提出新方法GISL,用基因扰动区分调控、混杂与选择偏倚。
Gene Regulatory Network Inference in the Presence of Selection Bias and Latent Confounders
- 利用基因扰动后依赖关系的对称性差异,区分调控、混杂和选择偏倚。
- 在合成与真实数据上验证,可准确识别调控关系与非调控机制。
- 适合研究基因网络因果关系的生物信息学者,尤其关注实验设计偏差者。
基因调控网络推断(GRNI)旨在从基因表达数据中发现基因间的因果调控关系。众所周知,观察数据中的统计依赖不必然意味着因果关系,虚假依赖可能源于隐变量混杂(如非编码RNA)。尽管已有多种方法应对混杂问题,但选择偏倚——仅可观测满足特定生存或纳入标准的细胞——常被忽视,其导致的虚假依赖同样影响因果推断。本文表明,此类选择偏倚普遍存在,若忽略或与真实调控混淆,将导致错误的因果解读和干预建议。核心问题是:能否区分由调控、混杂和选择引起的依赖?我们发现,基因扰动下,选择诱导的依赖具有对称性,而调控或混杂引起的依赖则无此特性。基于此,提出GISL算法,利用扰动数据揭示真实的基因调控关系以及非调控机制(选择与混杂),结果可达等价类。在合成与真实基因表达数据上的实验验证了该方法的有效性。
原文摘要 · Abstract (English)
Gene regulatory network inference (GRNI) aims to discover how genes causally regulate each other from gene expression data. It is well-known that statistical dependencies in observed data do not necessarily imply causation, as spurious dependencies may arise from latent confounders, such as non-coding RNAs. Numerous GRNI methods have thus been proposed to address this confounding issue. However, dependencies may also result from selection--only cells satisfying certain survival or inclusion criteria are observed--while these selection-induced spurious dependencies are frequently overlooked in gene expression data analyses. In this work, we show that such selection is ubiquitous and, when ignored or conflated with true regulations, can lead to flawed causal interpretation and misguided intervention recommendations. To address this challenge, a fundamental question arises: can we distinguish dependencies due to regulation, confounding, and crucially, selection? We show that gene perturbations offer a simple yet effective answer: selection-induced dependencies are symmetric under perturbation, while those from regulation or confounding are not. Building on this motivation, we propose GISL (Gene regulatory network Inference in the presence of Selection bias and Latent confounders), a principled algorithm that leverages perturbation data to uncover both true gene regulatory relations and non-regulatory mechanisms of selection and confounding up to the equivalence class. Experiments on synthetic and real-world gene expression data demonstrate the effectiveness of our method.
Thank you to arXiv for use of its open access interoperability. PaperDance 不是 arXiv 官方产品;中文卡片由大模型生成,请以原文为准。