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Genetics. 2017 Jan;205(1):89-100. doi: 10.1534/genetics.116.189191. Epub 2016 Nov 9.

Pathway-Structured Predictive Model for Cancer Survival Prediction: A Two-Stage Approach.

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Department of Biostatistics, University of Alabama at Birmingham, Alabama 35294.
Department of Epidemiology, University of Alabama at Birmingham, Alabama 35294.
Department of Drug Discovery and Biomedical Sciences, The South Carolina College of Pharmacy, The University of South Carolina, Columbia, South Carolina 29208.
Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, Indiana 47405.
Department of Oncology, Southern Research Institute, Birmingham, Alabama 35205.
Department of Biostatistics, University of Alabama at Birmingham, Alabama 35294


Heterogeneity in terms of tumor characteristics, prognosis, and survival among cancer patients has been a persistent problem for many decades. Currently, prognosis and outcome predictions are made based on clinical factors and/or by incorporating molecular profiling data. However, inaccurate prognosis and prediction may result by using only clinical or molecular information directly. One of the main shortcomings of past studies is the failure to incorporate prior biological information into the predictive model, given strong evidence of the pathway-based genetic nature of cancer, i.e., the potential for oncogenes to be grouped into pathways based on biological functions such as cell survival, proliferation, and metastatic dissemination. To address this problem, we propose a two-stage approach to incorporate pathway information into the prognostic modeling using large-scale gene expression data. In the first stage, we fit all predictors within each pathway using the penalized Cox model and Bayesian hierarchical Cox model. In the second stage, we combine the cross-validated prognostic scores of all pathways obtained in the first stage as new predictors to build an integrated prognostic model for prediction. We apply the proposed method to analyze two independent breast and ovarian cancer datasets from The Cancer Genome Atlas (TCGA), predicting overall survival using large-scale gene expression profiling data. The results from both datasets show that the proposed approach not only improves survival prediction compared with the alternative analyses that ignore the pathway information, but also identifies significant biological pathways.


The Cancer Genome Atlas (TCGA); cancer prognosis; hierarchical Cox model; pathway; penalized Cox regression

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