Dataset Information

AGNEP: An Agglomerative Nesting Clustering Algorithm for Phenotypic Dimension Reduction in Joint Analysis of Multiple Phenotypes.

ABSTRACT: Genome-wide association study (GWAS) has identified thousands of genetic variants associated with complex traits and diseases. Compared with analyzing a single phenotype at a time, the joint analysis of multiple phenotypes can improve statistical power by taking into account the information from phenotypes. However, most established joint algorithms ignore the different level of correlations between multiple phenotypes; instead of that, they simultaneously analyze all phenotypes in a genetic model. Thus, they may fail to capture the genetic structure of phenotypes and consequently reduce the statistical power. In this study, we develop a novel method agglomerative nesting clustering algorithm for phenotypic dimension reduction analysis (AGNEP) to jointly analyze multiple phenotypes for GWAS. First, AGNEP uses an agglomerative nesting clustering algorithm to group correlated phenotypes and then applies principal component analysis (PCA) to generate representative phenotypes for each group. Finally, multivariate analysis is employed to test associations between genetic variants and the representative phenotypes rather than all phenotypes. We perform three simulation experiments with various genetic structures and a real dataset analysis for 19 Arabidopsis phenotypes. Compared to established methods, AGNEP is more powerful in terms of statistical power, computing time, and the number of quantitative trait nucleotides (QTNs). The analysis of the Arabidopsis real dataset further illustrates the efficiency of AGNEP for detecting QTNs, which are confirmed by The Arabidopsis Information Resource gene bank.

SUBMITTER: Liu F

PROVIDER: S-EPMC8107386 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The major interest domains of single-cell RNA sequential analysis are identification of existing and novel types of cells, depiction of cells, cell fate prediction, classification of several types of tumor, and investigation of heterogeneity in different cells. Single-cell clustering plays an important role to solve the aforementioned questions of interest. Cluster identification in high dimensional single-cell sequencing data faces some challenges due to its nature. Dimensionality reduction models can solve the problem. Here, we introduce a potential cluster specified frequent biomarkers discovery framework using dimensionality reduction and hierarchical agglomerative clustering Louvain for single-cell RNA sequencing data analysis. First, we pre-filtered the features with fewer number of cells and the cells with fewer number of features. Then we created a Seurat object to store data and analysis together and used quality control metrics to discard low quality or dying cells. Afterwards we applied global-scaling normalization method "LogNormalize" for data normalization. Next, we computed cell-to-cell highly variable features from our dataset. Then, we applied a linear transformation and linear dimensionality reduction technique, Principal Component Analysis (PCA) to project high dimensional data to an optimal low-dimensional space. After identifying fifty "significant"principal components (PCs) based on strong enrichment of low p-value features, we implemented a graph-based clustering algorithm Louvain for the cell clustering of 10 top significant PCs. We applied our model to a single-cell RNA sequential dataset for a rare intestinal cell type in mice (NCBI accession ID:GSE62270, 23,630 features and 1872 samples (cells)). We obtained 10 cell clusters with a maximum modularity of 0.885 1. After detecting the cell clusters, we found 3871 cluster-specific biomarkers using an expression feature extraction statistical tool for single-cell sequencing data, Model-based Analysis of Single-cell Transcriptomics (MAST) with a log 2 FC threshold of 0.25 and a minimum feature detection of 25%. From these cluster-specific biomarkers, we found 1892 most frequent markers, i.e., overlapping biomarkers. We performed degree hub gene network analysis using Cytoscape and reported the five highest degree genes (Rps4x, Rps18, Rpl13a, Rps12 and Rpl18a). Subsequently, we performed KEGG pathway and Gene Ontology enrichment analysis of cluster markers using David 6.8 software tool. In summary, our proposed framework that integrated dimensionality reduction and agglomerative hierarchical clustering provides a robust approach to efficiently discover cluster-specific frequent biomarkers, i.e., overlapping biomarkers from single-cell RNA sequencing data.

Dataset Information

AGNEP: An Agglomerative Nesting Clustering Algorithm for Phenotypic Dimension Reduction in Joint Analysis of Multiple Phenotypes.

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