Multi-omics driven computational framework for cancer molecular subtype classification.

Cancer molecular subtype classification is an essential component of precision oncology which provides insights into cancer prognosis and guides targeted therapy. Despite the growing applications of AI for cancer molecular subtype classification, challenges persist due to non-standardized dataset configurations, diverse omics modalities, and inconsistent evaluation measures. These issues limit the comparability, reproducibility, and generalizability of AI classifiers across different cancers and hinder the development of robust and accurate AI-driven tools. This study performs comparative analyses of 35 unique AI classifiers across 153 datasets, covering 8 omics modalities and 20 different cancers. Particularly, it investigates 6 different research questions, and based on comprehensive performance analyses of the 35 AI classifiers it elucidates the research questions with the following answers: (i) out of 17 different configurations for 5 out of the 8 tested omics modalities, RPPA (RPPA), Gistic2-all-data-by-genes (CNV), HM27 (Meth), and HiSeqV2-exon (Exon) configurations consistently yield better performance; (ii) in terms of 8 omics modalities, RNASeq, miRNA, CNV, and Exon generally achieve higher macro-accuracy (MACC) compared to Meth., Array, SNP and RPPA; (iii) SNP and RPPA modalities are prone to biases due to technical noise; (iv) traditional machine learning (ML) models (SVM, XGB, HGB) perform best on small and low-dimensional datasets, while deep learning (DL) models (ResNet18, CNN, NN, MLP) excel on large and high-dimensional datasets; (v) SVM achieves the highest mean MACC across all classifiers, with NN, ResNet18, DEEPGENE, and MLP also demonstrate strong performance; and (vi) DL classifiers show superior MACC as compared to ML classifiers in 12 out of 20 cancers. The findings offer key insights to guide the development of standardized, robust, and efficient AI-driven pipelines for cancer molecular subtype classification. This study enhances reproducibility and facilitates better comparison across AI methods, ultimately advancing precision oncology.