The text below is taken from the GRADE workinggroup official JCE series, article number 9:
GRADE guidelines: 9. Rating up the quality of evidence
Factors that may increase the quality of evidence
- Large magnitude of effect (direct evidence, relative risk [RR]=2–5 or RR=0.5–0.2 with no plausible confounders); very large with RR>5 or RR<0.2 and no serious problems with risk of bias or precision (sufficiently narrow confidence intervals); more likely to rate up if effect rapid and out of keeping with prior trajectory; usually supported by indirect evidence.
- Dose-response gradient.
- All plausible residual confounders or biases would reduce a demonstrated effect, or suggest a spurious effect when results show no effect.
The circumstances under which we may wish to rate up the quality of evidence for intervention studies will likely occur infrequently and are primarily relevant to observational studies (including cohort, case–control, before–after, and time series studies) and to nonrandomized experimental or interventional studies (e.g., providing treatment to one of the two matched groups). Indeed, although it is theoretically possible to rate up results from randomized control trials (RCTs), we have yet to find a compelling example of such an instance.
The presence of a dose–response gradient has long been recognized as an important criterion for believing a putative cause–effect relationship . Such a gradient may increase our confidence in the findings of observational studies and thus enhance the assigned quality of evidence (Table 1).
For example, our confidence in the results of observational studies that show an increased risk of bleeding in patients who have supra-therapeutic anticoagulation levels is increased by the finding that there is a dose–response gradient between higher levels of the international normalized ratio and the increased risk of bleeding . Similarly, infant growth is slowest in infants fed exclusively with breast milk, accelerated to some extent in infants fed in part with breast milk and part formula, and further accelerated in infants fed exclusively with formula . A systematic review of observational studies investigating the effect of cyclooxygenase-2 inhibitors on cardiovascular events found an RR with rofecoxib of 1.33 (95% CI: 1.00, 1.79) with doses less than 25mg/d and an RR of 2.19 (95% CI: 1.64, 2.91) with doses more than 25mg/d .
A final example is the striking dose–response gradient associated with the rapidity of antibiotic administration in patients presenting with sepsis and hypotension (Fig. 1) . This dose–response relationship increases our confidence that the effect on mortality (large absolute increases in mortality with each hour's delay) is real and substantial.
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Large magnitude of effect
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