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1.  A novel cell nuclei segmentation method for 3D C. elegans embryonic time-lapse images 
BMC Bioinformatics  2013;14:328.
Background
Recently a series of algorithms have been developed, providing automatic tools for tracing C. elegans embryonic cell lineage. In these algorithms, 3D images collected from a confocal laser scanning microscope were processed, the output of which is cell lineage with cell division history and cell positions with time. However, current image segmentation algorithms suffer from high error rate especially after 350-cell stage because of low signal-noise ratio as well as low resolution along the Z axis (0.5-1 microns). As a result, correction of the errors becomes a huge burden. These errors are mainly produced in the segmentation of nuclei. Thus development of a more accurate image segmentation algorithm will alleviate the hurdle for automated analysis of cell lineage.
Results
This paper presents a new type of nuclei segmentation method embracing an bi-directional prediction procedure, which can greatly reduce the number of false negative errors, the most common errors in the previous segmentation. In this method, we first use a 2D region growing technique together with the level-set method to generate accurate 2D slices. Then a modified gradient method instead of the existing 3D local maximum method is adopted to detect all the 2D slices located in the nuclei center, each of which corresponds to one nucleus. Finally, the bi-directional pred- iction method based on the images before and after the current time point is introduced into the system to predict the nuclei in low quality parts of the images. The result of our method shows a notable improvement in the accuracy rate. For each nucleus, its precise location, volume and gene expression value (gray value) is also obtained, all of which will be useful in further downstream analyses.
Conclusions
The result of this research demonstrates the advantages of the bi-directional prediction method in the nuclei segmentation over that of StarryNite/MatLab StarryNite. Several other modifications adopted in our nuclei segmentation system are also discussed.
doi:10.1186/1471-2105-14-328
PMCID: PMC3903074  PMID: 24252066
2.  AceTree: a tool for visual analysis of Caenorhabditis elegans embryogenesis 
BMC Bioinformatics  2006;7:275.
Background
The invariant lineage of the nematode Caenorhabditis elegans has potential as a powerful tool for the description of mutant phenotypes and gene expression patterns. We previously described procedures for the imaging and automatic extraction of the cell lineage from C. elegans embryos. That method uses time-lapse confocal imaging of a strain expressing histone-GFP fusions and a software package, StarryNite, processes the thousands of images and produces output files that describe the location and lineage relationship of each nucleus at each time point.
Results
We have developed a companion software package, AceTree, which links the images and the annotations using tree representations of the lineage. This facilitates curation and editing of the lineage. AceTree also contains powerful visualization and interpretive tools, such as space filling models and tree-based expression patterning, that can be used to extract biological significance from the data.
Conclusion
By pairing a fast lineaging program written in C with a user interface program written in Java we have produced a powerful software suite for exploring embryonic development.
doi:10.1186/1471-2105-7-275
PMCID: PMC1501046  PMID: 16740163
3.  Comparative Analysis of Embryonic Cell Lineage between Caenorhabditis briggsae and C. elegans 
Developmental biology  2007;314(1):93-99.
Comparative genomic analysis of important signaling pathways in C. briggase and C. elegans reveals both conserved features and also differences. To build a framework to address the significance of these features we determined the C. briggsae embryonic cell lineage, using the tools StarryNite and AceTree. We traced both cell divisions and cell positions for all cells through all but the last round of cell division and for selected cells through the final round. We found the lineage to be remarkably similar to that of C. elegans. Not only did the founder cells give rise to similar numbers of progeny, the relative cell division timing and positions were largely maintained. These lineage similarities appear to give rise to similar cell fates as judged both by the positions of lineally-equivalent cells and by the patterns of cell deaths in both species. However, some reproducible differences were seen, e.g., the P4 cell cycle length is more than 40% longer in C. briggsae than that in C. elegans (p < 0.01). The extensive conservation of embryonic development between such divergent species suggests that substantial evolutionary distance between these two species has not altered these early developmental cellular events, although the developmental defects of transpecies hybrids suggest that the details of the underlying molecular pathways have diverged sufficiently so as to not be interchangeable.
doi:10.1016/j.ydbio.2007.11.015
PMCID: PMC2696483  PMID: 18164284
C. briggsae; C. elegans; embryo; cell lineage; signaling pathway
4.  Automatically identifying and annotating mouse embryo gene expression patterns 
Bioinformatics  2011;27(8):1101-1107.
Motivation: Deciphering the regulatory and developmental mechanisms for multicellular organisms requires detailed knowledge of gene interactions and gene expressions. The availability of large datasets with both spatial and ontological annotation of the spatio-temporal patterns of gene expression in mouse embryo provides a powerful resource to discover the biological function of embryo organization. Ontological annotation of gene expressions consists of labelling images with terms from the anatomy ontology for mouse development. If the spatial genes of an anatomical component are expressed in an image, the image is then tagged with a term of that anatomical component. The current annotation is done manually by domain experts, which is both time consuming and costly. In addition, the level of detail is variable, and inevitably errors arise from the tedious nature of the task. In this article, we present a new method to automatically identify and annotate gene expression patterns in the mouse embryo with anatomical terms.
Results: The method takes images from in situ hybridization studies and the ontology for the developing mouse embryo, it then combines machine learning and image processing techniques to produce classifiers that automatically identify and annotate gene expression patterns in these images. We evaluate our method on image data from the EURExpress study, where we use it to automatically classify nine anatomical terms: humerus, handplate, fibula, tibia, femur, ribs, petrous part, scapula and head mesenchyme. The accuracy of our method lies between 70% and 80% with few exceptions. We show that other known methods have lower classification performance than ours. We have investigated the images misclassified by our method and found several cases where the original annotation was not correct. This shows our method is robust against this kind of noise.
Availability: The annotation result and the experimental dataset in the article can be freely accessed at http://www2.docm.mmu.ac.uk/STAFF/L.Han/geneannotation/.
Contact: l.han@mmu.ac.uk
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr105
PMCID: PMC3072560  PMID: 21357576
5.  Metabolic network prediction through pairwise rational kernels 
BMC Bioinformatics  2014;15(1):318.
