iProMix: A Mixture Model for Studying the Function of ACE2 based on Bulk Proteogenomic Data

• 成果类型: Article
• 署名作者: Song, Xiaoyu; Ji, Jiayi; Wang, Pei
• 署名单位: Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai
• 刊物名称: JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION
• ISSN/ISSBN: 0162-1459
• DOI: 10.1080/01621459.2022.2110876
• 发表日期: 2023
• 页码: 43-55
• 关键词: tumor samples; cell; deconvolution; reveals

摘要

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over six million deaths in the ongoing COVID-19 pandemic. SARS-CoV-2 uses ACE2 protein to enter human cells, raising a pressing need to characterize proteins/pathways interacted with ACE2. Large-scale proteomic profiling technology is not mature at single-cell resolution to examine the protein activities in disease-relevant cell types. We propose iProMix, a novel statistical framework to identify epithelial-cell specific associations between ACE2 and other proteins/pathways with bulk proteomic data. iProMix decomposes the data and models cell type-specific conditional joint distribution of proteins through a mixture model. It improves cell-type composition estimation from prior input, and uses a nonparametric inference framework to account for uncertainty of cell-type proportion estimates in hypothesis test. Simulations demonstrate iProMix has well-controlled false discovery rates and favorable powers in nonasymptotic settings. We apply iProMix to the proteomic data of 110 (tumor-adjacent) normal lung tissue samples from the Clinical Proteomic Tumor Analysis Consortium lung adenocarcinoma study, and identify interferon alpha/gamma response pathways as the most significant pathways associated with ACE2 protein abundances in epithelial cells. Strikingly, the association direction is sex-specific. This result casts light on the sex difference of COVID-19 incidences and outcomes, and motivates sex-specific evaluation for interferon therapies. for this article are available online.