arXiv:2605.04930cs.LGcs.AI2026-05

厘清单细胞数据中基因调控网络推断的失败原因,发现因果方法在特定条件下才有效。

When Does Gene Regulatory Network Inference Break? A Controlled Diagnostic Study of Causal and Correlational Methods on Single-Cell Data

论文配图:When Does Gene Regulatory Network Inference Break? A Controlled Diagnostic Study of Causal and Correlational Methods on Single-Cell Data
图 1 · 摘自论文原文
  • 构建受控诊断框架,逐一测试七种生物病理对推断的影响。
  • 因果方法在无噪声数据中表现最优,但掉失和隐藏混杂因素会使其失效。
  • 揭示不同方法错误类型差异,为模型改进提供精准方向。

尽管理论上具备优势,基于因果的基因调控网络(GRN)推断方法在真实或半真实单细胞数据基准测试中,始终无法超越基于相关性的基线方法,这一现象长期引发对因果性在该任务中价值的质疑。我们指出,现有基准测试缺乏足够控制,因真实数据中多种病理因素共存,混淆了不同方法的失败模式。为此,本文提出一个受控诊断框架,分离七种生物学相关的病理(丢弃、隐藏混杂因素、细胞类型混合、反馈环、网络密度、样本量、伪时间漂移),并测量六种代表性方法在三类推断范式下随各病理强度增加而性能退化的情况。在6,120次受控实验中,我们发现因果方法在干净且结构有利的条件下确实占优,但特定病理(尤其是掉失和隐藏混杂因素)会针对性地削弱其优势。进一步引入误差类型分解,揭示即使整体准确率相似,不同方法仍存在质的差异。通过在三种最具影响的病理间进行交互扫描,发现其联合效应为亚加性,并暴露出单因素分析无法察觉的密度依赖交叉点。研究结果提供了对不同方法在何时何地成功或失败的精细理解,为方法开发与实践提供可操作的指导。

原文摘要 · Abstract (English)

Despite theoretical advantages, causal methods for Gene Regulatory Network (GRN) inference from single-cell RNA-seq data consistently fail to match or outperform correlation-based baselines in many realistic benchmarks, a persistent puzzle which casts doubt on the value of causality for this task. We argue that existing benchmarks are insufficiently controlled to answer this question because they evaluate on real or semi-real data where multiple pathologies co-occur, confounding failure modes, and obscuring the specific conditions under which different inference methods excel or fail. To address this gap, we introduce a controlled diagnostic framework that isolates seven biologically motivated pathologies (dropout, latent confounders, cell-type mixing, feedback loops, network density, sample size, and pseudotime drift) and measure how six representative methods spanning three inference paradigms degrade as each pathology intensifies. Across 6,120 controlled experiments, we find that causal methods genuinely dominate in clean and structurally favorable regimes, but specific pathologies (notably dropout and latent confounders) selectively neutralize their advantages. We further introduce an error-type decomposition that reveals methods with similar aggregate accuracy commit qualitatively different errors. To probe whether single-pathology effects persist when multiple stressors co-occur, we perform an interaction sweep over the three most impactful pathologies and find that their joint effects are sub-additive, while also exposing density-conditional cross-overs invisible to single-dial analysis. Our findings offer a nuanced understanding of when and why different methods succeed or fail for GRN inference, providing actionable insights for method development and practical guidance for practitioners.

基因调控单细胞因果推断方法诊断

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