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1.  DDN: a caBIG® analytical tool for differential network analysis 
Bioinformatics  2011;27(7):1036-1038.
Summary: Differential dependency network (DDN) is a caBIG® (cancer Biomedical Informatics Grid) analytical tool for detecting and visualizing statistically significant topological changes in transcriptional networks representing two biological conditions. Developed under caBIG® 's In Silico Research Centers of Excellence (ISRCE) Program, DDN enables differential network analysis and provides an alternative way for defining network biomarkers predictive of phenotypes. DDN also serves as a useful systems biology tool for users across biomedical research communities to infer how genetic, epigenetic or environment variables may affect biological networks and clinical phenotypes. Besides the standalone Java application, we have also developed a Cytoscape plug-in, CytoDDN, to integrate network analysis and visualization seamlessly.
Availability: The Java and MATLAB source code can be downloaded at the authors' web site
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3065688  PMID: 21296752
2.  CAM-CM: a signal deconvolution tool for in vivo dynamic contrast-enhanced imaging of complex tissues 
Bioinformatics  2011;27(18):2607-2609.
Summary:In vivo dynamic contrast-enhanced imaging tools provide non-invasive methods for analyzing various functional changes associated with disease initiation, progression and responses to therapy. The quantitative application of these tools has been hindered by its inability to accurately resolve and characterize targeted tissues due to spatially mixed tissue heterogeneity. Convex Analysis of Mixtures – Compartment Modeling (CAM-CM) signal deconvolution tool has been developed to automatically identify pure-volume pixels located at the corners of the clustered pixel time series scatter simplex and subsequently estimate tissue-specific pharmacokinetic parameters. CAM-CM can dissect complex tissues into regions with differential tracer kinetics at pixel-wise resolution and provide a systems biology tool for defining imaging signatures predictive of phenotypes.
Availability: The MATLAB source code can be downloaded at the authors′ website
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3167053  PMID: 21785131
3.  Differential dependency network analysis to identify condition-specific topological changes in biological networks 
Bioinformatics  2008;25(4):526-532.
Motivation: Significant efforts have been made to acquire data under different conditions and to construct static networks that can explain various gene regulation mechanisms. However, gene regulatory networks are dynamic and condition-specific; under different conditions, networks exhibit different regulation patterns accompanied by different transcriptional network topologies. Thus, an investigation on the topological changes in transcriptional networks can facilitate the understanding of cell development or provide novel insights into the pathophysiology of certain diseases, and help identify the key genetic players that could serve as biomarkers or drug targets.
Results: Here, we report a differential dependency network (DDN) analysis to detect statistically significant topological changes in the transcriptional networks between two biological conditions. We propose a local dependency model to represent the local structures of a network by a set of conditional probabilities. We develop an efficient learning algorithm to learn the local dependency model using the Lasso technique. A permutation test is subsequently performed to estimate the statistical significance of each learned local structure. In testing on a simulation dataset, the proposed algorithm accurately detected all the genes with network topological changes. The method was then applied to the estrogen-dependent T-47D estrogen receptor-positive (ER+) breast cancer cell line datasets and human and mouse embryonic stem cell datasets. In both experiments using real microarray datasets, the proposed method produced biologically meaningful results. We expect DDN to emerge as an important bioinformatics tool in transcriptional network analyses. While we focus specifically on transcriptional networks, the DDN method we introduce here is generally applicable to other biological networks with similar characteristics.
Availability: The DDN MATLAB toolbox and experiment data are available at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2642641  PMID: 19112081
4.  BACOM: in silico detection of genomic deletion types and correction of normal cell contamination in copy number data 
Bioinformatics  2011;27(11):1473-1480.
Motivation: Identification of somatic DNA copy number alterations (CNAs) and significant consensus events (SCEs) in cancer genomes is a main task in discovering potential cancer-driving genes such as oncogenes and tumor suppressors. The recent development of SNP array technology has facilitated studies on copy number changes at a genome-wide scale with high resolution. However, existing copy number analysis methods are oblivious to normal cell contamination and cannot distinguish between contributions of cancerous and normal cells to the measured copy number signals. This contamination could significantly confound downstream analysis of CNAs and affect the power to detect SCEs in clinical samples.
Results: We report here a statistically principled in silico approach, Bayesian Analysis of COpy number Mixtures (BACOM), to accurately estimate genomic deletion type and normal tissue contamination, and accordingly recover the true copy number profile in cancer cells. We tested the proposed method on two simulated datasets, two prostate cancer datasets and The Cancer Genome Atlas high-grade ovarian dataset, and obtained very promising results supported by the ground truth and biological plausibility. Moreover, based on a large number of comparative simulation studies, the proposed method gives significantly improved power to detect SCEs after in silico correction of normal tissue contamination. We develop a cross-platform open-source Java application that implements the whole pipeline of copy number analysis of heterogeneous cancer tissues including relevant processing steps. We also provide an R interface, bacomR, for running BACOM within the R environment, making it straightforward to include in existing data pipelines.
