title: DegreeCox - a network-based regularization method for survival analysis.
abstract: BACKGROUND
  Modeling survival oncological data has become a major challenge as the increase in the amount of molecular information nowadays available means that the number of features greatly exceeds the number of observations. One possible solution to cope with this dimensionality problem is the use of additional constraints in the cost function optimization. LASSO and other sparsity methods have thus already been successfully applied with such idea. Although this leads to more interpretable models, these methods still do not fully profit from the relations between the features, specially when these can be represented through graphs. We propose DEGREECOX, a method that applies network-based regularizers to infer Cox proportional hazard models, when the features are genes and the outcome is patient survival. In particular, we propose to use network centrality measures to constrain the model in terms of significant genes.
  
  
  RESULTS
  We applied DEGREECOX to three datasets of ovarian cancer carcinoma and tested several centrality measures such as weighted degree, betweenness and closeness centrality. The a priori network information was retrieved from Gene Co-Expression Networks and Gene Functional Maps. When compared with RIDGE and LASSO, DEGREECOX shows an improvement in the classification of high and low risk patients in a par with NET-COX. The use of network information is especially relevant with datasets that are not easily separated. In terms of RMSE and C-index, DEGREECOX gives results that are similar to those of the best performing methods, in a few cases slightly better.
  
  
  CONCLUSIONS
  Network-based regularization seems a promising framework to deal with the dimensionality problem. The centrality metrics proposed can be easily expanded to accommodate other topological properties of different biological networks.
authors.affiliation: IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, 1049-001, Portugal.|Instituto Superior Técnico, Universidade de Lisboa, Lisbon, 1049-001, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Veríssimo
authors.affiliation: Instituto Superior Técnico, Universidade de Lisboa, Lisbon, 1049-001, Portugal.|Instituto de Engenharia de Sistemas e Computadores: Investigação e Desenvolvimento (INESC-ID), Lisbon, 1000-029, Portugal.
authors.forename: Arlindo Limede
authors.initials: AL
authors.lastname: Oliveira
authors.affiliation: ERABLE, Inria, Villeurbanne, France.|Laboratoire de Biométrie et Biologie Évolutive, Université de Lyon, CNRS UMR 5558, F-69622, Villeurbanne, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Sagot
authors.affiliation: IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, 1049-001, Portugal. susanavinga@tecnico.ulisboa.pt.
authors.forename: Susana
authors.initials: S
authors.lastname: Vinga
mesh_terms: D000465:Algorithms; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008957:Models, Genetic; D010051:Ovarian Neoplasms / Q000235:genetics*; D016016:Proportional Hazards Models
keywords: Cox proportional models; Network metrics; Regularization