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Detecting survival-associated biomarkers from heterogeneous populations.

ABSTRACT: Detection of prognostic factors associated with patients' survival outcome helps gain insights into a disease and guide treatment decisions. The rapid advancement of high-throughput technologies has yielded plentiful genomic biomarkers as candidate prognostic factors, but most are of limited use in clinical application. As the price of the technology drops over time, many genomic studies are conducted to explore a common scientific question in different cohorts to identify more reproducible and credible biomarkers. However, new challenges arise from heterogeneity in study populations and designs when jointly analyzing the multiple studies. For example, patients from different cohorts show different demographic characteristics and risk profiles. Existing high-dimensional variable selection methods for survival analysis, however, are restricted to single study analysis. We propose a novel Cox model based two-stage variable selection method called "Cox-TOTEM" to detect survival-associated biomarkers common in multiple genomic studies. Simulations showed our method greatly improved the sensitivity of variable selection as compared to the separate applications of existing methods to each study, especially when the signals are weak or when the studies are heterogeneous. An application of our method to TCGA transcriptomic data identified essential survival associated genes related to the common disease mechanism of five Pan-Gynecologic cancers.

SUBMITTER: Saegusa T

PROVIDER: S-EPMC7865037 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Detecting survival-associated biomarkers from heterogeneous populations.

Saegusa Takumi T Zhao Zhiwei Z Ke Hongjie H Ye Zhenyao Z Xu Zhongying Z Chen Shuo S Ma Tianzhou T

Scientific reports 20210205 1

Detection of prognostic factors associated with patients' survival outcome helps gain insights into a disease and guide treatment decisions. The rapid advancement of high-throughput technologies has yielded plentiful genomic biomarkers as candidate prognostic factors, but most are of limited use in clinical application. As the price of the technology drops over time, many genomic studies are conducted to explore a common scientific question in different cohorts to identify more reproducible and ...[more]

PMID: 33547332

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Project description:Flow cytometric methods for detecting and quantifying reduced intracellular thiol content using fluorescein-5-maleimide (F5M) in viable eukaryotic cells date back to 1983 (Durand and Olive [1]). There has been little development in these methodologies since that time, a period that has witnessed huge technological advances, particularly with the emergence of digital multi-parameter flow cytometric systems. Concurrent advancement in our understanding of redox regulation within eukaryotic cellular systems has also followed, whereby it is now accepted that cysteine thiols partake in redox reactions, which regulate protein activity and function (Groitl and Jakob (2014), Won et al. (2012)). Moreover, we are at the dawn of a new era in redox biology whereby the importance of 'reductive stress' in eukaryotic cellular systems is gathering momentum (Wadley et al. (2018) [4]). It is therefore critical that methods be continually advanced to better understand these concepts in more detail at the cellular level. Flow cytometry is a powerful technique that may be used for this purpose. Henceforth we have rejuvenated these methods to address modern scientific questions. In this paper, essential detail is provided on: •The adaption of a protocol initially described by Durand and Olive [1] for use with modern digital flow cytometer configurations. Here we provide optimal conditions for labelling intracellular thiols with F5M for detection using digital flow cytometers. Our modifications avoid the use of methanol fixation thus preserving cell viability in single cell suspension cultures.•Demonstration that flow cytometry can detect the gain and loss of reduced intracellular thiols in cells exposed to physiological doses of hydrogen peroxide mediated by glucose oxidase (Hole et al. (2013) [5]).•Validation of F5M protein labelling by coupling method to confocal microscopy and downstream proteomics, thus permitting a powerful experimental platform for potential use with next generation flow cytometry e.g. CyTOF (Lin and Maecker (2018) [6]).

Dataset Information

Detecting survival-associated biomarkers from heterogeneous populations.

Publications

Detecting survival-associated biomarkers from heterogeneous populations.

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