Availability: The cross-platform, stand-alone Java application, BACOM, the R interface, bacomR, all source code and the simulation data used in this article are freely available at authors' web site:
Supplementary Information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3102226  PMID: 21498400
5.  Multilevel support vector regression analysis to identify condition-specific regulatory networks 
Bioinformatics  2010;26(11):1416-1422.
Motivation: The identification of gene regulatory modules is an important yet challenging problem in computational biology. While many computational methods have been proposed to identify regulatory modules, their initial success is largely compromised by a high rate of false positives, especially when applied to human cancer studies. New strategies are needed for reliable regulatory module identification.
Results: We present a new approach, namely multilevel support vector regression (ml-SVR), to systematically identify condition-specific regulatory modules. The approach is built upon a multilevel analysis strategy designed for suppressing false positive predictions. With this strategy, a regulatory module becomes ever more significant as more relevant gene sets are formed at finer levels. At each level, a two-stage support vector regression (SVR) method is utilized to help reduce false positive predictions by integrating binding motif information and gene expression data; a significant analysis procedure is followed to assess the significance of each regulatory module. To evaluate the effectiveness of the proposed strategy, we first compared the ml-SVR approach with other existing methods on simulation data and yeast cell cycle data. The resulting performance shows that the ml-SVR approach outperforms other methods in the identification of both regulators and their target genes. We then applied our method to breast cancer cell line data to identify condition-specific regulatory modules associated with estrogen treatment. Experimental results show that our method can identify biologically meaningful regulatory modules related to estrogen signaling and action in breast cancer.
Availability and implementation: The ml-SVR MATLAB package can be downloaded at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2872001  PMID: 20375112
6.  Stable feature selection and classification algorithms for multiclass microarray data 
Biology Direct  2012;7:33.
Recent studies suggest that gene expression profiles are a promising alternative for clinical cancer classification. One major problem in applying DNA microarrays for classification is the dimension of obtained data sets. In this paper we propose a multiclass gene selection method based on Partial Least Squares (PLS) for selecting genes for classification. The new idea is to solve multiclass selection problem with the PLS method and decomposition to a set of two-class sub-problems: one versus rest (OvR) and one versus one (OvO). We use OvR and OvO two-class decomposition for other recently published gene selection method. Ranked gene lists are highly unstable in the sense that a small change of the data set often leads to big changes in the obtained ordered lists. In this paper, we take a look at the assessment of stability of the proposed methods. We use the linear support vector machines (SVM) technique in different variants: one versus one, one versus rest, multiclass SVM (MSVM) and the linear discriminant analysis (LDA) as a classifier. We use balanced bootstrap to estimate the prediction error and to test the variability of the obtained ordered lists.
This paper focuses on effective identification of informative genes. As a result, a new strategy to find a small subset of significant genes is designed. Our results on real multiclass cancer data show that our method has a very high accuracy rate for different combinations of classification methods, giving concurrently very stable feature rankings.
This paper shows that the proposed strategies can improve the performance of selected gene sets substantially. OvR and OvO techniques applied to existing gene selection methods improve results as well. The presented method allows to obtain a more reliable classifier with less classifier error. In the same time the method generates more stable ordered feature lists in comparison with existing methods.
This article was reviewed by Prof Marek Kimmel, Dr Hans Binder (nominated by Dr Tomasz Lipniacki) and Dr Yuriy Gusev
PMCID: PMC3599581  PMID: 23031190
7.  An algorithm for learning maximum entropy probability models of disease risk that efficiently searches and sparingly encodes multilocus genomic interactions 
Bioinformatics  2009;25(19):2478-2485.
Motivation: In both genome-wide association studies (GWAS) and pathway analysis, the modest sample size relative to the number of genetic markers presents formidable computational, statistical and methodological challenges for accurately identifying markers/interactions and for building phenotype-predictive models.
Results: We address these objectives via maximum entropy conditional probability modeling (MECPM), coupled with a novel model structure search. Unlike neural networks and support vector machines (SVMs), MECPM makes explicit and is determined by the interactions that confer phenotype-predictive power. Our method identifies both a marker subset and the multiple k-way interactions between these markers. Additional key aspects are: (i) evaluation of a select subset of up to five-way interactions while retaining relatively low complexity; (ii) flexible single nucleotide polymorphism (SNP) coding (dominant, recessive) within each interaction; (iii) no mathematical interaction form assumed; (iv) model structure and order selection based on the Bayesian Information Criterion, which fairly compares interactions at different orders and automatically sets the experiment-wide significance level; (v) MECPM directly yields a phenotype-predictive model. MECPM was compared with a panel of methods on datasets with up to 1000 SNPs and up to eight embedded penetrance function (i.e. ground-truth) interactions, including a five-way, involving less than 20 SNPs. MECPM achieved improved sensitivity and specificity for detecting both ground-truth markers and interactions, compared with previous methods.
