistently distinguish patients with milder disease from those with more severe disease. CONCLUSION The WHODAS II had good psychometric properties in patients with SSc and should be considered a valid measure of health-related quality of life in SSc.

Cigarette smoking in patients with systemic sclerosis.

OBJECTIVE To determine the effects of cigarette smoking on vascular, gastrointestinal, and respiratory outcomes in patients with systemic sclerosis (SSc). METHODS Subjects were patients enrolled in the Canadian Scleroderma Research Group cohort. Smoking history was obtained by patient self-report. The effect of smoking was assessed using multiple regression analysis of each SSc clinical outcome of interest (vascular, gastrointestinal, and respiratory). Smoking was modeled both as categorical variables (current, past, and never) and using the Comprehensive Smoking Index (CSI), which integrates smoking intensity, duration of smoking, and time since cessation into a single covariate of smoking effect. All regression models were adjusted for age, sex, disease duration, and limited or diffuse skin involvement. RESULTS This study included 606 patients with SSc, of whom 87% were women and 90% were white, and the mean age was 55 years, mean disease duration was 11 years, and 36% had diffuse disease. Of these patients, 16% were current smokers, 42% were past smokers, and 42% were never smokers. The regression analyses showed that smoking had a significant negative effect on almost all vascular, gastrointestinal, and respiratory outcomes. The effects of smoking were in some cases long-lasting (e.g., persistent respiratory abnormalities), and smoking cessation appeared beneficial with respect to some outcomes (e.g., reduced severity of Raynauds phenomenon). CONCLUSION Physicians caring for patients with SSc should prioritize smoking cessation as a recommendation to patients, and resources directed to supporting smoking cessation in patients with SSc should be more readily available.