Heart failure events in randomized controlled trials for adults receiving maintenance dialysis: a meta-epidemiologic study.

BACKGROUND AND HYPOTHESIS: Heart failure is characterized as cardiac dysfunction resulting in elevated cardiac filling pressures with symptoms and signs of congestion. Distinguishing heart failure from other causes of similar presentations in patients with kidney failure is challenging but necessary, and is needed in randomized controlled trials (RCTs) to accurately estimate treatment effects. The objective of this study was to review heart failure events, their diagnostic criteria and adjudication in RCTs of patients with kidney failure treated with dialysis. We hypothesized that heart failure events, diagnostic criteria and adjudication were infrequently reported in RCTs in dialysis. METHODS: We conducted a meta-epidemiologic systematic review of RCTs from high impact medical, nephrology and cardiology journals from 2000 to 2020. RCTs were eligible if they enrolled adults receiving maintenance dialysis for kidney failure and evaluated any intervention. Results. Of 561 RCTs in patients receiving dialysis, 36 (6.4%) reported heart failure events as primary (10, 27.8%) or secondary (31, 86.1%) outcomes. 10 of the 36 (27.8%) RCTs provided heart failure event diagnostic criteria and 5 of these 10 (50%) adjudicated heart failure events. These 10 RCTs included event diagnostic criteria for heart failure or heart failure hospitalizations, and their criteria included dyspnea (5/10), edema (2/10), rales/crackles (4/10), chest x-ray pulmonary edema or vascular redistribution (4/10), treatment in an acute setting (6/10) and ultrafiltration or dialysis (4/10). No study explicitly distinguished heart failure from volume overload secondary to non-adherence or underdialysis. CONCLUSION: Overall, we found that heart failure events are infrequently reported in RCTs in dialysis and are heterogeneously defined. Further research is required to develop standardized diagnostic criteria that are practical and meaningful to patients and clinicians.

Substantial discrepancies exist between registered protocol and published manuscript in trials on exercise interventions for chronic low back pain: a metaresearch study.

OBJECTIVES: Reporting bias, prevalent in biomedical fields, can undermine evidence credibility. Our objective was to evaluate the proportion of discrepancies between registered protocols and published manuscripts in randomized controlled trials (RCTs) on exercise interventions for patients with chronic low back pain (CLBP). STUDY DESIGN AND SETTING: We conducted a cross-sectional meta-research study, starting from the 2021 "Exercise therapy for CLBP" Cochrane Review. We selected all RCTs reporting a protocol registration on a primary register of the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) or in ClinicalTrials.gov. We extracted data from both registered protocol and published manuscript of RCTs, collecting recruitment and administrative information (eg, record dates) and details of trial characteristics (eg, outcomes, arms, statistical analysis plan details [SAPs]). Independent pairs of reviewers assessed discrepancies between registered protocol and published manuscript for the reporting of primary and secondary outcomes domains, measurement instruments, time-points, number of arms and SAPs(if attached). Outcome discrepancies were characterized as addition, omission, upgrade or downgrade. RESULTS: We included 116 RCTs reporting an available protocol registration. Overall, 100 RCTs (86.2%) distinguished between primary and secondary outcomes. Of these, 39 RCTs (39.0%) reported one or more discrepancies in primary outcomes, and 78 RCTs (78.0%) reported one or more discrepancies in secondary outcomes. Focusing on discrepancies for the primary outcome, 64.5% of added, upgraded or downgraded outcomes favored statistically significant effects. Few RCTs (n = 6) reported discrepancies in the number of arms. SAPs were poorly reported in the registered protocols (n = 3) for being compared to the publications. CONCLUSION: We found substantial outcome discrepancies comparing registered protocols and published manuscripts in RCTs assessing exercise interventions for patients with CLBP, with some impacting the statistical significance of the effects. Readers are encouraged to approach RCTs results in this field with caution.

Blinding Assessments in Neonatal Ventilation Meta-Analyses: A Systematic Meta-Epidemiological Review.

