Starting GRADE	Phase of investigation
HIGH	Phase 3 Explanatory Study: Explanatory research aimed at understanding prognostic pathways; or Phase 2 Explanatory Study: Explanatory research aimed at confirming independent associations between potential prognostic factor and the outcome
MODERATE	Phase 1 Explanatory Study: Explanatory research aimed at identifying associations between potential prognostic factors and the outcome, or Outcome prediction research providing evidence about prognostic factor associations
Downgrade if:		Upgrade if:
Study limitations	Serious limitations when most evidence is from studies with moderate or unclear risk of bias for most bias domains	Moderate or large effect	For meta‐analysis: pooled effect is moderate or large
	Very serious limitations when most evidence is from studies with high risk of bias for almost all bias domains		For narrative summary: moderate or large similar effect is reported by most studies
Inconsistency	Unexplained heterogeneity or variability in results across studies with differences in results not clinically meaningful. This may be supported by: ‐ For meta‐analysis: significant heterogeneity detected by test of heterogeneity and large I2 value ‐ For narrative summary: variations in effect estimates across studies with points of effect on either side of the line of no effect, and confidence intervals showing minimal overlap	Exposure‐gradient response	For meta‐analysis: gradient is present between analyses for factors measured at different doses For narrative summary: possible gradient exists within and between primary studies.
Indirectness	The study sample, the prognostic factor, and/or the outcome in the primary studies do not accurately reflect the review question
Imprecision	For meta‐analysis: (1) insufficient sample size and (2) no precise estimate of the effect size in the meta‐analysis: confidence interval is excessively wide and overlaps the value of no effect and contains values implying that the factor plays an important role in protecting or putting the individual at risk
	For narrative summary: Within‐study imprecision, (1) sample size justification is not provided and there are fewer than 10 outcome events for each prognostic variable (for dichotomous outcomes) OR there are fewer than 100 cases reaching endpoint (for continuous outcomes); and (2) no precision in the estimation of the effect size within each primary study, AND
	Across‐study imprecision: there are few studies and small numbers of participants across studies
Publication bias:	We recommend downgrading unless the value of the risk/protective factor in predicting the outcome has been repetitively investigated, ideally by phase 2 and 3 studies
Table modified (with permission) from Table 4, Huguet 2013