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Generally, essential genes identified using shRNA and CRISPR are not always the same, raising questions about the choice between these two screening platforms. To address this, we systematically compared the performance of CRISPR and shRNA to identify essential genes across different gene expression levels in 254 cell lines. As both platforms have a notable false positive rate, to correct this confounding factor, we first developed a graph-based unsupervised machine learning model to predict common essential genes. Furthermore, to maintain the unique characteristics of individual cell lines, we intersect essential genes derived from the biological experiment with the predicted common essential genes. Finally, we employed statistical methods to compare the ability of these two screening platforms to identify essential genes that exhibit differential expression across various cell lines. Our analysis yielded several noteworthy findings: (1) shRNA outperforms CRISPR in the identification of lowly expressed essential genes; (2) both screening methodologies demonstrate strong performance in identifying highly expressed essential genes but with limited overlap, so we suggest using a combination of these two platforms for highly expressed essential genes; (3) notably, we did not observe a single gene that becomes universally essential across all cancer cell lines.

Abstract Processing images with heterogeneous blur remains challenging due to multiple degradation aspects that could affect structural properties. This study proposes a deep learning‐based multi‐scaled generative adversarial network (GAN) with residual image learning to process variant and in‐variant blur. Different scaled images with corresponding gradients are concatenated as a multi‐channel single input for the proposed GAN. Residual‐ and dense‐networks are combined to explore salient features in the bottleneck section while addressing the vanishing gradient problem. A hybrid content loss function with a gradient penalty minimises the error between generated and ground truth images. Due to structure sparsity, the generated output may lose some information that leads to artifacts. Residual image learning with dilation and end‐to‐end training is used to resolve this issue by recovering high‐resolution anatomical details. Three different datasets: GoPro, Köhler, and Lai, with variant and in‐variant blur, are used to perform qualitative and quantitative analyses. Experiments show the proposed method is effective in reducing blur while preserving structural properties compared to multiple preprocessing techniques for image analysis. Moreover, the consistently improved performance over multiple publicly available datasets validates the merits of the proposed method for large data analysis.

With accumulating dysregulated circular RNAs (circRNAs) in pathological processes, the regulatory functions of circRNAs, especially circRNAs as microRNA (miRNA) sponges and their interactions with RNA-binding proteins (RBPs), have been widely validated. However, the collected information on experimentally validated circRNA–disease associations is only preliminary. Therefore, an updated CircR2Disease database providing a comprehensive resource and web tool to clarify the relationships between circRNAs and diseases in diverse species is necessary. Here, we present an updated CircR2Disease v2.0 with the increased number of circRNA–disease associations and novel characteristics. CircR2Disease v2.0 provides more than 5-fold experimentally validated circRNA–disease associations compared to its previous version. This version includes 4201 entries between 3077 circRNAs and 312 disease subtypes. Secondly, the information of circRNA–miRNA, circRNA–miRNA–target, and circRNA–RBP interactions has been manually collected for various diseases. Thirdly, the gene symbols of circRNAs and disease name IDs can be linked with various nomenclature databases. Detailed descriptions such as samples and journals have also been integrated into the updated version. Thus, CircR2Disease v2.0 can serve as a platform for users to systematically investigate the roles of dysregulated circRNAs in various diseases and further explore the posttranscriptional regulatory function in diseases. Finally, we propose a computational method named circDis based on the graph convolutional network (GCN) and gradient boosting decision tree (GBDT) to illustrate the applications of the CircR2Disease v2.0 database. CircR2Disease v2.0 is available at http://bioinfo.snnu.edu.cn/CircR2Disease_v2.0 and https://github.com/bioinforlab/CircR2Disease-v2.0.

Cervical cancer is one of the most common cancers among women. Fortunately, cervical cancer is treatable if it is diagnosed timely and administered appropriately. The death rate of cervical cancer has been greatly reduced since Pap smear test was applied. However, Pap smear test is a time-consuming and error-prone process. Moreover, classifying cervical cells into different categories is clinically meaningful but also challenging in the field of cervical cancer detection. To address these concerns, computer-aided diagnosis systems with deep learning need to be designed to automatically analyze cervical cytology images. In this study, we construct a deep convolutional neural network with feature representations learned via multiple kernels with different sizes to automatically classify cervical cytology images, named DeepCELL. Firstly, we design three different basic modules of DeepCELL to capture feature information via multiple kernels with different sizes. Then, we stack several such basic modules to form the cervical cell classification model. Finally, we perform a series of experiments to evaluate the proposed method on two cervical cytology datasets: Herlev and SIPaKMeD. Our method achieves the accuracy of 95.628%, precision of 95.685%, recall of 95.647% and F-score of 95.636% on SIPaKMeD dataset, which are the highest among all competing methods. Similarly, our method also achieves satisfactory result on Herlev dataset. In summary, extensive experimental results demonstrate that our proposed method has a promising performance in cervical cell image classification.

Abstract Background With the development of the technology of single-cell sequence, revealing homogeneity and heterogeneity between cells has become a new area of computational systems biology research. However, the clustering of cell types becomes more complex with the mutual penetration between different types of cells and the instability of gene expression. One way of overcoming this problem is to group similar, related single cells together by the means of various clustering analysis methods. Although some methods such as spectral clustering can do well in the identification of cell types, they only consider the similarities between cells and ignore the influence of dissimilarities on clustering results. This methodology may limit the performance of most of the conventional clustering algorithms for the identification of clusters, it needs to develop special methods for high-dimensional sparse categorical data. Results Inspired by the phenomenon that same type cells have similar gene expression patterns, but different types of cells evoke dissimilar gene expression patterns, we improve the existing spectral clustering method for clustering single-cell data that is based on both similarities and dissimilarities between cells. The method first measures the similarity/dissimilarity among cells, then constructs the incidence matrix by fusing similarity matrix with dissimilarity matrix, and, finally, uses the eigenvalues of the incidence matrix to perform dimensionality reduction and employs the K-means algorithm in the low dimensional space to achieve clustering. The proposed improved spectral clustering method is compared with the conventional spectral clustering method in recognizing cell types on several real single-cell RNA-seq datasets. Conclusions In summary, we show that adding intercellular dissimilarity can effectively improve accuracy and achieve robustness and that improved spectral clustering method outperforms the traditional spectral clustering method in grouping cells.

