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BMC Medical Research Methodology

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Open Access 01-12-2015 | Research article

Subgroup identification for treatment selection in biomarker adaptive design

Authors: Tzu-Pin Lu, James J. Chen

Published in: BMC Medical Research Methodology | Issue 1/2015

Abstract

Background

Advances in molecular technology have shifted new drug development toward targeted therapy for treatments expected to benefit subpopulations of patients. Adaptive signature design (ASD) has been proposed to identify the most suitable target patient subgroup to enhance efficacy of treatment effect. There are two essential aspects in the development of biomarker adaptive designs: 1) an accurate classifier to identify the most appropriate treatment for patients, and 2) statistical tests to detect treatment effect in the relevant population and subpopulations. We propose utilization of classification methods to identity patient subgroups and present a statistical testing strategy to detect treatment effects.

Methods

The diagonal linear discriminant analysis (DLDA) is used to identify targeted and non-targeted subgroups. For binary endpoints, DLDA is directly applied to classify patient into two subgroups; for continuous endpoints, a two-step procedure involving model fitting and determination of a cutoff-point is used for subgroup classification. The proposed strategy includes tests for treatment effect in all patients and in a marker-positive subgroup, with a possible follow-up estimation of treatment effect in the marker-negative subgroup. The proposed method is compared to the ASD classification method using simulated datasets and two publically available cancer datasets.

Results

The DLDA-based classifier performs well in terms of sensitivity, specificity, positive and negative predictive values, and accuracy in the simulation data and the two cancer datasets, with superior accuracy compared to the ASD method. The subgroup testing strategy is shown to be useful in detecting treatment effect in terms of power and control of study-wise error.

Conclusion

Accuracy of a classifier is essential for adaptive designs. A poor classifier not only assigns patients to inappropriate treatments, but also reduces the power of the test, resulting in incorrect conclusions. The proposed procedure provides an effective approach for subgroup identification and subgroup analysis.

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Title: Subgroup identification for treatment selection in biomarker adaptive design
Authors: Tzu-Pin Lu
James J. Chen
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Medical Research Methodology / Issue 1/2015
Electronic ISSN: 1471-2288
DOI: https://doi.org/10.1186/s12874-015-0098-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Subgroup identification for treatment selection in biomarker adaptive design

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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