8.13.2.1  Low risk of bias due to incomplete outcome data

To conclude that there are no missing outcome data, review authors should be confident that the participants included in the analysis are exactly those who were randomized into the trial. If the numbers randomized into each intervention group are not clearly reported, the risk of bias is unclear. As noted above, participants randomized but subsequently found not to be eligible need not always be considered as having missing outcome data.

 

Example (of low risk of bias): “All patients completed the study and there were no losses to follow up, no treatment withdrawals, no trial group changes and no major adverse events”.

 

Acceptable reasons for missing data

A healthy person’s decision to move house away from the geographical location of a clinical trial is unlikely to be connected with their subsequent outcome. For studies with a long duration of follow-up, some withdrawals for such reasons are inevitable.

 

For studies reporting time-to-event data, all participants who did not experience the event of interest are considered to be ‘censored’ on the date of their last follow-up (we do not know whether the outcome event occurred after follow-up ended). The important consideration for this type of analysis is whether such censoring can be assumed to be unbiased, i.e. that the intervention effect (e.g. assessed by a hazard ratio) in individuals who were censored before the scheduled end of follow-up is the same as the hazard ratio in other individuals. In other words, there is no bias if censoring is unrelated to prognosis.

 

If outcome data are missing in both intervention groups, but reasons for these are both reported and balanced across groups, then important bias would not be expected unless the reasons have different implications in the compared groups. For example, ‘refusal to participate’ may mean unwillingness to exercise in an exercise group, whereas refusal might imply dissatisfaction with the advice not to exercise in the other group. In practice, incomplete reporting of reasons for missing outcomes may prevent review authors from making this assessment.

 

Potential impact of missing data on effect estimates

The potential impact of missing dichotomous outcomes depends on the frequency (or risk) of the outcome. For example, if 10% of participants have missing outcomes, then their potential impact on the results is much greater if the risk of the event is 10% than if it is 50%. The following table illustrates the potential impact of observed risks. A and B represent two hypothetical trials of 1000 participants in which 90% of the individuals are observed, and the risk ratio among these 900 observed participants is 1. Furthermore, in both trials we suppose that missing participants in the intervention group have a high risk of event (80%) and those in the control group have a much lower risk (20%). The only difference between trials A and B is the risk among the observed participants. In trial A the risk is 50%, and the impact of the missing data, had they been observed, is low. In trial B the risk is 10%, and the impact of the same missing data, had they been observed, is large. Generally, the higher the ratio of participants with missing data to participants with events, the greater potential there is for bias. In trial A this ratio was 100/450 (0.2), whereas in Trial B it was 100/90 (1.1).

 

 

 

Number randomized

Risk among observed

Observed data

Hypothetical extreme risks among missing participants

Missing data

Complete data

Risk ratio based on all participants

Trial A

 

 

 

 

 

 

Intervention

500

50%

225/450

80%

40/50

265/500

1.13

Control

500

50%

225/450

20%

10/50

235/500

 

Trial B

 

 

 

 

 

 

Intervention

500

10%

  45/450

80%

40/50

85/500

1.55

Control

500

10%

  45/450

20%

10/50

55/500

 

The potential impact of missing continuous outcomes increases with the proportion of participants with missing data. It is also necessary to consider the plausible intervention effect among participants with missing outcomes. The following table illustrates the impact of different proportions of missing outcomes. A and B represent two hypothetical trials of 1000 participants in which the difference in mean response between intervention and control among the observed participants is 0. Furthermore, in both trials we suppose that missing participants in the intervention arm have a higher mean and those in the control arm have a lower mean. The only difference between trials A and B is the number of missing participants. In trial A, 90% of participants are observed and 10% missing, and the impact of the missing data on the observed mean difference is low. In trial B, half of the participants are missing, and the impact of the same missing data on the observed mean difference is large.

 

 

 

Number randomized

Number observed

Observed mean

Number missing

Hypothetical extreme mean among missing participants

Overall mean (weighted average)

Mean difference based on all participants

Trial A

 

 

 

 

 

 

Intervention

500

450

10

50

15

10.5

1

Control

500

450

10

50

5

9.5

 

Trial B

 

 

 

 

 

 

Intervention

500

250

 10

250

15

12.5

5

Control

500

250

  10

250

5

7.5