Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? Benefits outweigh harms/burden Benefits slightly outweigh harms/ burden Benefits and harms/burden are balanced Harms/burden slightly outweigh benefits Harms/burden outweigh benefits Confidence in the quality of the evidence Is there high or moderate quality evidence that answers this question? What is the overall certainty of this evidence? High Moderate Low Very low Values and preferences Are you confident about the typical values and preferences and are they similar across the target population? What are the patient s values and preferences? Are the assumed or identified relative values similar across the target population? Similar values Some variation Large variation Other implications (e.g., resource use, equity, acceptability, feasibility, subgroup considerations) Are the resources worth the expected net benefit from the recommendation? What are the costs per resource unit? Is this intervention generally available? Is this intervention and its effects worth withdrawing or not allocating resources from other interventions? Is there lots of variability in resource requirements across settings? Various considerations The strength of a recommendation is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects and is based on the framework above, which combines the four domains.[158] GRADE methodology does not allow for recommendations to be made based on expert opinion alone. While strong recommendations are usually based on high or moderate confidence in the estimates of effect (quality of the evidence) there may be instances where strong recommendations are warranted even when the quality of evidence is low.