INTRODUCTION: Randomization and blinding are generally important in randomized trials. In neonatology, blinding of ventilation strategies is unfeasible if not impossible and we hypothesized that its importance has been overestimated, while the peculiarities of the neonatal patient and the specific outcomes have not been considered. METHODS: For this meta-epidemiological review, we searched PubMed and Scopus databases in November 2023. We included all meta-analyses focusing on ventilation, published in past 5 years, and reporting either mortality or bronchopulmonary dysplasia (BPD) as an outcome. We extracted the information about how the authors had analyzed risk of bias and evidence certainty. RESULTS: We screened 494 abstracts and included 40 meta-analyses. Overall, 13 of the 40 reviews assessed blinding properly. Australian and European authors were most likely to perform correct assessment of the blinding (p = 0.03) and the use of RoB 2.0 tool was also associated with proper assessment (p < 0.001). In multivariate regression, the use of RoB 2.0 was the only factor associated with a proper assessment (Beta 0.57 [95% confidence interval: 0.29-0.99]). GRADE ratings were performed in 25 reviews, and the authors downgraded the evidence certainty due to risk of bias in 19 of these and none of these reviews performed the blinding assessment correctly. CONCLUSION: In past neonatal evidence syntheses, the role of blinding has been mostly overestimated, which has led to downgrading of evidence certainty. Objective outcomes (such as mortality and BPD) do not need to be downgraded due to lack of blinding, as the knowledge of the received intervention does not influence the outcome assessment.

The suboptimal clinical applicability of prognostic prediction models for severe postpartum hemorrhage: a meta-epidemiological study.

OBJECTIVES: To systematically investigate clinical applicability of the current prognostic prediction models for severe postpartum hemorrhage (SPPH). STUDY DESIGN AND SETTING: A meta-epidemiological study of prognostic prediction models was conducted for SPPH. A pre-designed structured questionnaire was adopted to extract the study characteristics, predictors and the outcome, modeling methods, predictive performance, the classification ability for high-risk individuals, and clinical use scenarios. The risk of bias among studies was assessed by the Prediction model Risk Of Bias ASsessment Tool (PROBAST). RESULTS: Twenty-two studies containing 27 prediction models were included. The number of predictors in the final models varied from 3 to 53. However, one-third of the models (11) did not clearly specify the timing of predictor measurement. Calibration was found to be lacking in 10 (37.0%) models. Among the 20 models with an incidence rate of predicted outcomes below 15.0%, none of the models estimated the area under the precision-recall curve, and all reported positive predictive values were below 40.0%. Only two (7.4%) models specified the target clinical setting, while seven (25.9%) models clarified the intended timing of model use. Lastly, all 22 studies were deemed to be at high risk of bias. CONCLUSION: Current SPPH prediction models have limited clinical applicability due to methodological flaws, including unclear predictor measurement, inadequate calibration assessment, and insufficient evaluation of classification ability. Additionally, there is a lack of clarity regarding the timing for model use, target users, and clinical settings. These limitations raise concerns about the reliability and usefulness of these models in real-world clinical practice.

Underserved groups could be better considered within population-based eye health surveys: a methodological study.

OBJECTIVES: In pursuit of health equity, the World Health Organization has recently called for more extensive monitoring of inequalities in eye health. Population-based eye health surveys can provide this information, but whether underserved groups are considered in the design, implementation, and reporting of surveys is unknown. We conducted a systematic methodological review of surveys published since 2000 to examine how many population-based eye health surveys have considered underserved groups in their design, implementation, or reporting. STUDY DESIGN AND SETTING: We identified all population-based cross-sectional surveys reporting the prevalence of objectively measured vision impairment or blindness. Using the PROGRESS + framework to identify underserved groups, we assessed whether each study considered underserved groups within 15 items across the rationale, sampling or recruitment methods, or the reporting of participation and prevalence rates. RESULTS: 388 eye health surveys were included in this review. Few studies prospectively considered underserved groups during study planning or implementation, for example within their sample size calculations (n = 5, ∼1%) or recruitment strategies (n = 70, 18%). The most common way that studies considered underserved groups was in the reporting of prevalence estimates (n = 374, 96%). We observed a modest increase in the number of distinct PROGRESS + factors considered by a publication over the study period. Gender/sex was considered within at least one item by 95% (n = 367) of studies. Forty-three percent (n = 166) of included studies were conducted primarily on underserved population groups, particularly for subnational studies of people living in rural areas, and we identified examples of robust population-based studies in socially excluded groups. CONCLUSION: More effort is needed to improve the design, implementation, and reporting of surveys to monitor inequality and promote equity in eye health. Ideally, national-level monitoring of vision impairment and service coverage would be supplemented with smaller-scale studies to understand the disparities experienced by the most underserved groups.

High certainty evidence is stable and trustworthy, whereas evidence of moderate or lower certainty may be equally prone to being unstable.

