GRADE requires a clear specification of the relevant setting, population, intervention, comparator(s), and outcomes (see Building a search question). A guideline question often involves an additional specification, i.e. the setting in which the guideline will be implemented. For instance, guidelines intended for resource-rich environments will often be inapplicable in resource-poor environments. Furthermore, in some cases it may be necessary to specify if the guideline needs to be implemented in an inpatient or an outpatient setting.
Questions must be sufficiently specific: across the range of populations, interventions, and outcomes, a more or less similar effect must be plausible. Because the relative risk associated with an intervention vs. a specific comparator is usually similar across a wide variety of baseline risks, it is usually appropriate for systematic reviews to generate single pooled estimates of relative effects across a wide range of patient subgroups. Recommendations, however, may differ across subgroups of patients at different baseline risk of an outcome, despite there being a single relative risk that applies to all of them. Absolute risk reductions are greater in higher-risk patients, warranting taking a higher risk of side effects and enduring inconvenience. Evidence quality may also differ across subgroups, and this may mandate differing recommendations (higher likelihood of recommending an intervention, or making a stronger recommendation when evidence is of higher quality). Thus, guideline panels must often define separate questions (and produce separate evidence summaries) for high- and low-risk patients, and patients in whom quality of evidence differs.
The case for warfarin therapy associated with both inconvenience and a higher risk of serious bleeding is much stronger in atrial fibrillation patients at substantial vs. minimal risk of stroke.