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Summary of Findings tables in Cochrane reviews Lets do it right Esther van Zuuren Department of Dermatology LEIDEN Agenda Introduction (20-25 min) What is GRADE? Where can we find information on GRADE GRADE approach Rating quality of the evidence Factors that decrease quality of evidence
Factors that increase quality of evidence Workshop Working in two three groups (40 min) Discussion within whole group and working all with GRADEproGDT (20-25 min) 2 2/7/20 What is ? Grading of Recommendations, Assessment, Development and Evaluation Systematic and explicit approach to making judgements about quality of evidence and strength of recommendations Quality of evidence rating includes reporting on: Methodological flaws
Consistency of results Generalizability Magnitude of effect is used by WHO, Cochrane, NICE and >70 other organizations for guideline making 3 2/7/20 GRADE getting information http://www.gradeworkinggroup.org/ 4 2/7/20 More tutorials and info http://cebgrade.mcmaster.ca/ 5
2/7/20 What is ? = = 6 ? ? ? 2/7/20
GRADE approach Health Care Question (PICO) Systematic review Studies S1 Outcomes OC1 S2 OC2 Critical outcomes S3
S4 OC3 S5 OC4 Important outcomes Generate an estimate of effect for each outcome Rate the quality of evidence for each outcome, across studies RCTs start high, observational studies low Rating is downgraded: Rating is upgraded: 1. 2. 3. 4. 5. 7
Study limitations 1. Large magnitude of effect Imprecision 2. Dose response Inconsistency of results 3. Confounders likely Indirectness of evidence minimize the effect Publication bias likely Rating of quality for each outcome: high, moderate, low or very low 2/7/20 Rating the quality of evidence The quality of the evidence reflects the extent of our confidence that the estimates of the effect are correct High : true effect lies close to the estimate of the effect Moderate O: true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low OO: true effect may be substantially different from the estimate of effect Very low OOO: true effect is likely to be substantially different from the estimate of effect 8 2/7/20 Factors that lower the quality of evidence 1. Study limitations 2. Inconsistency of results 3. Indirectness of evidence 4. Imprecision 5. Publication bias If factor is present: downgrade level of evidence by 1 (serious) or 2 levels (very serious) 9
2/7/20 Study limitations Limitations in design and execution Risk of Bias Inadequate randomisation Lack of allocation concealment Lack of blinding Large losses to follow-up Failure to adhere to an ITT analysis Failure to report outcomes Other bias (baseline imbalance, co-meds) 10 2/7/20 How does that look like? Question: Should ethinyl estradiol 35 g + cyproterone acetate 2 mg vs ethinyl estradiol 30 g + desogestrel 0.15 mg be used for hirsutism?
Quality assessment No of patients Effect Quality Importance No of studies Design Risk of bias Inconsistency Ethinyl estradiol 35 g g Ethinyl estradiol 30 Relative Other
Indirectness Imprecision + cyproterone acetate g g + desogestrel (95% considerations 2 mg 0.15 mg CI) Absolute Clinician's assessment of improvement of hirsutism (measured with: Ferriman-Gallwey score; range of scores: 0-36; Better indicated by lower values) 31 randomised Serious2 no serious trials inconsistency no serious indirectness
Downgraded one level due to serious risk of performance and detection bias as in 2 of the 3 studies participants, investigators and outcome assessors were not blinded 3 Downgraded one level due to serious imprecision (95% confidence interval around the pooled or best estimate of effect includes both no effect and appreciable benefit) 2 11 2/7/20 Inconsistency in results Unexplained heterogeneity of results across studies 1) Clinical heterogeneity may arise from differences in: Populations different effect in populations with more disease severity Interventions larger effect with higher doses or longer treatment duration Outcomes diminishing effect with time (duration in follow-up differ) 2) Methodological heterogeneity (differences in study design or differences in risk of bias)
12 2/7/20 Inconsistency Terbinafine versus placebo for tinea cruris and corporis Look at differences in effect size Not overlapping of CIs I2>75% 13 2/7/20 Indirectness Evidence comes from different research question Indirect comparison: terbinafine miconazole terbinafine placebo and miconazole placebo
Population: oral fumaric acid esters for psoriasis psoriatic arthritis Comparator: new drug different dosages isotretinoin fixed doses of isotretinoin Outcome: patient satisfaction or aesthetics (treatment varicose) ultrasound 14 2/7/20 Imprecision When are results precise enough? Consider: Sample size -calculation of optimal information size (OIS) http:// cebgrade.mcmaster.ca/Imprecision/index.html calculator at http://www.stat.ubc.ca/~rollin/stats/ssize/b2.html Number of events
-rule of thumbs rating down < 300 events in total group Wide confidence intervals -uncertainty about the magnitude of effect -CI includes both no effect AND appreciable benefit/harm (RR 0.75/1.25) 15 2/7/20 Examples of imprecision CI includes the threshold for appreciable benefit (0.75) and nearly no effect (1.0), very low number of events, low sample size (OIS would be 4238 participants ) 16 2/7/20 Publication bias Systematic under- or overestimate of the effect due to selective publication of studies
Trials including large numbers of patients are less likely to remain unpublished or ignored and tend to provide more precise estimates of the effect whether positive or negative Suspicion: evidence is limited to small number of trials, all showing benefit and funded by industry Check: funnel plot, trial registers, abstract books Publication bias: undetected (no change in quality) strongly suspected(downgrade by 1 level) very strongly suspected (downgrade by 2 levels) 17 2/7/20 Rating up the quality of evidence 1. Large magnitude of effect Large: RR >2 or RR <0.5 (1 level) Very large: RR >5 or RR <0.2 (2 levels)
2. Dose response relationship 3. All plausible residual confounding & bias 4. 18 Would reduce a demonstrated effect Would suggest a spurious effect if no effect was observed
Mainly applies to observational studies at low risk of bias 2/7/20 Rating up the quality of evidence Consideration of factors reducing quality of evidence must precede consideration of reasons for rating it up! Thus, the 5 factors for rating down quality of evidence (risk of bias, imprecision, inconsistency, indirectness, and publication bias) must be rated prior to the 3 factors for rating it up (large effect, dose-response and effects of residual confounding) The decision to rate up quality of evidence should only be made when serious limitations in any of the 5 areas reducing the quality of evidence are absent GRADE Handbook Although it is theoretically possible to rate up results from randomized control trials, we have yet to find a compelling example of such an instance 19 2/7/20
SoF tables in Cochrane reviews GRADE Handbook: Systematic reviews that address more than one main comparison (e.g. examining the effects of a number of interventions) will require separate SoF tables for each comparison. Moreover, for each comparison of alternative management strategies, all outcomes should be presented together in one SoF table. = 20 N FU 2/7/20 Workshop Making groups 3 studies on naftifine for tinea cruris and/or corporis Fill in the 4 SoF sheets for these 3 studies (divide tasks for RoB and data
extraction) MAXIMUM 40 min Two outcomes: mycological cure and adverse events -Use per protocol data for mycological cure -Use intention to treat analysis for adverse events After 40 min: Discussion within the whole group. Everybody works on own laptop with GRADEproGDT (20 mins) 21 2/7/20
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