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Open Access Research article

Survival models with preclustered gene groups as covariates

Kai Kammers1*, Michel Lang1, Jan G Hengstler2, Marcus Schmidt3 and Jörg Rahnenführer1

Author Affiliations

1 Department of Statistics, TU Dortmund University, Dortmund, Germany

2 Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany

3 Department of Obstetrics and Gynecology, Mainz University, Medical School, Mainz, Germany

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BMC Bioinformatics 2011, 12:478  doi:10.1186/1471-2105-12-478

Published: 16 December 2011

Abstract

Background

An important application of high dimensional gene expression measurements is the risk prediction and the interpretation of the variables in the resulting survival models. A major problem in this context is the typically large number of genes compared to the number of observations (individuals). Feature selection procedures can generate predictive models with high prediction accuracy and at the same time low model complexity. However, interpretability of the resulting models is still limited due to little knowledge on many of the remaining selected genes. Thus, we summarize genes as gene groups defined by the hierarchically structured Gene Ontology (GO) and include these gene groups as covariates in the hazard regression models. Since expression profiles within GO groups are often heterogeneous, we present a new method to obtain subgroups with coherent patterns. We apply preclustering to genes within GO groups according to the correlation of their gene expression measurements.

Results

We compare Cox models for modeling disease free survival times of breast cancer patients. Besides classical clinical covariates we consider genes, GO groups and preclustered GO groups as additional genomic covariates. Survival models with preclustered gene groups as covariates have similar prediction accuracy as models built only with single genes or GO groups.

Conclusions

The preclustering information enables a more detailed analysis of the biological meaning of covariates selected in the final models. Compared to models built only with single genes there is additional functional information contained in the GO annotation, and compared to models using GO groups as covariates the preclustering yields coherent representative gene expression profiles.