Supplementary information:Supplementary data are available at Bioinformatics online.
PMCID: PMC3140808  PMID: 19608708
8.  miRFam: an effective automatic miRNA classification method based on n-grams and a multiclass SVM 
BMC Bioinformatics  2011;12:216.
MicroRNAs (miRNAs) are ~22 nt long integral elements responsible for post-transcriptional control of gene expressions. After the identification of thousands of miRNAs, the challenge is now to explore their specific biological functions. To this end, it will be greatly helpful to construct a reasonable organization of these miRNAs according to their homologous relationships. Given an established miRNA family system (e.g. the miRBase family organization), this paper addresses the problem of automatically and accurately classifying newly found miRNAs to their corresponding families by supervised learning techniques. Concretely, we propose an effective method, miRFam, which uses only primary information of pre-miRNAs or mature miRNAs and a multiclass SVM, to automatically classify miRNA genes.
An existing miRNA family system prepared by miRBase was downloaded online. We first employed n-grams to extract features from known precursor sequences, and then trained a multiclass SVM classifier to classify new miRNAs (i.e. their families are unknown). Comparing with miRBase's sequence alignment and manual modification, our study shows that the application of machine learning techniques to miRNA family classification is a general and more effective approach. When the testing dataset contains more than 300 families (each of which holds no less than 5 members), the classification accuracy is around 98%. Even with the entire miRBase15 (1056 families and more than 650 of them hold less than 5 samples), the accuracy surprisingly reaches 90%.
Based on experimental results, we argue that miRFam is suitable for application as an automated method of family classification, and it is an important supplementary tool to the existing alignment-based small non-coding RNA (sncRNA) classification methods, since it only requires primary sequence information.
The source code of miRFam, written in C++, is freely and publicly available at:
PMCID: PMC3120706  PMID: 21619662
9.  Robust identification of transcriptional regulatory networks using a Gibbs sampler on outlier sum statistic 
Bioinformatics  2012;28(15):1990-1997.
Motivation: Identification of transcriptional regulatory networks (TRNs) is of significant importance in computational biology for cancer research, providing a critical building block to unravel disease pathways. However, existing methods for TRN identification suffer from the inclusion of excessive ‘noise’ in microarray data and false-positives in binding data, especially when applied to human tumor-derived cell line studies. More robust methods that can counteract the imperfection of data sources are therefore needed for reliable identification of TRNs in this context.
Results: In this article, we propose to establish a link between the quality of one target gene to represent its regulator and the uncertainty of its expression to represent other target genes. Specifically, an outlier sum statistic was used to measure the aggregated evidence for regulation events between target genes and their corresponding transcription factors. A Gibbs sampling method was then developed to estimate the marginal distribution of the outlier sum statistic, hence, to uncover underlying regulatory relationships. To evaluate the effectiveness of our proposed method, we compared its performance with that of an existing sampling-based method using both simulation data and yeast cell cycle data. The experimental results show that our method consistently outperforms the competing method in different settings of signal-to-noise ratio and network topology, indicating its robustness for biological applications. Finally, we applied our method to breast cancer cell line data and demonstrated its ability to extract biologically meaningful regulatory modules related to estrogen signaling and action in breast cancer.
Availability and implementation: The Gibbs sampler MATLAB package is freely available at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3400952  PMID: 22595208
10.  Impact of caBIG on the European cancer community 
ecancermedicalscience  2011;5:225.
The cancer Biomedical Informatics Grid (caBIG) was launched in 2003 by the US National Cancer Institute with the aim of connecting research teams through the use of shared infrastructure and software to collect, analyse and share data. It was an ambitious project, and the issue it aimed to address was huge and far-reaching. With such developments as the mapping of the human genome and the advancement of new technologies for the analysis of genes and proteins, cancer researchers have never produced so much complex data, nor have they understood so much about cancer on a molecular level. This new ‘molecular understanding’ of cancer, according to the caBIG 2007 ‘Pilot Report’[1], leads to molecular or ‘personalised’ medicine being the way forward in cancer research and treatment, and connects basic research to clinical care in an unprecedented way. But the former ‘silo-like’ nature of research does not lend itself to this brave new world of molecular medicine—individual labs and institutes working in isolation, “in effect, as cottage industries, each collecting and interpreting data using a unique language of their own”[2] will not advance cancer research as it should be advanced. The solution proposed by the NCI in caBIG was to produce an integrated informatics grid (‘caGrid’) to incorporate open source, open access tools to collect, analyse and share data, enabling everyone to use the same methods and language for these tasks.
caBIG is primarily a US-based endeavour, and though the tools are openly available for users worldwide, it is in US NCI-funded cancer centres that they have been actively introduced and promoted with the eventual hope, according to the pilot report, of being able to do the same worldwide. caBIG also has a collaboration in place with the UK organisation NCRI to exchange technologies and research data. The European Association for Cancer Research, a member association for cancer researchers, conducted an online survey in January 2011 to identify the penetration of the ambitious caBIG project into European laboratories. The survey was sent to 6396 researchers based in Europe, with 764 respondents, a total response rate of 11.94%.
