^aRandomized controlled trials start with an initial GRADE rating of high and can be downgraded for problems with risk of bias, inconsistency, indirectness, imprecision, and publication bias.

^bA GRADE rating of high implies that we are very confident that the true effect lies close to that of the estimate of the effect.

^cA GRADE rating of moderate implies that we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

^dObservational studies start with an initial GRADE rating of low and can be downgraded for problems with risk of bias, inconsistency, indirectness, imprecision, and publication bias.

^eA GRADE rating of low implies that our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.

^fA GRADE rating of very low implies that we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.