From genomic signals to prediction tools: a critical feature analysis and rigorous benchmark for phage–host prediction

Accurate prediction of virus–host interactions is critical for understanding viral ecology and developing applications like phage therapy. However, the growing number of computational tools has created a complex landscape, making direct performance comparison challenging due to inconsistent benchmarks and varying usability. Here, we provide a systematic review and a rigorous benchmark of 27 virus–host prediction tools. We formulate the host prediction task into two primary frameworks—link prediction and multi-class classification—and construct two benchmark datasets to evaluate tool performance in distinct scenarios: a database-centric dataset (RefSeq-VHDB) and a metagenomic discovery dataset (MetaHiC-VHDB). Our results reveal that no single tool is universally optimal. Performance is highly context-dependent, with tools like CHERRY and iPHoP demonstrating robust, broad applicability, while others, such as RaFAH and PHIST, excel in specific contexts. We further identify a critical trade-off between predictive accuracy, prediction rate, and computational cost. This work serves as a practical guide for researchers and establishes a standardized benchmark to drive future innovation in deciphering complex virus–host interactions.