GRADE Series - Guest Editors, Sharon Straus and Sasha Shepperd
GRADE guidelines: 2. Framing the question and deciding on important outcomes

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Abstract

GRADE requires a clear specification of the relevant setting, population, intervention, and comparator. It also requires specification of all important outcomes—whether evidence from research studies is, or is not, available. For a particular management question, the population, intervention, and outcome should be sufficiently similar across studies that a similar magnitude of effect is plausible. Guideline developers should specify the relative importance of the outcomes before gathering the evidence and again when evidence summaries are complete. In considering the importance of a surrogate outcome, authors should rate the importance of the patient-important outcome for which the surrogate is a substitute and subsequently rate down the quality of evidence for indirectness of outcome.

Introduction

Key points

  • GRADE requires a clear specification of the relevant setting, population, intervention, comparator(s), and outcomes.

  • Outcomes of interest should be those important to patients: if patient-important outcomes are represented by a surrogate, they will frequently require rating down the quality of evidence for indirectness.

  • Questions must be sufficiently specific: across the range of populations, interventions, and outcomes, a more or less similar effect must be plausible.

  • For a guideline, an initial rating of the importance of outcomes should precede the review of the evidence, and this rating should be confirmed or revised following the evidence review.

In the first article of this series, we introduced GRADE and the GRADE evidence profile and summary-of-findings tables that facilitate clinical decisions. This second article discusses GRADE’s approach in framing the relevant questions for systematic reviews and guidelines, choosing the relevant outcomes and deciding on their relative importance. We focus on conceptual issues: later articles will address who exactly should take on what roles.

Section snippets

Structured questions of patient management

This article will focus on questions about the effects of interventions. Guideline developers will, however, usually have important questions about prognosis, prevalence, and other types of questions that require a different framing structure than management issues (Box 1).

Framing questions involves specifying patients, interventions, comparators, and outcomes, and sometimes setting

A well-accepted methodology associated with framing of questions addressing alternative management strategies in systematic reviews mandates carefully specifying the patient population, the intervention of interest, the comparator, and the outcomes of interest. The value of the methodology—popularly known as PICO (patient/intervention/comparator/outcome)—in helping achieve focused recommendations is increasingly recognized not only by systematic review authors but also by guideline developers

Ensuring the question framing is appropriately specific

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 [6], [7], [8]. For instance, the relative risk reduction in vascular events associated with statins is very similar in those with and without underlying vascular disease; the relative risk reduction associated

Specification of outcomes: ensuring comprehensiveness

Many, if not most, systematic reviews fail to address some key outcomes, particularly harms, associated with an intervention. Systematic reviews may even focus on a single outcome (e.g., the impact of statins on stroke [10] or vitamin D on nonvertebral fractures [11]).

Guideline panels do not have this luxury. Sensible recommendations require consideration of all outcomes that are important to patients. In addition, they may require consideration of outcomes that are important to others,

Outcome importance: three categories

Guideline panels using GRADE will consider the importance of outcomes in three steps (Table 1). We will address the first two steps in this article. In subsequent articles, we will address the third step—making judgments about the balance between the desirable and undesirable effects of an intervention.

Guideline developers must, and authors of systematic reviews ideally will, specify all potential patient-important outcomes as the first step in their endeavor. Those using GRADE for guideline

Outcome importance: influence of perspective

Importance of outcomes is likely to vary within and across cultures or when considered from the perspective of patients, clinicians, or policy makers. Guideline panels must decide what perspective they are taking. Although different panels may elect to take different perspectives (e.g., that of individual patients, that of a third-party payer, or a societal perspective), the relative importance given to outcomes should reflect the perspective of those who are affected. When the target audiences

Importance of outcomes: using evidence

At the time of writing, a guideline panel sponsored by the American College of Chest Physicians (ACCP) is developing the ninth iteration of the ACCP antithrombotic guidelines. As part of this process, the group has conducted a systematic review of the evidence relating to patients’ values and preferences for antithrombotic therapy. Insights from this review have included the considerable variability of patients’ values, the limited burden of warfarin therapy that most patients experience, and

Outcome importance: missing evidence and surrogate outcomes

Systematic reviews—though they may reflect on the implications of what is measured and what is not measured—are limited to preparing quantitative summaries of outcomes that the investigators have included in their studies. Not infrequently, outcomes of most importance to patients remain unexplored. For example, in type 2 diabetes, clinical trials have failed to adequately address the long-term impact of alternative management strategies on diabetic complications of micro- and macrovascular

Outcome importance: preliminary and definitive ratings

Although it is worthwhile to specify critical and important outcomes before beginning the review of the evidence, results of that review may influence judgments about the importance of the outcomes. We describe two situations in which results of the evidence review may modify the selection of relevant outcomes or their relative importance as follows.

  • 1.

    A potential benefit on a particular outcome, initially judged critical, may no longer be critical on review of the results. This will be the case

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The GRADE system has been developed by the GRADE Working Group. The named authors drafted and revised this article. A complete list of contributors to this series can be found on the JCE Web site at www.jclinepi.com.

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