To develop standard optical biosensors, the simulation procedure takes a lot of time. For reducing that enormous amount of time and effort, machine learning might be a better solution. Effective indices, core power, total power, and effective area are the most crucial parameters for evaluating optical sensors. In this study, several machine learning (ML) approaches have been applied to predict those parameters while considering the core radius, cladding radius, pitch, analyte, and wavelength as the input vectors. We have utilized least squares (LS), LASSO, Elastic-Net (ENet), and Bayesian ridge regression (BRR) to make a comparative discussion using a balanced dataset obtained with the COMSOL Multiphysics simulation tool. Furthermore, a more extensive analysis of sensitivity, power fraction, and confinement loss is also demonstrated using the predicted and simulated data. The suggested models were also examined in terms of R2-score, mean average error (MAE), and mean squared error (MSE), with all of the models having an R2-score of more than 0.99, and it was also shown that optical biosensors had a design error rate of less than 3%. This research might pave the way for machine learning-based optimization approaches to be used to improve optical biosensors.

Abstract Gastro-esophageal (GE) cancers are one of the major causes of cancer-related death in the world. There is a need for novel biomarkers in the management of GE cancers, to yield predictive response to the available therapies. Our study aims to identify leading genes that are differentially regulated in patients with these cancers. We explored the expression data for those genes whose protein products can be detected in the plasma using the Cancer Genome Atlas to identify leading genes that are differentially regulated in patients with GE cancers. Our work predicted several candidates as potential biomarkers for distinct stages of GE cancers, including previously identified CST1, INHBA, STMN1, whose expression correlated with cancer recurrence, or resistance to adjuvant therapies or surgery. To define the predictive accuracy of these genes as possible biomarkers, we constructed a co-expression network and performed complex network analysis to measure the importance of the genes in terms of a ratio of closeness centrality (RCC). Furthermore, to measure the significance of these differentially regulated genes, we constructed an SVM classifier using machine learning approach and verified these genes by using receiver operator characteristic (ROC) curve as an evaluation metric. The area under the curve measure was > 0.9 for both the overexpressed and downregulated genes suggesting the potential use and reliability of these candidates as biomarkers. In summary, we identified leading differentially expressed genes in GE cancers that can be detected in the plasma proteome. These genes have potential to become diagnostic and therapeutic biomarkers for early detection of cancer, recurrence following surgery and for development of targeted treatment.

Accurate identification of cell types from single-cell RNA sequencing (scRNA-seq) data plays a critical role in a variety of scRNA-seq analysis studies. This task corresponds to solving an unsupervised clustering problem, in which the similarity measurement between cells affects the result significantly. Although many approaches for cell type identification have been proposed, the accuracy still needs to be improved. In this study, we proposed a novel single-cell clustering framework based on similarity learning, called SSRE. SSRE models the relationships between cells based on subspace assumption, and generates a sparse representation of the cell-to-cell similarity. The sparse representation retains the most similar neighbors for each cell. Besides, three classical pairwise similarities are incorporated with a gene selection and enhancement strategy to further improve the effectiveness of SSRE. Tested on ten real scRNA-seq datasets and five simulated datasets, SSRE achieved the superior performance in most cases compared to several state-of-the-art single-cell clustering methods. In addition, SSRE can be extended to visualization of scRNA-seq data and identification of differentially expressed genes. The matlab and python implementations of SSRE are available at https://github.com/CSUBioGroup/SSRE.

The understanding of therapeutic properties is important in drug repositioning and drug discovery. However, chemical or clinical trials are expensive and inefficient to characterize the therapeutic properties of drugs. Recently, artificial intelligence (AI)-assisted algorithms have received extensive attention for discovering the potential therapeutic properties of drugs and speeding up drug development. In this study, we propose a new method based on GraphSAGE and clustering constraints (DRGCC) to investigate the potential therapeutic properties of drugs for drug repositioning. First, the drug structure features and disease symptom features are extracted. Second, the drug–drug interaction network and disease similarity network are constructed according to the drug–gene and disease–gene relationships. Matrix factorization is adopted to extract the clustering features of networks. Then, all the features are fed to the GraphSAGE to predict new associations between existing drugs and diseases. Benchmark comparisons on two different datasets show that our method has reliable predictive performance and outperforms other six competing. We have also conducted case studies on existing drugs and diseases and aimed to predict drugs that may be effective for the novel coronavirus disease 2019 (COVID-19). Among the predicted anti-COVID-19 drug candidates, some drugs are being clinically studied by pharmacologists, and their binding sites to COVID-19-related protein receptors have been found via the molecular docking technology.

Abstract Background DNA methylation in the human genome is acknowledged to be widely associated with biological processes and complex diseases. The Illumina Infinium methylation arrays have been approved as one of the most efficient and universal technologies to investigate the whole genome changes of methylation patterns. As methylation arrays may still be the dominant method for detecting methylation in the anticipated future, it is crucial to develop a reliable workflow to analysis methylation array data. Results In this study, we develop a web service MADA for the whole process of methylation arrays data analysis, which includes the steps of a comprehensive differential methylation analysis pipeline: pre-processing (data loading, quality control, data filtering, and normalization), batch effect correction, differential methylation analysis, and downstream analysis. In addition, we provide the visualization of pre-processing, differentially methylated probes or regions, gene ontology, pathway and cluster analysis results. Moreover, a customization function for users to define their own workflow is also provided in MADA. Conclusions With the analysis of two case studies, we have shown that MADA can complete the whole procedure of methylation array data analysis. MADA provides a graphical user interface and enables users with no computational skills and limited bioinformatics background to carry on complicated methylation array data analysis. The web server is available at: http://120.24.94.89:8080/MADA

Abstract Background Repetitive sequences account for a large proportion of eukaryotes genomes. Identification of repetitive sequences plays a significant role in many applications, such as structural variation detection and genome assembly. Many existing de novo repeat identification pipelines or tools make use of assembly of the high-frequency k-mers to obtain repeats. However, a certain degree of sequence coverage is required for assemblers to get the desired assemblies. On the other hand, assemblers cut the reads into shorter k-mers for assembly, which may destroy the structure of the repetitive regions. For the above reasons, it is difficult to obtain complete and accurate repetitive regions in the genome by using existing tools. Results In this study, we present a new method called RepAHR for de novo repeat identification by assembly of the high-frequency reads. Firstly, RepAHR scans next-generation sequencing (NGS) reads to find the high-frequency k-mers. Secondly, RepAHR filters the high-frequency reads from whole NGS reads according to certain rules based on the high-frequency k-mer. Finally, the high-frequency reads are assembled to generate repeats by using SPAdes, which is considered as an outstanding genome assembler with NGS sequences. Conlusions We test RepAHR on five data sets, and the experimental results show that RepAHR outperforms RepARK and REPdenovo for detecting repeats in terms of N50, reference alignment ratio, coverage ratio of reference, mask ratio of Repbase and some other metrics.