OBJECTIVES: To assess to what extent the overall quality of evidence indicates changes to observe intervention effect estimates when new data become available. METHODS: We conducted a meta-epidemiological study. We obtained evidence from meta-analyses of randomized trials of Cochrane reviews addressing the same health-care question that was updated with inclusion of additional data between January 2016 and May 2021. We extracted the reported effect estimates with 95% confidence intervals (CIs) from meta-analyses and corresponding GRADE (Grading of Recommendations Assessment, Development, and Evaluation) assessments of any intervention comparison for the primary outcome in the first and the last updated review version. We considered the reported overall quality (certainty) of evidence (CoE) and specific evidence limitations (no, serious or very serious for risk of bias, imprecision, inconsistency, and/or indirectness). We assessed the change in pooled effect estimates between the original and updated evidence using the ratio of odds ratio (ROR), absolute ratio of odds ratio (aROR), ratio of standard errors (RoSE), direction of effects, and level of statistical significance. RESULTS: High CoE without limitations characterized 19.3% (n = 29) out of 150 included original Cochrane reviews. The update with additional data did not systematically change the effect estimates (mean ROR 1.00; 95% CI 0.99-1.02), which deviated 1.06-fold from the older estimates (median aROR; interquartile range [IQR]: 1.01-1.15), gained precision (median RoSE 0.87; IQR 0.76-1.00), and maintained the same direction with the same level of statistical significance in 93% (27 of 29) of cases. Lower CoE with limitations characterized 121 original reviews and graded as moderate CoE in 30.0% (45 of 150), low CoE in 32.0% (48 of 150), and very low CoE in 18.7% (28 of 150) reviews. Their update had larger absolute deviations (median aROR 1.12 to 1.33) and larger gains in precision (median RoSE 0.78-0.86) without clear and consistent differences between these categories of CoE. Changes in effect direction or statistical significance were also more common in the lower quality evidence, again with a similar extent across categories (without change in 75.6%, 64.6%, and 75.0% for moderate, low, very low CoE). As limitations increased, effect estimates deviated more (aROR 1.05 with zero, 1.11 with one, 1.25 with two, 1.24 with three limitations) and changes in direction or significance became more frequent (93.2% stable with no limitations, 74.5% with one, 68.2% with two, and 61.5% with three limitations). CONCLUSION: High-quality evidence without methodological deficiencies is trustworthy and stable, providing reliable intervention effect estimates when updated with new data. Evidence of moderate and lower quality may be equally prone to being unstable and cannot indicate if available effect estimates are true, exaggerated, or underestimated.

Prevalence of and factors associated with potentially redundant randomized controlled trials: a cross-sectional study.

OBJECTIVES: To investigate the prevalence of meta-analyses containing potentially redundant randomized controlled trials (RCTs) and the factors associated with the presence of redundancy. STUDY DESIGN AND SETTING: This is a cross-sectional study, based on a random sample of references (n = 4500) that were published during 2020 and 2021, indexed in PubMed, Embase, or the Cochrane Database of Systematic Reviews, and retrieved through comprehensive searches using terms about systematic reviews and meta-analysis. From each systematic review, one meta-analysis fulfilling all the following criteria, if available, was included in this study: (1) assessing the effect of the intervention on a primary outcome of the systematic review; (2) combining RCTs only. The primary outcome was prevalence of meta-analyses containing potentially redundant RCTs. Potentially redundant RCTs referred to the trials that started 1 year after the overall effect estimate from cumulative meta-analysis had been statistically robust, as determined by trial sequential analysis when appropriate. The number of potentially redundant trials (if any) in each eligible meta-analysis and the number of participants involved in those trials were documented and contrasted across groups. Logistic regression analysis was conducted to explore the factors associated with presence of potential redundancy. RESULTS: Of the 448 eligible meta-analyses, 57 (12.7%, 95% confidence interval (CI) 9.8-16.2%) contained potentially redundant RCTs. When limited to the 333 low-heterogeneity meta-analyses, the prevalence was 17.1% (95% CI 13.5-21.5%). The total number of potentially redundant RCTs was 295 (involving 85,385 participants), accounting for 38.5% of the RCTs (and 30.3% of the participants) included in the 57 meta-analyses. In these meta-analyses, the median number of potentially redundant RCTs and the participants involved were 2 (range: 1-50) and 352 (range: 17-26997), respectively. Potentially redundant RCTs were more likely to be present in the meta-analyses evaluating pharmaceutical intervention (odds ratio [OR] 2.31, 95% CI 1.16-4.49), assessing efficacy outcomes (OR 7.25, 95% CI 0.85-61.87), containing more than 5 RCTs (OR 6.47, 95% CI 3.22-12.99), or with the earliest RCT reporting statistically significant effect estimate (OR 5.30, 95% CI 2.64-10.64). CONCLUSION: This study found that 12.7% to 17.1% of recently published meta-analyses contained potentially redundant RCTs, highlighting the importance of conducting or examining systematic reviews of existing evidence to justify new RCTs. More importantly, the study identified some scenarios in which redundancy was more likely to occur and thus has implications for trialists, funding agencies, ethics committees, and journal editors.

