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In Bioinformatics (Oxford, England)

MOTIVATION : Automated protein function prediction is a complex multi-class, multi-label, structured classification problem in which protein functions are organized in a controlled vocabulary, according to the Gene Ontology (GO). "Hierarchy-unaware" classifiers, also known as "flat" methods, predict GO terms without exploiting the inherent structure of the ontology, potentially violating the True-Path-Rule (TPR) that governs the GO, while "hierarchy-aware" approaches, even if they obey the TPR, do not always show clear improvements with respect to flat methods, or do not scale well when applied to the full GO.

RESULTS : To overcome these limitations, we propose Hierarchical Ensemble Methods for Directed Acyclic Graphs (HEMDAG), a family of highly modular hierarchical ensembles of classifiers, able to build upon any flat method and to provide "TPR-safe" predictions, by leveraging a combination of isotonic regression and TPR learning strategies. Extensive experiments on synthetic and real data across several organisms firstly show that HEMDAG can be used as a general tool to improve the predictions of flat classifiers, and secondly that HEMDAG is competitive versus state-of-the-art hierarchy-aware learning methods proposed in the last CAFA international challenges.

AVAILABILITY : Fully-tested R code freely available at Tutorial and documentation at

SUPPLEMENTARY INFORMATION : Supplementary data are available at Bioinformatics online.

Notaro Marco, Frasca Marco, Petrini Alessandro, Gliozzo Jessica, Casiraghi Elena, Robinson Peter N, Valentini Giorgio