Abstract Background MicroRNAs (miRNAs) are a kind of small noncoding RNA molecules that are direct posttranscriptional regulations of mRNA targets. Studies have indicated that miRNAs play key roles in complex diseases by taking part in many biological processes, such as cell growth, cell death and so on. Therefore, in order to improve the effectiveness of disease diagnosis and treatment, it is appealing to develop advanced computational methods for predicting the essentiality of miRNAs. Result In this study, we propose a method (PESM) to predict the miRNA essentiality based on gradient boosting machines and miRNA sequences. First, PESM extracts the sequence and structural features of miRNAs. Then it uses gradient boosting machines to predict the essentiality of miRNAs. We conduct the 5-fold cross-validation to assess the prediction performance of our method. The area under the receiver operating characteristic curve (AUC), F-measure and accuracy (ACC) are used as the metrics to evaluate the prediction performance. We also compare PESM with other three competing methods which include miES, Gaussian Naive Bayes and Support Vector Machine. Conclusion The results of experiments show that PESM achieves the better prediction performance (AUC: 0.9117, F-measure: 0.8572, ACC: 0.8516) than other three computing methods. In addition, the relative importance of all features also further shows that newly added features can be helpful to improve the prediction performance of methods.

Abstract Background Disease gene prediction is a critical and challenging task. Many computational methods have been developed to predict disease genes, which can reduce the money and time used in the experimental validation. Since proteins (products of genes) usually work together to achieve a specific function, biomolecular networks, such as the protein-protein interaction (PPI) network and gene co-expression networks, are widely used to predict disease genes by analyzing the relationships between known disease genes and other genes in the networks. However, existing methods commonly use a universal static PPI network, which ignore the fact that PPIs are dynamic, and PPIs in various patients should also be different. Results To address these issues, we develop an ensemble algorithm to predict disease genes from clinical sample-based networks (EdgCSN). The algorithm first constructs single sample-based networks for each case sample of the disease under study. Then, these single sample-based networks are merged to several fused networks based on the clustering results of the samples. After that, logistic models are trained with centrality features extracted from the fused networks, and an ensemble strategy is used to predict the finial probability of each gene being disease-associated. EdgCSN is evaluated on breast cancer (BC), thyroid cancer (TC) and Alzheimer’s disease (AD) and obtains AUC values of 0.970, 0.971 and 0.966, respectively, which are much better than the competing algorithms. Subsequent de novo validations also demonstrate the ability of EdgCSN in predicting new disease genes. Conclusions In this study, we propose EdgCSN, which is an ensemble learning algorithm for predicting disease genes with models trained by centrality features extracted from clinical sample-based networks. Results of the leave-one-out cross validation show that our EdgCSN performs much better than the competing algorithms in predicting BC-associated, TC-associated and AD-associated genes. de novo validations also show that EdgCSN is valuable for identifying new disease genes.

Computational drug repositioning aims to identify potential applications of existing drugs for the treatment of diseases for which they were not designed. This approach can considerably accelerate the traditional drug discovery process by decreasing the required time and costs of drug development. Tensor decomposition enables us to integrate multiple drug- and disease-related data to boost the performance of prediction. In this study, a nonnegative tensor decomposition for drug repositioning, NTD-DR, is proposed. In order to capture the hidden information in drug-target, drug-disease, and target-disease networks, NTD-DR uses these pairwise associations to construct a three-dimensional tensor representing drug-target-disease triplet associations and integrates them with similarity information of drugs, targets, and disease to make a prediction. We compare NTD-DR with recent state-of-the-art methods in terms of the area under the receiver operating characteristic (ROC) curve (AUC) and the area under the precision and recall curve (AUPR) and find that our method outperforms competing methods. Moreover, case studies with five diseases also confirm the reliability of predictions made by NTD-DR. Our proposed method identifies more known associations among the top 50 predictions than other methods. In addition, novel associations identified by NTD-DR are validated by literature analyses.

Background: The purpose of this project is to identify prognostic features in resectable pancreatic head adenocarcinoma and use these features to develop a machine learning algorithm that prognosticates survival for patients pursuing pancreaticoduodenectomy. Methods: A retrospective cohort study of 93 patients who underwent a pancreaticoduodenectomy was performed. The patients were analyzed in 2 groups: Group 1 (n = 38) comprised of patients who survived 2 years. After comparing the two groups, 9 categorical features and 2 continuous features (11 total) were selected to be statistically significant (p

In recent years, it has been increasingly clear that long non-coding RNAs (lncRNAs) are able to regulate their target genes at multi-levels, including transcriptional level, translational level, etc and play key regulatory roles in many important biological processes, such as cell differentiation, chromatin remodeling and more. Inferring potential lncRNA-disease associations is essential to reveal the secrets behind diseases, develop novel drugs, and optimize personalized treatments. However, biological experiments to validate lncRNA-disease associations are very time-consuming and costly. Thus, it is critical to develop effective computational models. In this study, we have proposed a method by alternating least squares based on matrix factorization to predict lncRNA-disease associations, referred to as ALSBMF. ALSBMF first decomposes the known lncRNA-disease correlation matrix into two characteristic matrices, then defines the optimization function using disease semantic similarity, lncRNA functional similarity and known lncRNA-disease associations and solves two optimal feature matrices by least squares method. The two optimal feature matrices are finally multiplied to reconstruct the scoring matrix, filling the missing values of the original matrix to predict lncRNA-disease associations. Compared to existing methods, ALSBMF has the same advantages as BPLLDA. It does not require negative samples and can predict associations related to novel lncRNAs or novel diseases. In addition, this study performs leave-one-out cross-validation (LOOCV) and five-fold cross-validation to evaluate the prediction performance of ALSBMF. The AUCs are 0.9501 and 0.9215, respectively, which are better than the existing methods. Furthermore colon cancer, kidney cancer, and liver cancer are selected as case studies. The predicted top three colon cancer, kidney cancer, and liver cancer-related lncRNAs were validated in the latest LncRNADisease database and related literature. In order to test the ability of ALSBMF to predict novel disease-associated lncRNAs and new lncRNA-associated diseases, all known associations of diseases and lncRNAs were eliminated, the predicted top five breast cancer, nasopharyngeal carcinoma cancer-related lncRNAs and top five H19, MALAT1 lncRNA-related cancers were validated in PubMed and dbSNP.