PMCID: PMC3223955  PMID: 22276064
11.  geWorkbench: an open source platform for integrative genomics 
Bioinformatics  2010;26(14):1779-1780.
Summary: geWorkbench (genomics Workbench) is an open source Java desktop application that provides access to an integrated suite of tools for the analysis and visualization of data from a wide range of genomics domains (gene expression, sequence, protein structure and systems biology). More than 70 distinct plug-in modules are currently available implementing both classical analyses (several variants of clustering, classification, homology detection, etc.) as well as state of the art algorithms for the reverse engineering of regulatory networks and for protein structure prediction, among many others. geWorkbench leverages standards-based middleware technologies to provide seamless access to remote data, annotation and computational servers, thus, enabling researchers with limited local resources to benefit from available public infrastructure.
Availability: The project site ( includes links to self-extracting installers for most operating system (OS) platforms as well as instructions for building the application from scratch using the source code [which is freely available from the project's SVN (subversion) repository]. geWorkbench support is available through the end-user and developer forums of the caBIG® Molecular Analysis Tools Knowledge Center,
Supplementary Information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2894520  PMID: 20511363
12.  Recognition of Multiple Imbalanced Cancer Types Based on DNA Microarray Data Using Ensemble Classifiers 
BioMed Research International  2013;2013:239628.
DNA microarray technology can measure the activities of tens of thousands of genes simultaneously, which provides an efficient way to diagnose cancer at the molecular level. Although this strategy has attracted significant research attention, most studies neglect an important problem, namely, that most DNA microarray datasets are skewed, which causes traditional learning algorithms to produce inaccurate results. Some studies have considered this problem, yet they merely focus on binary-class problem. In this paper, we dealt with multiclass imbalanced classification problem, as encountered in cancer DNA microarray, by using ensemble learning. We utilized one-against-all coding strategy to transform multiclass to multiple binary classes, each of them carrying out feature subspace, which is an evolving version of random subspace that generates multiple diverse training subsets. Next, we introduced one of two different correction technologies, namely, decision threshold adjustment or random undersampling, into each training subset to alleviate the damage of class imbalance. Specifically, support vector machine was used as base classifier, and a novel voting rule called counter voting was presented for making a final decision. Experimental results on eight skewed multiclass cancer microarray datasets indicate that unlike many traditional classification approaches, our methods are insensitive to class imbalance.
PMCID: PMC3770038  PMID: 24078908
13.  Discovery of dominant and dormant genes from expression data using a novel generalization of SNR for multi-class problems 
BMC Bioinformatics  2008;9:425.
The Signal-to-Noise-Ratio (SNR) is often used for identification of biomarkers for two-class problems and no formal and useful generalization of SNR is available for multiclass problems. We propose innovative generalizations of SNR for multiclass cancer discrimination through introduction of two indices, Gene Dominant Index and Gene Dormant Index (GDIs). These two indices lead to the concepts of dominant and dormant genes with biological significance. We use these indices to develop methodologies for discovery of dominant and dormant biomarkers with interesting biological significance. The dominancy and dormancy of the identified biomarkers and their excellent discriminating power are also demonstrated pictorially using the scatterplot of individual gene and 2-D Sammon's projection of the selected set of genes. Using information from the literature we have shown that the GDI based method can identify dominant and dormant genes that play significant roles in cancer biology. These biomarkers are also used to design diagnostic prediction systems.
Results and discussion
To evaluate the effectiveness of the GDIs, we have used four multiclass cancer data sets (Small Round Blue Cell Tumors, Leukemia, Central Nervous System Tumors, and Lung Cancer). For each data set we demonstrate that the new indices can find biologically meaningful genes that can act as biomarkers. We then use six machine learning tools, Nearest Neighbor Classifier (NNC), Nearest Mean Classifier (NMC), Support Vector Machine (SVM) classifier with linear kernel, and SVM classifier with Gaussian kernel, where both SVMs are used in conjunction with one-vs-all (OVA) and one-vs-one (OVO) strategies. We found GDIs to be very effective in identifying biomarkers with strong class specific signatures. With all six tools and for all data sets we could achieve better or comparable prediction accuracies usually with fewer marker genes than results reported in the literature using the same computational protocols. The dominant genes are usually easy to find while good dormant genes may not always be available as dormant genes require stronger constraints to be satisfied; but when they are available, they can be used for authentication of diagnosis.
Since GDI based schemes can find a small set of dominant/dormant biomarkers that is adequate to design diagnostic prediction systems, it opens up the possibility of using real-time qPCR assays or antibody based methods such as ELISA for an easy and low cost diagnosis of diseases. The dominant and dormant genes found by GDIs can be used in different ways to design more reliable diagnostic prediction systems.
PMCID: PMC2620271  PMID: 18842155
14.  Knowledge-fused differential dependency network models for detecting significant rewiring in biological networks 
BMC Systems Biology  2014;8:87.