The Uptake of the Core Outcome Set for Non-Specific Low Back Pain Clinical Trials is Poor: A Meta-Epidemiological Study of Trial Registrations.

We conducted a meta-epidemiological study on all non-specific low back pain (NSLBP) trial registrations on the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We aimed to 1) assess the uptake of the core outcome set (COS) for NSLBP in clinical trials; 2) assess the uptake of the core outcome measurement set for NSLBP in clinical trials; and 3) determine whether specific study characteristics are associated with the COS uptake. After applying the relevant filters for the condition, study type, and phase of the trial, 240 registry entries were included in this study. Only 50 (20.8%) entries showed a full COS uptake, and this rate did not increase over time. Most registry entries that planned to measure physical functioning (n = 152) used the Roland-Morris Disability Questionnaire (n = 74; 48.7%); a small percentage used the numeric rating scale (n = 60; 27.3%) or Short Form-12 (n = 5; 8.3%) if they planned to measure pain intensity (n = 220) or health-related quality of life (n = 60), respectively. Only the planned sample size (OR = 1.02; 95% CI = 1.01, 1.03) showed a significant but small association with COS uptake. The uptake of the COS for NSLBP is poor. Only 21% of the randomized controlled trials aimed to measure all COS domains in their study registration and COS uptake is not increased over time. Great heterogeneity in measurement instruments was also observed, revealing poor core outcome measurement set uptake. PERSPECTIVE: The Core Outcome Set (COS) for non-specific low back pain was published more than 20 years ago. We evaluated whether trial registrations are using this set of outcomes when testing interventions for low back pain. Full uptake was found only in 21% of the sample, and this is not increasing over time. Researchers should use the COS to ensure that trials measure relevant outcomes consistently.

Bias in the measurement of the outcome is associated with effect sizes in randomized clinical trials on exercise therapy for chronic low back pain: a meta-epidemiological study.

OBJECTIVES: To explore the relationships between the risk of bias and treatment effect estimates for exercise therapy interventions on pain intensity and physical functioning outcomes in randomized controlled trials (RCTs) involving patients with chronic low back pain. STUDY DESIGN AND SETTING: A cross-sectional meta-epidemiological study of the 230 RCTs (31,674 participants) in the 2021 'Exercise therapy for chronic low back pain' Cochrane Review were included. Study design characteristics, sample size, prospective trial registration, flowchart information, interventions, and comparisons were extracted. Independent pairs of reviewers assessed the risk of bias using the Cochrane Risk of Bias 2 tool. RESULTS: The metaregression included 220 (pain intensity) and 203 (physical functioning) effect sizes. Unadjusted and adjusted metaregression models showed no significant associations between the bias domains and pain intensity effect sizes. Only domain 'bias in the measurement of the outcome' was significantly associated with physical functioning (standardized mean difference: -0.40, 95% confidence interval: -0.77 to -0.02) when adjusted for flowchart reported (yes/no), prospective trial registration, sample size, and comparator type. CONCLUSION: The risk of bias in the measurement of the outcome could lead to slight overestimates of the effect size for physical functioning. Clinicians should consider this when they read and assess RCT results in this field. We encourage metaresearchers to replicate our findings using a consistent approach for evaluating the risk of bias (i.e., the RoB 2 tool) in other musculoskeletal conditions and interventions to investigate their generalizability.

No evidence of important difference in summary treatment effects between COVID-19 preprints and peer-reviewed publications: a meta-epidemiological study.

