Dmitrienko Wiens Tamhane Wang 2007

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Dmitrienko, A., Wiens, B.L., Tamhane, A.C., Wang, X. (2007). Tree-structured gatekeeping tests in clinical trials with hierarchically ordered multiple objectives. Statistics in Medicine. 26, 2465-2478.


This paper discusses a new class of multiple testing procedures, tree-structured gatekeeping procedures, with clinical trial applications. These procedures arise in clinical trials with hierarchically ordered multiple objectives, for example, in the context of multiple dose-control tests with logical restrictions or analysis of multiple endpoints. The proposed approach is based on the principle of closed testing and generalizes the serial and parallel gatekeeping approaches developed by Westfall and Krishen (2001) and Dmitrienko, Offen and Westfall (2003) Dmitrienko Offen Westfall 2003. The proposed testing methodology is illustrated using a clinical trial with multiple endpoints (primary, secondary and tertiary) and multiple objectives (superiority and non-inferiority testing) as well as a dose-finding trial with multiple endpoints.


Download Dmitrienko Wiens Tamhane Wang 2007. Note that there are two minor typos in the published paper (Table 2, Bonferroni-based tree gatekeeping procedure in the hypertension clinical trial). These typos have been corrected in this PDF file.


The algorithm for constructing tree-structured gatekeeping procedures developed in this paper may fail if the hypothesis weights used in the algorithm do not meet the monotonicity condition and, as a result, the gatekeeping property may be violated. The algorithm was corrected in Dmitrienko Tamhane Liu Wiens 2008.

Further, the methodology developed in this paper has been extended in the following papers:

Review papers and chapters

For more information on gatekeeping procedures in clinical trials, see

Software implementation

Bonferroni-based tree-structured gatekeeping procedures can be implemented using the TreeGatekeeper macro. The TreeGatekeeper macro can be downloaded from Implementation of Gatekeeping Procedures.

Other papers

For information on other publications on gatekeeping procedures in clinical trials, see Gatekeeping Papers.