Table 1

Guidelines used from Cochrane Collaboration Group and Grading of Recommendations Assessment, Development and Evaluation (GRADE) system of evaluation

Levels of quality of a body of evidence in the GRADE approach
Underlying methodology				Quality rating
Randomised trials; or double-upgraded observational studies Downgraded randomised trials; or upgraded observational studies Double-downgraded randomised trials; or observational studies Triple-downgraded randomised trials; or downgraded observational studies; or case series/case reports				High Moderate Low Very low
Factors that may decrease the quality level of a body of evidence
1. Limitations in the design and implementation of available studies suggesting high likelihood of bias of the intervention effect (randomised allocation sequence, blinding, allocation concealment, intention-to-treat analysis, losses to follow-up) 2. Indirectness of evidence (indirect population, intervention, control, outcomes) 3. Unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses) 4. Imprecision of results (wide CIs) or inconsistency (significant and unexplained variability in results from different trials) 5. High probability of publication bias (‘negative’ findings remain unpublished)
Factors that may increase the quality level of a body of evidence
1. Large magnitude of effect 2. All plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results show no effect 3. Dose–response gradient (result proportional to the degree of exposure)
Judgement about study limitations for main outcomes following assessment of risk of bias
Risk of bias	Across studies	Interpretation	Considerations	GRADE assessment of study limitations
Low risk of bias	Most information is from studies at low risk of bias	Plausible bias unlikely to seriously alter the results	No apparent limitations	No serious limitations, do not downgrade
Unclear risk of bias	Most information is from studies at low or unclear risk of bias	Plausible bias that raises some doubt about the results	Potential limitations are unlikely to lower confidence in the estimate of effect	No serious limitations, do not downgrade
			Potential limitations are likely to lower confidence in the estimate of effect	Serious limitations, downgrade one level
High risk of bias	The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results	Plausible bias that seriously weakens confidence in the results	Crucial limitation for one criterion, or some limitations for multiple criteria, sufficient to lower confidence in the estimate of effect Crucial limitation for one or more criteria sufficient to substantially lower confidence in the estimate of effect	Serious limitations, downgrade one level Very serious limitations, downgrade two levels
Quality of evidence according to GRADE approach
Code	Quality of evidence	Definition
A	High ⊕⊕⊕⊕	Further research is very unlikely to change the confidence in the estimate of effect Several high-quality studies with consistent results In special cases: one large, high-quality multicentre trial
B	Moderate ⊕⊕⊕	Further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate One high-quality study Several studies with some limitations
C	Low ⊕⊕	Further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate One or more studies with severe limitations
D	Very low ⊕	Any estimate of effect is very uncertain Expert opinion No direct research evidence One or more studies with very severe limitations
E	No evidence	No randomised controlled trials were identified that addressed this outcome

Data in the table were adapted from Cochrane Handbook for Systematic Reviews of Interventions 36