Abstract Background Advanced non-invasive neuroimaging techniques offer new approaches to study functions and structures of human brains. Whole-brain functional networks obtained from resting state functional magnetic resonance imaging has been widely used to study brain diseases like autism spectrum disorder (ASD). Auto-classification of ASD has become an important issue. Existing classification methods for ASD are based on features extracted from the whole-brain functional networks, which may be not discriminant enough for good performance. Methods In this study, we propose a network clustering based feature selection strategy for classifying ASD. In our proposed method, we first apply symmetric non-negative matrix factorization to divide brain networks into four modules. Then we extract features from one of four modules called default mode network (DMN) and use them to train several classifiers for ASD classification. Results The computational experiments show that our proposed method achieves better performances than those trained with features extracted from the whole brain network. Conclusion It is a good strategy to train the classifiers for ASD based on features from the default mode subnetwork.

Abstract Background Essential proteins are crucial for cellular life and thus, identification of essential proteins is an important topic and a challenging problem for researchers. Recently lots of computational approaches have been proposed to handle this problem. However, traditional centrality methods cannot fully represent the topological features of biological networks. In addition, identifying essential proteins is an imbalanced learning problem; but few current shallow machine learning-based methods are designed to handle the imbalanced characteristics. Results We develop DeepEP based on a deep learning framework that uses the node2vec technique, multi-scale convolutional neural networks and a sampling technique to identify essential proteins. In DeepEP, the node2vec technique is applied to automatically learn topological and semantic features for each protein in protein-protein interaction (PPI) network. Gene expression profiles are treated as images and multi-scale convolutional neural networks are applied to extract their patterns. In addition, DeepEP uses a sampling method to alleviate the imbalanced characteristics. The sampling method samples the same number of the majority and minority samples in a training epoch, which is not biased to any class in training process. The experimental results show that DeepEP outperforms traditional centrality methods. Moreover, DeepEP is better than shallow machine learning-based methods. Detailed analyses show that the dense vectors which are generated by node2vec technique contribute a lot to the improved performance. It is clear that the node2vec technique effectively captures the topological and semantic properties of PPI network. The sampling method also improves the performance of identifying essential proteins. Conclusion We demonstrate that DeepEP improves the prediction performance by integrating multiple deep learning techniques and a sampling method. DeepEP is more effective than existing methods.

Abstract Background Chromatin immunoprecipitation sequencing (ChIP-seq) is a technology that combines chromatin immunoprecipitation (ChIP) with next generation of sequencing technology (NGS) to analyze protein interactions with DNA. At present, most ChIP-seq analysis tools adopt the command line, which lacks user-friendly interfaces. Although some web services with graphical interfaces have been developed for ChIP-seq analysis, these sites cannot provide a comprehensive analysis of ChIP-seq from raw data to downstream analysis. Results In this study, we develop a web service for the whole process of ChIP-Seq Analysis (CSA), which covers mapping, quality control, peak calling, and downstream analysis. In addition, CSA provides a customization function for users to define their own workflows. And the visualization of mapping, peak calling, motif finding, and pathway analysis results are also provided in CSA. For the different types of ChIP-seq datasets, CSA can provide the corresponding tool to perform the analysis. Moreover, CSA can detect differences in ChIP signals between ChIP samples and controls to identify absolute binding sites. Conclusions The two case studies demonstrate the effectiveness of CSA, which can complete the whole procedure of ChIP-seq analysis. CSA provides a web interface for users, and implements the visualization of every analysis step. The website of CSA is available at http://CompuBio.csu.edu.cn

Abstract Background Viral infectious diseases are the serious threat for human health. The receptor-binding is the first step for the viral infection of hosts. To more effectively treat human viral infectious diseases, the hidden virus-receptor interactions must be discovered. However, current computational methods for predicting virus-receptor interactions are limited. Result In this study, we propose a new computational method (IILLS) to predict virus-receptor interactions based on Initial Interaction scores method via the neighbors and the Laplacian regularized Least Square algorithm. IILLS integrates the known virus-receptor interactions and amino acid sequences of receptors. The similarity of viruses is calculated by the Gaussian Interaction Profile (GIP) kernel. On the other hand, we also compute the receptor GIP similarity and the receptor sequence similarity. Then the sequence similarity is used as the final similarity of receptors according to the prediction results. The 10-fold cross validation (10CV) and leave one out cross validation (LOOCV) are used to assess the prediction performance of our method. We also compare our method with other three competing methods (BRWH, LapRLS, CMF). Conlusion The experiment results show that IILLS achieves the AUC values of 0.8675 and 0.9061 with the 10-fold cross validation and leave-one-out cross validation (LOOCV), respectively, which illustrates that IILLS is superior to the competing methods. In addition, the case studies also further indicate that the IILLS method is effective for the virus-receptor interaction prediction.

Abstract Background A drug-drug interaction (DDI) is defined as a drug effect modified by another drug, which is very common in treating complex diseases such as cancer. Many studies have evidenced that some DDIs could be an increase or a decrease of the drug effect. However, the adverse DDIs maybe result in severe morbidity and even morality of patients, which also cause some drugs to withdraw from the market. As the multi-drug treatment becomes more and more common, identifying the potential DDIs has become the key issue in drug development and disease treatment. However, traditional biological experimental methods, including in vitro and vivo, are very time-consuming and expensive to validate new DDIs. With the development of high-throughput sequencing technology, many pharmaceutical studies and various bioinformatics data provide unprecedented opportunities to study DDIs. Result In this study, we propose a method to predict new DDIs, namely DDIGIP, which is based on Gaussian Interaction Profile (GIP) kernel on the drug-drug interaction profiles and the Regularized Least Squares (RLS) classifier. In addition, we also use the k-nearest neighbors (KNN) to calculate the initial relational score in the presence of new drugs via the chemical, biological, phenotypic data of drugs. We compare the prediction performance of DDIGIP with other competing methods via the 5-fold cross validation, 10-cross validation and de novo drug validation. Conlusion In 5-fold cross validation and 10-cross validation, DDRGIP method achieves the area under the ROC curve (AUC) of 0.9600 and 0.9636 which are better than state-of-the-art method (L1 Classifier ensemble method) of 0.9570 and 0.9599. Furthermore, for new drugs, the AUC value of DDIGIP in de novo drug validation reaches 0.9262 which also outperforms the other state-of-the-art method (Weighted average ensemble method) of 0.9073. Case studies and these results demonstrate that DDRGIP is an effective method to predict DDIs while being beneficial to drug development and disease treatment.

