Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease: A Series of N-of-1 Diet Trials.

INTRODUCTION: Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD). METHODS: Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation. Following a 2-week baseline (UD), patients were randomized to 1 of 2 sequences of 4 alternating 8-week SCD and MSCD periods. Outcomes included fecal calprotectin and patient-reported symptoms. We report posterior probabilities from Bayesian models comparing diets. RESULTS: Twenty-one (39%) participants completed the trial, 9 (17%) completed a single crossover, and 24 (44%) withdrew. Withdrawal or early completion occurred commonly (lack of response [n = 11], adverse events [n = 11], and not desiring to continue [n = 6]). SCD and MSCD performed similarly for most individuals. On average, there was <1% probability of a clinically meaningful difference in IBD symptoms between SCD and MSCD. The average treatment difference was -0.3 (95% credible interval -1.2, 0.75). There was no significant difference in the ratio of fecal calprotectin geometric means comparing SCD and MSCD (0.77, 95% credible interval 0.51, 1.10). Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not. DISCUSSION: SCD and MSCD did not consistently improve symptoms or inflammation, although some individuals may have benefited. However, there are inherent difficulties in examining dietary changes that complicate study design and ultimately conclusions regarding effectiveness.

EMBRACE: An EM-based bias reduction approach through Copas-model estimation for quantifying the evidence of selective publishing in network meta-analysis.

Systematic reviews and meta-analyses synthesize results from well-conducted studies to optimize healthcare decision-making. Network meta-analysis (NMA) is particularly useful for improving precision, drawing new comparisons, and ranking multiple interventions. However, recommendations can be misled if published results are a selective sample of what has been collected by trialists, particularly when publication status is related to the significance of the findings. Unfortunately, the missing-not-at-random nature of this problem and the numerous parameters involved in modeling NMAs pose unique computational challenges to quantifying and correcting for publication bias, such that sensitivity analysis is used in practice. Motivated by this important methodological gap, we developed a novel and stable expectation-maximization (EM) algorithm to correct for publication bias in the network setting. We validate the method through simulation studies and show that it achieves substantial bias reduction in small to moderately sized NMAs. We also calibrate the method against a Bayesian analysis of a published NMA on antiplatlet therapies for maintaining vascular patency.

Assessing Heterogeneity of Treatment Effects in Observational Studies.

Here we describe methods for assessing heterogeneity of treatment effects over prespecified subgroups in observational studies, using outcome-model-based (g-formula), inverse probability weighting, doubly robust, and matching estimators of subgroup-specific potential outcome means, conditional average treatment effects, and measures of heterogeneity of treatment effects. We compare the finite-sample performance of different estimators in simulation studies where we vary the total sample size, the relative frequency of each subgroup, the magnitude of treatment effect in each subgroup, and the distribution of baseline covariates, for both continuous and binary outcomes. We find that the estimators' bias and variance vary substantially in finite samples, even when there is no unobserved confounding and no model misspecification. As an illustration, we apply the methods to data from the Coronary Artery Surgery Study (August 1975-December 1996) to compare the effect of surgery plus medical therapy with that of medical therapy alone for chronic coronary artery disease in subgroups defined by previous myocardial infarction or left ventricular ejection fraction.

Assessing the performance of clinical diagnostic models for dehydration among patients with cholera and undernutrition in Bangladesh.

OBJECTIVE: Accurately assessing dehydration severity is a critical step in reducing mortality from diarrhoea, but is complicated by cholera and undernutrition. This study seeks to assess the accuracy of two clinical diagnostic models for dehydration among patients over five years with cholera and undernutrition and compare their respective performance to the World Health Organization (WHO) algorithm. METHODS: In this secondary analysis of data collected from the NIRUDAK study, accuracy of the full and simplified NIRUDAK models for predicting severe and any dehydration was measured using the area under the Receiver Operator Characteristic curve (AUC) among patients over five with/without cholera and with/without wasting. Bootstrap with 1000 iterations was used to compare the m-index for each NIRUDAK model to that of the WHO algorithm. RESULTS: A total of 2,139 and 2,108 patients were included in the nutrition and cholera subgroups respectively with an overall median age of 35 years (IQR = 42) and 49.6% female. All subgroups had acceptable discrimination in diagnosing severe or any dehydration (AUC > 0.60); though the full NIRUDAK model performed best among patients without cholera, with an AUC of 0.82 (95%CI:0.79, 0.85) and among patients without wasting, with an AUC of 0.79 (95%CI:0.76, 0.81). Compared with the WHO's algorithm, both the full and simplified NIRUDAK models performed significantly better in terms of their m-index (p < 0.001) for all comparisons, except for the simplified NIRUDAK model in the wasting group. CONCLUSIONS: Both the full and simplified NIRUDAK models performed less well in patients over five years with cholera and/or wasting; however, both performed better than the WHO algorithm.