Background
Metabolic networks are represented by the set of metabolic pathways. Metabolic pathways are a series of biochemical reactions, in which the product (output) from one reaction serves as the substrate (input) to another reaction. Many pathways remain incompletely characterized. One of the major challenges of computational biology is to obtain better models of metabolic pathways. Existing models are dependent on the annotation of the genes. This propagates error accumulation when the pathways are predicted by incorrectly annotated genes. Pairwise classification methods are supervised learning methods used to classify new pair of entities. Some of these classification methods, e.g., Pairwise Support Vector Machines (SVMs), use pairwise kernels. Pairwise kernels describe similarity measures between two pairs of entities. Using pairwise kernels to handle sequence data requires long processing times and large storage. Rational kernels are kernels based on weighted finite-state transducers that represent similarity measures between sequences or automata. They have been effectively used in problems that handle large amount of sequence information such as protein essentiality, natural language processing and machine translations.
Results
We create a new family of pairwise kernels using weighted finite-state transducers (called Pairwise Rational Kernel (PRK)) to predict metabolic pathways from a variety of biological data. PRKs take advantage of the simpler representations and faster algorithms of transducers. Because raw sequence data can be used, the predictor model avoids the errors introduced by incorrect gene annotations. We then developed several experiments with PRKs and Pairwise SVM to validate our methods using the metabolic network of Saccharomyces cerevisiae. As a result, when PRKs are used, our method executes faster in comparison with other pairwise kernels. Also, when we use PRKs combined with other simple kernels that include evolutionary information, the accuracy values have been improved, while maintaining lower construction and execution times.
Conclusions
The power of using kernels is that almost any sort of data can be represented using kernels. Therefore, completely disparate types of data can be combined to add power to kernel-based machine learning methods. When we compared our proposal using PRKs with other similar kernel, the execution times were decreased, with no compromise of accuracy. We also proved that by combining PRKs with other kernels that include evolutionary information, the accuracy can also also be improved. As our proposal can use any type of sequence data, genes do not need to be properly annotated, avoiding accumulation errors because of incorrect previous annotations.
doi:10.1186/1471-2105-15-318
PMCID: PMC4261252  PMID: 25260372
Metabolic network; Pairwise rational kernels; Supervised network inference; Finite-state transducers; Pairwise support vector machine
6.  Using Twitter to Examine Smoking Behavior and Perceptions of Emerging Tobacco Products 
Background
Social media platforms such as Twitter are rapidly becoming key resources for public health surveillance applications, yet little is known about Twitter users’ levels of informedness and sentiment toward tobacco, especially with regard to the emerging tobacco control challenges posed by hookah and electronic cigarettes.
Objective
To develop a content and sentiment analysis of tobacco-related Twitter posts and build machine learning classifiers to detect tobacco-relevant posts and sentiment towards tobacco, with a particular focus on new and emerging products like hookah and electronic cigarettes.
Methods
We collected 7362 tobacco-related Twitter posts at 15-day intervals from December 2011 to July 2012. Each tweet was manually classified using a triaxial scheme, capturing genre, theme, and sentiment. Using the collected data, machine-learning classifiers were trained to detect tobacco-related vs irrelevant tweets as well as positive vs negative sentiment, using Naïve Bayes, k-nearest neighbors, and Support Vector Machine (SVM) algorithms. Finally, phi contingency coefficients were computed between each of the categories to discover emergent patterns.
Results
The most prevalent genres were first- and second-hand experience and opinion, and the most frequent themes were hookah, cessation, and pleasure. Sentiment toward tobacco was overall more positive (1939/4215, 46% of tweets) than negative (1349/4215, 32%) or neutral among tweets mentioning it, even excluding the 9% of tweets categorized as marketing. Three separate metrics converged to support an emergent distinction between, on one hand, hookah and electronic cigarettes corresponding to positive sentiment, and on the other hand, traditional tobacco products and more general references corresponding to negative sentiment. These metrics included correlations between categories in the annotation scheme (phihookah-positive=0.39; phie-cigs-positive=0.19); correlations between search keywords and sentiment (χ2 4=414.50, P<.001, Cramer’s V=0.36), and the most discriminating unigram features for positive and negative sentiment ranked by log odds ratio in the machine learning component of the study. In the automated classification tasks, SVMs using a relatively small number of unigram features (500) achieved best performance in discriminating tobacco-related from unrelated tweets (F score=0.85).
Conclusions
Novel insights available through Twitter for tobacco surveillance are attested through the high prevalence of positive sentiment. This positive sentiment is correlated in complex ways with social image, personal experience, and recently popular products such as hookah and electronic cigarettes. Several apparent perceptual disconnects between these products and their health effects suggest opportunities for tobacco control education. Finally, machine classification of tobacco-related posts shows a promising edge over strictly keyword-based approaches, yielding an improved signal-to-noise ratio in Twitter data and paving the way for automated tobacco surveillance applications.
doi:10.2196/jmir.2534
PMCID: PMC3758063  PMID: 23989137
social media; twitter messaging; smoking; natural language processing
7.  Cross-Sectional Relatedness Between Sentences in Breast Radiology Reports: Development of an SVM Classifier and Evaluation Against Annotations of Five Breast Radiologists 
Journal of Digital Imaging  2013;26(5):977-988.
Introduce the notion of cross-sectional relatedness as an informational dependence relation between sentences in the conclusion section of a breast radiology report and sentences in the findings section of the same report. Assess inter-rater agreement of breast radiologists. Develop and evaluate a support vector machine (SVM) classifier for automatically detecting cross-sectional relatedness. A standard reference is manually created from 444 breast radiology reports by the first author. A subset of 37 reports is annotated by five breast radiologists. Inter-rater agreement is computed among their annotations and standard reference. Thirteen numerical features are developed to characterize pairs of sentences; the optimal feature set is sought through forward selection. Inter-rater agreement is F-measure 0.623. SVM classifier has F-measure of 0.699 in the 12-fold cross-validation protocol against standard reference. Report length does not correlate with the classifier’s performance (correlation coefficient = −0.073). SVM classifier has average F-measure of 0.505 against annotations by breast radiologists. Mediocre inter-rater agreement is possibly caused by: (1) definition is insufficiently actionable, (2) fine-grained nature of cross-sectional relatedness on sentence level, instead of, for instance, on paragraph level, and (3) higher-than-average complexity of 37-report sample. SVM classifier performs better against standard reference than against breast radiologists’s annotations. This is supportive of (3). SVM’s performance on standard reference is satisfactory. Since optimal feature set is not breast specific, results may transfer to non-breast anatomies. Applications include a smart report viewing environment and data mining.