Modeling biological networks serves as both a major goal and an effective tool of systems biology in studying mechanisms that orchestrate the activities of gene products in cells. Biological networks are context-specific and dynamic in nature. To systematically characterize the selectively activated regulatory components and mechanisms, modeling tools must be able to effectively distinguish significant rewiring from random background fluctuations. While differential networks cannot be constructed by existing knowledge alone, novel incorporation of prior knowledge into data-driven approaches can improve the robustness and biological relevance of network inference. However, the major unresolved roadblocks include: big solution space but a small sample size; highly complex networks; imperfect prior knowledge; missing significance assessment; and heuristic structural parameter learning.
To address these challenges, we formulated the inference of differential dependency networks that incorporate both conditional data and prior knowledge as a convex optimization problem, and developed an efficient learning algorithm to jointly infer the conserved biological network and the significant rewiring across different conditions. We used a novel sampling scheme to estimate the expected error rate due to “random” knowledge. Based on that scheme, we developed a strategy that fully exploits the benefit of this data-knowledge integrated approach. We demonstrated and validated the principle and performance of our method using synthetic datasets. We then applied our method to yeast cell line and breast cancer microarray data and obtained biologically plausible results. The open-source R software package and the experimental data are freely available at
Experiments on both synthetic and real data demonstrate the effectiveness of the knowledge-fused differential dependency network in revealing the statistically significant rewiring in biological networks. The method efficiently leverages data-driven evidence and existing biological knowledge while remaining robust to the false positive edges in the prior knowledge. The identified network rewiring events are supported by previous studies in the literature and also provide new mechanistic insight into the biological systems. We expect the knowledge-fused differential dependency network analysis, together with the open-source R package, to be an important and useful bioinformatics tool in biological network analyses.
PMCID: PMC4131167  PMID: 25055984
Biological networks; Probabilistic graphical models; Differential dependency network; Network rewiring; Network analysis; Systems biology; Knowledge incorporation; Convex optimization
15.  Gene Selection for Multiclass Prediction by Weighted Fisher Criterion 
Gene expression profiling has been widely used to study molecular signatures of many diseases and to develop molecular diagnostics for disease prediction. Gene selection, as an important step for improved diagnostics, screens tens of thousands of genes and identifies a small subset that discriminates between disease types. A two-step gene selection method is proposed to identify informative gene subsets for accurate classification of multiclass phenotypes. In the first step, individually discriminatory genes (IDGs) are identified by using one-dimensional weighted Fisher criterion (wFC). In the second step, jointly discriminatory genes (JDGs) are selected by sequential search methods, based on their joint class separability measured by multidimensional weighted Fisher criterion (wFC). The performance of the selected gene subsets for multiclass prediction is evaluated by artificial neural networks (ANNs) and/or support vector machines (SVMs). By applying the proposed IDG/JDG approach to two microarray studies, that is, small round blue cell tumors (SRBCTs) and muscular dystrophies (MDs), we successfully identified a much smaller yet efficient set of JDGs for diagnosing SRBCTs and MDs with high prediction accuracies (96.9% for SRBCTs and 92.3% for MDs, resp.). These experimental results demonstrated that the two-step gene selection method is able to identify a subset of highly discriminative genes for improved multiclass prediction.
PMCID: PMC3171347  PMID: 17713593
16.  Pathway activity inference for multiclass disease classification through a mathematical programming optimisation framework 
BMC Bioinformatics  2014;15(1):390.
Applying machine learning methods on microarray gene expression profiles for disease classification problems is a popular method to derive biomarkers, i.e. sets of genes that can predict disease state or outcome. Traditional approaches where expression of genes were treated independently suffer from low prediction accuracy and difficulty of biological interpretation. Current research efforts focus on integrating information on protein interactions through biochemical pathway datasets with expression profiles to propose pathway-based classifiers that can enhance disease diagnosis and prognosis. As most of the pathway activity inference methods in literature are either unsupervised or applied on two-class datasets, there is good scope to address such limitations by proposing novel methodologies.
A supervised multiclass pathway activity inference method using optimisation techniques is reported. For each pathway expression dataset, patterns of its constituent genes are summarised into one composite feature, termed pathway activity, and a novel mathematical programming model is proposed to infer this feature as a weighted linear summation of expression of its constituent genes. Gene weights are determined by the optimisation model, in a way that the resulting pathway activity has the optimal discriminative power with regards to disease phenotypes. Classification is then performed on the resulting low-dimensional pathway activity profile.