Effect of Mobile Device-Assisted N-of-1 Trial Participation on Analgesic Prescribing for Chronic Pain: Randomized Controlled Trial.

OBJECTIVES: Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for chronic musculoskeletal pain, despite limited evidence of effectiveness and well-documented adverse effects. We assessed the effects of participating in a structured, personalized self-experiment ("N-of-1 trial") on analgesic prescribing in patients with chronic musculoskeletal pain. METHODS: We randomized 215 patients with chronic pain to participate in an N-of-1 trial facilitated by a mobile health app or to receive usual care. Medical records of participating patients were reviewed at enrollment and 6 months later to assess analgesic prescribing. We established thresholds of ≥ 50, ≥ 20, and > 0 morphine milligram equivalents (MMEs) per day to capture patients taking relatively high doses only, patients taking low-moderate as well as relatively high doses, and patients taking any dose of opioids, respectively. RESULTS: There was no significant difference between the N-of-1 and control groups in the percentage of patients prescribed any opioids (relative odds ratio (ROR) = 1.05; 95% confidence interval [CI] = 0.61 to 1.80, p = 0.87). There was a clinically substantial but statistically not significant reduction of the percentage of patients receiving ≥ 20 MME (ROR = 0.58; 95% CI = 0.33 to 1.04, p = 0.07) and also in the percentage receiving ≥ 50 MME (ROR = 0.50; 95% CI = 0.19 to 1.34, p = 0.17). There was a significant reduction in the proportion of patients in the N-of-1 group prescribed NSAIDs compared with control (relative odds ratio = 0.53; 95% CI = 0.29 to 0.96, p = 0.04), with no concomitant increase in average pain intensity. There was no significant change in use of adjunctive medications (acetaminophen, gabapentenoids, or topicals). DISCUSSION: These exploratory results suggest that participation in N-of-1 trials may reduce long-term use of NSAIDs; there is also a weak signal for an effect on use of opioids. Additional research is needed to confirm these results and elucidate possible mechanisms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02116621.

Comparison of revascularization strategies in patients with acute coronary syndrome and multivessel coronary disease: A systematic review and network meta-analysis.

BACKGROUND: Whether revascularization should be performed as multivessel intervention at the time of index procedure (MV-index), staged procedure (MV-staged), or culprit only intervention (COI) in patients with multivessel disease (MVD) presenting with acute coronary syndrome (ACS) is unclear. We performed a systematic review and network meta-analysis of randomized controlled trials to assess the optimal revascularization strategy in this patient population. METHODS: PubMed, Embase, and Cochrane Central databases were systematically searched to identify all relevant studies. The outcomes assessed were major cardiac adverse events (MACE), all-cause mortality, cardiovascular mortality, myocardial infarction (MI), and revascularization. A Bayesian random-effects network meta-analysis was used to calculate odds ratio (OR) with credible interval (CrI). RESULTS: Thirteen studies with 8,066 patients were included in the analysis. There was a decreased risk of MACE (MV-index vs. COI: OR, 0.35; 95% CrI, 0.23-0.55; MV-staged vs COI: OR, 0.52; 95% CrI, 0.31-0.81) and revascularization (MV-index vs. COI: OR, 0.27; 95% CrI, 0.15-0.49; MV-staged vs. COI: OR, 0.38; 95% CrI, 0.19-0.70) with MV-index intervention and MV-staged intervention compared with COI. However, MV-index intervention and not MV-staged intervention was associated with a decreased risk of MI (MV-index vs. COI: OR, 0.35; 95% CrI, 0.12-0.93; MV-staged vs. COI: OR, 0.65; 95% CrI, 0.24-1.59) compared with COI. CONCLUSIONS: Our analysis suggests that multivessel intervention either at index procedure or as staged intervention may be more efficacious compared to COI in patients with MVD presenting with ACS.

Active learning for efficiently training emulators of computationally expensive mathematical models.

