Abstract:
Background: A subgroup of clinical trial subjects identified by baseline characteristics is a proper
subgroup while a subgroup determined by post randomization events or measures is an improper
subgroup. Both types of subgroups are often analyzed in clinical trial papers. Yet, the extensive
scrutiny of subgroup analyses has almost exclusively attended to the former. The analysis of
improper subgroups thereby not only flourishes in numerous disguised ways but also does so
without a corresponding awareness of its pitfalls. Comparisons of the grade of angina in a heart
disease trial, for example, usually include only the survivors. This paper highlights some of the
distinct ways in which outcome based subgroup analysis occurs, describes the hazards associated
with it, and proposes a simple alternative approach to counter its analytic bias.
Results: Data from six published trials show that outcome based subgroup analysis, like proper
subgroup analysis, may be performed in a post-hoc fashion, overdone, selectively reported, and
over interpreted. Six hypothetical trial scenarios illustrate the forms of hidden bias related to it.
That bias can, however, be addressed by assigning clinically appropriate scores to the usually
excluded subjects and performing an analysis that includes all the randomized subjects.
Conclusion: A greater level of awareness about the practice and pitfalls of outcome based
subgroup analysis is needed. When required, such an analysis should maintain the integrity of
randomization. This issue needs greater practical and methodologic attention than has been
accorded to it thus far.
