APPENDIX 1:

SIGN grading

Levels of evidence
1++High quality meta analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
1+Well conducted meta analyses, systematic reviews, or RCTs with a low risk of bias
1−Meta analyses, systematic reviews, or RCTs with a high risk of bias
2++High quality systematic reviews of case-control or cohort studies
High quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal
2+Well conducted case-control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal
2−Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal
3Non-analytical studies, eg case reports, case series
4Expert opinion
Grades of recommendation
A At least one meta analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population, or
A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results
B A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results, or
Extrapolated evidence from studies rated 1++ or 1+
C A body of evidence including studies rated as 2+, directly applicable to the target population, and demonstrating overall consistency of results, or
Extrapolated evidence from studies rated 2++
D Evidence rated 3 or 4, or
Extrapolated evidence from studies rated 2+