用基因调控顺序指导单细胞扰动预测,提升准确性与可解释性。
$D^{2}R^{2}$: Discrete Diffusion with Regulation Reinforcement for Single-Cell Perturbation Prediction

- 将扰动预测重构为基因级逐步生成,按调控顺序逐步恢复表达
- 在Norman19上五项指标全最优,优于随机与基于不确定性的排序
- 生成顺序可解释,优先激活调控基因和特异性转录因子
预测基因扰动对单细胞转录组的影响是功能基因组学和虚拟细胞建模的核心。现有方法通常整体预测表达谱,未建模基因响应的生成顺序。为此,我们提出 $D^{2}R^{2}$(离散扩散与调控强化),将扰动预测重构为受调控引导的基因级渐进生成。掩码离散扩散模型将表达表示为有序令牌,逐步重建被完全遮蔽的表达谱,使已生成基因响应能条件化剩余未生成基因。调控策略模块从对照细胞推断的基因调控网络初始化生成策略,并根据扰动和当前部分生成状态进行适应。随后,基于最终扰动效应一致性的奖励,仅优化生成顺序策略。在 Norman19 与 VCC-H1 数据集上,$D^{2}R^{2}$ 在 Norman19 上所有五项指标均最优,且在 H1 上保持竞争力。控制消融实验表明,在固定生成器与预算条件下,生物先验排序优于随机排序,且比不确定性启发式更可靠;而反转生物先验顺序则导致各项指标下降。生物学分析进一步显示,优化后的策略优先生成调控基因,同时促进扰动特异性转录因子与响应基因。这些结果确立了基因生成顺序作为单细胞扰动预测中一种有效、可控且生物可解释的新维度。
原文摘要 · Abstract (English)
Predicting single-cell transcriptomic responses to genetic perturbations is central to functional genomics and virtual-cell modeling. Existing approaches, however, typically predict an entire expression profile as a whole, leaving the order in which individual gene responses are generated unmodeled. To address this problem, we introduce \textbf{$D^{2}R^{2}$} (\textbf{D}iscrete \textbf{D}iffusion with \textbf{R}egulation \textbf{R}einforcement), which reformulates perturbation prediction as regulation-guided gene-wise progressive generation. A Masked Discrete Diffusion Model represents expression as ordinal tokens and reconstructs a fully masked profile step by step, allowing generated gene responses to condition those that remain masked. A Regulatory Policy Module initializes the generation policy from a gene regulatory network inferred from control cells and adapts it to the perturbation and current partially generated state. Then, group-relative policy optimization refines only the ordering policy using final perturbation-effect agreement as reward. Across Norman19 and VCC-H1, $D^{2}R^{2}$ achieves the best performance on all five metrics on Norman19 and remains competitive on H1. Controlled ablations holding the generator and generation budget fixed show that biological-prior ordering improves over random ordering and is more reliable than uncertainty-based heuristics, whereas reversing the biological-prior ordering degrades every metric. Biological analyses further show that the refined policy prioritizes regulatory genes early while promoting perturbation-specific transcription factors and responsive genes. These results establish gene generation order as an effective, controllable, and biologically interpretable dimension of single-cell perturbation prediction.
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