Electronic supplementary material
The online version of this article (doi:10.1007/s10278-013-9612-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s10278-013-9612-9
PMCID: PMC3782592  PMID: 23817629
Radiology reports; Information retrieval; Support vector machine; Text mining; Inter-rater agreement; Textual entailment
8.  Context based mixture model for cell phase identification in automated fluorescence microscopy 
BMC Bioinformatics  2007;8:32.
Background
Automated identification of cell cycle phases of individual live cells in a large population captured via automated fluorescence microscopy technique is important for cancer drug discovery and cell cycle studies. Time-lapse fluorescence microscopy images provide an important method to study the cell cycle process under different conditions of perturbation. Existing methods are limited in dealing with such time-lapse data sets while manual analysis is not feasible. This paper presents statistical data analysis and statistical pattern recognition to perform this task.
Results
The data is generated from Hela H2B GFP cells imaged during a 2-day period with images acquired 15 minutes apart using an automated time-lapse fluorescence microscopy. The patterns are described with four kinds of features, including twelve general features, Haralick texture features, Zernike moment features, and wavelet features. To generate a new set of features with more discriminate power, the commonly used feature reduction techniques are used, which include Principle Component Analysis (PCA), Linear Discriminant Analysis (LDA), Maximum Margin Criterion (MMC), Stepwise Discriminate Analysis based Feature Selection (SDAFS), and Genetic Algorithm based Feature Selection (GAFS). Then, we propose a Context Based Mixture Model (CBMM) for dealing with the time-series cell sequence information and compare it to other traditional classifiers: Support Vector Machine (SVM), Neural Network (NN), and K-Nearest Neighbor (KNN). Being a standard practice in machine learning, we systematically compare the performance of a number of common feature reduction techniques and classifiers to select an optimal combination of a feature reduction technique and a classifier. A cellular database containing 100 manually labelled subsequence is built for evaluating the performance of the classifiers. The generalization error is estimated using the cross validation technique. The experimental results show that CBMM outperforms all other classifies in identifying prophase and has the best overall performance.
Conclusion
The application of feature reduction techniques can improve the prediction accuracy significantly. CBMM can effectively utilize the contextual information and has the best overall performance when combined with any of the previously mentioned feature reduction techniques.
doi:10.1186/1471-2105-8-32
PMCID: PMC1800869  PMID: 17263881
9.  Enzyme classification with peptide programs: a comparative study 
BMC Bioinformatics  2009;10:231.
Background
Efficient and accurate prediction of protein function from sequence is one of the standing problems in Biology. The generalised use of sequence alignments for inferring function promotes the propagation of errors, and there are limits to its applicability. Several machine learning methods have been applied to predict protein function, but they lose much of the information encoded by protein sequences because they need to transform them to obtain data of fixed length.
Results
We have developed a machine learning methodology, called peptide programs (PPs), to deal directly with protein sequences and compared its performance with that of Support Vector Machines (SVMs) and BLAST in detailed enzyme classification tasks. Overall, the PPs and SVMs had a similar performance in terms of Matthews Correlation Coefficient, but the PPs had generally a higher precision. BLAST performed globally better than both methodologies, but the PPs had better results than BLAST and SVMs for the smaller datasets.
Conclusion
The higher precision of the PPs in comparison to the SVMs suggests that dealing with sequences is advantageous for detailed protein classification, as precision is essential to avoid annotation errors. The fact that the PPs performed better than BLAST for the smaller datasets demonstrates the potential of the methodology, but the drop in performance observed for the larger datasets indicates that further development is required.
Possible strategies to address this issue include partitioning the datasets into smaller subsets and training individual PPs for each subset, or training several PPs for each dataset and combining them using a bagging strategy.
doi:10.1186/1471-2105-10-231
PMCID: PMC2724424  PMID: 19630945
10.  Semi-supervised clinical text classification with Laplacian SVMs: an application to cancer case management 
Journal of biomedical informatics  2013;46(5):869-875.
Objective
To compare linear and Laplacian SVMs on a clinical text classification task; to evaluate the effect of unlabeled training data on Laplacian SVM performance.
Background
The development of machine-learning based clinical text classifiers requires the creation of labeled training data, obtained via manual review by clinicians. Due to the effort and expense involved in labeling data, training data sets in the clinical domain are of limited size. In contrast, electronic medical record (EMR) systems contain hundreds of thousands of unlabeled notes that are not used by supervised machine learning approaches. Semi-supervised learning algorithms use both labeled and unlabeled data to train classifiers, and can outperform their supervised counterparts.
Methods
We trained support vector machines (SVMs) and Laplacian SVMs on a training reference standard of 820 abdominal CT, MRI, and Ultrasound reports labeled for the presence of potentially malignant liver lesions that require follow up (positive class prevalence 77%). The Laplacian SVM used 19,845 randomly sampled unlabeled notes in addition to the training reference standard. We evaluated SVMs and Laplacian SVMs on a test set of 520 labeled reports.
Results
The Laplacian SVM trained on labeled and unlabeled radiology reports significantly outperformed supervised SVMs (Macro-F1 0.773 vs. 0.741, Sensitivity 0.943 vs. 0.911, Positive Predictive value 0.877 vs. 0.883). Performance improved with the number of labeled and unlabeled notes used to train the Laplacian SVM (pearson’s ρ=0.529 for correlation between number of unlabeled notes and macro-F1 score). These results suggest that practical semi-supervised methods such as the Laplacian SVM can leverage the large, unlabeled corpora that reside within EMRs to improve clinical text classification.
doi:10.1016/j.jbi.2013.06.014
PMCID: PMC3806632  PMID: 23845911
Semi-supervised learning; Support vector machine; Graph Laplacian; Natural language processing
11.  Recognition of medication information from discharge summaries using ensembles of classifiers 
Background
Extraction of clinical information such as medications or problems from clinical text is an important task of clinical natural language processing (NLP). Rule-based methods are often used in clinical NLP systems because they are easy to adapt and customize. Recently, supervised machine learning methods have proven to be effective in clinical NLP as well. However, combining different classifiers to further improve the performance of clinical entity recognition systems has not been investigated extensively. Combining classifiers into an ensemble classifier presents both challenges and opportunities to improve performance in such NLP tasks.
