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1.  Regularized Machine Learning in the Genetic Prediction of Complex Traits 
PLoS Genetics  2014;10(11):e1004754.
PMCID: PMC4230844  PMID: 25393026
2.  Multiple Different Defense Mechanisms Are Activated in the Young Transgenic Tobacco Plants Which Express the Full Length Genome of the Tobacco Mosaic Virus, and Are Resistant against this Virus 
PLoS ONE  2014;9(9):e107778.
Previously described transgenic tobacco lines express the full length infectious Tobacco mosaic virus (TMV) genome under the 35S promoter (Siddiqui et al., 2007. Mol Plant Microbe Interact, 20: 1489–1494). Through their young stages these plants exhibit strong resistance against both the endogenously expressed and exogenously inoculated TMV, but at the age of about 7–8 weeks they break into TMV infection, with typical severe virus symptoms. Infections with some other viruses (Potato viruses Y, A, and X) induce the breaking of the TMV resistance and lead to synergistic proliferation of both viruses. To deduce the gene functions related to this early resistance, we have performed microarray analysis of the transgenic plants during the early resistant stage, and after the resistance break, and also of TMV-infected wild type tobacco plants. Comparison of these transcriptomes to those of corresponding wild type healthy plants indicated that 1362, 1150 and 550 transcripts were up-regulated in the transgenic plants before and after the resistance break, and in the TMV-infected wild type tobacco plants, respectively, and 1422, 1200 and 480 transcripts were down-regulated in these plants, respectively. These transcriptome alterations were distinctly different between the three types of plants, and it appears that several different mechanisms, such as the enhanced expression of the defense, hormone signaling and protein degradation pathways contributed to the TMV-resistance in the young transgenic plants. In addition to these alterations, we also observed a distinct and unique gene expression alteration in these plants, which was the strong suppression of the translational machinery. This may also contribute to the resistance by slowing down the synthesis of viral proteins. Viral replication potential may also be suppressed, to some extent, by the reduction of the translation initiation and elongation factors eIF-3 and eEF1A and B, which are required for the TMV replication complex.
PMCID: PMC4171492  PMID: 25244327
3.  A large-scale evaluation of computational protein function prediction 
Radivojac, Predrag | Clark, Wyatt T | Ronnen Oron, Tal | Schnoes, Alexandra M | Wittkop, Tobias | Sokolov, Artem | Graim, Kiley | Funk, Christopher | Verspoor, Karin | Ben-Hur, Asa | Pandey, Gaurav | Yunes, Jeffrey M | Talwalkar, Ameet S | Repo, Susanna | Souza, Michael L | Piovesan, Damiano | Casadio, Rita | Wang, Zheng | Cheng, Jianlin | Fang, Hai | Gough, Julian | Koskinen, Patrik | Törönen, Petri | Nokso-Koivisto, Jussi | Holm, Liisa | Cozzetto, Domenico | Buchan, Daniel W A | Bryson, Kevin | Jones, David T | Limaye, Bhakti | Inamdar, Harshal | Datta, Avik | Manjari, Sunitha K | Joshi, Rajendra | Chitale, Meghana | Kihara, Daisuke | Lisewski, Andreas M | Erdin, Serkan | Venner, Eric | Lichtarge, Olivier | Rentzsch, Robert | Yang, Haixuan | Romero, Alfonso E | Bhat, Prajwal | Paccanaro, Alberto | Hamp, Tobias | Kassner, Rebecca | Seemayer, Stefan | Vicedo, Esmeralda | Schaefer, Christian | Achten, Dominik | Auer, Florian | Böhm, Ariane | Braun, Tatjana | Hecht, Maximilian | Heron, Mark | Hönigschmid, Peter | Hopf, Thomas | Kaufmann, Stefanie | Kiening, Michael | Krompass, Denis | Landerer, Cedric | Mahlich, Yannick | Roos, Manfred | Björne, Jari | Salakoski, Tapio | Wong, Andrew | Shatkay, Hagit | Gatzmann, Fanny | Sommer, Ingolf | Wass, Mark N | Sternberg, Michael J E | Škunca, Nives | Supek, Fran | Bošnjak, Matko | Panov, Panče | Džeroski, Sašo | Šmuc, Tomislav | Kourmpetis, Yiannis A I | van Dijk, Aalt D J | ter Braak, Cajo J F | Zhou, Yuanpeng | Gong, Qingtian | Dong, Xinran | Tian, Weidong | Falda, Marco | Fontana, Paolo | Lavezzo, Enrico | Di Camillo, Barbara | Toppo, Stefano | Lan, Liang | Djuric, Nemanja | Guo, Yuhong | Vucetic, Slobodan | Bairoch, Amos | Linial, Michal | Babbitt, Patricia C | Brenner, Steven E | Orengo, Christine | Rost, Burkhard | Mooney, Sean D | Friedberg, Iddo
Nature methods  2013;10(3):221-227.
Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based Critical Assessment of protein Function Annotation (CAFA) experiment. Fifty-four methods representing the state-of-the-art for protein function prediction were evaluated on a target set of 866 proteins from eleven organisms. Two findings stand out: (i) today’s best protein function prediction algorithms significantly outperformed widely-used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is significant need for improvement of currently available tools.
PMCID: PMC3584181  PMID: 23353650
4.  Large-Scale Event Extraction from Literature with Multi-Level Gene Normalization 
PLoS ONE  2013;8(4):e55814.
Text mining for the life sciences aims to aid database curation, knowledge summarization and information retrieval through the automated processing of biomedical texts. To provide comprehensive coverage and enable full integration with existing biomolecular database records, it is crucial that text mining tools scale up to millions of articles and that their analyses can be unambiguously linked to information recorded in resources such as UniProt, KEGG, BioGRID and NCBI databases. In this study, we investigate how fully automated text mining of complex biomolecular events can be augmented with a normalization strategy that identifies biological concepts in text, mapping them to identifiers at varying levels of granularity, ranging from canonicalized symbols to unique gene and proteins and broad gene families. To this end, we have combined two state-of-the-art text mining components, previously evaluated on two community-wide challenges, and have extended and improved upon these methods by exploiting their complementary nature. Using these systems, we perform normalization and event extraction to create a large-scale resource that is publicly available, unique in semantic scope, and covers all 21.9 million PubMed abstracts and 460 thousand PubMed Central open access full-text articles. This dataset contains 40 million biomolecular events involving 76 million gene/protein mentions, linked to 122 thousand distinct genes from 5032 species across the full taxonomic tree. Detailed evaluations and analyses reveal promising results for application of this data in database and pathway curation efforts. The main software components used in this study are released under an open-source license. Further, the resulting dataset is freely accessible through a novel API, providing programmatic and customized access ( Finally, to allow for large-scale bioinformatic analyses, the entire resource is available for bulk download from, under the Creative Commons – Attribution – Share Alike (CC BY-SA) license.
PMCID: PMC3629104  PMID: 23613707
5.  University of Turku in the BioNLP'11 Shared Task 
BMC Bioinformatics  2012;13(Suppl 11):S4.
We present a system for extracting biomedical events (detailed descriptions of biomolecular interactions) from research articles, developed for the BioNLP'11 Shared Task. Our goal is to develop a system easily adaptable to different event schemes, following the theme of the BioNLP'11 Shared Task: generalization, the extension of event extraction to varied biomedical domains. Our system extends our BioNLP'09 Shared Task winning Turku Event Extraction System, which uses support vector machines to first detect event-defining words, followed by detection of their relationships.
Our current system successfully predicts events for every domain case introduced in the BioNLP'11 Shared Task, being the only system to participate in all eight tasks and all of their subtasks, with best performance in four tasks. Following the Shared Task, we improve the system on the Infectious Diseases task from 42.57% to 53.87% F-score, bringing performance into line with the similar GENIA Event Extraction and Epigenetics and Post-translational Modifications tasks. We evaluate the machine learning performance of the system by calculating learning curves for all tasks, detecting areas where additional annotated data could be used to improve performance. Finally, we evaluate the use of system output on external articles as additional training data in a form of self-training.
