Table 1.

Paradigmatic situations in which a strong recommendation may be warranted despite low or very low certainty in effect estimates (appropriate strength, consistent with Grading of Recommendations Assessment, Development and Evaluation (GRADE))

Situation	Certainty in estimates (quality of evidence)		Balance of benefits and harms	Values and preferences	Resource considerations	Recommendation	Example
	Benefits	Harms
1. Life-threatening (or catastrophical) situation	Low or very low	Immaterial (very low to high)	Intervention may reduce mortality in a life-threatening situation; adverse events not prohibitive	A very high value is placed on an uncertain but potentially life-preserving benefit	Small incremental cost (or resource use) relative to the benefits justify the intervention	Strong recommendation in favour of the intervention	Indirect evidence from seasonal influenza suggests that patients with avian influenza may benefit from the use of oseltamivir (low certainty in effect estimates). Given the high mortality of the disease and the absence of effective alternatives, the WHO made a strong recommendation in favour of the use of oseltamivir rather than no treatment in patients with avian influenza.
2. Uncertain benefit, certain harm	Low or very low	High or moderate	Possible but uncertain benefit; substantial established harm	A much higher value is placed on the adverse events in which we are confident than in the benefit, which is uncertain	High incremental cost (or resource use) relative to the benefits may not justify the intervention	Strong recommendation against the intervention	In patients with idiopathic pulmonary fibrosis, treatment with azathioprine plus prednisone offers a possible but uncertain benefit in comparison with no treatment. The intervention, however, is associated with a substantial established harm. An international guideline made a recommendation against the combination of corticosteroids plus azathioprine in patients with idiopathic pulmonary fibrosis.
3. Potential equivalence, one option clearly less risky or costly	Low or very low	High or moderate	Magnitude of benefit apparently similar—though uncertain—for alternatives; we are confident less harm or cost for one of the competing alternatives	A high value is placed on the reduction in harm	High incremental cost (or resource use) relative to the benefits may not justify one of the alternatives	Strong recommendation for less harmful/less expensive	Low-quality evidence suggests that initial Helicobacter pylori eradication in patients with early stage extranodal marginal zone (MALT) B-cell lymphoma results in similar rates of complete response in comparison with the alternatives of radiation therapy or gastrectomy but with high certainty of less harm, morbidity and cost. Consequently, UpToDate made a strong recommendation in favour of H. pylori eradication rather than radiotherapy in patients with MALT lymphoma.
4. High certainty in similar benefits, one option potentially more risky or costly	High or moderate	Low or very low	Established that magnitude of benefit is similar for alternative management strategies; best (though uncertain) estimate is that one alternative has appreciably greater harm	A high value is placed on avoiding the potential increase in harm	High incremental cost (or resource use) relative to the benefits may not justify one of the alternatives	Strong recommendation against the intervention with possible greater harm	In women requiring anticoagulation and planning conception or in pregnancy, high certainty estimates suggest similar effects of different anticoagulants. However, indirect evidence (low certainty in effect estimates) suggests potential harm to the unborn infant with oral direct thrombin (eg, dabigatran) and factor Xa inhibitors (eg, rivaroxaban, apixaban). The AT9 guidelines recommended against the use of such anticoagulants in women planning conception or in pregnancy.
5. Potential catastrophic harm	Immaterial (very low to high)	Low or very low	Potential important harm of the intervention, magnitude of benefit is variable	A high value is placed on avoiding potential increase in harm	High incremental cost (or resource use) relative to the benefits, may not justify the intervention	Strong recommendation against the intervention	In males with androgen deficiency, testosterone supplementation likely improves quality of life. Low-certainty evidence suggests that testosterone increases cancer spread in patients with prostate cancer. The US Endocrine Society made a recommendation against testosterone supplementation in patients with prostate cancer.

Reproduced and adapted from Neumann et al.¹³

MALT, mucosa-associated lymphoid tissue.