[Show abstract][Hide abstract] ABSTRACT: Background
Acute diarrhea and acute gastroenteritis (AD/AGE) are common among children in low- and middle-income countries (LMIC) and high-income countries (HIC). Supportive therapy including maintaining feeding, prevention of dehydration, and use of oral rehydration solution (ORS), is the mainstay of treatment in all children. Several additional treatments aiming to reduce the episode duration have been compared to placebo, but the differences in effectiveness among them are unknown.
Methods and analysis
We will conduct a systematic review of all randomized controlled trials evaluating the use of zinc, vitamin A, probiotics, prebiotics, synbiotics, racecadotril, smectite, and fermented and lactose-free milk/formula for AD/AGE treatment in children. The primary outcomes are diarrhea duration and mortality. Secondary outcomes are diarrhea lasting 3 or 7 days, stool frequency, treatment failure, hospitalizations, and adverse events. We will search MEDLINE, Ovid EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and LILACS through Ovid, as well as grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information, and assess the risk of bias (ROB) and the confidence in the estimate (with the grading of recommendations, assessment, development, and evaluation [GRADE] approach). Results will be summarized narratively and statistically. Subgroup analysis according to HIC vs. LMIC, age, nutrition status, and ROB is planned. We will perform a Bayesian network meta-analysis to combine the pooled direct and indirect treatment effect estimates for each outcome, if adequate data is available.
This is the first systematic review and network meta-analysis that aims to determine the relative effectiveness of pharmacological and nutritional treatments for reducing the duration of AD/AGE in children. The results will help to reduce the uncertainty of the effectiveness of the interventions, find knowledge gaps, and/or encourage further research for other therapeutic options.
Systematic review registration
PROSPERO registration number: CRD42015023778.
Full-text · Article · Dec 2016 · Systematic Reviews
[Show abstract][Hide abstract] ABSTRACT: Background:
The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) is a widely used methodology for the development of clinical practice guideline. Although its reproducibility is good for evaluating the quality of evidence, it has not been tested in context of developing recommendations. The objective of this study was to assess the reproducibility of all GRADE factors that determine the direction and strength of a recommendation among the guideline panel members with limited exposure to GRADE methodology.
The study was conducted as part of the clinical practice guideline development process of American Association of Blood Banking (AABB) for the use of prophylactic versus therapeutic platelet transfusion in patients with thrombocytopenia. The results from the systematic review and meta-analysis for each question were summarized as a GRADE evidence profile. Inter-rater agreement for all GRADE factors and strength of recommendations was summarized using a weighted kappa statistic with 95% confidence intervals (CI).
Eighteen members of the panel participated in the deliberation of making recommendations and completed the online questionnaire. They were given two one-hour lectures about GRADE. The agreement for all domains was better than chance. The inter-rater agreement for the domain of quality of evidence was good (kappa value: 0.68; 95% confidence intervals 0.54 to 0.84), and fair for balance of benefit and harms (kappa value: 0.4; 95% confidence intervals 0.25 to 0.57) and use of resources (kappa value: 0.28: 95% confidence intervals 0.12 to 0.42). The inter-rater agreement was moderate for the GRADE domain of patients' values and preferences (kappa value: 0.44; 95% confidence interval 0.31 to 0.56). The inter-rater agreement for making a for/against recommendation was good (kappa value: 0.74; 95% confidence intervals 0.33 to 0.91) and fair for strong/weak recommendation (kappa value: 0.39; 95% confidence intervals 0.18 to 0.68).
While not all elements of GRADE system had good agreement, the inter-rater agreement for assessing the quality of evidence and issuing a recommendation of for versus against among panel members who had limited exposure to GRADE methodology was good. This is probably because GRADE has operationalized these two areas in more detail than other domains. Further operationalization of all GRADE domains such as with the GRADE evidence to decision frameworks would likely improve its reproducibility.
