Multiplicity of Data: Subgroup Analysis

Question 1

Grouin et al 2005 suggest what purposes for sub-group analysis?

Answer 1

Confirm efficacy is consistent across subgroups
Identify subgroups with larger treatment effect (who benefits the most)
Explore subgroups with a priori larger/smaller benefits
Identify subgroup benefit in the case of non-significant overall effect
Identify safety issues restricted to specific subgroups

Question 2

What are the three cautions of handling subgroup data?

Answer 2

Studies may be underpowered to detect treatment differences in subgroups

Must guard against data-dredging

Beware of p-values. Best to use interaction tests

Question 3

List important considerations before undertaking a subgroup analysis

Answer 3

The subgroup category definitions should be explicitly defined in advance. It is important when defining these categories that they are relevant for decision making in clinical practice.
The total number of planned subgroups analyses
The proposed hypotheses with direction (biological plausibility of the expected effect) and the outcome for which each subgroup is to be tested
Whether the subgroup analysis is confirmatory or exploratory in nature
The method by which the subgroup analysis will be performed (i.e. test for interaction)
Whether the randomisation will be stratified by important subgroup categories. Stratification of the randomisation helps to ensure a balance of treatment assignment within subgroups. It also helps the researcher define and decide on important subgroups at the design stage, as stratification works best with a smaller number of strata.

Question 4

How should subgroup analyses be reported in the results section?

Answer 4

Presented numerically/graphically (Forrest plot)

Including numbers analysed, treatment effect within each group w 95% CIs and p-values for interaction tests

Outline if exploratory or confirmatory in nature

Question 5

List three types of interaction

Answer 5

Qualitative (observed treatment effect is opposite between two subgroups)

All or nothing (treatment only effective in one subgroup)

Quantitative (treatment effective in both groups but to different degree)

Question 6

Name one reason you might wish to conduct a subgroup analysis

Answer 6

Any one of the following:

To confirm that efficacy seen overall is consistently seen across subgroups
To identify subgroups with larger treatment effect when an overall benefit is observed i.e. looking at who will benefit the most from treatment
To explore subgroups that were expected a priori to have smaller or larger treatment benefit
To identify subgroups where the treatment appears to have an effect in the case of a non-significant overall effect
To identify any safety issues that may be restricted to particular subgroups.

Question 7

Describe the statistical problem that has to be considered in the interpretation of the results of subgroup analyses

Answer 7

Subgroup analyses create multiplicity issues and often the trial is not powered to detect subgroup effects.

Question 8

How should subgroups be analysed?

Answer 8

Interaction tests

Question 9

o improve the credibility of any subsequent subgroup finding what two things can a researcher do?

Answer 9

Pre-specify subgroups and limit the number of groups to biologically plausible and impactful subgroups only

Question 10

Which graphical technique can be used to display the results of subgroup analyses and what can be identified in such a plot?

Answer 10

Forest plots can be used to display subgroup results and they provide a visual representation of the heterogeneity of the results.