Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Impact of study quality on outcome in placebo-controlled trials of homeopathy. The use of dedicated methodology and statistical reviewers for peer review: a content analysis of comments to authors made by methodology and regular reviewers. Commercially funded and United States-based research is more likely to be published; good-quality studies with negative outcomes are not. Searching one or two databases was insufficient for meta-analysis of observational studies. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Correlation of quality measures with estimates of treatment effect in meta-analyses of randomized controlled trials. Systematic reviews of health effects of social interventions: 1. Finding the evidence: how far should you go? Discrepancy between results and abstract conclusions in industry- vs nonindustry-funded studies comparing topical prostaglandins.
To determine if inadequate approaches to randomized controlled trial design and execution are associated with evidence of bias in estimating treatment effects.
                An observational study in which we assessed the methodological quality of 250 controlled trials from 33 meta-analyses and then analyzed, using multiple logistic regression models, the associations between those assessments and estimated treatment effects.
                Meta-analyses from the Cochrane Pregnancy and Childbirth Database.
                The associations between estimates of treatment effects and inadequate allocation concealment, exclusions after randomization, and lack of double-blinding.
                Compared with trials in which authors reported adequately concealed treatment allocation, trials in which concealment was either inadequate or unclear (did not report or incompletely reported a concealment approach) yielded larger estimates of treatment effects (P < .001). Odds ratios were exaggerated by 41% for inadequately concealed trials and by 30% for unclearly concealed trials (adjusted for other aspects of quality). Trials in which participants had been excluded after randomization did not yield larger estimates of effects, but that lack of association may be due to incomplete reporting. Trials that were not double-blind also yielded larger estimates of effects (P = .01), with odds ratios being exaggerated by 17%.
                This study provides empirical evidence that inadequate methodological approaches in controlled trials, particularly those representing poor allocation concealment, are associated with bias. Readers of trial reports should be wary of these pitfalls, and investigators must improve their design, execution, and reporting of trials. We investigated the influence of indicators of methodological quality on study outcome in a set of 89 placebo-controlled clinical trials of homoeopathy in three different ways: (1) The results of studies meeting single criteria (explicit statement of random allocation, allocation concealment, double-blinding, completeness of follow-up) of methodological quality were compared with those of studies not meeting the criteria in univariate and multivariate analyses; (2) The results of studies scoring above and below predefined scores in two quality assessment scales were compared; (3) Primary studies were consecutively entered into a cumulative meta-analysis according to the summary scores derived from the quality assessment scales. All analyses were performed using meta-regression methods. Studies that were explicitly randomized and were double-blind as well as studies scoring above the cut-points yielded significantly less positive results than studies not meeting the criteria. In the cumulative meta-analyses, there was a trend for increasing effect sizes when more studies with lower-quality scores were added. However, there was no linear relationship between quality scores and study outcome. We conclude that in the study set investigated, there was clear evidence that studies with better methodological quality tended to yield less positive results. Because summarizing disparate study features into a single score is problematic, meta-regression methods simultaneously investigating the influence of single study features seem the best method for investigating the impact of study quality on outcome. In 1997, Annals of Emergency Medicine initiated a protocol by which every original research article, in addition to each regular review, was concurrently evaluated by 1 of 2 methodology and statistical reviewers. We characterized and contrasted comments made by the methodology and regular peer reviewers.
                After pilot testing, interrater reliability assessment, and revision, we finalized a 99-item taxonomy of reviewer comments organized in 8 categories. Two authors, uninvolved in the writing of reviews, classified each comment from a random sample of methodology reviews from 1999. For 30 of these reviews (15 for each methodology reviewer), the 2 authors also scored all (range 2 to 5) regular reviews.
                Sixty-five reviews by methodologist A, 60 by methodologist B, and 68 by regular reviewers were analyzed. Comments by methodologist A most frequently concerned the presentation of results (33% of all comments) and methods (17%). Methodologist B commented most frequently on presentation of results (28%) and statistical methods (16%). Regular reviewers most frequently made non-methodology/statistical comments (45%) and comments on presentation of results (18%). Of note, comments made by methodology and regular reviewers about methods issues were often contradictory.