Methods
We investigated ensemble classifiers that used different voting strategies to combine outputs from three individual classifiers: a rule-based system, a support vector machine (SVM) based system, and a conditional random field (CRF) based system. Three voting methods were proposed and evaluated using the annotated data sets from the 2009 i2b2 NLP challenge: simple majority, local SVM-based voting, and local CRF-based voting.
Results
Evaluation on 268 manually annotated discharge summaries from the i2b2 challenge showed that the local CRF-based voting method achieved the best F-score of 90.84% (94.11% Precision, 87.81% Recall) for 10-fold cross-validation. We then compared our systems with the first-ranked system in the challenge by using the same training and test sets. Our system based on majority voting achieved a better F-score of 89.65% (93.91% Precision, 85.76% Recall) than the previously reported F-score of 89.19% (93.78% Precision, 85.03% Recall) by the first-ranked system in the challenge.
Conclusions
Our experimental results using the 2009 i2b2 challenge datasets showed that ensemble classifiers that combine individual classifiers into a voting system could achieve better performance than a single classifier in recognizing medication information from clinical text. It suggests that simple strategies that can be easily implemented such as majority voting could have the potential to significantly improve clinical entity recognition.
doi:10.1186/1472-6947-12-36
PMCID: PMC3502425  PMID: 22564405
12.  Multiclass relevance units machine: benchmark evaluation and application to small ncRNA discovery 
BMC Genomics  2013;14(Suppl 2):S6.
Background
Classification is the problem of assigning each input object to one of a finite number of classes. This problem has been extensively studied in machine learning and statistics, and there are numerous applications to bioinformatics as well as many other fields. Building a multiclass classifier has been a challenge, where the direct approach of altering the binary classification algorithm to accommodate more than two classes can be computationally too expensive. Hence the indirect approach of using binary decomposition has been commonly used, in which retrieving the class posterior probabilities from the set of binary posterior probabilities given by the individual binary classifiers has been a major issue.
Methods
In this work, we present an extension of a recently introduced probabilistic kernel-based learning algorithm called the Classification Relevance Units Machine (CRUM) to the multiclass setting to increase its applicability. The extension is achieved under the error correcting output codes framework. The probabilistic outputs of the binary CRUMs are preserved using a proposed linear-time decoding algorithm, an alternative to the generalized Bradley-Terry (GBT) algorithm whose application to large-scale prediction settings is prohibited by its computational complexity. The resulting classifier is called the Multiclass Relevance Units Machine (McRUM).
Results
The evaluation of McRUM on a variety of real small-scale benchmark datasets shows that our proposed Naïve decoding algorithm is computationally more efficient than the GBT algorithm while maintaining a similar level of predictive accuracy. Then a set of experiments on a larger scale dataset for small ncRNA classification have been conducted with Naïve McRUM and compared with the Gaussian and linear SVM. Although McRUM's predictive performance is slightly lower than the Gaussian SVM, the results show that the similar level of true positive rate can be achieved by sacrificing false positive rate slightly. Furthermore, McRUM is computationally more efficient than the SVM, which is an important factor for large-scale analysis.
Conclusions
We have proposed McRUM, a multiclass extension of binary CRUM. McRUM with Naïve decoding algorithm is computationally efficient in run-time and its predictive performance is comparable to the well-known SVM, showing its potential in solving large-scale multiclass problems in bioinformatics and other fields of study.
doi:10.1186/1471-2164-14-S2-S6
PMCID: PMC3582431  PMID: 23445533
13.  Functional Knowledge Transfer for High-accuracy Prediction of Under-studied Biological Processes 
PLoS Computational Biology  2013;9(3):e1002957.
A key challenge in genetics is identifying the functional roles of genes in pathways. Numerous functional genomics techniques (e.g. machine learning) that predict protein function have been developed to address this question. These methods generally build from existing annotations of genes to pathways and thus are often unable to identify additional genes participating in processes that are not already well studied. Many of these processes are well studied in some organism, but not necessarily in an investigator's organism of interest. Sequence-based search methods (e.g. BLAST) have been used to transfer such annotation information between organisms. We demonstrate that functional genomics can complement traditional sequence similarity to improve the transfer of gene annotations between organisms. Our method transfers annotations only when functionally appropriate as determined by genomic data and can be used with any prediction algorithm to combine transferred gene function knowledge with organism-specific high-throughput data to enable accurate function prediction.
We show that diverse state-of-art machine learning algorithms leveraging functional knowledge transfer (FKT) dramatically improve their accuracy in predicting gene-pathway membership, particularly for processes with little experimental knowledge in an organism. We also show that our method compares favorably to annotation transfer by sequence similarity. Next, we deploy FKT with state-of-the-art SVM classifier to predict novel genes to 11,000 biological processes across six diverse organisms and expand the coverage of accurate function predictions to processes that are often ignored because of a dearth of annotated genes in an organism. Finally, we perform in vivo experimental investigation in Danio rerio and confirm the regulatory role of our top predicted novel gene, wnt5b, in leftward cell migration during heart development. FKT is immediately applicable to many bioinformatics techniques and will help biologists systematically integrate prior knowledge from diverse systems to direct targeted experiments in their organism of study.
Author Summary
Due to technical and ethical challenges many human diseases or biological processes are studied in model organisms. Discoveries in these organisms are then transferred back to human or other model organisms. Traditional methods for transferring novel gene function annotations have relied on finding genes with high sequence similarity believed to share evolutionary ancestry. However, sequence similarity does not guarantee a shared functional role in molecular pathways. In this study, we show that functional genomics can complement traditional sequence similarity measures to improve the transfer of gene annotations between organisms. We coupled our knowledge transfer method with current state-of-the-art machine learning algorithms and predicted gene function for 11,000 biological processes across six organisms. We experimentally validated our prediction of wnt5b's involvement in the determination of left-right heart asymmetry in zebrafish. Our results show that functional knowledge transfer can improve the coverage and accuracy of machine learning methods used for gene function prediction in a diverse set of organisms. Such an approach can be applied to additional organisms, and will be especially beneficial in organisms that have high-throughput genomic data with sparse annotations.
doi:10.1371/journal.pcbi.1002957
PMCID: PMC3597527  PMID: 23516347
14.  Automatic recognition of conceptualization zones in scientific articles and two life science applications 
Bioinformatics  2012;28(7):991-1000.
