An integrative sparse boosting analysis of cancer genomic commonality and difference.
Ontology highlight
ABSTRACT:
SUBMITTER: Sun Y
PROVIDER: S-EPMC7471599 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In high-throughput cancer genomic studies, markers identified from the analysis of single data sets often suffer a lack of reproducibility because of the small sample sizes. An ideal solution is to conduct large-scale prospective studies, which are extremely expensive and time consuming. A cost-effective remedy is to pool data from multiple comparable studies and conduct integrative analysis. Integrative analysis of multiple data sets is challenging because of the high dimensionality of genomic measurements and heterogeneity among studies. In this article, we propose a sparse boosting approach for marker identification in integrative analysis of multiple heterogeneous cancer diagnosis studies with gene expression measurements. The proposed approach can effectively accommodate the heterogeneity among multiple studies and identify markers with consistent effects across studies. Simulation shows that the proposed approach has satisfactory identification results and outperforms alternatives including an intensity approach and meta-analysis. The proposed approach is used to identify markers of pancreatic cancer and liver cancer.
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Project description:The analysis of cancer omics data is a "classic" problem; however, it still remains challenging. Advancing from early studies that are mostly focused on a single type of cancer, some recent studies have analyzed data on multiple "related" cancer types/subtypes, examined their commonality and difference, and led to insightful findings. In this article, we consider the analysis of multiple omics datasets, with each dataset on one type/subtype of "related" cancers. A Community Fusion (CoFu) approach is developed, which conducts marker selection and model building using a novel penalization technique, informatively accommodates the network community structure of omics measurements, and automatically identifies the commonality and difference of cancer omics markers. Simulation demonstrates its superiority over direct competitors. The analysis of TCGA lung cancer and melanoma data leads to interesting findings.
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Project description:In cancer research, high-throughput profiling studies have been extensively conducted, searching for markers associated with prognosis. Owing to the 'large d, small n' characteristic, results generated from the analysis of a single dataset can be unsatisfactory. Recent studies have shown that integrative analysis, which simultaneously analyses multiple datasets, can be more effective than single-dataset analysis and classic meta-analysis. In most of existing integrative analysis, the homogeneity model has been assumed, which postulates that different datasets share the same set of markers. Several approaches have been designed to reinforce this assumption. In practice, different datasets may differ in terms of patient selection criteria, profiling techniques, and many other aspects. Such differences may make the homogeneity model too restricted. In this study, we assume the heterogeneity model, under which different datasets are allowed to have different sets of markers. With multiple cancer prognosis datasets, we adopt the accelerated failure time model to describe survival. This model may have the lowest computational cost among popular semiparametric survival models. For marker selection, we adopt a sparse group minimax concave penalty approach. This approach has an intuitive formulation and can be computed using an effective group coordinate descent algorithm. Simulation study shows that it outperforms the existing approaches under both the homogeneity and heterogeneity models. Data analysis further demonstrates the merit of heterogeneity model and proposed approach.
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Project description:For the pathogenesis of complex diseases, gene-environment (G-E) interactions have been shown to have important implications. G-E interaction analysis can be challenging with the need to jointly analyze a large number of main effects and interactions and to respect the "main effects, interactions" hierarchical constraint. Extensive methodological developments on G-E interaction analysis have been conducted in recent literature. Despite considerable successes, most of the existing studies are still limited as they cannot accommodate long-tailed distributions/data contamination, make the restricted assumption of linear effects, and cannot effectively accommodate missingness in E variables. To directly tackle these problems, a semiparametric model is assumed to accommodate nonlinear effects, and the Huber loss function and Qn estimator are adopted to accommodate long-tailed distributions/data contamination. A regression-based multiple imputation approach is developed to accommodate missingness in E variables. For model estimation and selection of relevant variables, we adopt an effective sparse boosting approach. The proposed approach is practically well motivated, has intuitive formulations, and can be effectively realized. In extensive simulations, it significantly outperforms multiple direct competitors. The analysis of The Cancer Genome Atlas data on stomach adenocarcinoma and cutaneous melanoma shows that the proposed approach makes sensible discoveries with satisfactory prediction and stability.