                The distributions of comments made by the 2 methodology and statistical reviewers were similar, although reviewer A emphasized presentation and reviewer B stressed statistical issues. The regular reviewers (most of whom were unaware that a dedicated methodology and statistical reviewer would be reviewing the article) paid much less attention to methodology issues. The 2 dedicated methodology and statistical reviewers created reviews that were similarly focused and emphasized methodology issues that were distinct from the issues raised by regular reviewers. Prior studies implying associations between receipt of commercial funding and positive (significant and/or pro-industry) research outcomes have analyzed only published papers, which is an insufficiently robust approach for assessing publication bias. In this study, we tested the following hypotheses regarding orthopaedic manuscripts submitted for review: (1) nonscientific variables, including receipt of commercial funding, affect the likelihood that a peer-reviewed submission will conclude with a report of a positive study outcome, and (2) positive outcomes and other, nonscientific variables are associated with acceptance for publication.
                All manuscripts about hip or knee arthroplasty that were submitted to The Journal of Bone and Joint Surgery, American Volume, over seventeen months were evaluated to determine the study design, quality, and outcome. Analyses were carried out to identify associations between scientific factors (sample size, study quality, and level of evidence) and study outcome as well as between non-scientific factors (funding source and country of origin) and study outcome. Analyses were also performed to determine whether outcome, scientific factors, or nonscientific variables were associated with acceptance for publication.
                Two hundred and nine manuscripts were reviewed. Commercial funding was not found to be associated with a positive study outcome (p = 0.668). Studies with a positive outcome were no more likely to be published than were those with a negative outcome (p = 0.410). Studies with a negative outcome were of higher quality (p = 0.003) and included larger sample sizes (p = 0.05). Commercially funded (p = 0.027) and United States-based (p = 0.020) studies were more likely to be published, even though those studies were not associated with higher quality, larger sample sizes, or lower levels of evidence (p = 0.24 to 0.79).
                Commercially funded studies submitted for review were not more likely to conclude with a positive outcome than were nonfunded studies, and studies with a positive outcome were no more likely to be published than were studies with a negative outcome. These findings contradict those of most previous analyses of published (rather than submitted) research. Commercial funding and the country of origin predict publication following peer review beyond what would be expected on the basis of study quality. Studies with a negative outcome, although seemingly superior in quality, fared no better than studies with a positive outcome in the peer-review process; this may result in inflation of apparent treatment effects when the published literature is subjected to meta-analysis. To address methodologic issues in searching for observational studies by presenting database search methods and results.
                Results of two literature searches for publications reporting on observational studies of alcohol consumption and the risk of breast cancer and large bowel cancer were compared, to evaluate the sensitivity of various bibliographic databases and search strategies, including hand-searching reviews and meta-analyses.
                The target sensitivity of 90% of publications in the breast cancer search was achieved by starting with Medline, then adding Biosis, Embase, and SCI EXPANDED-SSCI, which provided a total of 72 (91%) of the 79 relevant publications. To reach a similar 89% sensitivity for large bowel cancer, at least Biosis, Dissertation Abstracts Online, Embase, ETOH, and Medline had to be searched, with the addition of hand search of reviews and meta-analyses.
                Limiting a search to one or two databases when conducting meta-analyses of observational studies will not provide a thorough summary of the existing literature. The findings support recommendations to implement a comprehensive search of electronic databases and the reference lists of recent review articles and meta-analyses. To explore whether reported methodologic quality affects estimated intervention effects in randomized trials and contributes to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses.
                Meta-analyses of randomized trials that included at least one large trial (>/=1000 participants) were included, regardless of the therapeutic area. Eligible meta-analyses were identified through electronic searches and bibliographies of relevant articles.
                Full-length randomized trials.
                Methodologic quality was assessed according to reported randomization, double blinding, and follow-up as separate components and by using the Jadad composite scale.
                Fourteen meta-analyses involving 190 randomized trials from eight therapeutic areas were included. Compared with large trials, intervention effects were exaggerated in small trials with inadequate allocation sequence generation (ratio of odds ratios, 0.46 [95% CI, 0.25 to 0.83]; P = 0.011), inadequate allocation concealment (ratio of odds ratios, 0.49 [CI, 0.27 to 0.86]; P = 0.014), and no double blinding (ratio of odds ratios, 0.52 [CI, 0.28 to 0.96]; P = 0.01). Large trials did not differ significantly from small trials with adequate generation of the allocation sequence, adequate allocation concealment, or adequate double blinding. No association was seen between reported follow-up and intervention effects. The Jadad scale provided no additional information because the scale and the quality components overlapped substantially.
