Applications of gene pair methods in clinical research: advancing precision medicine

The rapid evolution of high-throughput sequencing technologies has revolutionized biomedical research, producing vast amounts of gene expression data that hold immense potential for biological discovery and clinical applications. Effectively mining these large-scale, high-dimensional data is crucial for facilitating disease detection, subtype differentiation, and understanding the molecular mechanisms underlying disease progression. However, the conventional paradigm of single-gene profiling, measuring absolute expression levels of individual genes, faces critical limitations in clinical implementation. These include vulnerability to batch effects and platform-dependent normalization requirements. In contrast, emerging approaches analyzing relative expression relationships between gene pairs demonstrate unique advantages. By focusing on binary comparisons of two genes' expression magnitudes, these methods inherently normalize experimental variations while capturing biologically stable interaction patterns. In this review, we systematically evaluate gene pair-based analytical frameworks. We classify eleven computational approaches into two fundamental categories: expression value-based methods quantifying differential expression patterns, and rank-based methods exploiting transcriptional ordering relationships. To bridge methodological development with practical implementation, we establish a reproducible analytical pipeline incorporating feature selection, classifier construction, and model evaluation modules using real-world benchmark datasets from pulmonary tuberculosis studies. These findings position gene pair analysis as a transformative paradigm for mining high-dimensional omics data, with direct implications for precision biomarker discovery and mechanistic studies of disease progression.