No preview · Article · Feb 2016 · Journal of clinical epidemiology
[Show abstract][Hide abstract] ABSTRACT: An increasing number of organizations worldwide are using new and improved standards for developing trustworthy clinical guidelines. One of such approaches, developed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, offers systematic and transparent guidance in moving from evidence to recommendations. The GRADE strategy concentrates on four factors: The balance between benefits and harms, the certainty of the evidence, values and preferences and resource considerations. However, it also considers issues around feasibility, equity and acceptability of recommendations.
GRADE distinguishes two types of recommendations: strong and weak. Strong recommendations reflect a clear preference for one alternative and should apply to all or almost all patients, obviating the need for a careful review of the evidence with each patient. Weak recommendations are appropriate when there is a close balance between desirable and undesirable consequences of alternative management strategies, uncertainty regarding the effects of the alternatives, uncertainty or variability in patients’ values and preferences or questionable cost-effectiveness. Weak recommendations usually require accessing the underlying evidence and a shared decision-making approach. Clinicians using GRADE recommendations should understand the meaning of the strength of the recommendation, be able to critically appraise the recommendation, and apply trustworthy recommendations according to their strength.
No preview · Article · Jan 2016 · Journal of clinical epidemiology
[Show abstract][Hide abstract] ABSTRACT: Background: Chronic kidney disease-mineral and bone disorders (CKD-MBD) have been associated with poor health outcomes, including diminished quality and length of life. Standard management for CKD-MBD includes phosphate-restricted diet, active vitamin D, vitamin D analogs, and phosphate binders. Persistently elevated parathyroid hormone (PTH) levels may require the addition of Cinacalcet hydrochloride (cinacalcet) which sensitizes calcium receptors on the parathyroid glands. The objective of this systematic review is to compare the effect of cinacalcet versus standard treatment in patients with CKD-MBD. Methods/design: Data sources will include MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and Web of Science from 1996 to June 2015. Teams of two reviewers will, independently and in duplicate, screen titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstract data and assess risk of bias in eligible trials. We will calculate the effect estimates (risk ratios or mean differences) and 95 % confidence intervals, as well as statistical measures of variability in results across studies using random effect models for patient-important and intermediate outcomes. We will use the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence about estimates of effect on an outcome-by-outcome basis. We will present our results with a GRADE summary table. Discussion: Our review will explore the effect of cinacalcet versus standard treatment in patients with CKD-MBD. The results of this systematic review will help guide management of this patient population, and identify targets for future research. Systematic review registration: PROSPERO CRD42015020318 http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015020318.
Full-text · Article · Jan 2016 · Systematic Reviews
[Show abstract][Hide abstract] ABSTRACT: Objectives We conducted a systematic survey of the methodological literature to identify recommended approaches for how and what randomised clinical trial (RCT) authors should report on missing participant data and, on the basis of these approaches, to propose guidance for RCT authors.
Methods We defined missing participant data (MPD) as missing outcome data for trial participants. We considered both categorical and continuous outcome data. We searched MEDLINE and the Cochrane Methodology Register for articles in which authors proposed approaches to reporting MPD from RCTs. We selected eligible articles independently and in duplicate and extracted data in duplicate. Using an iterative process of discussion and revisions, we used the findings to develop guidance.
Results Of 10 501 unique citations identified, 13 articles reporting on 10 approaches proved eligible. The identified approaches recommend reporting the following aspects (from most to least frequently recommended): number of participants with MPD (n=10), reasons for MPD (n=7), methods used to handle MPD in the analysis (n=4), flow of participants (n=3), pattern of missingness (eg, whether at random) (n=3), differences in rates of MPD between trial arms (n=2), differences between participants with and without MPD (n=2), results of any sensitivity analyses (n=2), implication of MPD on interpreting the results (n=2) and methods used to prevent missing data (n=1). We propose a guide with nine items related to reporting the number, reasons, patterns, analytical methods and interpretation of MPD.
