Bias due to confounding
1.1 Is confounding of the effect of intervention unlikely in this study?	Y / PY / PN / N / NI
If Y or PY to 1.1, the study can be considered to be at low risk of bias due to confounding and no further signalling questions need be considered
For cohort‐type studies: 1.2. If N or PN to 1.1: Were participants analysed according to their initial intervention group throughout follow‐up?	Y / PY / PN / N / NI / NA
If Y or PY to 1.2, answer questions 1.4 to 1.6, which relate to baseline confounding
For cohort‐type studies: 1.3 If N or PN to 1.2: Were intervention discontinuations or switches unlikely to be related to factors that are prognostic for the outcome?	Y / PY / PN / N / NI / NA
If Y or PY to 1.3, answer questions 1.4 to 1.6, which relate to baseline confounding If N or PN to 1.1 and 1.2 and 1.3, answer questions 1.7 and 1.8, which relate to time‐varying confounding
1.4. Did the authors use an appropriate analysis method that adjusted for all the critically important confounding domains?	Y / PY / PN / N / NI / NA
1.5. If Y or PY to 1.4: Were confounding domains that were adjusted for measured validly and reliably by the variables available in this study?	Y / PY / PN / N / NI / NA
1.6. Did the authors avoid adjusting for postintervention variables?	Y / PY / PN / N / NI / NA
1.7. Did the authors use an appropriate analysis method that adjusted for all the critically important confounding domains and for time‐varying confounding?	Y / PY / PN / N / NI / NA
1.8. If Y or PY to 1.7: Were confounding domains that were adjusted for measured validly and reliably by the variables available in this study?	Y / PY / PN / N / NI / NA
'Risk of bias' judgement	Low / Moderate / Serious / Critical / NI
OPTIONAL 1.9: What is the predicted direction of bias due to confounding?	Favours experimental / Favours comparator / Unpredictable
Bias in selection of participants into the study
2.1. Was selection into the study unrelated to intervention or unrelated to outcome?	Y / PY / PN / N / NI
For cohort‐type studies: 2.2. Do start of follow‐up and start of intervention coincide for most participants?	Y / PY / PN / N / NI
2.3. If N or PN to 2.1 or 2.2: Were adjustment techniques used that are likely to correct for the presence of selection biases?	Y / PY / PN / N / NI / NA
For case‐control studies: 2.4 Were the controls sampled from the population that gave rise to the cases, or using another method that avoids selection bias?	Y / PY / PN / N / NI
'Risk of bias' judgement	Low / Moderate / Serious / Critical / NI
OPTIONAL 2.5: What is the predicted direction of bias due to selection of participants into the study?	Favours experimental / Favours comparator / Towards null / Away from null / Unpredictable
Bias in measurement of interventions
3.1 Is intervention status well defined?	Y / PY / PN / N / NI
3.2 Was information on intervention status recorded at the time of intervention?	Y / PY / PN / N / NI
3.3 Was information on intervention status unaffected by knowledge of the outcome or risk of the outcome?	Y / PY / PN / N / NI
'Risk of bias' judgement	Low / Moderate / Serious / Critical / NI
OPTIONAL 3.4: What is the predicted direction of bias due to measurement of outcomes or interventions?	Favours experimental / Favours comparator / Towards null / Away from null / Unpredictable
Bias due to departures from intended interventions
4.1. Were the critical co‐interventions balanced across intervention groups?	Y / PY / PN / N / NI
4.2. Were numbers of switches to other interventions low?	Y / PY / PN / N / NI
4.3. Was implementation failure minor?	Y / PY / PN / N / NI
For cohort‐type studies: 4.4. If N or PN to 4,1, 4.2, or 4.3: Were adjustment techniques used that are likely to correct for these issues?	Y / PY / PN / N / NI / NA
'Risk of bias' judgement	Low / Moderate / Serious / Critical / NI
OPTIONAL 4.5: What is the predicted direction of bias due to departures from the intended interventions?	Favours experimental / Favours comparator / Towards null / Away from null / Unpredictable
Bias due to missing data
For cohort‐type studies: 5.1 Are outcome data reasonably complete? For case‐control studies: 5.1 Was outcome status reasonably complete for those in whom it was sought?	Y / PY / PN / N / NI
For cohort‐type studies: 5.2 Was intervention status reasonably complete for those in whom it was sought? For case‐control studies: 5.2 Were data on intervention status reasonably complete?	Y / PY / PN / N / NI
5.3 Are data reasonably complete for other variables in the analysis?	Y / PY / PN / N / NI
For cohort‐type studies: 5.4 If N or PN to 5.1, 5.2, or 5.3: Are the proportion of participants and reasons for missing data similar across interventions? For case‐control studies: 5.4 If N or PN to 5.1, 5.2, or 5.3: Are the proportion of participants and reasons for missing data similar across cases and controls?	Y / PY / PN / N / NI / NA
5.5 If N or PN to 5.1, 5.2, or 5.3: Were appropriate statistical methods used to account for missing data?	Y / PY / PN / N / NI / NA
'Risk of bias' judgement	Low / Moderate / Serious / Critical / NI
OPTIONAL 5.6: What is the predicted direction of bias due to missing data?	Favours experimental / Favours comparator / Towards null / Away from null / Unpredictable
Bias in measurement of outcomes
For cohort‐type studies: 6.1 Was the outcome measure objective? For case‐control studies: 6.1 Was the definition of case status (and control status, if applicable) based on objective criteria?	Y / PY / PN / N / NI
For cohort‐type studies: 6.2 Were outcome assessors unaware of the intervention received by study participants? For case‐control studies: 6.2 Was the definition of case status (and control status, if applicable) applied without knowledge of the intervention received?	Y / PY / PN / N / NI
For cohort‐type studies: 6.3 Were the methods of outcome assessment comparable across intervention groups?	Y / PY / PN / N / NI
For cohort‐type studies: 6.4 Were any systematic errors in measurement of the outcome unrelated to intervention received?	Y / PY / PN / N / NI
'Risk of bias' judgement	Low / Moderate / Serious / Critical / NI
OPTIONAL 6.5: What is the predicted direction of bias due to measurement of outcomes?	Favours experimental / Favours comparator / Towards null / Away from null / Unpredictable
Bias in selection of the reported result
Is the reported effect estimate unlikely to be selected, on the basis of the results, from...
For cohort‐type studies: 7.1. ...multiple outcome measurements within the outcome domain? For case‐control studies: 7.1 ...multiple definitions of the intervention?	Y / PY / PN / N / NI
7.2 ...multiple analyses of the intervention‐outcome relationship?	Y / PY / PN / N / NI
7.3 ...different subgroups?	Y / PY / PN / N / NI
'Risk of bias' judgement	Low / Moderate / Serious / Critical / NI
OPTIONAL 7.4: What is the predicted direction of bias due to selection of the reported result?	Favours experimental / Favours comparator / Towards null / Away from null / Unpredictable
Abbreviations: Y: yes; PY: probably yes; PN: probably no; N: no; NI: no information; NA: not applicable