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Project description:In the analysis of gene expression data, dimension reduction techniques have been extensively adopted. The most popular one is perhaps the PCA (principal component analysis). To generate more reliable and more interpretable results, the SPCA (sparse PCA) technique has been developed. With the "small sample size, high dimensionality" characteristic of gene expression data, the analysis results generated from a single dataset are often unsatisfactory. Under contexts other than dimension reduction, integrative analysis techniques, which jointly analyze the raw data of multiple independent datasets, have been developed and shown to outperform "classic" meta-analysis and other multidatasets techniques and single-dataset analysis. In this study, we conduct integrative analysis by developing the iSPCA (integrative SPCA) method. iSPCA achieves the selection and estimation of sparse loadings using a group penalty. To take advantage of the similarity across datasets and generate more accurate results, we further impose contrasted penalties. Different penalties are proposed to accommodate different data conditions. Extensive simulations show that iSPCA outperforms the alternatives under a wide spectrum of settings. The analysis of breast cancer and pancreatic cancer data further shows iSPCA's satisfactory performance.
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Project description:BackgroundIn high throughput cancer genomic studies, results from the analysis of single datasets often suffer from a lack of reproducibility because of small sample sizes. Integrative analysis can effectively pool and analyze multiple datasets and provides a cost effective way to improve reproducibility. In integrative analysis, simultaneously analyzing all genes profiled may incur high computational cost. A computationally affordable remedy is prescreening, which fits marginal models, can be conducted in a parallel manner, and has low computational cost.ResultsAn integrative prescreening approach is developed for the analysis of multiple cancer genomic datasets. Simulation shows that the proposed integrative prescreening has better performance than alternatives, particularly including prescreening with individual datasets, an intensity approach and meta-analysis. We also analyze multiple microarray gene profiling studies on liver and pancreatic cancers using the proposed approach.ConclusionsThe proposed integrative prescreening provides an effective way to reduce the dimensionality in cancer genomic studies. It can be coupled with existing analysis methods to identify cancer markers.
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Project description:The multivariate regression model is a useful tool to explore complex associations between two kinds of molecular markers, which enables the understanding of the biological pathways underlying disease etiology. For a set of correlated response variables, accounting for such dependency can increase statistical power. Motivated by integrative genomic data analyses, we propose a new methodology-sparse multivariate factor analysis regression model (smFARM), in which correlations of response variables are assumed to follow a factor analysis model with latent factors. This proposed method not only allows us to address the challenge that the number of association parameters is larger than the sample size, but also to adjust for unobserved genetic and/or nongenetic factors that potentially conceal the underlying response-predictor associations. The proposed smFARM is implemented by the EM algorithm and the blockwise coordinate descent algorithm. The proposed methodology is evaluated and compared to the existing methods through extensive simulation studies. Our results show that accounting for latent factors through the proposed smFARM can improve sensitivity of signal detection and accuracy of sparse association map estimation. We illustrate smFARM by two integrative genomics analysis examples, a breast cancer dataset, and an ovarian cancer dataset, to assess the relationship between DNA copy numbers and gene expression arrays to understand genetic regulatory patterns relevant to the disease. We identify two trans-hub regions: one in cytoband 17q12 whose amplification influences the RNA expression levels of important breast cancer genes, and the other in cytoband 9q21.32-33, which is associated with chemoresistance in ovarian cancer.
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Project description:In the analysis of cancer studies with high-dimensional genomic measurements, integrative analysis provides an effective way of pooling information across multiple heterogeneous datasets. The genomic basis of multiple independent datasets, which can be characterized by the sets of genomic markers, can be described using the homogeneity model or heterogeneity model. Under the homogeneity model, all datasets share the same set of markers associated with responses. In contrast, under the heterogeneity model, different studies have overlapping but possibly different sets of markers. The heterogeneity model contains the homogeneity model as a special case and can be much more flexible. Marker selection under the heterogeneity model calls for bi-level selection to determine whether a covariate is associated with response in any study at all as well as in which studies it is associated with responses. In this study, we consider two minimax concave penalty-based penalization approaches for marker selection under the heterogeneity model. For each approach, we describe its rationale and an effective computational algorithm. We conduct simulations to investigate their performance and compare with the existing alternatives. We also apply the proposed approaches to the analysis of gene expression data on multiple cancers.
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