We show that the updated Turku Event Extraction System can easily be adapted to all presently available event extraction targets, with competitive performance in most tasks. The scope of the performance gains between the 2009 and 2011 BioNLP Shared Tasks indicates event extraction is still a new field requiring more work. We provide several analyses of event extraction methods and performance, highlighting potential future directions for continued development.
PMCID: PMC3384251  PMID: 22759458
6.  Semantically linking molecular entities in literature through entity relationships 
BMC Bioinformatics  2012;13(Suppl 11):S6.
Text mining tools have gained popularity to process the vast amount of available research articles in the biomedical literature. It is crucial that such tools extract information with a sufficient level of detail to be applicable in real life scenarios. Studies of mining non-causal molecular relations attribute to this goal by formally identifying the relations between genes, promoters, complexes and various other molecular entities found in text. More importantly, these studies help to enhance integration of text mining results with database facts.
We describe, compare and evaluate two frameworks developed for the prediction of non-causal or 'entity' relations (REL) between gene symbols and domain terms. For the corresponding REL challenge of the BioNLP Shared Task of 2011, these systems ranked first (57.7% F-score) and second (41.6% F-score). In this paper, we investigate the performance discrepancy of 16 percentage points by benchmarking on a related and more extensive dataset, analysing the contribution of both the term detection and relation extraction modules. We further construct a hybrid system combining the two frameworks and experiment with intersection and union combinations, achieving respectively high-precision and high-recall results. Finally, we highlight extremely high-performance results (F-score >90%) obtained for the specific subclass of embedded entity relations that are essential for integrating text mining predictions with database facts.
The results from this study will enable us in the near future to annotate semantic relations between molecular entities in the entire scientific literature available through PubMed. The recent release of the EVEX dataset, containing biomolecular event predictions for millions of PubMed articles, is an interesting and exciting opportunity to overlay these entity relations with event predictions on a literature-wide scale.
PMCID: PMC3384255  PMID: 22759460
7.  Exploring Biomolecular Literature with EVEX: Connecting Genes through Events, Homology, and Indirect Associations 
Advances in Bioinformatics  2012;2012:582765.
Technological advancements in the field of genetics have led not only to an abundance of experimental data, but also caused an exponential increase of the number of published biomolecular studies. Text mining is widely accepted as a promising technique to help researchers in the life sciences deal with the amount of available literature. This paper presents a freely available web application built on top of 21.3 million detailed biomolecular events extracted from all PubMed abstracts. These text mining results were generated by a state-of-the-art event extraction system and enriched with gene family associations and abstract generalizations, accounting for lexical variants and synonymy. The EVEX resource locates relevant literature on phosphorylation, regulation targets, binding partners, and several other biomolecular events and assigns confidence values to these events. The search function accepts official gene/protein symbols as well as common names from all species. Finally, the web application is a powerful tool for generating homology-based hypotheses as well as novel, indirect associations between genes and proteins such as coregulators.
PMCID: PMC3375141  PMID: 22719757
8.  Wrapper-based selection of genetic features in genome-wide association studies through fast matrix operations 
Through the wealth of information contained within them, genome-wide association studies (GWAS) have the potential to provide researchers with a systematic means of associating genetic variants with a wide variety of disease phenotypes. Due to the limitations of approaches that have analyzed single variants one at a time, it has been proposed that the genetic basis of these disorders could be determined through detailed analysis of the genetic variants themselves and in conjunction with one another. The construction of models that account for these subsets of variants requires methodologies that generate predictions based on the total risk of a particular group of polymorphisms. However, due to the excessive number of variants, constructing these types of models has so far been computationally infeasible.
We have implemented an algorithm, known as greedy RLS, that we use to perform the first known wrapper-based feature selection on the genome-wide level. The running time of greedy RLS grows linearly in the number of training examples, the number of features in the original data set, and the number of selected features. This speed is achieved through computational short-cuts based on matrix calculus. Since the memory consumption in present-day computers can form an even tighter bottleneck than running time, we also developed a space efficient variation of greedy RLS which trades running time for memory. These approaches are then compared to traditional wrapper-based feature selection implementations based on support vector machines (SVM) to reveal the relative speed-up and to assess the feasibility of the new algorithm. As a proof of concept, we apply greedy RLS to the Hypertension – UK National Blood Service WTCCC dataset and select the most predictive variants using 3-fold external cross-validation in less than 26 minutes on a high-end desktop. On this dataset, we also show that greedy RLS has a better classification performance on independent test data than a classifier trained using features selected by a statistical p-value-based filter, which is currently the most popular approach for constructing predictive models in GWAS.
