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Geographically weighted linear combination test for gene-set analysis of a continuous spatial phenotype as applied to intratumor heterogeneity.

ABSTRACT: Background: The impact of gene-sets on a spatial phenotype is not necessarily uniform across different locations of cancer tissue. This study introduces a computational platform, GWLCT, for combining gene set analysis with spatial data modeling to provide a new statistical test for location-specific association of phenotypes and molecular pathways in spatial single-cell RNA-seq data collected from an input tumor sample. Methods: The main advantage of GWLCT consists of an analysis beyond global significance, allowing the association between the gene-set and the phenotype to vary across the tumor space. At each location, the most significant linear combination is found using a geographically weighted shrunken covariance matrix and kernel function. Whether a fixed or adaptive bandwidth is determined based on a cross-validation cross procedure. Our proposed method is compared to the global version of linear combination test (LCT), bulk and random-forest based gene-set enrichment analyses using data created by the Visium Spatial Gene Expression technique on an invasive breast cancer tissue sample, as well as 144 different simulation scenarios. Results: In an illustrative example, the new geographically weighted linear combination test, GWLCT, identifies the cancer hallmark gene-sets that are significantly associated at each location with the five spatially continuous phenotypic contexts in the tumors defined by different well-known markers of cancer-associated fibroblasts. Scan statistics revealed clustering in the number of significant gene-sets. A spatial heatmap of combined significance over all selected gene-sets is also produced. Extensive simulation studies demonstrate that our proposed approach outperforms other methods in the considered scenarios, especially when the spatial association increases. Conclusion: Our proposed approach considers the spatial covariance of gene expression to detect the most significant gene-sets affecting a continuous phenotype. It reveals spatially detailed information in tissue space and can thus play a key role in understanding the contextual heterogeneity of cancer cells.

SUBMITTER: Amini P

PROVIDER: S-EPMC10044624 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Geographically weighted linear combination test for gene-set analysis of a continuous spatial phenotype as applied to intratumor heterogeneity.

Amini Payam P Hajihosseini Morteza M Pyne Saumyadipta S Dinu Irina I

Frontiers in cell and developmental biology 20230309

<b>Background:</b> The impact of gene-sets on a spatial phenotype is not necessarily uniform across different locations of cancer tissue. This study introduces a computational platform, GWLCT, for combining gene set analysis with spatial data modeling to provide a new statistical test for location-specific association of phenotypes and molecular pathways in spatial single-cell RNA-seq data collected from an input tumor sample. <b>Methods:</b> The main advantage of GWLCT consists of an analysis b ...[more]

PMID: 36998245

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Project description:Gene set analysis (GSA) methods test the association of sets of genes with a phenotype in gene expression microarray studies. Many GSA methods have been proposed, especially methods for use with a binary phenotype. Equally, if not more importantly however, is the ability to test the enrichment of a gene signature or pathway against the continuous phenotypes which are routinely and commonly observed in, for example, clinicopathological measurements. It is not always easy or meaningful to dichotomize continuous phenotypes into two classes, and attempting to do this may lead to the inaccurate classification of samples, which would affect the downstream enrichment analysis. In the present study, we have build on recent efforts to incorporate correlation structure within gene sets and pathways into the GSA test statistic. To address the issue of continuous phenotypes directly without the need for artificial discrete classification and thus increase the power of the test while ensuring computational efficiency and rigor, new GSA methods that can incorporate a covariance matrix estimator for a continuous phenotype may present an effective approach.We have designed a new method by extending the GSA approach called Linear Combination Test (LCT) from a binary to a continuous phenotype. Simulation studies and a real microarray dataset were used to compare the proposed LCT for a continuous phenotype, a modification of LCT (referred to as LCT2), and two publicly available GSA methods for continuous phenotypes.We found that the LCT methods performed better than the other two GSA methods; however, this finding should be understood in the context of our specific simulation studies and the real microarray dataset that were used to compare the methods. Free R-codes to perform LCT for binary and continuous phenotypes are available at http://www.ualberta.ca/~yyasui/homepage.html. The R-code to perform LCT for a continuous phenotype is available as Additional file 1.

Project description:BACKGROUND:Although microarray studies have greatly contributed to recent genetic advances, lack of replication has been a continuing concern in this area. Complex study designs have the potential to address this concern, though they remain undervalued by investigators due to the lack of proper analysis methods. The primary challenge in the analysis of complex microarray study data is handling the correlation structure within data while also dealing with the combination of large number of genetic measurements and small number of subjects that are ubiquitous even in standard microarray studies. Motivated by the lack of available methods for analysis of repeatedly measured phenotypic or transcriptomic data, herein we develop a longitudinal linear combination test (LLCT). RESULTS:LLCT is a two-step method to analyze multiple longitudinal phenotypes when there is high dimensionality in response and/or explanatory variables. Alternating between calculating within-subjects and between-subjects variations in two steps, LLCT examines if the maximum possible correlation between a linear combination of the time trends and a linear combination of the predictors given by the gene expressions is statistically significant. A generalization of this method can handle family-based study designs when the subjects are not independent. This method is also applicable to time-course microarray, with the ability to identify gene sets that exhibit significantly different expression patterns over time. Based on the results from a simulation study, LLCT outperformed its alternative: pathway analysis via regression. LLCT was shown to be very powerful in the analysis of large gene sets even when the sample size is small. CONCLUSIONS:This self-contained pathway analysis method is applicable to a wide range of longitudinal genomics, proteomics, metabolomics (OMICS) data, allows adjusting for potentially time-dependent covariates and works well with unbalanced and incomplete data. An important potential application of this method could be time-course linkage of OMICS, an attractive possibility for future genetic researchers. AVAILABILITY:R package of LLCT is available at: https://github.com/its-likeli-jeff/LLCT.

Dataset Information

Geographically weighted linear combination test for gene-set analysis of a continuous spatial phenotype as applied to intratumor heterogeneity.

Publications

Geographically weighted linear combination test for gene-set analysis of a continuous spatial phenotype as applied to intratumor heterogeneity.

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