Motivation: Scholarly biomedical publications report on the findings of a research investigation. Scientists use a well-established discourse structure to relate their work to the state of the art, express their own motivation and hypotheses and report on their methods, results and conclusions. In previous work, we have proposed ways to explicitly annotate the structure of scientific investigations in scholarly publications. Here we present the means to facilitate automatic access to the scientific discourse of articles by automating the recognition of 11 categories at the sentence level, which we call Core Scientific Concepts (CoreSCs). These include: Hypothesis, Motivation, Goal, Object, Background, Method, Experiment, Model, Observation, Result and Conclusion. CoreSCs provide the structure and context to all statements and relations within an article and their automatic recognition can greatly facilitate biomedical information extraction by characterizing the different types of facts, hypotheses and evidence available in a scientific publication.
Results: We have trained and compared machine learning classifiers (support vector machines and conditional random fields) on a corpus of 265 full articles in biochemistry and chemistry to automatically recognize CoreSCs. We have evaluated our automatic classifications against a manually annotated gold standard, and have achieved promising accuracies with ‘Experiment’, ‘Background’ and ‘Model’ being the categories with the highest F1-scores (76%, 62% and 53%, respectively). We have analysed the task of CoreSC annotation both from a sentence classification as well as sequence labelling perspective and we present a detailed feature evaluation. The most discriminative features are local sentence features such as unigrams, bigrams and grammatical dependencies while features encoding the document structure, such as section headings, also play an important role for some of the categories. We discuss the usefulness of automatically generated CoreSCs in two biomedical applications as well as work in progress.
Availability: A web-based tool for the automatic annotation of articles with CoreSCs and corresponding documentation is available online at http://www.sapientaproject.com/software http://www.sapientaproject.com also contains detailed information pertaining to CoreSC annotation and links to annotation guidelines as well as a corpus of manually annotated articles, which served as our training data.
Contact: liakata@ebi.ac.uk
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts071
PMCID: PMC3315721  PMID: 22321698
15.  Applying active learning to supervised word sense disambiguation in MEDLINE 
Objectives
This study was to assess whether active learning strategies can be integrated with supervised word sense disambiguation (WSD) methods, thus reducing the number of annotated samples, while keeping or improving the quality of disambiguation models.
Methods
We developed support vector machine (SVM) classifiers to disambiguate 197 ambiguous terms and abbreviations in the MSH WSD collection. Three different uncertainty sampling-based active learning algorithms were implemented with the SVM classifiers and were compared with a passive learner (PL) based on random sampling. For each ambiguous term and each learning algorithm, a learning curve that plots the accuracy computed from the test set as a function of the number of annotated samples used in the model was generated. The area under the learning curve (ALC) was used as the primary metric for evaluation.
Results
Our experiments demonstrated that active learners (ALs) significantly outperformed the PL, showing better performance for 177 out of 197 (89.8%) WSD tasks. Further analysis showed that to achieve an average accuracy of 90%, the PL needed 38 annotated samples, while the ALs needed only 24, a 37% reduction in annotation effort. Moreover, we analyzed cases where active learning algorithms did not achieve superior performance and identified three causes: (1) poor models in the early learning stage; (2) easy WSD cases; and (3) difficult WSD cases, which provide useful insight for future improvements.
Conclusions
This study demonstrated that integrating active learning strategies with supervised WSD methods could effectively reduce annotation cost and improve the disambiguation models.
doi:10.1136/amiajnl-2012-001244
PMCID: PMC3756255  PMID: 23364851
Active Learning; Word Sense Disambiguation; Natural Language Processing; Machine Learning; Uncertainty Sampling; Annotation
16.  SVM-Fold: a tool for discriminative multi-class protein fold and superfamily recognition 
BMC Bioinformatics  2007;8(Suppl 4):S2.
Background
Predicting a protein's structural class from its amino acid sequence is a fundamental problem in computational biology. Much recent work has focused on developing new representations for protein sequences, called string kernels, for use with support vector machine (SVM) classifiers. However, while some of these approaches exhibit state-of-the-art performance at the binary protein classification problem, i.e. discriminating between a particular protein class and all other classes, few of these studies have addressed the real problem of multi-class superfamily or fold recognition. Moreover, there are only limited software tools and systems for SVM-based protein classification available to the bioinformatics community.
Results
We present a new multi-class SVM-based protein fold and superfamily recognition system and web server called SVM-Fold, which can be found at . Our system uses an efficient implementation of a state-of-the-art string kernel for sequence profiles, called the profile kernel, where the underlying feature representation is a histogram of inexact matching k-mer frequencies. We also employ a novel machine learning approach to solve the difficult multi-class problem of classifying a sequence of amino acids into one of many known protein structural classes. Binary one-vs-the-rest SVM classifiers that are trained to recognize individual structural classes yield prediction scores that are not comparable, so that standard "one-vs-all" classification fails to perform well. Moreover, SVMs for classes at different levels of the protein structural hierarchy may make useful predictions, but one-vs-all does not try to combine these multiple predictions. To deal with these problems, our method learns relative weights between one-vs-the-rest classifiers and encodes information about the protein structural hierarchy for multi-class prediction. In large-scale benchmark results based on the SCOP database, our code weighting approach significantly improves on the standard one-vs-all method for both the superfamily and fold prediction in the remote homology setting and on the fold recognition problem. Moreover, our code weight learning algorithm strongly outperforms nearest-neighbor methods based on PSI-BLAST in terms of prediction accuracy on every structure classification problem we consider.
