Browsing by Author "Lu, Yingzhou"

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    Cosbin: cosine score-based iterative normalization of biologically diverse samples
    Wu, Chiung-Ting; Shen, Minjie; Du, Dongping; Cheng, Zuolin; Parker, Sarah J.; Lu, Yingzhou; Van Eyk, Jennifer E.; Yu, Guoqiang; Clarke, Robert; Herrington, David M.; Wang, Yue (Oxford University Press, 2022)
    Motivation: Data normalization is essential to ensure accurate inference and comparability of gene expression measures across samples or conditions. Ideally, gene expression data should be rescaled based on consistently expressed reference genes. However, to normalize biologically diverse samples, the most commonly used reference genes exhibit striking expression variability and size-factor or distribution-based normalization methods can be problematic when the amount of asymmetry in differential expression is significant. Results: We report an efficient and accurate data-driven method-Cosine score-based iterative normalization (Cosbin)-to normalize biologically diverse samples. Based on the Cosine scores of cross-condition expression patterns, the Cosbin pipeline iteratively eliminates asymmetric differentially expressed genes, identifies consistently expressed genes, and calculates sample-wise normalization factors. We demonstrate the superior performance and enhanced utility of Cosbin compared with six representative peer methods using both simulation and real multi-omics expression datasets. Implemented in open-source R scripts and specifically designed to address normalization bias due to significant asymmetry in differential expression across multiple conditions, the Cosbin tool complements rather than replaces the existing methods and will allow biologists to more accurately detect true molecular signals among diverse phenotypic groups. Availability and implementation: The R scripts of Cosbin pipeline are freely available at https://github.com/MinjieSh/Cosbin. Supplementary information: Supplementary data are available at Bioinformatics Advances online.
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    COT: an efficient and accurate method for detecting marker genes among many subtypes
    Lu, Yingzhou; Wu, Chiung-Ting; Parker, Sarah J.; Cheng, Zuolin; Saylor, Georgia; Van Eyk, Jennifer E.; Yu, Guoqiang; Clarke, Robert; Herrington, David M.; Wang, Yue (Oxford University Press, 2022)
    Motivation: Ideally, a molecularly distinct subtype would be composed of molecular features that are expressed uniquely in the subtype of interest but in no others-so-called marker genes (MGs). MG plays a critical role in the characterization, classification or deconvolution of tissue or cell subtypes. We and others have recognized that the test statistics used by most methods do not exactly satisfy the MG definition and often identify inaccurate MG. Results: We report an efficient and accurate data-driven method, formulated as a Cosine-based One-sample Test (COT) in scatter space, to detect MG among many subtypes using subtype expression profiles. Fundamentally different from existing approaches, the test statistic in COT precisely matches the mathematical definition of an ideal MG. We demonstrate the performance and utility of COT on both simulated and real gene expression and proteomics data. The open source Python/R tool will allow biologists to efficiently detect MG and perform a more comprehensive and unbiased molecular characterization of tissue or cell subtypes in many biomedical contexts. Nevertheless, COT complements not replaces existing methods. Availability and implementation: The Python COT software with a detailed user's manual and a vignette are freely available at https://github.com/MintaYLu/COT. Supplementary information: Supplementary data are available at Bioinformatics Advances online.
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    Data-driven detection of subtype-specific differentially expressed genes
    Chen, Lulu; Lu, Yingzhou; Wu, Chiung-Ting; Clarke, Robert; Yu, Guoqiang; Van Eyk, Jennifer E.; Herrington, David M.; Wang, Yue (2021-01-11)
    Among multiple subtypes of tissue or cell, subtype-specific differentially-expressed genes (SDEGs) are defined as being most-upregulated in only one subtype but not in any other. Detecting SDEGs plays a critical role in the molecular characterization and deconvolution of multicellular complex tissues. Classic differential analysis assumes a null hypothesis whose test statistic is not subtype-specific, thus can produce a high false positive rate and/or lower detection power. Here we first introduce a One-Versus-Everyone Fold Change (OVE-FC) test for detecting SDEGs. We then propose a scaled test statistic (OVE-sFC) for assessing the statistical significance of SDEGs that applies a mixture null distribution model and a tailored permutation test. The OVE-FC/sFC test was validated on both type 1 error rate and detection power using extensive simulation data sets generated from real gene expression profiles of purified subtype samples. The OVE-FC/sFC test was then applied to two benchmark gene expression data sets of purified subtype samples and detected many known or previously unknown SDEGs. Subsequent supervised deconvolution results on synthesized bulk expression data, obtained using the SDEGs detected from the independent purified expression data by the OVE-FC/sFC test, showed superior performance in deconvolution accuracy when compared with popular peer methods.
