A Simplified Input Strategy for Predicting Multi-type Associations in miRNA-lncRNA-disease Network via Stacked Deep Matrix Factorization

Understanding the associations among microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and various diseases as biomarkers holds significant biological importance. Developing efficient, straightforward prediction models is essential to reduce the high cost of experimental research. However, most existing methods typically predict miRNA-disease associations (MDAs), lncRNA-disease associations (LDAs), and lncRNA miRNA interactions (LMIs) separately, often relying on both similarities and associations as inputs. These approaches complicate their application across diverse biological and medical domains. Moreover, few models are capable of simultaneously predicting all three types of associations in a unified framework. In this work, we propose a novel and simplified model, called Simplified input strategy for Multiple Associations Prediction (SimpleMAP). Unlike previous approaches, SimpleMAP eliminates the need for similarity networks or external biological data and instead uses only known associations as input, reducing feature contamination and ensuring better generalization. SimpleMAP is designed to predict MDAs, LDAs, and LMIs concurrently, by constructing a three-layer heterogeneous biomolecular network that captures the associations among miRNAs, lncRNAs, and diseases. Our method employs a single, end-to-end architecture based on stacked deep matrix factorization (SDMF) to process sparse input data and learn latent features effectively. SimpleMAP is designed to concurrently predict MDAs, LDAs, and LMIs by constructing a three-layer heterogeneous biomolecular network that captures multi-relational associations among miRNAs, lncRNAs, and diseases. To enhance predictive performance, we incorporate multiple feature integration strategies to fuse representations extracted by SDMF. This streamlined design makes SimpleMAP one of the first models to predict multiple bio-entity associations jointly using only minimal input data, offering a highly scalable and biologically meaningful solution. SimpleMAP demonstrates superior performance against strong baselines. Further validation on two additional datasets involving miRNA-circRNA-disease associations confirms the models robustness and adaptability. Finally, biologically validated case studies underscore the realworld applicability of SimpleMAP for biomarker discovery in complex biological systems. Overall, SimpleMAP introduces a new paradigm in bio-entity association predictionłachieving multi-type, high-performance prediction with minimal input complexityłmaking it a valuable tool for computational biology and biomedical research.