Robust Cancer Biomarker Identification From Matched Transcriptomic Data Via Bootstrapped Regularized Conditional Logistic Regression

Objectives: With the increasing application of high-throughput transcriptomic data in cancer research, identifying reliable cancer biomarkers in high-dimensional settings remains a major challenge. This study aims to systematically evaluate various regularized conditional logistic regression (CLR) methods under a matched case-control (MCC) design, focusing on their performance in variable selection, parameter estimation, and predictive accuracy. Special emphasis is placed on the importance of the matching design in reducing confounding effects and improving model interpretability. Methods: We utilize RNA-seq data from The Cancer Genome Atlas (TCGA), specifically datasets for liver, thyroid, and lung cancers, which include paired tumor and adjacent normal tissue samples. In our analysis, we apply 4 regularized CLR methods implemented in R packages-namely "clogitL1," "pclogit," "clogitLasso," and "penalizedclr"-to analyze over 20 000 gene expression features. We evaluate the comparative performance of these methods based on metrics such as gene selection stability, predictive accuracy, and interpretability. Additionally, we employ a bootstrap resampling framework to estimate gene selection probabilities, which serve as a measure of gene importance. Results: Our results show that incorporating the MCC design significantly enhances feature selection performance by mitigating confounding noise. The regularized CLR models successfully identify several well-established cancer-related genes with high selection consistency and statistical significance. In contrast, models that ignore the matched design tend to miss critical biomarkers or produce excessive false positives, leading to potentially misleading interpretations. Conclusions: This study highlights the value of integrating a matched case-control design with regularized CLR methods for the analysis of high-dimensional transcriptomic data. The proposed analytical framework offers improved accuracy, robustness, and biological relevance, providing a practical and scalable approach for cancer genomics research. It also supports the advancement of precision medicine and translational applications.