75 Risk factors: a systematic review 2 Application Study phase was defined per included study. Phase 3 and 2 = high quality of evidence Phase 1 = moderate quality of evidence Present (x) when less than 50% of the included studies were of higher quality in the QUIPS assessment. Present (x) when studies report both positive and negative results. Not applicable (NA) when only one included study. Present (x) when the included studies do not reflect the predefined research question (as defined by Patient/ Intervention/ Comparison/ Outcome (PICO)) Present (x) when more than 50% of included studies have imprecision. Unclear when not described in more than 50% of included studies. Do not downgrade when specifically investigated in multiple included studies Present (√) when moderate or large effect is reported. Unclear when effect is reported without use of appropriate statistics. Present (√) when higher levels of the risk factor lead to a larger effect size over lower levels of the factor. Unclear when no appropriate effect size reported. Not applicable (NA) when a gradient is not possible (e.g. boy/girl). 1. Start with highest study phase and accompanying quality of evidence 2. Downgrade if: study limitations, inconsistency, indirectness, imprecision or publication bias are present (x) or unclear. 3. Upgrade if: moderate/large effect sizes or dose effect are present (√)
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