为模糊聚类开发统计推断框架,解决小样本群被大群掩盖的问题。
Statistical Inference for Fuzzy Clustering
- 引入加权模糊聚类,通过权重平衡大小不一的群组影响。
- 在单细胞和阿尔茨海默病数据中实现稳定不确定性量化与生物合理软归属。
- 适用于存在群体不平衡的生物医学研究,如疾病进展连续体分析。
聚类是生物医学研究中发现患者亚群的核心工具,而群组边界常呈模糊而非清晰分离。传统方法生成硬划分,而模糊 $c$-均值(FCM)允许混合隶属关系,更好捕捉不确定性与渐变过程。尽管 FCM 广泛使用,其统计推断仍不完善。本文提出加权模糊 $c$-均值(WFCM)框架,应对潜在的群组规模不平衡问题。通过群组特异性权重重新平衡经典 FCM 目标函数,避免小群被主导群淹没;加权目标函数诱导出带尺度参数 $σ$ 与模糊度参数 $m$ 的归一化密度模型。估计采用分块极大极小(MM)算法,交替进行闭式隶属度与质心更新,以及基于似然的 $(σ,w)$ 更新。不可计算的归一化常数通过基于数据自适应高斯混合提议的重要性采样近似。进一步提供用于比较群组中心的似然比检验及基于自助法的置信区间。建立最大似然估计量的一致性与渐近正态性,通过模拟验证方法性能,并应用于单细胞 RNA-seq 与阿尔茨海默病神经影像计划(ADNI)数据。结果表明该方法能稳定量化不确定性,获得具有生物学意义的软成员关系,涵盖不平衡下分离良好的细胞群,也包括符合疾病进展的 AD 与非 AD 连续谱。
原文摘要 · Abstract (English)
Clustering is a central tool in biomedical research for discovering heterogeneous patient subpopulations, where group boundaries are often diffuse rather than sharply separated. Traditional methods produce hard partitions, whereas soft clustering methods such as fuzzy $c$-means (FCM) allow mixed memberships and better capture uncertainty and gradual transitions. Despite the widespread use of FCM, principled statistical inference for fuzzy clustering remains limited. We develop a new framework for weighted fuzzy $c$-means (WFCM) for settings with potential cluster size imbalance. Cluster-specific weights rebalance the classical FCM criterion so that smaller clusters are not overwhelmed by dominant groups, and the weighted objective induces a normalized density model with scale parameter $σ$ and fuzziness parameter $m$. Estimation is performed via a blockwise majorize--minimize (MM) procedure that alternates closed-form membership and centroid updates with likelihood-based updates of $(σ,\bw)$. The intractable normalizing constant is approximated by importance sampling using a data-adaptive Gaussian mixture proposal. We further provide likelihood ratio tests for comparing cluster centers and bootstrap-based confidence intervals. We establish consistency and asymptotic normality of the maximum likelihood estimator, validate the method through simulations, and illustrate it using single-cell RNA-seq and Alzheimer disease Neuroimaging Initiative (ADNI) data. These applications demonstrate stable uncertainty quantification and biologically meaningful soft memberships, ranging from well-separated cell populations under imbalance to a graded AD versus non-AD continuum consistent with disease progression.
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