Conclusions Most identified approaches invite trial authors to report the extent of MPD and the underlying reasons. Fewer approaches focus on reporting missingness patterns, methods for handling MPD and implications of MPD on results. Our proposed guidance could help RCT authors to better report, and readers to better identify participants with missing data.
[Show abstract][Hide abstract] ABSTRACT: Background and Overview. Clinicians using evidence to inform decisions on a daily basis have access to a number of tools to help them judge the importance of discriminating studies conducted using suboptimal methods from more rigorous ones. Many checklists have been developed to facilitate and guide clinicians to identify and critically appraise clinical studies. However, only limited guidance is available addressing how clinicians can identify misleading claims from those that can be supported reliably by study results. Practical Implications. In this final article of a series of 10, the authors provide key concepts that clinicians can use to help them avoid using biased inferences or statements that are "too good to be true."
No preview · Article · Dec 2015 · Journal of the American Dental Association (1939)
[Show abstract][Hide abstract] ABSTRACT: Pregnant women with prior venous thromboembolism (VTE) are at risk of recurrence. Prophylaxis with low molecular weight heparin (LWMH) reduces that risk but is inconvenient, costly, and may be associated with increased risks of obstetrical bleeding. The views of pregnant women, crucial when making prophylaxis recommendations, are currently unknown.
No preview · Article · Dec 2015 · Thrombosis Research
[Show abstract][Hide abstract] ABSTRACT: The impact of transfusing fresher versus older red blood cells on patient-important outcomes remains controversial. Two recently published large trials have provided new evidence. We summarized results of randomized trials evaluating the impact of the age of transfused red blood cells. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Database for Systematic Reviews and Cochrane CENTRAL for randomized controlled trials enrolling patients who were transfused fresher versus older red blood cells and reported on outcomes of death, adverse events, and infection. Independently and in duplicate, reviewers determined eligibility, risk of bias, and abstracted data. We conducted random effects meta-analyses and rated certainty (quality or confidence) of evidence using the GRADE approach. Of 12 trials that enrolled 5,229 participants, 6 compared fresher red blood cells to older red blood cells and six compared fresher red blood cells to current standard practice. There was little or no impact of fresher versus older red blood cells on mortality (relative risk (RR) 1.04, 95% CI 0.94-1.14, p=0.45, I(2)=0%, moderate certainty evidence) or on adverse events (RR 1.02, 95% CI 0.91-1.14, p=0.74, I(2)=0%, low certainty evidence). Fresher red blood cells appeared to increase the risk of nosocomial infection (RR 1.09, 95% CI 1.00-1.18, p=0.04, I(2)=0%, risk difference 4.3%, low certainty evidence). Current evidence provides moderate certainty that use of fresher red blood cells does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates. The existing evidence provides no support for changing practices towards fresher red blood cell transfusion.
[Show abstract][Hide abstract] ABSTRACT: Background:
Expressing treatment effects in relative terms yields larger numbers than expressions in absolute terms, affecting the judgement of the clinicians and patients regarding the treatment options. It is uncertain how authors of systematic reviews (SRs) absolute effect estimates are reported in). We therefore undertook a systematic survey to identify and describe the reporting and methods for calculating absolute effect estimates in SRs.
Two reviewers independently screened title, abstract and full text, and extracted data from a sample of Cochrane and non-Cochrane SRs. We used regression analyses to examine the association between study characteristics and the reporting of absolute estimates for the most patient-important outcome.
