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.