OBJECTIVES: Preprints became a major source of research communication during the COVID-19 pandemic. We aimed to evaluate whether summary treatment effect estimates differ between preprint and peer-reviewed journal trials. STUDY DESIGN AND SETTING: A meta-epidemiological study. Data were derived from the COVID-NMA living systematic review (covid-nma.com) up to July 20, 2022. We identified all meta-analyses evaluating pharmacological treatments vs. standard of care or placebo for patients with COVID-19 that included at least one preprint and one peer-reviewed journal article. Difference in effect estimates between preprint and peer-reviewed journal trials were estimated by the ratio of odds ratio (ROR); ROR <1 indicated larger effects in preprint trials. RESULTS: Thirty-seven meta-analyses including 114 trials (44 preprints and 70 peer-reviewed publications) were selected. The median number of randomized controlled trials (RCTs) per meta-analysis was 2 (interquartile range [IQR], 2-4; maximum, 11), median sample size of RCTs was 199 (IQR, 99-478). Overall, there was no statistically significant difference in summary effect estimates between preprint and peer-reviewed journal trials (ROR, 0.88; 95% CI, 0.71-1.09; I2 = 17.8%; τ2 = 0.06). CONCLUSION: We did not find an important difference between summary treatment effects of preprints and summary treatment effects of peer-reviewed publications. Systematic reviewers and guideline developers should assess preprint inclusion individually, accounting for risk of bias and completeness of reporting.

The interpretation of clinical relevance in randomised clinical trials in patients with chronic low back pain: protocol for a meta-research study.

Chronic low back pain (cLBP) is one of the leading worldwide causes of disability. The smallest worthwhile effect (SWE) parameter has been proposed to find a threshold of clinical relevance. Specific values of the SWE have been calculated in patients with cLBP for pain intensity, physical functioning and time to recovery for physiotherapy compared with no intervention. Our objectives are 1) To evaluate how authors have interpreted the clinical relevance of the effect of physiotherapy compared to no-intervention on pain, physical functioning and time to recovery; 2) To reinterpret the clinical relevance of these between-group differences based on the available SWE estimates; 3) To evaluate, for descriptive purposes, whether the studies are adequately powered or underpowered considering the published SWE values and a power threshold of 80%. A systematic search in Medline, PEDro, Embase and Cochrane CENTRAL will be conducted. We will search for RCT investigating the effectiveness of physiotherapy as compared to no interventions in people with cLBP. We will compare the authors' interpretation of results for clinical relevance with their results to determine if they meet their a-priori definitions. Then, we will perform a re-interpretation of the between-group differences based on SWE values published for cLBP.

Heterogeneity in the definition of delirium in ICUs and association with the intervention effect in randomized controlled trials: a meta-epidemiological study.

PURPOSE: To evaluate the heterogeneity in the definition of delirium in randomized controlled trials (RCTs) included in meta-analyses of delirium in intensive care units (ICUs) and to explore whether intervention effect depends on the definition used. METHODS: We searched PubMed for meta-analyses including RCTs evaluating prevention or treatment strategies of delirium in ICU. The definition of delirium was collected from RCTs and classified as validated (DSM criteria, CAM-ICU, ICDSC, NEECHAM, DRS-R98) or non-validated (non-validated scales, set of symptoms, physician appreciation or not reported). We conducted a meta-epidemiological analysis to compare intervention effects between trials using or not a validated definition by a two-step method as primary analysis and a multilevel model as secondary analysis. A ratio of odds ratios (ROR) < 1 indicated larger intervention effects in trials using a non-validated definition. RESULTS: Of 149 RCTs (41 meta-analyses), 109 (73.1%) used a validated definition and 40 (26.8%) did not (including 31 [20.8%] not reporting the definition). The primary analysis of 7 meta-analyses (30 RCTs) found no significant difference in intervention effects between trials using a validated definition and the others (ROR = 0.54, 95% CI 0.27-1.08), whereas the secondary multilevel analysis including 12 meta-analyses (67 RCTs) found significantly larger effects for trials using a non-validated versus a validated definition (ROR = 0.36, 95% CI 0.21-0.62). CONCLUSION: The definition of delirium was heterogeneous across RCTs, with one-fifth not reporting how they evaluated delirium. We did not find a significant association with intervention effect in the primary analysis. The secondary analysis including more studies revealed significantly larger intervention effects in trials using a non-validated versus a validated definition.

Constructing Relative Effect Priors for Research Prioritization and Trial Design: A Meta-epidemiological Analysis.