Conclusion
By combining state-of-the-art SVM kernel methods with a novel multi-class algorithm, the SVM-Fold system delivers efficient and accurate protein fold and superfamily recognition.
doi:10.1186/1471-2105-8-S4-S2
PMCID: PMC1892081  PMID: 17570145
17.  Automatic categorization of diverse experimental information in the bioscience literature 
BMC Bioinformatics  2012;13:16.
Background
Curation of information from bioscience literature into biological knowledge databases is a crucial way of capturing experimental information in a computable form. During the biocuration process, a critical first step is to identify from all published literature the papers that contain results for a specific data type the curator is interested in annotating. This step normally requires curators to manually examine many papers to ascertain which few contain information of interest and thus, is usually time consuming. We developed an automatic method for identifying papers containing these curation data types among a large pool of published scientific papers based on the machine learning method Support Vector Machine (SVM). This classification system is completely automatic and can be readily applied to diverse experimental data types. It has been in use in production for automatic categorization of 10 different experimental datatypes in the biocuration process at WormBase for the past two years and it is in the process of being adopted in the biocuration process at FlyBase and the Saccharomyces Genome Database (SGD). We anticipate that this method can be readily adopted by various databases in the biocuration community and thereby greatly reducing time spent on an otherwise laborious and demanding task. We also developed a simple, readily automated procedure to utilize training papers of similar data types from different bodies of literature such as C. elegans and D. melanogaster to identify papers with any of these data types for a single database. This approach has great significance because for some data types, especially those of low occurrence, a single corpus often does not have enough training papers to achieve satisfactory performance.
Results
We successfully tested the method on ten data types from WormBase, fifteen data types from FlyBase and three data types from Mouse Genomics Informatics (MGI). It is being used in the curation work flow at WormBase for automatic association of newly published papers with ten data types including RNAi, antibody, phenotype, gene regulation, mutant allele sequence, gene expression, gene product interaction, overexpression phenotype, gene interaction, and gene structure correction.
Conclusions
Our methods are applicable to a variety of data types with training set containing several hundreds to a few thousand documents. It is completely automatic and, thus can be readily incorporated to different workflow at different literature-based databases. We believe that the work presented here can contribute greatly to the tremendous task of automating the important yet labor-intensive biocuration effort.
doi:10.1186/1471-2105-13-16
PMCID: PMC3305665  PMID: 22280404
18.  Elastic SCAD as a novel penalization method for SVM classification tasks in high-dimensional data 
BMC Bioinformatics  2011;12:138.
Background
Classification and variable selection play an important role in knowledge discovery in high-dimensional data. Although Support Vector Machine (SVM) algorithms are among the most powerful classification and prediction methods with a wide range of scientific applications, the SVM does not include automatic feature selection and therefore a number of feature selection procedures have been developed. Regularisation approaches extend SVM to a feature selection method in a flexible way using penalty functions like LASSO, SCAD and Elastic Net.
We propose a novel penalty function for SVM classification tasks, Elastic SCAD, a combination of SCAD and ridge penalties which overcomes the limitations of each penalty alone.
Since SVM models are extremely sensitive to the choice of tuning parameters, we adopted an interval search algorithm, which in comparison to a fixed grid search finds rapidly and more precisely a global optimal solution.
Results
Feature selection methods with combined penalties (Elastic Net and Elastic SCAD SVMs) are more robust to a change of the model complexity than methods using single penalties. Our simulation study showed that Elastic SCAD SVM outperformed LASSO (L1) and SCAD SVMs. Moreover, Elastic SCAD SVM provided sparser classifiers in terms of median number of features selected than Elastic Net SVM and often better predicted than Elastic Net in terms of misclassification error.
Finally, we applied the penalization methods described above on four publicly available breast cancer data sets. Elastic SCAD SVM was the only method providing robust classifiers in sparse and non-sparse situations.
Conclusions
The proposed Elastic SCAD SVM algorithm provides the advantages of the SCAD penalty and at the same time avoids sparsity limitations for non-sparse data. We were first to demonstrate that the integration of the interval search algorithm and penalized SVM classification techniques provides fast solutions on the optimization of tuning parameters.
The penalized SVM classification algorithms as well as fixed grid and interval search for finding appropriate tuning parameters were implemented in our freely available R package 'penalizedSVM'.
We conclude that the Elastic SCAD SVM is a flexible and robust tool for classification and feature selection tasks for high-dimensional data such as microarray data sets.
doi:10.1186/1471-2105-12-138
PMCID: PMC3113938  PMID: 21554689
19.  Improving the Caenorhabditis elegans Genome Annotation Using Machine Learning 
PLoS Computational Biology  2007;3(2):e20.
For modern biology, precise genome annotations are of prime importance, as they allow the accurate definition of genic regions. We employ state-of-the-art machine learning methods to assay and improve the accuracy of the genome annotation of the nematode Caenorhabditis elegans. The proposed machine learning system is trained to recognize exons and introns on the unspliced mRNA, utilizing recent advances in support vector machines and label sequence learning. In 87% (coding and untranslated regions) and 95% (coding regions only) of all genes tested in several out-of-sample evaluations, our method correctly identified all exons and introns. Notably, only 37% and 50%, respectively, of the presently unconfirmed genes in the C. elegans genome annotation agree with our predictions, thus we hypothesize that a sizable fraction of those genes are not correctly annotated. A retrospective evaluation of the Wormbase WS120 annotation [1] of C. elegans reveals that splice form predictions on unconfirmed genes in WS120 are inaccurate in about 18% of the considered cases, while our predictions deviate from the truth only in 10%–13%. We experimentally analyzed 20 controversial genes on which our system and the annotation disagree, confirming the superiority of our predictions. While our method correctly predicted 75% of those cases, the standard annotation was never completely correct. The accuracy of our system is further corroborated by a comparison with two other recently proposed systems that can be used for splice form prediction: SNAP and ExonHunter. We conclude that the genome annotation of C. elegans and other organisms can be greatly enhanced using modern machine learning technology.
