ViroBench: Benchmarking Nucleotide Foundation Models on Viral Genomics Tasks
Authors: Dongxin Ye, Fang Hu, Han Hu, Shu Hu, Yang Tan, Wanli Ouyang, Stan Z. Li, Jie Cui, +1 more
Abstract
Nucleotide sequences constitute the fundamental genetic basis of biological systems, rendering viral genomic analysis critical for biomedical advancement. Despite progress in biological foundation models, specifically nucleotide foundation models (NFMs), the field lacks a unified standard for viral genomics to facilitate community development and enforce biosecurity constraints. To address this, we introduce ViroBench, the first comprehensive and large-scale benchmark specifically designed for NFMs in viral settings. ViroBench evaluates models across two critical dimensions: biological understanding and latent biosecurity risk, covering 18 diverse scenarios within 4 task types. Extensive evaluation of 66 NFMs across diverse architectures yields three critical conclusions. Firstly, NFMs exhibit a performance degradation in biological understanding under phylogenetic and temporal shifts, indicating weak extrapolation capabilities. Secondly, generation tasks reveal a decoupling between statistical likelihood and biological functional validity, posing latent biosecurity risks. Thirdly, controlled ablation studies reveal that taxonomic diversity in pretraining data outweighs parameter scale. Specifically, a lightweight baseline trained on diverse data achieves a 67.5% performance gain over its original model. Overall, ViroBench provides interpretable, diagnostic evaluations and a reproducible measurement framework for future research on viral nucleotide foundation models. The datasets and code are publicly available at https://github.com/QIANJINYDX/ViroBench.
Progress in genomic foundation models is difficult to assess due to fragmented benchmarks, incompatible evaluation protocols, and task-specific reporting. As a result, claims of superiority or generality across models are often not directly comparable. We introduce GENEB, a large-scale diagnostic benchmark that evaluates frozen representations from 40 genomic foundation models across 100 tasks spanning 13 functional categories under a unified probing-based protocol, including few-shot regimes. GENEB enables controlled comparison across model scale, architecture, tokenization, and pretraining data while explicitly exposing task-level trade-offs. Our analysis shows that aggregate leaderboards are unstable: model rankings vary sharply across task categories, scale provides only modest and inconsistent gains, and architectural and pretraining alignment frequently outweigh parameter count. These results highlight limitations of current evaluation practices and position GENEB as a reference framework for principled comparison and category-aware model selection in genomic machine learning.
Viruses represent the most abundant biological entities on Earth and play a pivotal role in microbial ecosystems, yet, as prominent human pathogens, they are closely linked to human morbidity and mortality. Accurate identification of viral sequences from viral genome sequences is therefore essential, but existing genome-based classification models that largely relying on composition- or frequency-based subsequence features often suffer from limited interpretability and reduced accuracy, particularly on complex or imbalanced datasets. To address these limitations, we propose GeneNSPCla (Genomic Negative Sequential Pattern-based Classification), a novel viral classification framework based on Negative Sequential Patterns (NSPs) that extracts discriminative absence-based features from nucleotide sequences of RNA viral genomes. By transforming these NSPs into numerical feature vectors and integrating them into multiple supervised classifiers, GeneNSPCla effectively captures both presence and absence signals in viral sequences. Furthermore, we propose a negative pattern mining algorithm adapted for processing genomic data: GONPM+, which can discover longer and more biologically meaningful negative sequential patterns. The experimental results demonstrate that the average accuracy of GONPM+ in 8 classifiers has improved by 10.03% compared to the original negative pattern mining algorithm and by 24.75% compared to the positive pattern mining algorithm. These findings highlight the effectiveness of incorporating absence-based sequential information, providing a new and complementary perspective for viral genome analysis and classification.
As pathogen genomic surveillance scales, the bottleneck is shifting from data generation to analysis. We present BioSecBench-Surveillance, a verifiable benchmark of 100 evaluations testing whether AI agents can infer the right analysis pipeline from raw sequencing data and surveillance context. Each evaluation gives an agent only the data and context a human analyst would have, then grades its structured answer deterministically. The tasks span seven categories, from taxonomic classification to genetic-engineering detection, across diverse sample types and sequencing technologies. Across 3,962 gradable attempts from sixteen model-harness pairs, the strongest configuration cleared only about half. Opus 4.8 with PI led at 50.2 percent, with a 95 percent confidence interval of 40.1 to 60.3 percent across 83 evaluations, tied with GPT-5.5 with Codex at 50.2 percent, with a 95 percent confidence interval of 40.8 to 59.6 percent, followed by Opus 4.7 with PI at 49.6 percent, with a 95 percent confidence interval of 40.0 to 59.2 percent, and Sonnet 4.6 with PI at 48.6 percent, with a 95 percent confidence interval of 38.9 to 58.3 percent. Even when agents invoked the correct workflows, their mistakes came from the choices around them, such as which references, thresholds, filters, and normalization to apply. BioSecBench-Surveillance provides a standard for measuring whether agents can be trusted to perform genomic surveillance when the next outbreak arrives.