Dataset Information

A data similarity-based strategy for meta-analysis of transcriptional profiles in cancer.

ABSTRACT:

Background

Robust transcriptional signatures in cancer can be identified by data similarity-driven meta-analysis of gene expression profiles. An unbiased data integration and interrogation strategy has not previously been available.

Methods and findings

We implemented and performed a large meta-analysis of breast cancer gene expression profiles from 223 datasets containing 10,581 human breast cancer samples using a novel data similarity-based approach (iterative EXALT). Cancer gene expression signatures extracted from individual datasets were clustered by data similarity and consolidated into a meta-signature with a recurrent and concordant gene expression pattern. A retrospective survival analysis was performed to evaluate the predictive power of a novel meta-signature deduced from transcriptional profiling studies of human breast cancer. Validation cohorts consisting of 6,011 breast cancer patients from 21 different breast cancer datasets and 1,110 patients with other malignancies (lung and prostate cancer) were used to test the robustness of our findings. During the iterative EXALT analysis, 633 signatures were grouped by their data similarity and formed 121 signature clusters. From the 121 signature clusters, we identified a unique meta-signature (BRmet50) based on a cluster of 11 signatures sharing a phenotype related to highly aggressive breast cancer. In patients with breast cancer, there was a significant association between BRmet50 and disease outcome, and the prognostic power of BRmet50 was independent of common clinical and pathologic covariates. Furthermore, the prognostic value of BRmet50 was not specific to breast cancer, as it also predicted survival in prostate and lung cancers.

Conclusions

We have established and implemented a novel data similarity-driven meta-analysis strategy. Using this approach, we identified a transcriptional meta-signature (BRmet50) in breast cancer, and the prognostic performance of BRmet50 was robust and applicable across a wide range of cancer-patient populations.

SUBMITTER: Qiu Q

PROVIDER: S-EPMC3558433 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

A data similarity-based strategy for meta-analysis of transcriptional profiles in cancer.

Qiu Qingchao Q Lu Pengcheng P Xiang Yuzhu Y Shyr Yu Y Chen Xi X Lehmann Brian David BD Viox Daniel Joseph DJ George Alfred L AL Yi Yajun Y

PloS one 20130129 1

<h4>Background</h4>Robust transcriptional signatures in cancer can be identified by data similarity-driven meta-analysis of gene expression profiles. An unbiased data integration and interrogation strategy has not previously been available.<h4>Methods and findings</h4>We implemented and performed a large meta-analysis of breast cancer gene expression profiles from 223 datasets containing 10,581 human breast cancer samples using a novel data similarity-based approach (iterative EXALT). Cancer gen ...[more]

PMID: 23383020

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Project description:BackgroundMethods for inference and comparison of biological networks are emerging as powerful tools for the identification of groups of tightly connected genes whose activity may be altered during disease progression or due to chemical perturbations. Connectivity-based comparisons help identify aggregate changes that would be difficult to detect with differential analysis methods comparing individual genes.MethodsIn this study, we describe a pipeline for network comparison and its application to the analysis of gene expression datasets from chemical perturbation experiments, with the goal of elucidating the modes of actions of the profiled perturbations. We apply our pipeline to the analysis of the DrugMatrix and the TG-GATEs, two of the largest toxicogenomics resources available, containing gene expression measurements for model organisms exposed to hundreds of chemical compounds with varying carcinogenicity and genotoxicity.ResultsStarting from chemical-specific transcriptional networks inferred from these data, we show that the proposed comparative analysis of their associated networks identifies groups of chemicals with similar functions and similar carcinogenicity/genotoxicity profiles. We also show that the in-silico annotation by pathway enrichment analysis of the gene modules with a significant gain or loss of connectivity for specific groups of compounds can reveal molecular pathways significantly associated with the chemical perturbations and their likely modes of action.ConclusionsThe proposed pipeline for transcriptional network inference and comparison is highly reproducible and allows grouping chemicals with similar functions and carcinogenicity/genotoxicity profiles. In the context of drug discovery or drug repositioning, the methods presented here could help assign new functions to novel or existing drugs, based on the similarity of their associated network with those built for other known compounds. Additionally, the method has broad applicability beyond the uses here described and could be used as an alternative or as a complement to standard approaches of differential gene expression analysis.

Project description:BACKGROUND:Case-based reasoning is a proven method that relies on learned cases from the past for decision support of a new case. The accuracy of such a system depends on the applied similarity measure, which quantifies the similarity between two cases. This work proposes a collection of methods for similarity measures especially for comparison of clinical cases based on survival data, as they are available for example from clinical trials. METHODS:Our approach is intended to be used in scenarios, where it is of interest to use longitudinal data, such as survival data, for a case-based reasoning approach. This might be especially important, where uncertainty about the ideal therapy decision exists. The collection of methods consists of definitions of the local similarity of nominal as well as numeric attributes, a calculation of attribute weights, a feature selection method and finally a global similarity measure. All of them use survival time (consisting of survival status and overall survival) as a reference of similarity. As a baseline, we calculate a survival function for each value of any given clinical attribute. RESULTS:We define the similarity between values of the same attribute by putting the estimated survival functions in relation to each other. Finally, we quantify the similarity by determining the area between corresponding curves of survival functions. The proposed global similarity measure is designed especially for cases from randomized clinical trials or other collections of clinical data with survival information. Overall survival can be considered as an eligible and alternative solution for similarity calculations. It is especially useful, when similarity measures that depend on the classic solution-describing attribute "applied therapy" are not applicable. This is often the case for data from clinical trials containing randomized arms. CONCLUSIONS:In silico evaluation scenarios showed that the mean accuracy of biomarker detection in k = 10 most similar cases is higher (0.909-0.998) than for competing similarity measures, such as Heterogeneous Euclidian-Overlap Metric (0.657-0.831) and Discretized Value Difference Metric (0.535-0.671). The weight calculation method showed a more than six times (6.59-6.95) higher weight for biomarker attributes over non-biomarker attributes. These results suggest that the similarity measure described here is suitable for applications based on survival data.

Dataset Information

A data similarity-based strategy for meta-analysis of transcriptional profiles in cancer.

Background

Methods and findings

Conclusions

Publications

A data similarity-based strategy for meta-analysis of transcriptional profiles in cancer.

Similar Datasets

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