We included 202 SR (98 Cochrane and 104 non-Cochrane), the majority of which (92.1%) included standard meta-analyses including relative estimates of effect. Of the 202 SRs, 73 (36.1%) reported absolute effect estimates for the most patient-important outcome. SRs with statistically significant effects were more likely to report absolute estimates (odds ratio: 2.26, 95%-CI: 1.08 to 4.74). The most commonly reported absolute estimates were: for each intervention, risk of adverse outcomes expressed as a percentage (41.1%); number needed to treat (26.0%); and risk for each intervention expressed as natural units or natural frequencies (24.7%). In 12.3% of the SRs that reported absolute effect estimates for both benefit and harm outcomes, harm outcomes were reported exclusively as absolute estimates. Exclusively reporting of beneficial outcomes as absolute estimates occurred in 6.8% of the SRs.
Most SRs do not report absolute effects. Those that do often report them inadequately, thus requiring users of SRs to generate their own estimates of absolute effects. For any apparently effective or harmful intervention, SR authors should report both absolute and relative estimates to optimise the interpretation of their findings.
Full-text · Article · Nov 2015 · Journal of clinical epidemiology
[Show abstract][Hide abstract] ABSTRACT: Background/objective:
Prior studies regarding whether single centre trial estimates are larger than multi-centre are equivocal. We examined the extent to which single centre trials yield systematically larger effects than multi-centre trials.
We searched the 119 core clinical journals and the Cochrane Database of Systematic Reviews for meta-analyses (MAs) of RCTs published during 2012. In this meta-epidemiological study, for binary variables we computed the pooled ratio of ORs (ROR), and for continuous outcomes mean difference in SMDs, and conducted weighted random-effects meta-regression and random-effects meta-analyses modeling. Our primary analyses were restricted to MAs that included at least 5 RCTs and in which at least 25% of the studies used each of SC and MC designs.
We identified 81 MAs for the OR and 43 for the SMD outcome measures. Based on our analytic plan, our primary analysis (core) is based on 25 MAs/241 RCTs (binary outcome) and 18 MAs/173 RCTs (continuous outcome). Based on the core analysis, we found no difference in magnitude of effect between SC and MC for binary outcomes (RORs: 1.02, 95% CI 0.83-1.24, I(2) 20.2%). Effect sizes were systematically larger for SC than MC for the continuous outcome measure (mean difference in SMDs: -0.13, 95% CI -0.21- -0.05, I(2) 0 %).
Our results do not support prior findings of larger effects in SC than MC trials addressing binary outcomes, but show a very similar small increase in effect in SC than MC trials addressing continuous outcomes. Authors of systematic reviews would be wise to include all trials irrespective of SC versus MC design and address SC versus MC status as a possible explanation of heterogeneity (and consider sensitivity analyses).
No preview · Article · Nov 2015 · Journal of clinical epidemiology
[Show abstract][Hide abstract] ABSTRACT: Background:
Meta-analyses of continuous outcomes typically provide enough information for decision-makers to evaluate the extent to which chance can explain apparent differences between interventions. The interpretation of the magnitude of these differences - from trivial to large - can, however, be challenging. We investigated clinicians' understanding and perceptions of usefulness of 6 statistical formats for presenting continuous outcomes from meta-analyses (standardized mean difference, minimal important difference units, mean difference in natural units, ratio of means, relative risk and risk difference).
We invited 610 staff and trainees in internal medicine and family medicine programs in 8 countries to participate. Paperbased, self-administered questionnaires presented summary estimates of hypothetical interventions versus placebo for chronic pain. The estimates showed either a small or a large effect for each of the 6 statistical formats for presenting continuous outcomes. Questions addressed participants' understanding of the magnitude of treatment effects and their perception of the usefulness of the presentation format. We randomly assigned participants 1 of 4 versions of the questionnaire, each with a different effect size (large or small) and presentation order for the 6 formats (1 to 6, or 6 to 1).
Overall, 531 (87.0%) of the clinicians responded. Respondents best understood risk difference, followed by relative risk and ratio of means. Similarly, they perceived the dichotomous presentation of continuous outcomes (relative risk and risk difference) to be most useful. Presenting results as a standardized mean difference, the longest standing and most widely used approach, was poorly understood and perceived as least useful.