An emulator is a fast-to-evaluate statistical approximation of a detailed mathematical model (simulator). When used in lieu of simulators, emulators can expedite tasks that require many repeated evaluations, such as sensitivity analyses, policy optimization, model calibration, and value-of-information analyses. Emulators are developed using the output of simulators at specific input values (design points). Developing an emulator that closely approximates the simulator can require many design points, which becomes computationally expensive. We describe a self-terminating active learning algorithm to efficiently develop emulators tailored to a specific emulation task, and compare it with algorithms that optimize geometric criteria (random latin hypercube sampling and maximum projection designs) and other active learning algorithms (treed Gaussian Processes that optimize typical active learning criteria). We compared the algorithms' root mean square error (RMSE) and maximum absolute deviation from the simulator (MAX) for seven benchmark functions and in a prostate cancer screening model. In the empirical analyses, in simulators with greatly varying smoothness over the input domain, active learning algorithms resulted in emulators with smaller RMSE and MAX for the same number of design points. In all other cases, all algorithms performed comparably. The proposed algorithm attained satisfactory performance in all analyses, had smaller variability than the treed Gaussian Processes, and, on average, had similar or better performance as the treed Gaussian Processes in six out of seven benchmark functions and in the prostate cancer model.

Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses.

BACKGROUND: Most randomized controlled trials (RCTs) and meta-analyses of RCTs examine effect modification (also called a subgroup effect or interaction), in which the effect of an intervention varies by another variable (e.g., age or disease severity). Assessing the credibility of an apparent effect modification presents challenges; therefore, we developed the Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN). METHODS: To develop ICEMAN, we established a detailed concept; identified candidate credibility considerations in a systematic survey of the literature; together with experts, performed a consensus study to identify key considerations and develop them into instrument items; and refined the instrument based on feedback from trial investigators, systematic review authors and journal editors, who applied drafts of ICEMAN to published claims of effect modification. RESULTS: The final instrument consists of a set of preliminary considerations, core questions (5 for RCTs, 8 for meta-analyses) with 4 response options, 1 optional item for additional considerations and a rating of credibility on a visual analogue scale ranging from very low to high. An accompanying manual provides rationales, detailed instructions and examples from the literature. Seventeen potential users tested ICEMAN; their suggestions improved the user-friendliness of the instrument. INTERPRETATION: The Instrument for assessing the Credibility of Effect Modification Analyses offers explicit guidance for investigators, systematic reviewers, journal editors and others considering making a claim of effect modification or interpreting a claim made by others.

Discussion of "quantifying publication bias in meta-analysis" by Lin et al.

Inspection and analysis of funnel plots cannot reliably identify publication and reporting bias, the non-publication of results that are not statistically significant. Instead, researchers should thoroughly and systematically search available information sources such as databases, registries and unpublished reports. Even then, it is not possible to ever know whether a systematic review has uncovered all available studies, but the search can inform attempts to construct plausible statistical models of the missing data mechanism.

A simple and robust method for multivariate meta-analysis of diagnostic test accuracy.

Meta-analysis of diagnostic test accuracy often involves mixture of case-control and cohort studies. The existing bivariate random-effects models, which jointly model bivariate accuracy indices (e.g., sensitivity and specificity), do not differentiate cohort studies from case-control studies and thus do not utilize the prevalence information contained in the cohort studies. The recently proposed trivariate generalized linear mixed-effects models are only applicable to cohort studies, and more importantly, they assume a common correlation structure across studies and trivariate normality on disease prevalence, test sensitivity, and specificity after transformation by some pre-specified link functions. In practice, very few studies provide justifications of these assumptions, and sometimes these assumptions are violated. In this paper, we evaluate the performance of the commonly used random-effects model under violations of these assumptions and propose a simple and robust method to fully utilize the information contained in case-control and cohort studies. The proposed method avoids making the aforementioned assumptions and can provide valid joint inferences for any functions of overall summary measures of diagnostic accuracy. Through simulation studies, we find that the proposed method is more robust to model misspecifications than the existing methods. We apply the proposed method to a meta-analysis of diagnostic test accuracy for the detection of recurrent ovarian carcinoma. Copyright © 2016 John Wiley & Sons, Ltd.

Comparative Effectiveness of Tai Chi Versus Physical Therapy for Knee Osteoarthritis: A Randomized Trial.

