Item

Judgment

Description

1. Random sequence generation (selection bias)

Low risk

The investigators describe a random component in the sequence generation process such as: random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization

High risk

The investigators describe a non‐random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; results of a laboratory test or a series of tests; availability of the intervention

Observational prospective study

Unclear risk

Insufficient information to permit judgment of low or high risk

2. Allocation concealment (selection bias)

Low risk

Investigators enroling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based, and pharmacy‐controlled, randomization); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes

High risk

Investigators enroling participants could possibly foresee assignments because one of the following method was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure

Observational prospective study

Unclear risk

Insufficient information to permit judgment of low or high risk. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgment

3. Blinding of participants and providers (performance bias)

Objective outcomes

Low risk

No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding;

blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

High risk

No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding;

blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding

Unclear risk

Insufficient information to permit judgment of low or high risk

4. Blinding of participants and providers (performance bias)

Subjective outcomes

Low risk

Blinding of participants and providers and unlikely that the blinding could have been broken

High risk

No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding;

blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding

Unclear risk

Insufficient information to permit judgment of low or high risk

5. Blinding of outcome assessor (detection bias)

Objective outcomes

Low risk

No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding;

blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

Record linkage

High risk

No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding;

blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding

Unclear risk

Insufficient information to permit judgment of low or high risk

6. Blinding of outcome assessor (detection bias)

Subjective outcomes

Low risk

No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding;

blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

High risk

No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding;

blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding

Unclear risk

Insufficient information to permit judgment of low or high risk

7. Incomplete outcome data (attrition bias)

For all outcomes except retention in treatment or drop out

Low risk

No missing outcome data;

reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias);

missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups;

for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; f

or continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; m

issing data have been imputed using appropriate methods;

all randomized participants are reported/analyzed in the group they were allocated to by randomization irrespective of noncompliance and cointerventions (intention to treat)

High risk

Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; f

or dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; f

or continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size;

‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomization

Unclear risk

Insufficient information to permit judgment of low or high risk (e.g. number randomized not stated, no reasons for missing data provided; number of drop outs not reported for each group)

8. Selective reporting (reporting bias)

Low risk

The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way;

the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon)

High risk

Not all of the study’s prespecified primary outcomes have been reported;

one or more primary outcomes is reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified;

one or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect);

one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis;

the study report fails to include results for a key outcome that would be expected to have been reported for such a study

Unclear risk

Insufficient information to permit judgment of low or high risk

9. Free of other bias:

comparability of cohorts for baseline characteristics and outcome measures on the basis of the design or analysis

Low risk

Exposed and nonexposed individuals are matched in the design for most important confounding factors;

authors demonstrated balance between group for the confounders;

analysis are adjusted for most important confounding factors and imbalance;

randomized controlled trial.

High risk

No matching or no adjustment for most important confounding factor

Unclear risk

No information about comparability of cohort

10. Free of other bias: selection of the nonexposed cohort

Low risk

The sample has been drawn from the same community as the exposed cohort

High risk

The sample has been drawn from a different source

Unclear risk

No description of the derivation of the nonexposed cohort

11. Free of other bias: protection against contamination

Low risk

Allocation was by community, institution, or practice and it is unlikely that the control group received the intervention

High risk

It is likely that the control group received the intervention

Unclear risk

It is possible that communication between intervention and control groups could have occurred