Author Summary
Eukaryotic genes contain introns, which are intervening sequences that are excised from a gene transcript with the concomitant ligation of flanking segments called exons. The process of removing introns is called splicing. It involves biochemical mechanisms that to date are too complex to be modeled comprehensively and accurately. However, abundant sequencing results can serve as a blueprint database exemplifying what this process accomplishes. Using this database, we employ discriminative machine learning techniques to predict the mature mRNA given the unspliced pre-mRNA. Our method utilizes support vector machines and recent advances in label sequence learning, originally developed for natural language processing. The system, called mSplicer, was trained and evaluated on the genome of the nematode C. elegans, a well-studied model organism. We were able to show that mSplicer correctly predicts the splice form in most cases. Surprisingly, our predictions on currently unconfirmed genes deviate considerably from the public genome annotation. It is hypothesized that a sizable fraction of those genes are not correctly annotated. A retrospective evaluation and additional sequencing results show the superiority of mSplicer's predictions. It is concluded that the annotation of nematode and other genomes can be greatly enhanced using modern machine learning.
doi:10.1371/journal.pcbi.0030020
PMCID: PMC1808025  PMID: 17319737
20.  Support vector machines classifiers of physical activities in preschoolers 
Physiological Reports  2013;1(1):e00006.
The goal of this study is to develop, test, and compare multinomial logistic regression (MLR) and support vector machines (SVM) in classifying preschool-aged children physical activity data acquired from an accelerometer. In this study, 69 children aged 3–5 years old were asked to participate in a supervised protocol of physical activities while wearing a triaxial accelerometer. Accelerometer counts, steps, and position were obtained from the device. We applied K-means clustering to determine the number of natural groupings presented by the data. We used MLR and SVM to classify the six activity types. Using direct observation as the criterion method, the 10-fold cross-validation (CV) error rate was used to compare MLR and SVM classifiers, with and without sleep. Altogether, 58 classification models based on combinations of the accelerometer output variables were developed. In general, the SVM classifiers have a smaller 10-fold CV error rate than their MLR counterparts. Including sleep, a SVM classifier provided the best performance with a 10-fold CV error rate of 24.70%. Without sleep, a SVM classifier-based triaxial accelerometer counts, vector magnitude, steps, position, and 1- and 2-min lag and lead values achieved a 10-fold CV error rate of 20.16% and an overall classification error rate of 15.56%. SVM supersedes the classical classifier MLR in categorizing physical activities in preschool-aged children. Using accelerometer data, SVM can be used to correctly classify physical activities typical of preschool-aged children with an acceptable classification error rate.
doi:10.1002/phy2.6
PMCID: PMC3831935  PMID: 24303099
Accelerometers; activity monitoring; classification; multinomial logistic regression classifiers; support vector machines classifiers
21.  Towards a Physiology-Based Measure of Pain: Patterns of Human Brain Activity Distinguish Painful from Non-Painful Thermal Stimulation 
PLoS ONE  2011;6(9):e24124.
Pain often exists in the absence of observable injury; therefore, the gold standard for pain assessment has long been self-report. Because the inability to verbally communicate can prevent effective pain management, research efforts have focused on the development of a tool that accurately assesses pain without depending on self-report. Those previous efforts have not proven successful at substituting self-report with a clinically valid, physiology-based measure of pain. Recent neuroimaging data suggest that functional magnetic resonance imaging (fMRI) and support vector machine (SVM) learning can be jointly used to accurately assess cognitive states. Therefore, we hypothesized that an SVM trained on fMRI data can assess pain in the absence of self-report. In fMRI experiments, 24 individuals were presented painful and nonpainful thermal stimuli. Using eight individuals, we trained a linear SVM to distinguish these stimuli using whole-brain patterns of activity. We assessed the performance of this trained SVM model by testing it on 16 individuals whose data were not used for training. The whole-brain SVM was 81% accurate at distinguishing painful from non-painful stimuli (p<0.0000001). Using distance from the SVM hyperplane as a confidence measure, accuracy was further increased to 84%, albeit at the expense of excluding 15% of the stimuli that were the most difficult to classify. Overall performance of the SVM was primarily affected by activity in pain-processing regions of the brain including the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, primary motor cortex, and cingulate cortex. Region of interest (ROI) analyses revealed that whole-brain patterns of activity led to more accurate classification than localized activity from individual brain regions. Our findings demonstrate that fMRI with SVM learning can assess pain without requiring any communication from the person being tested. We outline tasks that should be completed to advance this approach toward use in clinical settings.
doi:10.1371/journal.pone.0024124
PMCID: PMC3172232  PMID: 21931652
22.  Performance assessment for EEG-based neonatal seizure detectors 
Clinical Neurophysiology  2011;122(3):474-482.
Objective
This study discusses an appropriate framework to measure system performance for the task of neonatal seizure detection using EEG. The framework is used to present an extended overview of a multi-channel patient-independent neonatal seizure detection system based on the Support Vector Machine (SVM) classifier.
Methods
The appropriate framework for performance assessment of neonatal seizure detectors is discussed in terms of metrics, experimental setups, and testing protocols. The neonatal seizure detection system is evaluated in this framework. Several epoch-based and event-based metrics are calculated and curves of performance are reported. A new metric to measure the average duration of a false detection is proposed to accompany the event-based metrics. A machine learning algorithm (SVM) is used as a classifier to discriminate between seizure and non-seizure EEG epochs. Two post-processing steps proposed to increase temporal precision and robustness of the system are investigated and their influence on various metrics is shown. The resulting system is validated on a large clinical dataset of 267 h.
Results
In this paper, it is shown how a complete set of metrics and a specific testing protocol are necessary to extensively describe neonatal seizure detection systems, objectively assess their performance and enable comparison with existing alternatives. The developed system currently represents the best published performance to date with an ROC area of 96.3%. The sensitivity and specificity were ∼90% at the equal error rate point. The system was able to achieve an average good detection rate of ∼89% at a cost of 1 false detection per hour with an average false detection duration of 2.7 min.
Conclusions
It is shown that to accurately assess the performance of EEG-based neonatal seizure detectors and to facilitate comparison with existing alternatives, several metrics should be reported and a specific testing protocol should be followed. It is also shown that reporting only event-based metrics can be misleading as they do not always reflect the true performance of the system.
