Machine learning assessment of zoonotic potential in avian influenza viruses using PB2 segment

Experimental analyses demonstrated that the Random Forest regression model outperformed other models in most cases, and we validated the target value settings for risk regression through ablation studies. Our SHAP-based analysis identified key residues (271A, 627K, 591R, 588A, 292I, 684S, 684A, 81M, 199S, and 368Q) and mutations (T271A, Q368R/K, E627K, Q591R, A588T/I/V, and I292V/T) critical for zoonotic risk assessment. Using the SHAP-based risk assessment model, we found that influenza A viruses from Phasianidae showed elevated zoonotic risk scores compared to those from other avian species. Additionally, mutations I292V/T, Q368R, A588T/I, V598A/I/T, and E/V627K were identified as significant mutations in the Phasianidae. These PB2-focused quantitative methods provide a robust and generalizable framework for both rapid screening of avians' zoonotic potential and analytical quantification of risks associated with specific residues or mutations.