Exact simultaneous confidence intervals for logical selection of a biomarker cut-point

Yang Han, Szu-Yu Tang, Hui-Min Lin, Jason C Hsu

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This article proposes four new principles for logical biomarker cut-point selection methods to adhere to: subgroup sensibility, sensitivity, specificity, and target monotonicity. At every cut-point value, our method gives confidence intervals not only for the efficacy at that cut-point value, but also efficacies in the marker-positive and marker-negative subgroups defined by that cut-point. These confidence intervals are given simultaneously for all possible cut-point values. Using Alzheimer's disease (AD) and type 2 diabetes (T2DM) as examples, we show our method achieves the four principles. Our method strongly controls familywise type I error rate (FWER) across both levels of multiplicity: the multiplicity of having marker-positive and marker-negative subgroups at each cut-point, and the multiplicity of searching through infinitely many cut-points. This is in contrast to other available methods. The confidence level of our simultaneous confidence intervals is in fact exact (not conservative). An application (app) is available, which implements the method we propose.

Original languageEnglish
Pages (from-to)1-18
Number of pages18
JournalBiometrical Journal
Early online date26 Feb 2021
Publication statusPublished - 26 Feb 2021


  • Alzheimer's disease; cut-points; exact confidence bands; multiple comparisons; principles for subgroup identification.


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