Abstract Background To infer gene regulatory networks (GRNs) from gene-expression data is still a fundamental and challenging problem in systems biology. Several existing algorithms formulate GRNs inference as a regression problem and obtain the network with an ensemble strategy. Recent studies on data driven dynamic network construction provide us a new perspective to solve the regression problem. Results In this study, we propose a data driven dynamic network construction method to infer gene regulatory network (D3GRN), which transforms the regulatory relationship of each target gene into functional decomposition problem and solves each sub problem by using the Algorithm for Revealing Network Interactions (ARNI). To remedy the limitation of ARNI in constructing networks solely from the unit level, a bootstrapping and area based scoring method is taken to infer the final network. On DREAM4 and DREAM5 benchmark datasets, D3GRN performs competitively with the state-of-the-art algorithms in terms of AUPR. Conclusions We have proposed a novel data driven dynamic network construction method by combining ARNI with bootstrapping and area based scoring strategy. The proposed method performs well on the benchmark datasets, contributing as a competitive method to infer gene regulatory networks in a new perspective.

Abstract Background Detecting protein complex in protein-protein interaction (PPI) networks plays a significant part in bioinformatics field. It enables us to obtain the better understanding for the structures and characteristics of biological systems. Methods In this study, we present a novel algorithm, named Improved Flower Pollination Algorithm (IFPA), to identify protein complexes in multi-relation reconstructed dynamic PPI networks. Specifically, we first introduce a concept called co-essentiality, which considers the protein essentiality to search essential interactions, Then, we devise the multi-relation reconstructed dynamic PPI networks (MRDPNs) and discover the potential cores of protein complexes in MRDPNs. Finally, an IFPA algorithm is put forward based on the flower pollination mechanism to generate protein complexes by simulating the process of pollen find the optimal pollination plants, namely, attach the peripheries to the corresponding cores. Results The experimental results on three different datasets (DIP, MIPS and Krogan) show that our IFPA algorithm is more superior to some representative methods in the prediction of protein complexes. Conclusions Our proposed IFPA algorithm is powerful in protein complex detection by building multi-relation reconstructed dynamic protein networks and using improved flower pollination algorithm. The experimental results indicate that our IFPA algorithm can obtain better performance than other methods.

Lung cancer is a kind of cancer with high morbidity and mortality which is associated with various gene mutations. Individualized targeted-drug therapy has become the optimized treatment of lung cancer, especially benefit for patients who are not qualified for lung lobectomy. It is crucial to accurately identify mutant genes within tumor region from stained pathological slice. Therefore, we mainly focus on identifying mutant gene of lung cancer by analyzing the pathological images. In this study, we have proposed a method by identifying gene mutations in lung cancer with histopathological stained image and deep learning to predict target-drug therapy, referred to as DeepIMLH. The DeepIMLH algorithm first downloaded 180 hematoxylin-eosin staining (H&E) images of lung cancer from the Cancer Gene Atlas (TCGA). Then deep convolution Gaussian mixture model (DCGMM) was used to perform color normalization. Convolutional neural network (CNN) and residual network (Res-Net) were used to identifying mutated gene from H&E stained imaging and achieved good accuracy. It demonstrated that our method can be used to choose targeted-drug therapy which might be applied to clinical practice. More studies should be conducted though.

MicroRNAs (miRNAs) are small single-stranded noncoding RNAs that have shown to play a critical role in regulating gene expression. In past decades, cumulative experimental studies have verified that miRNAs are implicated in many complex human diseases and might be potential biomarkers for various types of diseases. With the increase of miRNA-related data and the development of analysis methodologies, some computational methods have been developed for predicting miRNA-disease associations, which are more economical and time-saving than traditional biological experimental approaches. In this study, a novel computational model, deep belief network (DBN)-based matrix factorization (DBN-MF), is proposed for miRNA-disease association prediction. First, the raw interaction features of miRNAs and diseases were obtained from the miRNA-disease adjacent matrix. Second, 2 DBNs were used for unsupervised learning of the features of miRNAs and diseases, respectively, based on the raw interaction features. Finally, a classifier consisting of 2 DBNs and a cosine score function was trained with the initial weights of DBN from the last step. During the training, the miRNA-disease adjacent matrix was factorized into 2 feature matrices for the representation of miRNAs and diseases, and the final prediction label was obtained according to the feature matrices. The experimental results show that the proposed model outperforms the state-of-the-art approaches in miRNA-disease association prediction based on the 10-fold cross-validation. Besides, the effectiveness of our model was further demonstrated by case studies.

Autism spectrum disorder (ASD) is a neuro dysfunction which causes the repetitive behavior and social instability of patients. Diagnosing ASD has been of great interest. However, due to the lack of discriminate differences between neuroimages of healthy persons and ASD patients, there has been no powerful diagnosis approach. In this study, we have designed brain network-based features for the diagnosis of ASD. Specifically, we have used the 264 regions based parcellation scheme to construct a brain network from a brain functional magnetic resonance imaging (fMRI). Then we have defined 264 raw brain features by the 264 eigenvalues of the Laplacian matrix of the brain network and another three features by network centralities. By applying a feature selection algorithm, we have obtained 64 discriminate features. Furthermore, we have trained several machine learning models for diagnosing ASD with our obtained features on ABIDE (Autism Brain Imaging Data Exchange) dataset. With our derived features, the linear discriminant analysis has achieved the classification accuracy of 77.7%, which is better than the state-of-the-art results.

Identifying driver genes that contribute to cancer progression from numerous passenger genes, although a central goal, is a major challenge. The protein–protein interaction network provides convenient and reasonable assistance for driver gene discovery. Random walk–based methods have been widely used to prioritize nodes in social or biological networks. However, most studies select the next arriving node uniformly from the random walker's neighbors. Few consider transiting preference according to the degree of random walker's neighbors. In this study, based on the random walk method, we propose a novel approach named Driver_IRW (Driver genes discovery with Improved Random Walk method), to prioritize cancer genes in cancer-related network. The key idea of Driver_IRW is to assign different transition probabilities for different edges of a constructed cancer-related network in accordance with the degree of the nodes' neighbors. Furthermore, the global centrality (here is betweenness centrality) and Katz feedback centrality are incorporated into the framework to evaluate the probability to walk to the seed nodes. Experimental results on four cancer types indicate that Driver_IRW performs more efficiently than some previously published methods for uncovering known cancer-related genes. In conclusion, our method can aid in prioritizing cancer-related genes and complement traditional frequency and network-based methods.