None of the presentation formats were well understood or perceived as extremely useful. Clinicians best understood the dichotomous presentations of continuous outcomes and perceived them to be the most useful. Further initiatives to help clinicians better grasp the magnitude of the treatment effect are needed.
Full-text · Article · Oct 2015 · Canadian Medical Association Journal
[Show abstract][Hide abstract] ABSTRACT: SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan.
We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken.
This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results.
ClinicalTrials.gov: NCT01109693 (registered on 21 April 2010).
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND The management of open fractures requires wound irrigation and debridement to remove contaminants, but the effectiveness of various pressures and solutions for irrigation remains controversial. We investigated the effects of castile soap versus normal saline irrigation delivered by means of high, low, or very low irrigation pressure. METHODS In this study with a 2-by-3 factorial design, conducted at 41 clinical centers, we randomly assigned patients who had an open fracture of an extremity to undergo irrigation with one of three irrigation pressures (high pressure [>20 psi], low pressure [5 to 10 psi], or very low pressure [1 to 2 psi]) and one of two irrigation solutions (castile soap or normal saline). The primary end point was reoperation within 12 months after the index surgery for promotion of wound or bone healing or treatment of a wound infection. RESULTS A total of 2551 patients underwent randomization, of whom 2447 were deemed eligible and included in the final analyses. Reoperation occurred in 109 of 826 patients (13.2%) in the high-pressure group, 103 of 809 (12.7%) in the low-pressure group, and 111 of 812 (13.7%) in the very-low-pressure group. Hazard ratios for the three pairwise comparisons were as follows: for low versus high pressure, 0.92 (95% confidence interval [CI], 0.70 to 1.20; P = 0.53), for high versus very low pressure, 1.02 (95% CI, 0.78 to 1.33; P = 0.89), and for low versus very low pressure, 0.93 (95% CI, 0.71 to 1.23; P = 0.62). Reoperation occurred in 182 of 1229 patients (14.8%) in the soap group and in 141 of 1218 (11.6%) in the saline group (hazard ratio, 1.32, 95% CI, 1.06 to 1.66; P = 0.01). CONCLUSIONS The rates of reoperation were similar regardless of irrigation pressure, a finding that indicates that very low pressure is an acceptable, low-cost alternative for the irrigation of open fractures. The reoperation rate was higher in the soap group than in the saline group.
Full-text · Article · Oct 2015 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Background: Community-acquired pneumonia (CAP) is common and often severe. Purpose: To examine the effect of adjunctive corticosteroid therapy on mortality, morbidity, and duration of hospitalization in patients with CAP. Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through 24 May 2015. Study Selection: Randomized trials of systemic corticosteroids in hospitalized adults with CAP. Data Extraction: Two reviewers independently extracted study data and assessed risk of bias. Quality of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation system by consensus among the authors. Data Synthesis: The median age was typically in the 60s, and approximately 60% of patients were male. Adjunctive corticosteroids were associated with possible reductions in all-cause mortality (12 trials; 1974 patients; risk ratio [RR], 0.67 [95% CI, 0.45 to 1.01]; risk difference [RD], 2.8%; moderate certainty), need for mechanical ventilation (5 trials; 1060 patients; RR, 0.45 [CI, 0.26 to 0.79]; RD, 5.0%; moderate certainty), and the acute respiratory distress syndrome (4 trials; 945 patients; RR, 0.24 [CI, 0.10 to 0.56]; RD, 6.2%; moderate certainty). They also decreased time to clinical stability (5 trials; 1180 patients; mean difference,-1.22 days [CI, -2.08 to -0.35 days]; high certainty) and duration of hospitalization (6 trials; 1499 patients; mean difference, -1.00 day [CI, -1.79 to -0.21 days]; high certainty). Adjunctive corticosteroids increased frequency of hyperglycemia requiring treatment (6 trials; 1534 patients; RR, 1.49 [CI, 1.01 to 2.19]; RD, 3.5%; high certainty) but did not increase frequency of gastrointestinal hemorrhage. Limitations: There were few events and trials for many outcomes. Trials often excluded patients at high risk for adverse events. Conclusion: For hospitalized adults with CAP, systemic corticosteroid therapy may reduce mortality by approximately 3%, need for mechanical ventilation by approximately 5%, and hospital stay by approximately 1 day. Primary Funding Source: None.