BACKGROUND: Few remedies effectively treat long-term pain and disability from knee osteoarthritis. Studies suggest that Tai Chi alleviates symptoms, but no trials have directly compared Tai Chi with standard therapies for osteoarthritis. OBJECTIVE: To compare Tai Chi with standard physical therapy for patients with knee osteoarthritis. DESIGN: Randomized, 52-week, single-blind comparative effectiveness trial. (ClinicalTrials.gov: NCT01258985). SETTING: An urban tertiary care academic hospital. PATIENTS: 204 participants with symptomatic knee osteoarthritis (mean age, 60 years; 70% women; 53% white). INTERVENTION: Tai Chi (2 times per week for 12 weeks) or standard physical therapy (2 times per week for 6 weeks, followed by 6 weeks of monitored home exercise). MEASUREMENTS: The primary outcome was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 12 weeks. Secondary outcomes included physical function, depression, medication use, and quality of life. RESULTS: At 12 weeks, the WOMAC score was substantially reduced in both groups (Tai Chi, 167 points [95% CI, 145 to 190 points]; physical therapy, 143 points [CI, 119 to 167 points]). The between-group difference was not significant (24 points [CI, -10 to 58 points]). Both groups also showed similar clinically significant improvement in most secondary outcomes, and the benefits were maintained up to 52 weeks. Of note, the Tai Chi group had significantly greater improvements in depression and the physical component of quality of life. The benefit of Tai Chi was consistent across instructors. No serious adverse events occurred. LIMITATION: Patients were aware of their treatment group assignment, and the generalizability of the findings to other settings remains undetermined. CONCLUSION: Tai Chi produced beneficial effects similar to those of a standard course of physical therapy in the treatment of knee osteoarthritis. PRIMARY FUNDING SOURCE: National Center for Complementary and Integrative Health of the National Institutes of Health.

The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement.

We developed a reporting guideline to provide authors with guidance about what should be reported when writing a paper for publication in a scientific journal using a particular type of research design: the single-case experimental design. This report describes the methods used to develop the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016. As a result of 2 online surveys and a 2-day meeting of experts, the SCRIBE 2016 checklist was developed, which is a set of 26 items that authors need to address when writing about single-case research. This article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016 ) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. We recommend that the SCRIBE 2016 is used by authors preparing manuscripts describing single-case research for publication, as well as journal reviewers and editors who are evaluating such manuscripts. SCIENTIFIC ABSTRACT Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012 ). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008 ) provides suitable guidance for reporting between-groups intervention studies in the behavioural sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015 ; Vohra et al., 2015 ), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioural sciences. We developed the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016 ) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated.

Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis.

BACKGROUND: The role of change in proteinuria as a surrogate end point for randomized trials in immunoglobulin A nephropathy (IgAN) has previously not been thoroughly evaluated. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & POPULATION: Individual-patient data for 830 patients from 11 randomized trials evaluating 4 intervention types (renin-angiotensin system [RAS] blockade, fish oil, immunosuppression, and steroids) examining associations between changes in urine protein and clinical end points at the individual and trial levels. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials of IgAN with measurements of proteinuria at baseline and a median of 9 (range, 5-12) months follow-up, with at least 1 further year of follow-up for the clinical outcome. PREDICTOR: 9-month change in proteinuria. OUTCOME: Doubling of serum creatinine level, end-stage renal disease, or death. RESULTS: Early decline in proteinuria at 9 months was associated with lower risk for the clinical outcome (HR per 50% reduction in proteinuria, 0.40; 95% CI, 0.32-0.48) and was consistent across studies. Proportions of treatment effect on the clinical outcome explained by early decline in proteinuria were estimated at 11% (95% CI, -19% to 41%) for RAS blockade and 29% (95% CI, 6% to 53%) for steroid therapy. The direction of the pooled treatment effect on early change in proteinuria was in accord with the direction of the treatment effect on the clinical outcome for steroids and RAS blockade. Trial-level analyses estimated that the slope for the regression line for the association of treatment effects on the clinical end points and for the treatment effect on proteinuria was 2.15 (95% Bayesian credible interval, 0.10-4.32). LIMITATIONS: Study population restricted to 11 trials, all having fewer than 200 patients each with a limited number of clinical events. CONCLUSIONS: Results of this analysis offer novel evidence supporting the use of an early reduction in proteinuria as a surrogate end point for clinical end points in IgAN in selected settings.

Leukotriene-receptor antagonists versus placebo in the treatment of asthma in adults and adolescents: a systematic review and meta-analysis.