The model was evaluated through a variety of published gene expression profiles that cover different types of disease. We show that not only does it improve classification accuracy, but it can also perform well in multiclass disease datasets, a limitation of other approaches from the literature. Desirable features of the model include the ability to control the maximum number of genes that may participate in determining pathway activity, which may be pre-specified by the user. Overall, this work highlights the potential of building pathway-based multi-phenotype classifiers for accurate disease diagnosis and prognosis problems.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0390-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4269079  PMID: 25475756
Disease classification; Microarray; Pathway activity; Mathematical programming; Optimisation
17.  Multiclass Cancer Classification by Using Fuzzy Support Vector Machine and Binary Decision Tree With Gene Selection 
We investigate the problems of multiclass cancer classification with gene selection from gene expression data. Two different constructed multiclass classifiers with gene selection are proposed, which are fuzzy support vector machine (FSVM) with gene selection and binary classification tree based on SVM with gene selection. Using F test and recursive feature elimination based on SVM as gene selection methods, binary classification tree based on SVM with F test, binary classification tree based on SVM with recursive feature elimination based on SVM, and FSVM with recursive feature elimination based on SVM are tested in our experiments. To accelerate computation, preselecting the strongest genes is also used. The proposed techniques are applied to analyze breast cancer data, small round blue-cell tumors, and acute leukemia data. Compared to existing multiclass cancer classifiers and binary classification tree based on SVM with F test or binary classification tree based on SVM with recursive feature elimination based on SVM mentioned in this paper, FSVM based on recursive feature elimination based on SVM can find most important genes that affect certain types of cancer with high recognition accuracy.
PMCID: PMC1184049  PMID: 16046822
18.  Support Vector Machine Implementations for Classification & Clustering 
BMC Bioinformatics  2006;7(Suppl 2):S4.
We describe Support Vector Machine (SVM) applications to classification and clustering of channel current data. SVMs are variational-calculus based methods that are constrained to have structural risk minimization (SRM), i.e., they provide noise tolerant solutions for pattern recognition. The SVM approach encapsulates a significant amount of model-fitting information in the choice of its kernel. In work thus far, novel, information-theoretic, kernels have been successfully employed for notably better performance over standard kernels. Currently there are two approaches for implementing multiclass SVMs. One is called external multi-class that arranges several binary classifiers as a decision tree such that they perform a single-class decision making function, with each leaf corresponding to a unique class. The second approach, namely internal-multiclass, involves solving a single optimization problem corresponding to the entire data set (with multiple hyperplanes).
Each SVM approach encapsulates a significant amount of model-fitting information in its choice of kernel. In work thus far, novel, information-theoretic, kernels were successfully employed for notably better performance over standard kernels. Two SVM approaches to multiclass discrimination are described: (1) internal multiclass (with a single optimization), and (2) external multiclass (using an optimized decision tree). We describe benefits of the internal-SVM approach, along with further refinements to the internal-multiclass SVM algorithms that offer significant improvement in training time without sacrificing accuracy. In situations where the data isn't clearly separable, making for poor discrimination, signal clustering is used to provide robust and useful information – to this end, novel, SVM-based clustering methods are also described. As with the classification, there are Internal and External SVM Clustering algorithms, both of which are briefly described.
PMCID: PMC1683575  PMID: 17118147
19.  Multiclass classification of FDG PET scans for the distinction between Parkinson's disease and atypical parkinsonian syndromes☆☆☆ 
NeuroImage : Clinical  2013;2:883-893.
Most available pattern recognition methods in neuroimaging address binary classification problems. Here, we used relevance vector machine (RVM) in combination with booststrap resampling (‘bagging’) for non-hierarchical multiclass classification. The method was tested on 120 cerebral 18fluorodeoxyglucose (FDG) positron emission tomography (PET) scans performed in patients who exhibited parkinsonian clinical features for 3.5 years on average but that were outside the prevailing perception for Parkinson's disease (PD). A radiological diagnosis of PD was suggested for 30 patients at the time of PET imaging. However, at follow-up several years after PET imaging, 42 of them finally received a clinical diagnosis of PD. The remaining 78 APS patients were diagnosed with multiple system atrophy (MSA, N = 31), progressive supranuclear palsy (PSP, N = 26) and corticobasal syndrome (CBS, N = 21), respectively. With respect to this standard of truth, classification sensitivity, specificity, positive and negative predictive values for PD were 93% 83% 75% and 96%, respectively using binary RVM (PD vs. APS) and 90%, 87%, 79% and 94%, respectively, using multiclass RVM (PD vs. MSA vs. PSP vs. CBS). Multiclass RVM achieved 45%, 55% and 62% classification accuracy for, MSA, PSP and CBS, respectively. Finally, a majority confidence ratio was computed for each scan on the basis of class pairs that were the most frequently assigned by RVM. Altogether, the results suggest that automatic multiclass RVM classification of FDG PET scans achieves adequate performance for the early differentiation between PD and APS on the basis of cerebral FDG uptake patterns when the clinical diagnosis is felt uncertain. This approach cannot be recommended yet as an aid for distinction between the three APS classes under consideration.
•Multiclass classification is one of the challenges of computer-aided diagnosis.•This was addressed here using relevance vector machine and bootstrap aggregation.•Performance was tested on FDG-PET scans from 120 parkinsonian patients.•Four diagnostic classes under consideration as defined on average 3.5 years after PET.•Confusion matrices, majority confidence ratio and discriminant maps were computed.
