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Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey.

ABSTRACT: OBJECTIVE:To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question. DESIGN:Meta-epidemiological survey. DATA SOURCES:PubMed searched up to November 2014. METHODS:Eligible RCD studies were published up to 2010 that used propensity scores to address confounding bias and reported comparative effects of interventions for mortality. The analysis included only RCD studies conducted before any trial was published on the same topic. The direction of treatment effects, confidence intervals, and effect sizes (odds ratios) were compared between RCD studies and randomized controlled trials. The relative odds ratio (that is, the summary odds ratio of trial(s) divided by the RCD study estimate) and the summary relative odds ratio were calculated across all pairs of RCD studies and trials. A summary relative odds ratio greater than one indicates that RCD studies gave more favorable mortality results. RESULTS:The evaluation included 16 eligible RCD studies, and 36 subsequent published randomized controlled trials investigating the same clinical questions (with 17,275 patients and 835 deaths). Trials were published a median of three years after the corresponding RCD study. For five (31%) of the 16 clinical questions, the direction of treatment effects differed between RCD studies and trials. Confidence intervals in nine (56%) RCD studies did not include the RCT effect estimate. Overall, RCD studies showed significantly more favorable mortality estimates by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I(2)=0%)). CONCLUSIONS:Studies of routinely collected health data could give different answers from subsequent randomized controlled trials on the same clinical questions, and may substantially overestimate treatment effects. Caution is needed to prevent misguided clinical decision making.

SUBMITTER: Hemkens LG

PROVIDER: S-EPMC4772787 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey.

Hemkens Lars G LG Contopoulos-Ioannidis Despina G DG Ioannidis John P A JP

BMJ (Clinical research ed.) 20160208

<h4>Objective</h4>To assess differences in estimated treatment effects for mortality between observational studies with routinely collected health data (RCD; that are published before trials are available) and subsequent evidence from randomized controlled trials on the same clinical question.<h4>Design</h4>Meta-epidemiological survey.<h4>Data sources</h4>PubMed searched up to November 2014.<h4>Methods</h4>Eligible RCD studies were published up to 2010 that used propensity scores to address conf ...[more]

PMID: 26858277

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Project description:Objective To examine whether a very large effect (VLE; defined as a relative risk of ?0.2 or ?5) in a randomised trial could be an empirical marker that subsequent trials are unnecessary.Design Meta-epidemiological assessment of existing published data on randomised trials.Data sources Cochrane Database of Systematic Reviews (2010, issue 7) with data on subsequent large trials updated to 2015, issue 12.Eligibility criteria All binary outcome forest plots were selected, which contained an index randomised trial with a VLE that was nominally statistically significant (P<0.05), included a subsequent large randomised trial (?200 events and ?200 non-events) for validation of the effect, assessed a primary outcome of the review, and was not a subgroup or sensitivity analysis.Results Of 3082 reviews yielding 85?002 forest plots, only 44 (0.05%) satisfied the inclusion criteria. Index trials were generally small, with a median sample of 99 (median 14 events). Few index trials were rated at low risk of bias (9 of 44; 20%). The relative risk was closer to the null in the subsequent large trials in 43 of 44 cases. Subsequent large trial data failed to find a statistically significant (P<0.05) effect in the same direction in 19 cases (43%, 95% confidence interval 29% to 58%). Even when the subsequent large trials did find a significant effect in the same direction, the additional primary outcomes in most of these trials would have to be considered before deciding in favour of using the intervention. Subsequent large trial data found a statistically significant effect in the same direction in 19 of 21 cases when the index trial also had a value of P<0.001.Conclusions The frequency of VLEs followed by a large trial is vanishingly small, and where they occur they do not appear to be a reliable marker for a benefit that is reproducible and directly actionable. An empirical rule using a VLE in a randomised controlled trial as a marker that further trials are unnecessary would be neither practical nor useful. Caution should be taken when interpreting small studies with very large treatment effects.

