The perils and pitfalls of sub-group analysis (Pulse Article 2001)

This article is part of a series on Critical Reading.

Controlled clinical trials are designed to investigate the effect of a treatment in a given population of patients, for example aspirin is given to patients with ischaemic heart disease. Inevitably there will be differences between the patients included in the trial (men versus women, older versus younger, hypertensive versus non-hypertensive).

It is tempting to look at the effects of treatment separately in different types of patient in order to decide who will benefit most from being given the treatment. Although this analysis of the sub-groups of patients is widely carried out in the medical literature, it is not very reliable. And the ISIS-2 trial gives a clear example of how this can be misleading [1]. The trial looked at the effect of aspirin given after acute myocardial infarction, and when the results were reported the editorial team at the Lancet wished to publish a table of sub-group analyses. The authors agreed as long as the first line in the table compared the effects in patients with different birth signs [2].

The analysis showed that aspirin was beneficial in all patients except those with the star signs of Libra and Gemini. This served as a warning against the over interpretation of the results of the other sub-groups reported in the paper. The problem is that the play of chance can lead to apparently significant differences between sub-groups, and these are really only helpful in very large trials which show really big overall differences in the treatment and control groups.

Two examples of the use of sub-group analysis are somewhat contentious. The first was reported in the Lancet and looked at the evidence from different trials of mammography to try to reduce deaths from breast cancer[3]. The overall result from all the trials together showed mammography to be of significant benefit, but the authors looked at the characteristics of the trials and felt that some were more reliable than others. The data from these selected trials did not show a benefit from mammography. On this basis the authors concluded that screening for breast cancer was unjustified.

Use of aspirin

Similarly a recent paper in the BMJ suggested that aspirin may not be useful for primary prevention in patients with mildly elevated blood pressure on the basis of the results of patients in this sub-group [4]. I would suggest that before deciding about aspirin for such patients you ask yourself whether you would still treat those with the Libra and Gemini birth signs with aspirin following an MI. Moreover if patients on aspirin for secondary prevention of ischaemic heart disease ask whether they should stop if their blood pressure is up a bit, my answer would be no.

The bottom line is that the best overall estimate of the effect of a treatment comes from the average effect on all the patients and not from the individual sub-groups [5]. Sub-group analysis is generally best restricted to the realm of generating hypotheses for further testing rather than evidence that should change practice.


1. Horton R. From star signs to trial guidelines. Lancet 2000;355:1033-34

2. ISIS-2 Collaboration group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected myocardial infarction. Lancet 1988; ii:39-60

3. Gotzche PC, Olsen O. Is screening for breast cancer with mammography justifiable? Lancet 2000;355:129-34

4. Meade TW, Brennan PJ, on behalf of the MRC General Practice Research framework. Determination of who may derive the most benefit from aspirin in primary prevention; subgroup results from a randomised controlled trial. BMJ 2000; 321:13-7.

5. Gotzsche PC. Why we need a broad perspective on meta-analysis. BMJ 2000; 321:585-6