PMCID: PMC3778264  PMID: 24179839
Computer-aided diagnosis; Data mining; Pattern recognition; Boostrap resampling; Bagging; Error-Correcting Output Code; Multiclass classification; Relevance vector machine; FDG PET; Parkinson's disease; Multiple system atrophy; Progressive supranuclear palsy; Corticobasal syndrome
20.  Improvement of classification accuracy in a phase-tagged steady-state visual evoked potential-based brain computer interface using multiclass support vector machine 
Brain computer interface (BCI) is an emerging technology for paralyzed patients to communicate with external environments. Among current BCIs, the steady-state visual evoked potential (SSVEP)-based BCI has drawn great attention due to its characteristics of easy preparation, high information transfer rate (ITR), high accuracy, and low cost. However, electroencephalogram (EEG) signals are electrophysiological responses reflecting the underlying neural activities which are dependent upon subject’s physiological states (e.g., emotion, attention, etc.) and usually variant among different individuals. The development of classification approaches to account for each individual’s difference in SSVEP is needed but was seldom reported.
This paper presents a multiclass support vector machine (SVM)-based classification approach for gaze-target detections in a phase-tagged SSVEP-based BCI. In the training steps, the amplitude and phase features of SSVEP from off-line recordings were used to train a multiclass SVM for each subject. In the on-line application study, effective epochs which contained sufficient SSVEP information of gaze targets were first determined using Kolmogorov-Smirnov (K-S) test, and the amplitude and phase features of effective epochs were subsequently inputted to the multiclass SVM to recognize user’s gaze targets.
The on-line performance using the proposed approach has achieved high accuracy (89.88 ± 4.76%), fast responding time (effective epoch length = 1.13 ± 0.02 s), and the information transfer rate (ITR) was 50.91 ± 8.70 bits/min.
The multiclass SVM-based classification approach has been successfully implemented to improve the classification accuracy in a phase-tagged SSVEP-based BCI. The present study has shown the multiclass SVM can be effectively adapted to each subject’s SSVEPs to discriminate SSVEP phase information from gazing at different gazed targets.
PMCID: PMC3671978  PMID: 23692974
21.  GPCRpred: an SVM-based method for prediction of families and subfamilies of G-protein coupled receptors 
Nucleic Acids Research  2004;32(Web Server issue):W383-W389.
G-protein coupled receptors (GPCRs) belong to one of the largest superfamilies of membrane proteins and are important targets for drug design. In this study, a support vector machine (SVM)-based method, GPCRpred, has been developed for predicting families and subfamilies of GPCRs from the dipeptide composition of proteins. The dataset used in this study for training and testing was obtained from The method classified GPCRs and non-GPCRs with an accuracy of 99.5% when evaluated using 5-fold cross-validation. The method is further able to predict five major classes or families of GPCRs with an overall Matthew's correlation coefficient (MCC) and accuracy of 0.81 and 97.5% respectively. In recognizing the subfamilies of the rhodopsin-like family, the method achieved an average MCC and accuracy of 0.97 and 97.3% respectively. The method achieved overall accuracy of 91.3% and 96.4% at family and subfamily level respectively when evaluated on an independent/blind dataset of 650 GPCRs. A server for recognition and classification of GPCRs based on multiclass SVMs has been set up at We have also suggested subfamilies for 42 sequences which were previously identified as unclassified ClassA GPCRs. The supplementary information is available at
PMCID: PMC441554  PMID: 15215416
22.  Building multiclass classifiers for remote homology detection and fold recognition 
BMC Bioinformatics  2006;7:455.
Protein remote homology detection and fold recognition are central problems in computational biology. Supervised learning algorithms based on support vector machines are currently one of the most effective methods for solving these problems. These methods are primarily used to solve binary classification problems and they have not been extensively used to solve the more general multiclass remote homology prediction and fold recognition problems.
We present a comprehensive evaluation of a number of methods for building SVM-based multiclass classification schemes in the context of the SCOP protein classification. These methods include schemes that directly build an SVM-based multiclass model, schemes that employ a second-level learning approach to combine the predictions generated by a set of binary SVM-based classifiers, and schemes that build and combine binary classifiers for various levels of the SCOP hierarchy beyond those defining the target classes.
Analyzing the performance achieved by the different approaches on four different datasets we show that most of the proposed multiclass SVM-based classification approaches are quite effective in solving the remote homology prediction and fold recognition problems and that the schemes that use predictions from binary models constructed for ancestral categories within the SCOP hierarchy tend to not only lead to lower error rates but also reduce the number of errors in which a superfamily is assigned to an entirely different fold and a fold is predicted as being from a different SCOP class. Our results also show that the limited size of the training data makes it hard to learn complex second-level models, and that models of moderate complexity lead to consistently better results.
PMCID: PMC1635067  PMID: 17042943
23.  A new regularized least squares support vector regression for gene selection 
BMC Bioinformatics  2009;10:44.
