Browsing by Author "Fang, Jiyuan"
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Item Open Access EVALUATING AND INTERPRETING MACHINE LEARNING OUTPUTS IN GENOMICS DATA(2022) Fang, JiyuanIn my dissertation, we have developed statistical and computational tools to evaluate and interpret machine learning outputs in genomics data. The first two projects focus on single-cell RNA-sequencing (scRNA-seq) data. In project 1, we evaluated the fitting of widely-used distribution families on scRNA-seq UMI counts and concluded that UMI counts of polyclonal cells following gene-specific cell-type-specific NB distributions without zero- inflation. Based on this modeling, we proposed the working dispersion score (WDS) to select genes that differentially express across cell types. In project 2, we developed a new internal (unsupervised) index, Clustering Deviation Index (CDI), to evaluate cell label sets obtained from clustering algorithms. We conducted in silico and experimental scRNA-seq studies to show that CDI can select the optimal clustering label set. We also benchmarked CDI by comparing it with other internal indices in terms of the agreement with external indices using high-quality benchmark label sets. In addition, we demonstrated that CDI is more computationally efficient than other internal indices, especially for million-scale datasets. In project 3, we proposed a model-agnostic hypothesis testing framework to interpret feature interactions underneath complex machine learning models. The simulation study results demonstrated large power while controlling the type I error rate.
Item Open Access Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD.(JCI insight, 2023-06) Poe, Jonathan C; Fang, Jiyuan; Zhang, Dadong; Lee, Marissa R; DiCioccio, Rachel A; Su, Hsuan; Qin, Xiaodi; Zhang, Jennifer Y; Visentin, Jonathan; Bracken, Sonali J; Ho, Vincent T; Wang, Kathy S; Rose, Jeremy J; Pavletic, Steven Z; Hakim, Frances T; Jia, Wei; Suthers, Amy N; Curry-Chisolm, Itaevia M; Horwitz, Mitchell E; Rizzieri, David A; McManigle, William C; Chao, Nelson J; Cardones, Adela R; Xie, Jichun; Owzar, Kouros; Sarantopoulos, StefanieAlloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.