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    Machine learning enabled bioinformatics tools for  analysis of biologically diverse samples
    Lu, Yingzhou (Virginia Tech, 2023-08-25)
    Advanced molecular profiling technologies, utilizing the entire human genome, have opened new avenues to study biological systems. In recent decades, the generation of vast volumes of multi-omics data, spanning a broad range of phenotypes. Development of advanced bioinformatics tools to identify informative biomarkers from these data becomes increasingly important. These tools are crucial to extract meaningful biomarkers from this data, especially for understanding the biological pathways responsible for disease development. The identification of signature genes and the analysis of differentially networked genes are two fundamental and critically important tasks. However, many current methodologies employ test statistics that don't align perfectly with the signature definition, potentially leading to the identification of imprecise signatures. It may be challenging because the test statistics employed by many prevailing methods fall short of fulfilling the exact definition of a marker genes, inherently leaving them susceptible to deriving inaccurate features. The problem is further compounded when attempting to identify marker genes across biologically diverse samples, especially when comparing more than two biological conditions. Additionally, traditional differential group analysis or co-expression analysis under singular conditions often falls short in certain scenarios. For instance, the subtle expression levels of transcription factors (TFs) make their detection daunting, despite their pivotal role in guiding gene expression. Pinpointing the intricate network landscape of complex ailments and isolating core genes for subsequent analysis are challenging tasks. Yet, these marker genes are instrumental in identifing potential pivotal pathways. Multi-omics data, with its inherent complexity and diversity, presents unique challenges that traditional methods might struggle to address effectively. Recognizing this, our team sought to introduce new and innovative techniques specifically designed to handle this intricate dataset. To overcome these challenges, it is vital to develop and adopt innovative methods tailored to handle the complexity and diversity inherent in multi-omics data. In response to these challenges, we have pioneered the Cosine-based One-sample Test (COT), a method meticulously crafted for the analysis of biologically diverse samples. Tailored to discern marker genes across a spectrum of subtypes using their expression profiles, COT employs a one-sample test framework. The test statistic within COT utilizes cosine similarity, comparing a molecule's expression profile across various subtypes with the precise mathematical representation of ideal marker genes. To ensure ease of application and accessibility, we've encapsulated the COT workflow within a Python package. To assess its effectiveness, we undertook an exhaustive evaluation, juxtaposing the marker genes detection capabilities of COT against its contemporaries. This evaluation employed realistic simulation data. Our findings indicated that COT was not only adept at handling gene expression data but was also proficient with proteomics data. This data, sourced from enriched tissue or cell subtype samples, further accentuated COT's superior performance. We demonstrated the heightened effectiveness of COT when applied to gene expression and proteomics data originating from distinct tissue or cell subtypes. This led to innovative findings and hypotheses in several biomedical case studies. Additionally, we have enhanced the Differential Dependency Network (DDN) framework to detect network rewiring between different conditions where significantly rewired network modes serve as informative biomarkers. Using cross-condition data and a block-wise Lasso network model, DDN detects significant network rewiring together with a subnetwork of hub molecular entities. In DDN 3.0, we took the imbalanced sample size into the consideration, integrated several acceleration strategies to enable it to handle large datasets, and enhanced the network presentation for more informative network displays including color-coded differential dependency network and gradient heatmap. We applied it to the simulated data and real data to detect critical changes in molecular network topology. The current tool stands as a valuable blueprint for the development and validation of mechanistic disease models. This foundation aids in offering a coherent interpretation of data, deepening our understanding of disease biology, and sparking new hypotheses ripe for subsequent validation and exploration. As we chart our future course, our vision is to expand the scope of tools like COT and DDN 3.0, explore the vast realm of multi-omics data, including those from longitudinal studies or clinical trials. We're looking at incorporating datasets from longitudinal studies and clinical trials – domains where data complexity scales to new heights. We believe that these tools can facilitate more nuanced and comprehensive understanding of disease development and progression. Furthermore, by integrating these methods with other advanced bioinformatics and machine learning tools, we aim to create a holistic pipeline that will allow for seamless extraction of significant biomarkers and actionable insights from multi-omics data. This is a promising step towards precision medicine, where individual genomic information can guide personalized treatment strategies.
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    Multi-omics Data Integration for Identifying Disease Specific Biological Pathways
    Lu, Yingzhou (Virginia Tech, 2018-06-05)
    Pathway analysis is an important task for gaining novel insights into the molecular architecture of many complex diseases. With the advancement of new sequencing technologies, a large amount of quantitative gene expression data have been continuously acquired. The springing up omics data sets such as proteomics has facilitated the investigation on disease relevant pathways. Although much work has previously been done to explore the single omics data, little work has been reported using multi-omics data integration, mainly due to methodological and technological limitations. While a single omic data can provide useful information about the underlying biological processes, multi-omics data integration would be much more comprehensive about the cause-effect processes responsible for diseases and their subtypes. This project investigates the combination of miRNAseq, proteomics, and RNAseq data on seven types of muscular dystrophies and control group. These unique multi-omics data sets provide us with the opportunity to identify disease-specific and most relevant biological pathways. We first perform t-test and OVEPUG test separately to define the differential expressed genes in protein and mRNA data sets. In multi-omics data sets, miRNA also plays a significant role in muscle development by regulating their target genes in mRNA dataset. To exploit the relationship between miRNA and gene expression, we consult with the commonly used gene library - Targetscan to collect all paired miRNA-mRNA and miRNA-protein co-expression pairs. Next, by conducting statistical analysis such as Pearson's correlation coefficient or t-test, we measured the biologically expected correlation of each gene with its upstream miRNAs and identify those showing negative correlation between the aforementioned miRNA-mRNA and miRNA-protein pairs. Furthermore, we identify and assess the most relevant disease-specific pathways by inputting the differential expressed genes and negative correlated genes into the gene-set libraries respectively, and further characterize these prioritized marker subsets using IPA (Ingenuity Pathway Analysis) or KEGG. We will then use Fisher method to combine all these p-values derived from separate gene sets into a joint significance test assessing common pathway relevance. In conclusion, we will find all negative correlated paired miRNA-mRNA and miRNA-protein, and identifying several pathophysiological pathways related to muscular dystrophies by gene set enrichment analysis. This novel multi-omics data integration study and subsequent pathway identification will shed new light on pathophysiological processes in muscular dystrophies and improve our understanding on the molecular pathophysiology of muscle disorders, preventing and treating disease, and make people become healthier in the long term.