Significance
This is the first study to present a thorough method for performance assessment of EEG-based seizure detection systems. The evaluated SVM-based seizure detection system can greatly assist clinical staff, in a neonatal intensive care unit, to interpret the EEG.
doi:10.1016/j.clinph.2010.06.035
PMCID: PMC3036796  PMID: 20716492
Performance assessment; Metrics; Neonatal EEG; Automated seizure detection; Machine learning; Support Vector Machines
23.  A preliminary study on automated freshwater algae recognition and classification system 
BMC Bioinformatics  2012;13(Suppl 17):S25.
Background
Freshwater algae can be used as indicators to monitor freshwater ecosystem condition. Algae react quickly and predictably to a broad range of pollutants. Thus they provide early signals of worsening environment. This study was carried out to develop a computer-based image processing technique to automatically detect, recognize, and identify algae genera from the divisions Bacillariophyta, Chlorophyta and Cyanobacteria in Putrajaya Lake. Literature shows that most automated analyses and identification of algae images were limited to only one type of algae. Automated identification system for tropical freshwater algae is even non-existent and this study is partly to fill this gap.
Results
The development of the automated freshwater algae detection system involved image preprocessing, segmentation, feature extraction and classification by using Artificial neural networks (ANN). Image preprocessing was used to improve contrast and remove noise. Image segmentation using canny edge detection algorithm was then carried out on binary image to detect the algae and its boundaries. Feature extraction process was applied to extract specific feature parameters from algae image to obtain some shape and texture features of selected algae such as shape, area, perimeter, minor and major axes, and finally Fourier spectrum with principal component analysis (PCA) was applied to extract some of algae feature texture. Artificial neural network (ANN) is used to classify algae images based on the extracted features. Feed-forward multilayer perceptron network was initialized with back propagation error algorithm, and trained with extracted database features of algae image samples. System's accuracy rate was obtained by comparing the results between the manual and automated classifying methods. The developed system was able to identify 93 images of selected freshwater algae genera from a total of 100 tested images which yielded accuracy rate of 93%.
Conclusions
This study demonstrated application of automated algae recognition of five genera of freshwater algae. The result indicated that MLP is sufficient, and can be used for classification of freshwater algae. However for future studies, application of support vector machine (SVM) and radial basis function (RBF) should be considered for better classifying as the number of algae species studied increases.
doi:10.1186/1471-2105-13-S17-S25
PMCID: PMC3521397  PMID: 23282059
24.  A comparative study of cell classifiers for image-based high-throughput screening 
BMC Bioinformatics  2014;15(1):342.
Background
Millions of cells are present in thousands of images created in high-throughput screening (HTS). Biologists could classify each of these cells into a phenotype by visual inspection. But in the presence of millions of cells this visual classification task becomes infeasible. Biologists train classification models on a few thousand visually classified example cells and iteratively improve the training data by visual inspection of the important misclassified phenotypes. Classification methods differ in performance and performance evaluation time. We present a comparative study of computational performance of gentle boosting, joint boosting CellProfiler Analyst (CPA), support vector machines (linear and radial basis function) and linear discriminant analysis (LDA) on two data sets of HT29 and HeLa cancer cells.
Results
For the HT29 data set we find that gentle boosting, SVM (linear) and SVM (RBF) are close in performance but SVM (linear) is faster than gentle boosting and SVM (RBF). For the HT29 data set the average performance difference between SVM (RBF) and SVM (linear) is 0.42 %. For the HeLa data set we find that SVM (RBF) outperforms other classification methods and is on average 1.41 % better in performance than SVM (linear).
Conclusions
Our study proposes SVM (linear) for iterative improvement of the training data and SVM (RBF) for the final classifier to classify all unlabeled cells in the whole data set.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-342) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2105-15-342
PMCID: PMC4287552  PMID: 25336059
25.  Machine learning and word sense disambiguation in the biomedical domain: design and evaluation issues 
BMC Bioinformatics  2006;7:334.
Background
Word sense disambiguation (WSD) is critical in the biomedical domain for improving the precision of natural language processing (NLP), text mining, and information retrieval systems because ambiguous words negatively impact accurate access to literature containing biomolecular entities, such as genes, proteins, cells, diseases, and other important entities. Automated techniques have been developed that address the WSD problem for a number of text processing situations, but the problem is still a challenging one. Supervised WSD machine learning (ML) methods have been applied in the biomedical domain and have shown promising results, but the results typically incorporate a number of confounding factors, and it is problematic to truly understand the effectiveness and generalizability of the methods because these factors interact with each other and affect the final results. Thus, there is a need to explicitly address the factors and to systematically quantify their effects on performance.
Results
Experiments were designed to measure the effect of "sample size" (i.e. size of the datasets), "sense distribution" (i.e. the distribution of the different meanings of the ambiguous word) and "degree of difficulty" (i.e. the measure of the distances between the meanings of the senses of an ambiguous word) on the performance of WSD classifiers. Support Vector Machine (SVM) classifiers were applied to an automatically generated data set containing four ambiguous biomedical abbreviations: BPD, BSA, PCA, and RSV, which were chosen because of varying degrees of differences in their respective senses. Results showed that: 1) increasing the sample size generally reduced the error rate, but this was limited mainly to well-separated senses (i.e. cases where the distances between the senses were large); in difficult cases an unusually large increase in sample size was needed to increase performance slightly, which was impractical, 2) the sense distribution did not have an effect on performance when the senses were separable, 3) when there was a majority sense of over 90%, the WSD classifier was not better than use of the simple majority sense, 4) error rates were proportional to the similarity of senses, and 5) there was no statistical difference between results when using a 5-fold or 10-fold cross-validation method. Other issues that impact performance are also enumerated.
Conclusion
Several different independent aspects affect performance when using ML techniques for WSD. We found that combining them into one single result obscures understanding of the underlying methods. Although we studied only four abbreviations, we utilized a well-established statistical method that guarantees the results are likely to be generalizable for abbreviations with similar characteristics. The results of our experiments show that in order to understand the performance of these ML methods it is critical that papers report on the baseline performance, the distribution and sample size of the senses in the datasets, and the standard deviation or confidence intervals. In addition, papers should also characterize the difficulty of the WSD task, the WSD situations addressed and not addressed, as well as the ML methods and features used. This should lead to an improved understanding of the generalizablility and the limitations of the methodology.
doi:10.1186/1471-2105-7-334
PMCID: PMC1550263  PMID: 16822321

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