BACKGROUND: Leukotriene-receptor antagonists (LTRAs) are recommended as an alternative treatment in patients with mild asthma, but their effect compared with placebo is unclear. PURPOSE: To determine the benefits and harms of LTRAs as monotherapy or in combination with inhaled corticosteroids compared with placebo in adults and adolescents with asthma. DATA SOURCES: MEDLINE and the Cochrane Central Register of Controlled Trials from inception through June 2015. STUDY SELECTION: Peer-reviewed, English-language, randomized, controlled trials in patients with asthma that reported the effect of LTRAs versus placebo on measures of asthma control. DATA EXTRACTION: Three researchers extracted data on study population, interventions, outcome measures, and adverse events. One researcher assessed risk of bias. DATA SYNTHESIS: Of the 2008 abstracts that were screened, 50 trials met eligibility criteria. Random-effects meta-analyses of 6 trials of LTRA monotherapy showed that LTRAs reduced the risk for an exacerbation (summary risk ratio [RR], 0.60 [95% CI, 0.44 to 0.81]). In 4 trials of LTRAs as add-on therapy to inhaled corticosteroids, the summary RR for exacerbation was 0.80 (CI, 0.60 to 1.07). Leukotriene-receptor antagonists either as monotherapy or as add-on therapy to inhaled corticosteroids increased FEV1, whereas FEV1 percentage of predicted values was improved only in trials of LTRA monotherapy. Adverse event rates were similar in the intervention and comparator groups. LIMITATION: Variation in definitions and reporting of outcomes, high risk of bias in some studies, heterogeneity of findings, possible selective outcome reporting bias, and inability to assess the effect of asthma severity on summary estimates. CONCLUSION: Leukotriene-receptor antagonists as monotherapy improved asthma control compared with placebo, but which patients are most likely to respond to treatment with LTRAs remains unclear. PRIMARY FUNDING SOURCE: National Institutes of Health.

Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis.

BACKGROUND: The relative efficacy of available treatments of knee osteoarthritis (OA) must be determined for rational treatment algorithms to be formulated. PURPOSE: To examine the efficacy of treatments of primary knee OA using a network meta-analysis design, which estimates relative effects of all treatments against each other. DATA SOURCES: MEDLINE, EMBASE, Web of Science, Google Scholar, Cochrane Central Register of Controlled Trials from inception through 15 August 2014, and unpublished data. STUDY SELECTION: Randomized trials of adults with knee OA comparing 2 or more of the following: acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, intra-articular (IA) corticosteroids, IA hyaluronic acid, oral placebo, and IA placebo. DATA EXTRACTION: Two reviewers independently abstracted study data and assessed study quality. Standardized mean differences were calculated for pain, function, and stiffness at 3-month follow-up. DATA SYNTHESIS: Network meta-analysis was performed using a Bayesian random-effects model; 137 studies comprising 33,243 participants were identified. For pain, all interventions significantly outperformed oral placebo, with effect sizes from 0.63 (95% credible interval [CrI], 0.39 to 0.88) for the most efficacious treatment (hyaluronic acid) to 0.18 (CrI, 0.04 to 0.33) for the least efficacious treatment (acetaminophen). For function, all interventions except IA corticosteroids were significantly superior to oral placebo. For stiffness, most of the treatments did not significantly differ from one another. LIMITATION: Lack of long-term data, inadequate reporting of safety data, possible publication bias, and few head-to-head comparisons. CONCLUSION: This method allowed comparison of common treatments of knee OA according to their relative efficacy. Intra-articular treatments were superior to nonsteroidal anti-inflammatory drugs, possibly because of the integrated IA placebo effect. Small but robust differences were observed between active treatments. All treatments except acetaminophen showed clinically significant improvement from baseline pain. This information, along with the safety profiles and relative costs of included treatments, will be helpful for individualized patient care decisions. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials.

BACKGROUND: Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials. OBJECTIVE: To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis. DATA SOURCES: MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data. STUDY SELECTION: 149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos. DATA EXTRACTION: Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool. DATA SYNTHESIS: Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior. LIMITATIONS: Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos. CONCLUSION: All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.

The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses. A group of experts participated in a systematic review, Delphi survey, and face-to-face discussion and consensus meeting to establish new checklist items for this extension statement. Current PRISMA items were also clarified. A modified, 32-item PRISMA extension checklist was developed to address what the group considered to be immediately relevant to the reporting of network meta-analyses. This document presents the extension and provides examples of good reporting, as well as elaborations regarding the rationale for new checklist items and the modification of previously existing items from the PRISMA statement. It also highlights educational information related to key considerations in the practice of network meta-analysis. The target audience includes authors and readers of network meta-analyses, as well as journal editors and peer reviewers.

The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement.

Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012). Many such guidelines exist, and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008) provides suitable guidance for reporting between-groups intervention studies in the behavioral sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015; Vohra et al., 2015), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioral sciences. We developed the Single-Case Reporting guideline In Behavioral interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated.

Estimating glomerular filtration rate from serum creatinine and cystatin C.

BACKGROUND: Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR. METHODS: Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials. RESULTS: Mean measured GFRs were 68 and 70 ml per minute per 1.73 m(2) of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine-cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m(2) with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m(2) with the creatinine equation and the cystatin C equation (P=0.07 and P=0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m(2), respectively [P=0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m(2), the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m(2) or greater than or equal to 60 ml per minute per 1.73 m(2) (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m(2) as having a GFR of 60 ml or higher per minute per 1.73 m(2). CONCLUSIONS: The combined creatinine-cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients.

BACKGROUND: Modern immunosuppressive regimens after kidney transplantation usually use a combination of two or three agents of different classes to prevent rejection and maintain graft function. Most frequently, calcineurin-inhibitors (CNI) are combined with corticosteroids and a proliferation-inhibitor, either azathioprine (AZA) or mycophenolic acid (MPA). MPA has largely replaced AZA as a first line agent in primary immunosuppression, as MPA is believed to be of stronger immunosuppressive potency than AZA. However, treatment with MPA is more costly, which calls for a comprehensive assessment of the comparative effects of the two drugs. OBJECTIVES: This review of randomised controlled trials (RCTs) aimed to look at the benefits and harms of MPA versus AZA in primary immunosuppressive regimens after kidney transplantation. Both agents were compared regarding their efficacy for maintaining graft and patient survival, prevention of acute rejection, maintaining graft function, and their safety, including infections, malignancies and other adverse events. Furthermore, we investigated potential effect modifiers, such as transplantation era and the concomitant immunosuppressive regimen in detail. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register (to 21 September 2015) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: All RCTs about MPA versus AZA in primary immunosuppression after kidney transplantation were included, without restriction on language or publication type. DATA COLLECTION AND ANALYSIS: Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included 23 studies (94 reports) that involved 3301 participants. All studies tested mycophenolate mofetil (MMF), an MPA, and 22 studies reported at least one outcome relevant for this review. Assessment of methodological quality indicated that important information on factors used to judge susceptibility for bias was infrequently and inconsistently reported.MMF treatment reduced the risk for graft loss including death (RR 0.82, 95% CI 0.67 to 1.0) and for death-censored graft loss (RR 0.78, 95% CI 0.62 to 0.99, P < 0.05). No statistically significant difference for MMF versus AZA treatment was found for all-cause mortality (16 studies, 2987 participants: RR 0.95, 95% CI 0.70 to 1.29). The risk for any acute rejection (22 studies, 3301 participants: RR 0.65, 95% CI 0.57 to 0.73, P < 0.01), biopsy-proven acute rejection (12 studies, 2696 participants: RR 0.59, 95% CI 0.52 to 0.68) and antibody-treated acute rejection (15 studies, 2914 participants: RR 0.48, 95% CI 0.36 to 0.65, P < 0.01) were reduced in MMF treated patients. Meta-regression analyses suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rate (relative risk reduction (RRR) 0.34, 95% CI 0.10 to 1.09, P = 0.08), AZA dose (RRR 1.01, 95% CI 1.00 to 1.01, P = 0.10) and the use of cyclosporin A micro-emulsion (RRR 1.27, 95% CI 0.98 to 1.65, P = 0.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures.Data on malignancies and infections were sparse, except for cytomegalovirus (CMV) infections. The risk for CMV viraemia/syndrome (13 studies, 2880 participants: RR 1.06, 95% CI 0.85 to 1.32) was not statistically significantly different between MMF and AZA treated patients, whereas the likelihood of tissue-invasive CMV disease was greater with MMF therapy (7 studies, 1510 participants: RR 1.70, 95% CI 1.10 to 2.61). Adverse event profiles varied: gastrointestinal symptoms were more likely in MMF treated patients and thrombocytopenia and elevated liver enzymes were more common in AZA treatment. AUTHORS' CONCLUSIONS: MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation. These benefits must be weighed against potential harms such as tissue-invasive CMV disease. However, assessment of the evidence on safety outcomes was limited due to rare events in the observation periods of the studies (e.g. malignancies) and inconsistent reporting and definitions (e.g. infections, adverse events). Thus, balancing benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent the individual patient should be started on.