                Inadequate generation of the allocation sequence, allocation concealment, and double blinding lead to exaggerated estimates of intervention benefit and may contribute to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses. Specific features of trial quality may be associated with exaggeration or shrinking of the observed treatment effect in randomized studies. Therefore, assessment of trial quality is often used in meta-analysis. However, the degree to which specific quality measures are associated with treatment effects has not been well established across a broad range of clinical areas.
                To determine if quality measures are associated with treatment effect size in randomized controlled trials (RCTs).
                Quality measures from published quality assessment scales were evaluated in RCTs included in meta-analyses from 4 medical areas (cardiovascular disease, infectious disease, pediatrics, and surgery). Included meta-analyses incorporated at least 6 RCTs, examined dichotomous outcomes, and demonstrated significant between-study heterogeneity in the odds ratio (OR) scale.
                Relative ORs comparing overall treatment effect (summary OR) of high vs low-quality studies, as determined by each quality measure, with relative ORs less than 1 indicating larger treatment effect in low-quality studies.
                Twenty-four quality measures were analyzed for 276 RCTs from 26 meta-analyses. Relative ORs of high vs low-quality studies for these quality measures ranged from 0.83 to 1.26; none was statistically significantly associated with treatment effect. The proportion of studies fulfilling specific quality measures varied widely in the 4 medical areas. In analyses limited to specific medical areas, placebo control, multicenter studies, study country, caregiver blinding, and statistical methods were significantly associated with treatment effect on 7 occasions. These relative ORs ranged from 0.40 to 1.74. However, the directions of these associations were not consistent.
                Individual quality measures are not reliably associated with the strength of treatment effect across studies and medical areas. Although use of specific quality measures may be appropriate in specific well-defined areas in which there is pertinent evidence, findings of associations with treatment effect cannot be generalized to all clinical areas or meta-analyses. There is little guidance on how to identify useful evidence about the health effects of social interventions. The aim of this study was to assess the value of different ways of finding this type of information.
                Retrospective analysis of the sources of studies for one systematic review.
                Case study of a systematic review of the effectiveness of interventions in promoting a population shift from using cars towards walking and cycling.
                Only four of the 69 relevant studies were found in a "first-line" health database such as Medline. About half of all relevant studies were found through the specialist Transport database. Nine relevant studies were found through purposive internet searches and seven relevant studies were found by chance. The unique contribution of experts was not to identify additional studies, but to provide more information about those already found in the literature.
                Most of the evidence needed for this review was not found in studies indexed in familiar literature databases. Applying a sensitive search strategy across multiple databases and interfaces is very labour intensive. Retrospective analysis suggests that a more efficient method might have been to search a few key resources, then to ask authors and experts directly for the most robust reports of studies identified. However, internet publications and serendipitous discoveries did make a significant contribution to the total set of relevant evidence. Undertaking a comprehensive search may provide unique evidence and insights that would not be obtained using a more focused search. To investigate the relationship between industry- vs nonindustry-funded publications comparing the efficacy of topical prostaglandin analogs by evaluating the correspondence between the statistical significance of the publication's main outcome measure and its abstract conclusions.
                Retrospective, observational cohort study.
                English publications comparing the ocular hypotensive efficacy between any or all of latanoprost, travoprost, and bimatoprost were searched from the MEDLINE database. Each article was reviewed by three independent observers and was evaluated for source of funding, study quality, statistically significant main outcome measure, correspondence between results of main outcome measure and abstract conclusion, number of intraocular pressure outcomes compared, and journal impact factor. Funding was determined by published disclosure or, in cases of no documented disclosure, the corresponding author was contacted directly to confirm industry funding. Discrepancies were resolved by consensus. The main outcome measure was correspondence between abstract conclusion and reported statistical significance of the publications' main outcome measure.
                Thirty-nine publications were included, of which 29 were industry funded and 10 were nonindustry funded. The published abstract conclusion was not consistent with the results of the main outcome measure in 18 (62%) of 29 of the industry-funded studies compared with zero (0%) of 10 of the nonindustry-funded studies (P = .0006). Twenty-six (90%) of the industry-funded studies had proindustry abstract conclusions.
                Twenty-four percent of the industry-funded publications had a statistically significant main outcome measure; however, 90% of the industry-funded studies had proindustry abstract conclusions. Both readers and reviewers should scrutinize publications carefully to ensure that data support the authors' conclusions.
The conclusions of this review are limited by the lack of data. More research of higher methodological quality is needed.