用数据驱动的软标签提升单细胞分类,实现全身体细胞类型精准解卷积。
Data-Driven Soft Labeling Scales DNA Read Classification to Whole-Body Cell-Type Deconvolution

- 基于单个DNA读段的甲基化模式,生成每个读段的细胞类型概率分布
- 在39种细胞类型的全身体图谱上,误差比现有最优方法降低2.56倍
- 方法可扩展至大规模细胞类型分析,适用于生物与医疗研究
细胞类型解卷积旨在估计混合生物样本中各类细胞的比例,是计算生物学的核心问题。依赖表观遗传标记(如DNA甲基化)的方法通常使用聚合甲基化数据,丢失了单个DNA读段携带的模式信息。现有的读段级方法稀缺,且仅限于少数类别;规模化时,非区分性读段占主导,硬标签与甲基化模式到细胞类型的多对多映射冲突,导致分类器无法收敛。为此,我们提出数据驱动的软标签,为每个读段估计条件细胞类型分布,并集成至新型模块化框架Syto中。在包含39种人类细胞类型的全身体图谱上,Syto将均方误差降低2.56倍,且在涵盖16个组织的分布外数据集上仍保持优势。该方法为建模更大规模细胞类型面板奠定基础,有望推动生物学与医疗应用。所提软标签方案亦可推广至任何存在多对多信号-标签映射的场景。
原文摘要 · Abstract (English)
Cell-type deconvolution, the task of estimating the proportions of constituent cell types in a heterogeneous biological sample, is a core problem in computational biology. Methods that rely on epigenetic marks such as DNA methylation typically operate on aggregated methylation estimates, discarding the pattern-level information carried by individual DNA reads. Existing read-level approaches that exploit this information are scarce, and all remain restricted to few-class settings; scaling them further is an open problem because, at scale, non-discriminative reads dominate and hard labels conflict with the many-to-many mapping between methylation patterns and cell types, preventing classifier convergence. To overcome this, we propose data-driven soft labels that estimate the conditional cell-type distribution for each read, and integrate this scheme into Syto, a new modular framework for read-level classification-based deconvolution. On a whole-body atlas of 39 human cell types, Syto reduces MSE by 2.56$\times$ over SoTA, with gains transferring to an out-of-distribution dataset spanning 16 tissues. Syto lays the foundation for modeling increasingly large cell-type panels, with improved applications in biology and healthcare. The proposed soft-labeling scheme is further translatable to any setting with a many-to-many signal-to-label mapping.
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