Greedy RLS is the first known implementation of a machine learning based method with the capability to conduct a wrapper-based feature selection on an entire GWAS containing several thousand examples and over 400,000 variants. In our experiments, greedy RLS selected a highly predictive subset of genetic variants in a fraction of the time spent by wrapper-based selection methods used together with SVM classifiers. The proposed algorithms are freely available as part of the RLScore software library at
PMCID: PMC3606421  PMID: 22551170
GWAS; Genome-wide association study; Machine learning; Feature selection
10.  Complex event extraction at PubMed scale 
Bioinformatics  2010;26(12):i382-i390.
Motivation: There has recently been a notable shift in biomedical information extraction (IE) from relation models toward the more expressive event model, facilitated by the maturation of basic tools for biomedical text analysis and the availability of manually annotated resources. The event model allows detailed representation of complex natural language statements and can support a number of advanced text mining applications ranging from semantic search to pathway extraction. A recent collaborative evaluation demonstrated the potential of event extraction systems, yet there have so far been no studies of the generalization ability of the systems nor the feasibility of large-scale extraction.
Results: This study considers event-based IE at PubMed scale. We introduce a system combining publicly available, state-of-the-art methods for domain parsing, named entity recognition and event extraction, and test the system on a representative 1% sample of all PubMed citations. We present the first evaluation of the generalization performance of event extraction systems to this scale and show that despite its computational complexity, event extraction from the entire PubMed is feasible. We further illustrate the value of the extraction approach through a number of analyses of the extracted information.
Availability: The event detection system and extracted data are open source licensed and available at
PMCID: PMC2881365  PMID: 20529932
11.  All-paths graph kernel for protein-protein interaction extraction with evaluation of cross-corpus learning 
BMC Bioinformatics  2008;9(Suppl 11):S2.
Automated extraction of protein-protein interactions (PPI) is an important and widely studied task in biomedical text mining. We propose a graph kernel based approach for this task. In contrast to earlier approaches to PPI extraction, the introduced all-paths graph kernel has the capability to make use of full, general dependency graphs representing the sentence structure.
We evaluate the proposed method on five publicly available PPI corpora, providing the most comprehensive evaluation done for a machine learning based PPI-extraction system. We additionally perform a detailed evaluation of the effects of training and testing on different resources, providing insight into the challenges involved in applying a system beyond the data it was trained on. Our method is shown to achieve state-of-the-art performance with respect to comparable evaluations, with 56.4 F-score and 84.8 AUC on the AImed corpus.
We show that the graph kernel approach performs on state-of-the-art level in PPI extraction, and note the possible extension to the task of extracting complex interactions. Cross-corpus results provide further insight into how the learning generalizes beyond individual corpora. Further, we identify several pitfalls that can make evaluations of PPI-extraction systems incomparable, or even invalid. These include incorrect cross-validation strategies and problems related to comparing F-score results achieved on different evaluation resources. Recommendations for avoiding these pitfalls are provided.
PMCID: PMC2586751  PMID: 19025688
12.  Comparative analysis of five protein-protein interaction corpora 
BMC Bioinformatics  2008;9(Suppl 3):S6.
Growing interest in the application of natural language processing methods to biomedical text has led to an increasing number of corpora and methods targeting protein-protein interaction (PPI) extraction. However, there is no general consensus regarding PPI annotation and consequently resources are largely incompatible and methods are difficult to evaluate.
We present the first comparative evaluation of the diverse PPI corpora, performing quantitative evaluation using two separate information extraction methods as well as detailed statistical and qualitative analyses of their properties. For the evaluation, we unify the corpus PPI annotations to a shared level of information, consisting of undirected, untyped binary interactions of non-static types with no identification of the words specifying the interaction, no negations, and no interaction certainty.