Selection of influential genes with microarray data often faces the difficulties of a large number of genes and a relatively small group of subjects. In addition to the curse of dimensionality, many gene selection methods weight the contribution from each individual subject equally. This equal-contribution assumption cannot account for the possible dependence among subjects who associate similarly to the disease, and may restrict the selection of influential genes.
A novel approach to gene selection is proposed based on kernel similarities and kernel weights. We do not assume uniformity for subject contribution. Weights are calculated via regularized least squares support vector regression (RLS-SVR) of class levels on kernel similarities and are used to weight subject contribution. The cumulative sum of weighted expression levels are next ranked to select responsible genes. These procedures also work for multiclass classification. We demonstrate this algorithm on acute leukemia, colon cancer, small, round blue cell tumors of childhood, breast cancer, and lung cancer studies, using kernel Fisher discriminant analysis and support vector machines as classifiers. Other procedures are compared as well.
This approach is easy to implement and fast in computation for both binary and multiclass problems. The gene set provided by the RLS-SVR weight-based approach contains a less number of genes, and achieves a higher accuracy than other procedures.
PMCID: PMC2669483  PMID: 19187562
24.  Deletion of the CaBIG1 Gene Reduces β-1,6-Glucan Synthesis, Filamentation, Adhesion, and Virulence in Candida albicans  
Infection and Immunity  2006;74(4):2373-2381.
The human fungal pathogen Candida albicans is able to change its shape in response to various environmental signals. We analyzed the C. albicans BIG1 homolog, which might be involved in β-1,6-glucan biosynthesis in Saccharomyces cerevisiae. C. albicans BIG1 is a functional homolog of an S. cerevisiae BIG1 gene, because the slow growth of an S. cerevisiae big1 mutant was restored by introduction of C. albicans BIG1. CaBig1p was expressed constitutively in both the yeast and hyphal forms. A specific localization of CaBig1p at the endoplasmic reticulum or plasma membrane similar to the subcellular localization of S. cerevisiae Big1p was observed in yeast form. The content of β-1,6-glucan in the cell wall was decreased in the Cabig1Δ strain in comparison with the wild-type or reconstituted strain. The C. albicans BIG1 disruptant showed reduced filamentation on a solid agar medium and in a liquid medium. The Cabig1Δ mutant showed markedly attenuated virulence in a mouse model of systemic candidiasis. Adherence to human epithelial HeLa cells and fungal burden in kidneys of infected mice were reduced in the Cabig1Δ mutant. Deletion of CaBIG1 abolished hyphal growth and invasiveness in the kidneys of infected mice. Our results indicate that adhesion failure and morphological abnormality contribute to the attenuated virulence of the Cabig1Δ mutant.
PMCID: PMC1418944  PMID: 16552067
25.  Global Discriminative Learning for Higher-Accuracy Computational Gene Prediction 
PLoS Computational Biology  2007;3(3):e54.
Most ab initio gene predictors use a probabilistic sequence model, typically a hidden Markov model, to combine separately trained models of genomic signals and content. By combining separate models of relevant genomic features, such gene predictors can exploit small training sets and incomplete annotations, and can be trained fairly efficiently. However, that type of piecewise training does not optimize prediction accuracy and has difficulty in accounting for statistical dependencies among different parts of the gene model. With genomic information being created at an ever-increasing rate, it is worth investigating alternative approaches in which many different types of genomic evidence, with complex statistical dependencies, can be integrated by discriminative learning to maximize annotation accuracy. Among discriminative learning methods, large-margin classifiers have become prominent because of the success of support vector machines (SVM) in many classification tasks. We describe CRAIG, a new program for ab initio gene prediction based on a conditional random field model with semi-Markov structure that is trained with an online large-margin algorithm related to multiclass SVMs. Our experiments on benchmark vertebrate datasets and on regions from the ENCODE project show significant improvements in prediction accuracy over published gene predictors that use intrinsic features only, particularly at the gene level and on genes with long introns.
Author Summary
We describe a new approach to statistical learning for sequence data that is broadly applicable to computational biology problems and that has experimentally demonstrated advantages over current hidden Markov model (HMM)-based methods for sequence analysis. The methods we describe in this paper, implemented in the CRAIG program, allow researchers to modularly specify and train sequence analysis models that combine a wide range of weakly informative features into globally optimal predictions. Our results for the gene prediction problem show significant improvements over existing ab initio gene predictors on a variety of tests, including the specially challenging ENCODE regions. Such improved predictions, particularly on initial and single exons, could benefit researchers who are seeking more accurate means of recognizing such important features as signal peptides and regulatory regions. More generally, we believe that our method, by combining the structure-describing capabilities of HMMs with the accuracy of margin-based classification methods, provides a general tool for statistical learning in biological sequences that will replace HMMs in any sequence modeling task for which there is annotated training data.
PMCID: PMC1828702  PMID: 17367206

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