Since similar complex diseases are much alike in clinical symptoms, patients are easily misdiagnosed and mistreated. It is crucial to accurately predict the disease status and identify markers with high sensitivity and specificity for classifying similar complex diseases. Many approaches incorporating network information have been put forward to predict outcomes, but they are not robust because of their low reproducibility. Several pathway-based methods are robust and functionally interpretable. However, few methods characterize the disease-specific states of single samples from the perspective of pathways. In this study, we propose a novel framework, Pathway Activation for Single Sample (PASS), which utilizes the pathway information in a single sample way to better recognize the differences between two similar complex diseases. PASS can mainly be divided into two parts: for each pathway, the extent of perturbation of edges and the statistic difference of genes caused by a single disease sample are quantified; then, a novel method, named as an AUCpath, is applied to evaluate the pathway activation for single samples from the perspective of genes and their interactions. We have applied PASS to two main types of inflammatory bowel disease (IBD) and widely verified the characteristics of PASS. For a new patient, PASS features can be used as the indicators or potential pathway biomarkers to precisely diagnose complex diseases, discover significant features with interpretability and explore changes in the biological mechanisms of diseases.

Abstract Background Many evidences have demonstrated that circRNAs (circular RNA) play important roles in controlling gene expression of human, mouse and nematode. More importantly, circRNAs are also involved in many diseases through fine tuning of post-transcriptional gene expression by sequestering the miRNAs which associate with diseases. Therefore, identifying the circRNA-disease associations is very appealing to comprehensively understand the mechanism, treatment and diagnose of diseases, yet challenging. As the complex mechanism between circRNAs and diseases, wet-lab experiments are expensive and time-consuming to discover novel circRNA-disease associations. Therefore, it is of dire need to employ the computational methods to discover novel circRNA-disease associations. Result In this study, we develop a method (DWNN-RLS) to predict circRNA-disease associations based on Regularized Least Squares of Kronecker product kernel. The similarity of circRNAs is computed from the Gaussian Interaction Profile(GIP) based on known circRNA-disease associations. In addition, the similarity of diseases is integrated by the mean of GIP similarity and sematic similarity which is computed by the direct acyclic graph (DAG) representation of diseases. The kernels of circRNA-disease pairs are constructed from the Kronecker product of the kernels of circRNAs and diseases. DWNN (decreasing weight k-nearest neighbor) method is adopted to calculate the initial relational score for new circRNAs and diseases. The Kronecker product kernel based regularised least squares approach is used to predict new circRNA-disease associations. We adopt 5-fold cross validation (5CV), 10-fold cross validation (10CV) and leave one out cross validation (LOOCV) to assess the prediction performance of our method, and compare it with other six competing methods (RLS-avg, RLS-Kron, NetLapRLS, KATZ, NBI, WP). Conlusion The experiment results show that DWNN-RLS reaches the AUC values of 0.8854, 0.9205 and 0.9701 in 5CV, 10CV and LOOCV, respectively, which illustrates that DWNN-RLS is superior to the competing methods RLS-avg, RLS-Kron, NetLapRLS, KATZ, NBI, WP. In addition, case studies also show that DWNN-RLS is an effective method to predict new circRNA-disease associations.

Abstract Background Identifying protein complexes plays an important role for understanding cellular organization and functional mechanisms. As plenty of evidences have indicated that dense sub-networks in dynamic protein-protein interaction network (DPIN) usually correspond to protein complexes, identifying protein complexes is formulated as density-based clustering. Methods In this paper, a new approach named iOPTICS-GSO is developed, which is the improved Ordering Points to Identify the Clustering Structure (OPTICS) algorithm with Glowworm swarm optimization algorithm (GSO) to optimize the parameters in OPTICS when finding dense sub-networks. In our iOPTICS-GSO, the concept of core node is redefined and the Euclidean distance in OPTICS is replaced with the improved similarity between the nodes in the PPI network according to their interaction strength, and dense sub-networks are considered as protein complexes. Results The experiment results have shown that our iOPTICS-GSO outperforms of algorithms such as DBSCAN, CFinder, MCODE, CMC, COACH, ClusterOne MCL and OPTICS_PSO in terms of f-measure and p-value on four DPINs, which are from the DIP, Krogan, MIPS and Gavin datasets. In addition, our predicted protein complexes have a small p-value and thus are highly likely to be true protein complexes. Conclusion The proposed iOPTICS-GSO gains optimal clustering results by adopting GSO algorithm to optimize the parameters in OPTICS, and the result on four datasets shows superior performance. What’s more, the results provided clues for biologists to verify and find new protein complexes.

Abstract Background Methylation is a common modification of DNA. It has been a very important and hot topic to study the correlation between methylation and diseases in medical science. Because of the special process with bisulfite treatment, traditional mapping tools do not work well with such methylation experimental reads. Traditional aligners are not designed for mapping bisulfite-treated reads, where the un-methylated ‘C’s are converted to ‘T’s. Results In this paper, we develop a reliable and visual tool, named VAliBS, for mapping bisulfate sequences to a genome reference. VAliBS works well even on large scale data or high noise data. By comparing with other state-of-the-art tools (BisMark, BSMAP, BS-Seeker2), VAliBS can improve the accuracy of bisulfite mapping. Moreover, VAliBS is a visual tool which makes its operations more easily and the alignment results are shown with colored marks which makes it easier to be read. VAliBS provides fast and accurate mapping of bisulfite-converted reads, and a friendly window system to visualize the detail of mapping of each read. Conclusions VAliBS works well on both simulated data and real data. It can be useful in DNA methylation research. VALiBS implements an X-Window user interface where the methylation positions are visual and the operations are friendly.

Schizophrenia (SZ) is a functional mental disorder that seriously affects the social life of patients. Therefore, accurate diagnosis of SZ has raised extensive attention of researchers. At present, study of brain network based on resting-state functional magnetic resonance imaging (rs-fMRI) has provided promising results for SZ identification by studying functional network alteration. However, previous studies based on brain network analysis are not very effective for SZ identification. Therefore, we propose an improved SZ identification method using multi-view graph measures of functional brain networks. Firstly, we construct an individual functional connectivity network based on Brainnetome atlas for each subject. Then, multi-view graph measures are calculated by the brain network analysis method as feature representations. Next, in order to consider the relationships between measures within the same brain region in feature selection, multi-view measures are grouped according to the corresponding regions and Sparse Group Lasso is applied to identify discriminative features based on this feature grouping structure. Finally, a support vector machine (SVM) classifier is employed to perform SZ identification task. To evaluate our proposed method, computational experiments are conducted on 145 subjects (71 schizophrenic patients and 74 healthy controls) using a leave-one-out cross-validation (LOOCV) scheme. The results show that our proposed method can obtain an accuracy of 93.10% for SZ identification. By comparison, our method is more effective for SZ identification than some existing methods.

