基于生物结构预测未见过基因扰动的转录响应,提升泛化能力。
Stable-Shift: Biologically Structured Prediction of Transcriptional Responses to Unseen Gene Perturbations

- 用低秩响应基底建模基因扰动,结合生物网络与功能注释预测未知基因反应
- 在K562数据集上达0.592的余弦相似度,优于GEARS等方法
- 适合关注基因调控机制和跨基因泛化的计算生物学研究者
预测基因扰动引起的转录响应可减少功能基因组学的实验负担,但对训练中从未扰动过的基因进行外推仍具挑战。我们提出Stable-Shift,一种结构化方法来估算未见基因的响应。该方法将单细胞测量聚合为扰动水平的表达变化,仅使用训练扰动拟合低秩响应基底,并通过生物上下文(包括STRING互作、网络结构、对照细胞表达统计及基因本体注释)推断未见基因在该基底中的坐标。评估中采用图卷积整合输入。在提供的K562 Perturb-seq基准上,Stable-Shift取得0.592的余弦相似度,高于GEARS的0.569,且在斯皮尔曼相关性和前导基因精度上表现更优。五次未见基因分割的平均余弦相似度为0.589 ± 0.008。在图感知、残差化、基因空间及Norman数据集比较中均呈现一致趋势。结果支持进一步研究生物结构化潜在响应预测,但基因空间准确率较低且对稀疏图邻域敏感,限制了当前结论范围。
原文摘要 · Abstract (English)
Predicting transcriptional responses to genetic perturbations could reduce the experimental burden of functional genomics, but extrapolation to genes that were never perturbed during training remains difficult. We present Stable-Shift, a structured method for estimating unseen-gene responses. Stable-Shift aggregates single-cell measurements into perturbation-level expression shifts, fits a low-rank response basis using training perturbations only, and predicts an unseen gene's coordinates in that basis from biological context. The context combines STRING interactions, network structure, control-cell expression statistics, and Gene Ontology annotations; the evaluated implementation uses graph convolution to integrate these inputs. On the supplied K562 Perturb-seq benchmark, Stable-Shift obtained 0.592 cosine similarity, compared with 0.569 for GEARS, together with higher Spearman correlation and top-gene precision among the evaluated methods. Its mean cosine similarity over five unseen-gene splits was 0.589 +/- 0.008. The same ordering was observed in the supplied graph-aware, residualized, gene-space, and Norman-dataset comparisons. These results support further study of biologically structured latent-response prediction, while the lower gene-space accuracy and sensitivity to sparse graph neighborhoods limit the scope of the present conclusions.
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