We find that the F-score performance of a state-of-the-art PPI extraction method varies on average 19 percentage units and in some cases over 30 percentage units between the different evaluated corpora. The differences stemming from the choice of corpus can thus be substantially larger than differences between the performance of PPI extraction methods, which suggests definite limits on the ability to compare methods evaluated on different resources. We analyse a number of potential sources for these differences and identify factors explaining approximately half of the variance. We further suggest ways in which the difficulty of the PPI extraction tasks codified by different corpora can be determined to advance comparability. Our analysis also identifies points of agreement and disagreement in PPI corpus annotation that are rarely explicitly stated by the authors of the corpora.
Our comparative analysis uncovers key similarities and differences between the diverse PPI corpora, thus taking an important step towards standardization. In the course of this study we have created a major practical contribution in converting the corpora into a shared format. The conversion software is freely available at .
PMCID: PMC2349296  PMID: 18426551
13.  BioInfer: a corpus for information extraction in the biomedical domain 
BMC Bioinformatics  2007;8:50.
Lately, there has been a great interest in the application of information extraction methods to the biomedical domain, in particular, to the extraction of relationships of genes, proteins, and RNA from scientific publications. The development and evaluation of such methods requires annotated domain corpora.
We present BioInfer (Bio Information Extraction Resource), a new public resource providing an annotated corpus of biomedical English. We describe an annotation scheme capturing named entities and their relationships along with a dependency analysis of sentence syntax. We further present ontologies defining the types of entities and relationships annotated in the corpus. Currently, the corpus contains 1100 sentences from abstracts of biomedical research articles annotated for relationships, named entities, as well as syntactic dependencies. Supporting software is provided with the corpus. The corpus is unique in the domain in combining these annotation types for a single set of sentences, and in the level of detail of the relationship annotation.
We introduce a corpus targeted at protein, gene, and RNA relationships which serves as a resource for the development of information extraction systems and their components such as parsers and domain analyzers. The corpus will be maintained and further developed with a current version being available at .
PMCID: PMC1808065  PMID: 17291334
14.  Lexical adaptation of link grammar to the biomedical sublanguage: a comparative evaluation of three approaches 
BMC Bioinformatics  2006;7(Suppl 3):S2.
We study the adaptation of Link Grammar Parser to the biomedical sublanguage with a focus on domain terms not found in a general parser lexicon. Using two biomedical corpora, we implement and evaluate three approaches to addressing unknown words: automatic lexicon expansion, the use of morphological clues, and disambiguation using a part-of-speech tagger. We evaluate each approach separately for its effect on parsing performance and consider combinations of these approaches.
In addition to a 45% increase in parsing efficiency, we find that the best approach, incorporating information from a domain part-of-speech tagger, offers a statistically significant 10% relative decrease in error.
When available, a high-quality domain part-of-speech tagger is the best solution to unknown word issues in the domain adaptation of a general parser. In the absence of such a resource, surface clues can provide remarkably good coverage and performance when tuned to the domain. The adapted parser is available under an open-source license.
PMCID: PMC1764446  PMID: 17134475
15.  Contextual weighting for Support Vector Machines in literature mining: an application to gene versus protein name disambiguation 
BMC Bioinformatics  2005;6:157.
The ability to distinguish between genes and proteins is essential for understanding biological text. Support Vector Machines (SVMs) have been proven to be very efficient in general data mining tasks. We explore their capability for the gene versus protein name disambiguation task.
We incorporated into the conventional SVM a weighting scheme based on distances of context words from the word to be disambiguated. This weighting scheme increased the performance of SVMs by five percentage points giving performance better than 85% as measured by the area under ROC curve and outperformed the Weighted Additive Classifier, which also incorporates the weighting, and the Naive Bayes classifier.
We show that the performance of SVMs can be improved by the proposed weighting scheme. Furthermore, our results suggest that in this study the increase of the classification performance due to the weighting is greater than that obtained by selecting the underlying classifier or the kernel part of the SVM.
PMCID: PMC1180820  PMID: 15972097

Results 1-15 (15)