74 Chapter 2 Supplemental Table 3. Definition and application of GRADE (Grading of Recommendations Assessment, Development and Evaluation) domains GRADE factor Explanation Phase of the study Phase 3 study: cohort study design that seeks to generate understanding of the underlying processes for the prognosis of a health condition. Phase 2 study: cohort study design that seeks to confirm independent associations between the prognostic factor and the outcome Phase 1 study: Outcome prediction research or explanatory research aimed to identify associations between potential prognostic factors and the outcome. Study limitations Overall limitations based on the QUIPS assessment. Inconsistency Unexplained heterogeneity or variability in results across studies with differences of results not clinically meaningful. Indirectness The study sample, the prognostic factor, and/or the outcome in the primary studies do not accurately reflect the review question. Imprecision Within-study imprecision: sample size justification is not provided and there are less than 10 outcome events for each prognostic variable (for dichotomous outcomes) OR there are less than 100 cases reaching endpoint (for continuous outcomes), and no precision in the estimation of the effect size within each primary study Across study imprecision: there are few studies and small number of participants across studies. Publication bias Downgrade, unless the value of the risk/protective factor in predicting the outcome has been repetitively investigated Moderate/large effect sizes Moderate or large similar effect is reported by most studies Dose effect Possible gradient exists within and between primary studies Overall quality High / Moderate / Low / Very low Modified from: Huguet A, Hayden JA, Stinson J, McGrath PJ, Chambers CT, Tougas ME, et al. Judging the quality of evidence in reviews of prognostic factor research: adapting the GRADE framework. Syst Rev. 2013;2:71
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