用生物先验知识优化基因扰动设计,提升药物研发效率
BioBO: Biology-informed Bayesian Optimization for Perturbation Design
- 融合基因嵌入与富集分析,引导搜索聚焦潜在有效基因
- 在基准测试中减少25%-40%实验标注量,表现优于传统方法
- 提供通路层面解释,揭示扰动背后的生物学机制
高效设计基因组扰动实验对加速药物发现和治疗靶点识别至关重要,但受制于人类基因组中巨大的遗传互作搜索空间与实验约束,全面扰动仍不可行。贝叶斯优化(BO)已成为选择信息丰富干预措施的有力框架,但现有方法常无法利用领域特异的生物先验知识。本文提出生物学引导的贝叶斯优化(BioBO),将贝叶斯优化与多模态基因嵌入及富集分析(一种广泛用于基因优先排序的工具)结合,增强代理建模与获取策略。BioBO以合理方式整合生物先验与获取函数,使搜索偏向有潜力的基因,同时保留探索不确定区域的能力。在公开基准和数据集上的实验表明,BioBO可提升标注效率25%-40%,并更有效地识别出表现最佳的扰动。此外,通过引入富集分析,BioBO为所选扰动提供通路级解释,实现机制可解释性,将设计结果与生物学上一致的调控回路相联系。
原文摘要 · Abstract (English)
Efficient design of genomic perturbation experiments is crucial for accelerating drug discovery and therapeutic target identification, yet exhaustive perturbation of the human genome remains infeasible due to the vast search space of potential genetic interactions and experimental constraints. Bayesian optimization (BO) has emerged as a powerful framework for selecting informative interventions, but existing approaches often fail to exploit domain-specific biological prior knowledge. We propose Biology-Informed Bayesian Optimization (BioBO), a method that integrates Bayesian optimization with multimodal gene embeddings and enrichment analysis, a widely used tool for gene prioritization in biology, to enhance surrogate modeling and acquisition strategies. BioBO combines biologically grounded priors with acquisition functions in a principled framework, which biases the search toward promising genes while maintaining the ability to explore uncertain regions. Through experiments on established public benchmarks and datasets, we demonstrate that BioBO improves labeling efficiency by 25-40%, and consistently outperforms conventional BO by identifying top-performing perturbations more effectively. Moreover, by incorporating enrichment analysis, BioBO yields pathway-level explanations for selected perturbations, offering mechanistic interpretability that links designs to biologically coherent regulatory circuits.
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