Project description:ObjectiveTo evaluate the agreement between diet-disease effect estimates of bodies of evidence from randomised controlled trials and those from cohort studies in nutrition research, and to investigate potential factors for disagreement.DesignMeta-epidemiological study.Data sourcesCochrane Database of Systematic Reviews, and Medline.Review methodsPopulation, intervention or exposure, comparator, outcome (PI/ECO) elements from a body of evidence from cohort studies (BoE(CS)) were matched with corresponding elements of a body of evidence from randomised controlled trials (BoE(RCT)). Pooled ratio of risk ratios or difference of mean differences across all diet-disease outcome pairs were calculated. Subgroup analyses were conducted to explore factors for disagreement. Heterogeneity was assessed through I2 and τ2. Prediction intervals were calculated to assess the range of possible values for the difference in the results between evidence from randomised controlled trials and evidence from cohort studies in future comparisons.Results97 diet-disease outcome pairs (that is, matched BoE(RCT) and BoE(CS)) were identified overall. For binary outcomes, the pooled ratio of risk ratios comparing estimates from BoE(RCT) with BoE(CS) was 1.09 (95% confidence interval 1.04 to 1.14; I2=68%; τ2=0.021; 95% prediction interval 0.81 to 1.46). The prediction interval indicated that the difference could be much more substantial, in either direction. We further explored heterogeneity and found that PI/ECO dissimilarities, especially for the comparisons of dietary supplements in randomised controlled trials and nutrient status in cohort studies, explained most of the differences. When the type of intake or exposure between both types of evidence was identical, the estimates were similar. For continuous outcomes, small differences were observed between randomised controlled trials and cohort studies.ConclusionOn average, the difference in pooled results between estimates from BoE(RCT) and BoE(CS) was small. But wide prediction intervals and some substantial statistical heterogeneity in cohort studies indicate that important differences or potential bias in individual comparisons or studies cannot be excluded. Observed differences were mainly driven by dissimilarities in population, intervention or exposure, comparator, and outcome. These findings could help researchers further understand the integration of such evidence into prospective nutrition evidence syntheses and improve evidence based dietary guidelines.

Project description:BackgroundThe Cochrane risk of bias (CROB) tool and Physiotherapy Evidence Database (PEDro) scale are used to evaluate risk of bias of randomized controlled trials. We assessed the level of agreement between the instruments.MethodsWe searched the Cochrane Library to identify trials included in systematic reviews evaluating physical therapy interventions. For trials that met our inclusion criteria (primary reference in Cochrane review, review used CROB (2008 version), indexed in PEDro), CROB items were extracted from the reviews and PEDro items and total score were downloaded from PEDro. Kappa statistics were used to determine the agreement between CROB and PEDro scale items that evaluate similar constructs (e.g., randomization). The total PEDro score was compared to the CROB summary score (% of items met) using an Intraclass Correlation Coefficient. Sensitivity analyses explored the impact of the CROB "unclear" category and variants of CROB blinding items. Kappa statistics were used to determine agreement between different thresholds for "acceptable" risk of bias between CROB and PEDro scale summary scores.ResultsWe included 1442 trials from 108 Cochrane reviews. Agreement was "moderate" for three of the six CROB and PEDro scale items that evaluate similar constructs (allocation concealment, participant blinding, assessor blinding; Kappa = 0.479-0.582). Agreement between the summary scores was "poor" (Intraclass Correlation Coefficient = 0.285). Agreement was highest when the CROB "unclear" category was collapsed with "high" and when participant, personnel and assessor blinding were evaluated separately in CROB. Agreement for different thresholds for "acceptable" risk of bias between CROB and PEDro summary scores was, at best, "fair".ConclusionThere was moderate agreement for half of the PEDro and CROB items that evaluate similar constructs. Interpretation of the CROB "unclear" category and variants of the CROB blinding items substantially influenced agreement. Either instrument can be used to quantify risk of bias, but they can't be used interchangeably.

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Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey.

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Agreement of treatment effects for mortality from routinely collected data and subsequent randomized trials: meta-epidemiological survey.

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