No preview · Article · Oct 2015 · Annals of internal medicine
[Show abstract][Hide abstract] ABSTRACT: Introduction
Patient-reported outcomes (PROs) are often the outcomes of greatest importance to patients. The minimally important difference (MID) provides a measure of the smallest change in the PRO that patients perceive as important. An anchor-based approach is the most appropriate method for MID determination. No study or database currently exists that provides all anchor-based MIDs associated with PRO instruments; nor are there any accepted standards for appraising the credibility of MID estimates. Our objectives are to complete a systematic survey of the literature to collect and characterise published anchor-based MIDs associated with PRO instruments used in evaluating the effects of interventions on chronic medical and psychiatric conditions and to assess their credibility.
Methods and analysis
We will search MEDLINE, EMBASE and PsycINFO (1989 to present) to identify studies addressing methods to estimate anchor-based MIDs of target PRO instruments or reporting empirical ascertainment of anchor-based MIDs. Teams of two reviewers will screen titles and abstracts, review full texts of citations, and extract relevant data. On the basis of findings from studies addressing methods to estimate anchor-based MIDs, we will summarise the available methods and develop an instrument addressing the credibility of empirically ascertained MIDs. We will evaluate the credibility of all studies reporting on the empirical ascertainment of anchor-based MIDs using the credibility instrument, and assess the instrument's inter-rater reliability. We will separately present reports for adult and paediatric populations.
Ethics and dissemination
No research ethics approval was required as we will be using aggregate data from published studies. Our work will summarise anchor-based methods available to establish MIDs, provide an instrument to assess the credibility of available MIDs, determine the reliability of that instrument, and provide a comprehensive compendium of published anchor-based MIDs associated with PRO instruments which will help improve the interpretability of outcome effects in systematic reviews and practice guidelines.
[Show abstract][Hide abstract] ABSTRACT: Objectives
To describe how systematic reviewers are reporting missing data for dichotomous outcomes, handling them in the analysis and assessing the risk of associated bias.
We searched MEDLINE and the Cochrane Database of Systematic Reviews for systematic reviews of randomised trials published in 2010, and reporting a meta-analysis of a dichotomous outcome. We randomly selected 98 Cochrane and 104 non-Cochrane systematic reviews. Teams of 2 reviewers selected eligible studies and abstracted data independently and in duplicate using standardised, piloted forms with accompanying instructions. We conducted regression analyses to explore factors associated with using complete case analysis and with judging the risk of bias associated with missing participant data.
Of Cochrane and non-Cochrane reviews, 47% and 7% (p<0.0001), respectively, reported on the number of participants with missing data, and 41% and 9% reported a plan for handling missing categorical data. The 2 most reported approaches for handling missing data were complete case analysis (8.5%, out of the 202 reviews) and assuming no participants with missing data had the event (4%). The use of complete case analysis was associated only with Cochrane reviews (relative to non-Cochrane: OR=7.25; 95% CI 1.58 to 33.3, p=0.01). 65% of reviews assessed risk of bias associated with missing data; this was associated with Cochrane reviews (relative to non-Cochrane: OR=6.63; 95% CI 2.50 to 17.57, p=0.0001), and the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (OR=5.02; 95% CI 1.02 to 24.75, p=0.047).
Though Cochrane reviews are somewhat less problematic, most Cochrane and non-Cochrane systematic reviews fail to adequately report and handle missing data, potentially resulting in misleading judgements regarding risk of bias.