BACKGROUND: Bayesian methods have potential for efficient design of randomized clinical trials (RCTs) by incorporating existing evidence. Furthermore, value of information (VOI) methods estimate the value of reducing decision uncertainty, aiding transparent research prioritization. These methods require a prior distribution describing current uncertainty in key parameters, such as relative treatment effect (RTE). However, at the time of designing and commissioning research, there may be no data to base the prior on. The aim of this article is to present methods to construct priors for RTEs based on a collection of previous RCTs. METHODS: We developed 2 Bayesian hierarchical models that captured variability in RTE between studies within disease area accounting for study characteristics. We illustrate the methods using a data set of 743 published RCTs across 9 disease areas to obtain predictive distributions for RTEs for a range of disease areas. We illustrate how the priors from such an analysis can be used in a VOI analysis for an RCT in bladder cancer and compare the results with those using an uninformative prior. RESULTS: For most disease areas, the predicted RTE favored new interventions over comparators. The predicted effects and uncertainty differed across the 9 disease areas. VOI analysis showed that the expected value of research is much lower with our empirically derived prior compared with an uninformative prior. CONCLUSIONS: This study demonstrates a novel approach to generating informative priors that can be used to aid research prioritization and trial design. The methods can also be used to combine RCT evidence with expert opinion. Further work is needed to create a rich database of RCT evidence that can be used to form off-the-shelf priors. HIGHLIGHTS: Bayesian methods have potential to aid the efficient design of randomized clinical trials (RCTs) by incorporating existing evidence. Value-of-information (VOI) methods can be used to aid research prioritization by calculating the value of current decision uncertainty.These methods require a distribution describing current uncertainty in key parameters, that is, "prior distributions."This article demonstrates a methodology to estimate prior distributions for relative treatment effects (odds and hazard ratios) estimated from a collection of previous RCTs.These results may be combined with expert elicitation to facilitate 1) value-of-information methods to prioritize research or 2) Bayesian methods for research design.

Study results from journals with a higher impact factor are closer to "truth": a meta-epidemiological study.

BACKGROUND: Scientists, physicians, and the general public legitimately expect scholarly publications to give true answers to study questions raised. We investigated whether findings from studies published in journals with higher Journal Impact Factors (JIFs) are closer to truth than findings from studies in less-cited journals via a meta-epidemiological approach. METHODS: We screened intervention reviews from the Cochrane Database of Systematic Reviews (CDSR) and sought well-appraised meta-analyses. We used the individual RCT study estimates' relative deviation from the pooled effect estimate as a proxy for the deviation of the study results from the truth. The effect of the JIF on the relative deviation was estimated with linear regression and with local polynomial regression, both with adjustment for the relative size of studies. Several sensitivity analyses for various sub-group analyses and for alternative impact metrics were conducted. RESULTS: In 2459 results from 446 meta-analyses, results with a higher JIF were on average closer to "truth" than the results with a lower JIF. The relative deviation decreased on average by -0.023 per JIF (95% CI -0.32 to -0.21). A decrease was consistently found in all sensitivity analyses. CONCLUSIONS: Our results indicate that study results published in higher-impact journals are on average closer to truth. However, the JIF is only one weak and impractical indicator among many that determine a studies' accuracy.

Sex and Gender in Randomized Controlled Trials of Adults Receiving Maintenance Dialysis: A Meta-epidemiologic Study.

RATIONALE & OBJECTIVE: How sex and gender concepts are incorporated into randomized controlled trials (RCTs) in adults with kidney failure receiving maintenance dialysis is largely unknown. We describe these practices in published journal articles as well as investigate the proportion of women and female participants in these studies. STUDY DESIGN: Meta-epidemiologic study. SETTING & STUDY POPULATIONS: RCTs in maintenance dialysis. SELECTION CRITERIA FOR STUDIES: Trials published in high-impact journals in 2000-2020. DATA EXTRACTION: Implemented in duplicate with conflicts resolved by a third reviewer. ANALYTICAL APPROACH: Meta-regression was performed to identify trial characteristics independently associated with the proportion of women and female participants. RESULTS: Among 561 included RCTs, 69.7% were parallel and 28.0% were crossover in design; 80.6% were conducted in the hemodialysis population; and 25% of trials compared the treatment of interest with a placebo arm, 25% with a usual care treatment arm, and 50% with an active alternative therapy arm. Of the RCTS, 37.6% were masked. The median size was 60 (IQR, 26-151) participants, and the median follow-up period was 154 (IQR, 42-365) days. The mean proportion of women or female participants was 0.40±0.13 (SD): 39.0% of trials reported sex, and 26.6% reported the gender of the participants. Also, 56.2% referred to participants as females, 25.3% referred to participants as women, and 15.5% referred to both females and women. No trial characteristic other than region (ß of 0.062 [95% CI, 0.007-0.117] for Asia) was associated with the proportion of women or female participants. Considering trial design and conduct, 2.7% of trials used sex and/or gender as an inclusion criterion, 26.6% as an exclusion criterion, 4.5% for randomization, 4.8% for subgroup analyses, and 15.7% for covariate adjustment. LIMITATIONS: Only high-impact journal articles were studied; and the included studies lacked pediatric trials, those addressing chronic kidney disease or kidney transplantation, any trials from Africa and underrepresentation of other regions, and missing data. CONCLUSIONS: RCTs in dialysis are representative of the general dialysis population with regard to sex and gender but they uncommonly report both and often do not include either in their reporting or analysis.