With the generation of a large amount of sequencing data, different assemblers have emerged to perform de novo genome assembly. As a single strategy is hard to fit various biases of datasets, none of these tools outperforms the others on all species. The process of assembly reconciliation is to merge multiple assemblies and generate a high-quality consensus assembly. Several assembly reconciliation tools have been proposed. However, the existing reconciliation tools cannot produce a merged assembly which has better contiguity and contains less errors simultaneously, and the results of these tools usually depend on the ranking of input assemblies. In this study, we propose a novel assembly reconciliation tool MAC, which merges assemblies by using the adjacency algebraic model and classification. In order to solve the problem of uneven sequencing depth and sequencing errors, MAC identifies consensus blocks between contig sets to construct an adjacency graph. To solve the problem of repetitive region, MAC employs classification to optimize the adjacency algebraic model. What’s more, MAC designs an overall scoring function to solve the problem of unknown ranking of input assembly sets. The experimental results from four species of GAGE-B demonstrate that MAC outperforms other assembly reconciliation tools.

Identification of potential drug-associated indications is critical for either approved or novel drugs in drug repositioning. Current computational methods based on drug similarity and disease similarity have been developed to predict drug-disease associations. When more reliable drug- or disease-related information becomes available and is integrated, the prediction precision can be continuously improved. However, it is a challenging problem to effectively incorporate multiple types of prior information, representing different characteristics of drugs and diseases, to identify promising drug-disease associations. In this study, we propose an overlap matrix completion (OMC) for bilayer networks (OMC2) and tri-layer networks (OMC3) to predict potential drug-associated indications, respectively. OMC is able to efficiently exploit the underlying low-rank structures of the drug-disease association matrices. In OMC2, first of all, we construct one bilayer network from drug-side aspect and one from disease-side aspect, and then obtain their corresponding block adjacency matrices. We then propose the OMC2 algorithm to fill out the values of the missing entries in these two adjacency matrices, and predict the scores of unknown drug-disease pairs. Moreover, we further extend OMC2 to OMC3 to handle tri-layer networks. Computational experiments on various datasets indicate that our OMC methods can effectively predict the potential drug-disease associations. Compared with the other state-of-the-art approaches, our methods yield higher prediction accuracy in 10-fold cross-validation and de novo experiments. In addition, case studies also confirm the effectiveness of our methods in identifying promising indications for existing drugs in practical applications.

Complex diseases are known to be associated with disease genes. Uncovering disease-gene associations is critical for diagnosis, treatment, and prevention of diseases. Computational algorithms which effectively predict candidate disease-gene associations prior to experimental proof can greatly reduce the associated cost and time. Most existing methods are disease-specific which can only predict genes associated with a specific disease at a time. Similarities among diseases are not used during the prediction. Meanwhile, most methods predict new disease genes based on known associations, making them unable to predict disease genes for diseases without known associated genes.In this study, a manifold learning-based method is proposed for predicting disease-gene associations by assuming that the geodesic distance between any disease and its associated genes should be shorter than that of other non-associated disease-gene pairs. The model maps the diseases and genes into a lower dimensional manifold based on the known disease-gene associations, disease similarity and gene similarity to predict new associations in terms of the geodesic distance between disease-gene pairs. In the 3-fold cross-validation experiments, our method achieves scores of 0.882 and 0.854 in terms of the area under of the receiver operating characteristic (ROC) curve (AUC) for diseases with more than one known associated genes and diseases with only one known associated gene, respectively. Further de novo studies on Lung Cancer and Bladder Cancer also show that our model is capable of identifying new disease-gene associations.

With the advances in high-throughput technologies, millions of somatic mutations have been reported in the past decade. Identifying driver genes with oncogenic mutations from these data is a critical and challenging problem. Many computational methods have been proposed to predict driver genes. Among them, machine learning-based methods usually train a classifier with representations that concatenate various types of features extracted from different kinds of data. Although successful, simply concatenating different types of features may not be the best way to fuse these data. We notice that a few types of data characterize the similarities of genes, to better integrate them with other data and improve the accuracy of driver gene prediction, in this study, a deep learning-based method (deepDriver) is proposed by performing convolution on mutation-based features of genes and their neighbors in the similarity networks. The method allows the convolutional neural network to learn information within mutation data and similarity networks simultaneously, which enhances the prediction of driver genes. deepDriver achieves AUC scores of 0.984 and 0.976 on breast cancer and colorectal cancer, which are superior to the competing algorithms. Further evaluations of the top 10 predictions also demonstrate that deepDriver is valuable for predicting new driver genes.

Circular RNAs (circRNAs) are extensively expressed in cells and tissues, and play crucial roles in human diseases and biological processes. Recent studies have reported that circRNAs could function as RNA binding protein (RBP) sponges, meanwhile RBPs can also be involved in back-splicing. The interaction with RBPs is also considered an important factor for investigating the function of circRNAs. Hence, it is necessary to understand the interaction mechanisms of circRNAs and RBPs, especially in human cancers. Here, we present a novel method based on deep learning to identify cancer-specific circRNA−RBP binding sites (CSCRSites), only using the nucleotide sequences as the input. In CSCRSites, an architecture with multiple convolution layers is utilized to detect the features of the raw circRNA sequence fragments, and further identify the binding sites through a fully connected layer with the softmax output. The experimental results show that CSCRSites outperform the conventional machine learning classifiers and some representative deep learning methods on the benchmark data. In addition, the features learnt by CSCRSites are converted to sequence motifs, some of which can match to human known RNA motifs involved in human diseases, especially cancer. Therefore, as a deep learning-based tool, CSCRSites could significantly contribute to the function analysis of cancer-associated circRNAs.

