Conrad: gene prediction using conditional random fields.

We present Conrad, the first comparative gene predictor based on semi-Markov conditional random fields (SMCRFs). Unlike the best standalone gene predictors, which are based on generalized hidden Markov models (GHMMs) and trained by maximum likelihood, Conrad is discriminatively trained to maximize annotation accuracy. In addition, unlike the best annotation pipelines, which rely on heuristic and ad hoc decision rules to combine standalone gene predictors with additional information such as ESTs and protein homology, Conrad encodes all sources of information as features and treats all features equally in the training and inference algorithms. Conrad outperforms the best standalone gene predictors in cross-validation and whole chromosome testing on two fungi with vastly different gene structures. The performance improvement arises from the SMCRF's discriminative training methods and their ability to easily incorporate diverse types of information by encoding them as feature functions. On Cryptococcus neoformans, configuring Conrad to reproduce the predictions of a two-species phylo-GHMM closely matches the performance of Twinscan. Enabling discriminative training increases performance, and adding new feature functions further increases performance, achieving a level of accuracy that is unprecedented for this organism. Similar results are obtained on Aspergillus nidulans comparing Conrad versus Fgenesh. SMCRFs are a promising framework for gene prediction because of their highly modular nature, simplifying the process of designing and testing potential indicators of gene structure. Conrad's implementation of SMCRFs advances the state of the art in gene prediction in fungi and provides a robust platform for both current application and future research.