Commercial funding and estimated intervention effects in randomized clinical trials: Systematic review of meta-epidemiological studies.

We investigated to which degree commercial funding is associated with estimated intervention effects in randomized trials. We included meta-epidemiological studies with published data on the association between commercial funding and results or conclusions of randomized trials. We searched five databases and other sources. We selected one result per meta-epidemiological study, preferably unadjusted ratio of odds ratios (ROR), for example, odds ratio(commercial funding)/odds ratio(noncommercial funding). We pooled RORs in random-effects meta-analyses (ROR <1 indicated exaggerated intervention effects in commercially funded trials), subgrouped (preplanned) by study aim: commercial funding per se versus risk of commercial funder influence. We included eight meta-epidemiological studies (264 meta-analyses, 2725 trials). The summary ROR was 0.95 (95% confidence interval 0.85-1.06). Subgroup analysis revealed a difference (p = 0.02) between studies of commercial funding per se, ROR 1.06 (0.95-1.17) and studies of risk of commercial funder influence, ROR 0.88 (0.79-0.97). In conclusion, we found no statistically significant association between commercial funding and estimated intervention effects when combining studies of commercial funding per se and studies of risk of commercial funder influence. A preplanned subgroup analysis indicated that trials with high risk of commercial funder influence exaggerated intervention effects by 12% (21%-3%), on average. Our results differ from previous theoretical considerations and findings from methodological studies and therefore call for confirmation. We suggest it is prudent to interpret results from commercially funded trials with caution, especially when there is a risk that the funder had direct influence on trial design, conduct, analysis, or reporting.

Fragility of cardiovascular outcome trials (CVOTs) examining nutrition interventions among patients with diabetes mellitus: a systematic review of randomized controlled trials.

PURPOSE: There is controversy regarding the optimal statistical method to interpret how robust is a statistically significant result. The fragility index (FI) and the reverse fragility index (RFI) are quantitative measures that can facilitate the appraisal of a clinical trial's robustness. This study was performed to evaluate the FI and RFI of randomized controlled trials (RCTs) examining nutritional interventions in patients with diabetes mellitus, focusing on cardiovascular outcomes. METHODS: A systematic search was conducted and relevant RCTs were identified in three databases. RCTs examining nutritional interventions (supplements or dietary patterns) in patients with DM with dichotomous primary endpoints involving cardiovascular outcomes were eligible. Data were extracted to compose 2 × 2 event tables and the FI and RFI were calculated for each comparison, using Fisher's exact test. Risk of bias (RoB) of the included RCTs was assessed with the Cochrane RoB 2.0 tool. RESULTS: A total of 14,315 records were screened and 10 RCTs were included in the analyses. The median FI of the paired comparisons was 3 (IQR: 2-4) and the median RFI was 8 (IQR: 4.5-17). RoB and heterogeneity were low. CONCLUSIONS: RCTs examining nutritional interventions and cardiovascular outcomes among patients with diabetes mellitus appear to be statistically fragile. Τhe FI and the RFI can be reported and interpreted as an additional perspective of a trial's robustness. HIGHLIGHTS: • In the evidence-healthcare era, assessing how robust statistically significant results are remains a matter of controversy. • Recently, the fragility index (FI) and reverse fragility index (RFI) were proposed to assess the robustness of randomized controlled trials (RCTs) with 2 × 2 comparisons. • When applying the FI and RFI, RCTs examining nutritional interventions and cardiovascular outcomes among patients with diabetes mellitus (DM) appear to be statistically fragile. • Τhe FI and the RFI can be reported and interpreted as an additional perspective of a trial's robustness. • RCTs implementing nutrition interventions among patients with DM can improve their methodology.