It is well known that drug discovery for complex diseases via biological experiments is a time-consuming and expensive process. Alternatively, the computational methods provide a low-cost and high-efficiency way for predicting drug-target interactions (DTIs) from biomolecular networks. However, the current computational methods mainly deal with DTI predictions of known drugs; there are few methods for large-scale prediction of failed drugs and new chemical entities that are currently stored in some biological databases may be effective for other diseases compared with their originally targeted diseases. In this study, we propose a method (called SDTRLS) which predicts DTIs through RLS-Kron model with chemical substructure similarity fusion and Gaussian Interaction Profile (GIP) kernels. SDTRLS can be an effective predictor for targets of old drugs, failed drugs, and new chemical entities from large-scale biomolecular network databases. Our computational experiments show that SDTRLS outperforms the state-of-the-art SDTNBI method; specifically, in the G protein-coupled receptors (GPCRs) external validation, the maximum and the average AUC values of SDTRLS are 0.842 and 0.826, respectively, which are superior to those of SDTNBI, which are 0.797 and 0.766, respectively. This study provides an important basis for new drug development and drug repositioning based on biomolecular networks.

Protein complexes play a critical role in understanding the biological processes and the functions of cellular mechanisms. Most existing protein complex detection algorithms cannot reflect dynamics of protein complexes. In this paper, a novel algorithm named Improved Cuckoo Search Clustering (ICSC) algorithm is proposed to detect protein complexes in weighted dynamic protein-protein interaction (PPI) networks. First, we constructed weighted dynamic PPI networks and detected protein complex cores in each dynamic subnetwork. Then, ICSC algorithm was used to cluster the protein attachments to the cores. The experimental results on both DIP dataset and Krogan dataset demonstrated that ICSC algorithm is more effective in identifying protein complexes than other competing methods.

It is well known that most brain disorders are complex diseases, such as Alzheimer’s disease (AD) and schizophrenia (SCZ). In general, brain regions and their interactions can be modeled as complex brain network, which describe highly efficient information transmission in a brain. Therefore, complex brain network analysis plays an important role in the study of complex brain diseases. With the development of noninvasive neuroimaging and electrophysiological techniques, experimental data can be produced for constructing complex brain networks. In recent years, researchers have found that brain networks constructed by using neuroimaging data and electrophysiological data have many important topological properties, such as small-world property, modularity, and rich club. More importantly, many brain disorders have been found to be associated with the abnormal topological structures of brain networks. These findings provide not only a new perspective to explore the pathological mechanisms of brain disorders, but also guidance for early diagnosis and treatment of brain disorders. The purpose of this survey is to provide a comprehensive overview for complex brain network analysis and its applications to brain disorders.

Clustering periodically expressed genes from their time-course expression data could help understand the molecular mechanism of those biological processes. In this paper, we propose a nonlinear model-based clustering method for periodically expressed gene profiles. As periodically expressed genes are associated with periodic biological processes, the proposed method naturally assumes that a periodically expressed gene dataset is generated by a number of periodical processes. Each periodical process is modelled by a linear combination of trigonometric sine and cosine functions in time plus a Gaussian noise term. A two stage method is proposed to estimate the model parameter, and a relocation-iteration algorithm is employed to assign each gene to an appropriate cluster. A bootstrapping method and an average adjusted Rand index (AARI) are employed to measure the quality of clustering. One synthetic dataset and two biological datasets were employed to evaluate the performance of the proposed method. The results show that our method allows the better quality clustering than other clustering methods (e.g., k-means) for periodically expressed gene data, and thus it is an effective cluster analysis method for periodically expressed gene data.

Protein essentiality is fundamental to comprehend the function and evolution of genes. The prediction of protein essentiality is pivotal in identifying disease genes and potential drug targets. Since the experimental methods need many investments in time and funds, it is of great value to predict protein essentiality with high accuracy using computational methods. In this study, we present a novel feature selection named Elite Search mechanism-based Flower Pollination Algorithm (ESFPA) to determine protein essentiality. Unlike other protein essentiality prediction methods, ESFPA uses an improved swarm intelligence–based algorithm for feature selection and selects optimal features for protein essentiality prediction. The first step is to collect numerous features with the highly predictive characteristics of essentiality. The second step is to develop a feature selection strategy based on a swarm intelligence algorithm to obtain the optimal feature subset. Furthermore, an elite search mechanism is adopted to further improve the quality of feature subset. Subsequently a hybrid classifier is applied to evaluate the essentiality for each protein. Finally, the experimental results show that our method is competitive to some well-known feature selection methods. The proposed method aims to provide a new perspective for protein essentiality determination.

Essential proteins are indispensable for living organisms to maintain life activities and play important roles in the studies of pathology, synthetic biology, and drug design. Therefore, besides experiment methods, many computational methods are proposed to identify essential proteins. Based on the centrality-lethality rule, various centrality methods are employed to predict essential proteins in a Protein-protein Interaction Network (PIN). However, neglecting the temporal and spatial features of protein-protein interactions, the centrality scores calculated by centrality methods are not effective enough for measuring the essentiality of proteins in a PIN. Moreover, many methods, which overfit with the features of essential proteins for one species, may perform poor for other species. In this paper, we demonstrate that the centrality-lethality rule also exists in Protein Subcellular Localization Interaction Networks (PSLINs). To do this, a method based on Localization Specificity for Essential protein Detection (LSED), was proposed, which can be combined with any centrality method for calculating the improved centrality scores by taking into consideration PSLINs in which proteins play their roles. In this study, LSED was combined with eight centrality methods separately to calculate Localization-specific Centrality Scores (LCSs) for proteins based on the PSLINs of four species (Saccharomyces cerevisiae, Homo sapiens, Mus musculus and Drosophila melanogaster). Compared to the proteins with high centrality scores measured from the global PINs, more proteins with high LCSs measured from PSLINs are essential. It indicates that proteins with high LCSs measured from PSLINs are more likely to be essential and the performance of centrality methods can be improved by LSED. Furthermore, LSED provides a wide applicable prediction model to identify essential proteins for different species.

Microarray technology has produced a huge body of time-course gene expression data and will continue to produce more. Such gene expression data has been proved useful in genomic disease diagnosis and drug design. The challenge is how to uncover useful information from such data by proper analysis methods such as significance analysis and clustering analysis. Many statistic-based significance analysis methods and distance/correlation-based clustering analysis methods have been applied to time-course expression data. However, these techniques are unable to account for the dynamics of such data. It is the dynamics that characterizes such data and that should be considered in analysis of such data. In this paper, we employ a nonlinear model to analyse time-course gene expression data. We firstly develop an efficient method for estimating the parameters in the nonlinear model. Then we utilize this model to perform the significance analysis of individually differentially expressed genes and clustering analysis of a set of gene expression profiles. The verification with two synthetic datasets shows that our developed significance analysis method and cluster analysis method outperform some existing methods. The application to one real-life biological dataset illustrates that the analysis results of our developed methods are in agreement with the existing results.