Evaluating reporting of patient-reported outcomes in peptic ulcer disease: a meta-epidemiological study of randomized controlled trials.

OBJECTIVES: Peptic ulcer disease (PUD) can significantly affect quality of life (QoL). These QoL outcomes are often patient-reported, and their inclusion in clinical trials supplements efficacy outcomes to provide the patients' perspective. This assese existing literature for completeness of PRO reporting across randomized controlled trials (RCTs) evaluating PUD. METHODS: This meta-epidemiological, cross-sectional study that assessed completeness of reporting among RCTs addressing management of PUD. We conducted a comprehensive literature search] to identify RCTs with a PRO as a primary or secondary outcome. These RCTs were assessed for completion of reporting according to the PRO adaptation of CONSORT checklist. RCTs were also assessed for Risk of Bias (RoB) using the Cochrane RoB 2.0 tool. RESULTS: Masked, duplicate screening of 829 results = yielded a final sample of 35 RCTs. The average completeness of reporting was 32.9% according to the CONSORT-PRO adaptation. Twenty-one (of 35; 60%) of the RCTs were assessed as having 'high' risk of bias and nine (of 35; 25.71%) were assessed as having 'some concerns' for risk of bias. Bivariate regression found completeness of reporting to be positively associated with increased PRO follow-up duration, sample size, and studies with conflicts of interest. CONCLUSION: RCTs examining the treatment and prevention of PUD with PROs as an outcome measure have deficient reporting and 'high' risk of bias according to the CONSORT-PRO and Cochrane RoB guidelines.

The Doctors' Effect on Patients' Physical Health Outcomes Beyond the Intervention: A Methodological Review.

Background: Previous research suggests that when a treatment is delivered, patients' outcomes may vary systematically by medical practitioner. Objective: To conduct a methodological review of studies reporting on the effect of doctors on patients' physical health outcomes and to provide recommendations on how this effect could be measured and reported in a consistent and appropriate way. Methods: The data source was 79 included studies and randomized controlled trials from a systematic review of doctors' effects on patients' physical health. We qualitatively assessed the studies and summarized how the doctors' effect was measured and reported. Results: The doctors' effects on patients' physical health outcomes were reported as fixed effects, identifying high and low outliers, or random effects, which estimate the variation in patient health outcomes due to the doctor after accounting for all available variables via the intra-class correlation coefficient. Multivariable multilevel regression is commonly used to adjust for patient risk, doctor experience and other demographics, and also to account for the clustering effect of hospitals in estimating both fixed and random effects. Conclusion: This methodological review identified inconsistencies in how the doctor's effect on patients' physical health outcomes is measured and reported. For grading doctors from worst to best performances and estimating random effects, specific recommendations are given along with the specific data points to report.

Investigating the transparency of reporting in two-sample summary data Mendelian randomization studies using the MR-Base platform.

BACKGROUND: Two-sample Mendelian randomization (2SMR) is an increasingly popular epidemiological method that uses genetic variants as instruments for making causal inferences. Clear reporting of methods employed in such studies is important for evaluating their underlying quality. However, the quality of methodological reporting of 2SMR studies is currently unclear. We aimed to assess the reporting quality of studies that used MR-Base, one of the most popular platforms for implementing 2SMR analysis. METHODS: We created a bespoke reporting checklist to evaluate reporting quality of 2SMR studies. We then searched Web of Science Core Collection, PsycInfo, MEDLINE, EMBASE and Google Scholar citations of the MR-Base descriptor paper to identify published MR studies that used MR-Base for any component of the MR analysis. Study screening and data extraction were performed by at least two independent reviewers. RESULTS: In the primary analysis, 87 studies were included. Reporting quality was generally poor across studies, with a mean of 53% (SD = 14%) of items reported in each study. Many items required for evaluating the validity of key assumptions made in MR were poorly reported: only 44% of studies provided sufficient details for assessing if the genetic variant associates with the exposure ('relevance' assumption), 31% for assessing if there are any variant-outcome confounders ('independence' assumption), 89% for the assessing if the variant causes the outcome independently of the exposure ('exclusion restriction' assumption) and 32% for assumptions of falsification tests. We did not find evidence of a change in reporting quality over time or a difference in reporting quality between studies that used MR-Base and a random sample of MR studies that did not use this platform. CONCLUSIONS: The quality of reporting of two-sample Mendelian randomization studies in our sample was generally poor. Journals and researchers should consider using the STROBE-MR guidelines to improve reporting quality.