NN-RNALoc: Neural network-based model for prediction of mRNA sub-cellular localization using distance-based sub-sequence profiles.

The localization of messenger RNAs (mRNAs) is a frequently observed phenomenon and a crucial aspect of gene expression regulation. It is also a mechanism for targeting proteins to a specific cellular region. Moreover, prior research and studies have shown the significance of intracellular RNA positioning during embryonic and neural dendrite formation. Incorrect RNA localization, which can be caused by a variety of factors, such as mutations in trans-regulatory elements, has been linked to the development of certain neuromuscular diseases and cancer. In this study, we introduced NN-RNALoc, a neural network-based method for predicting the cellular location of mRNA using novel features extracted from mRNA sequence data and protein interaction patterns. In fact, we developed a distance-based subsequence profile for RNA sequence representation that is more memory and time-efficient than well-known k-mer sequence representation. Combining protein-protein interaction data, which is essential for numerous biological processes, with our novel distance-based subsequence profiles of mRNA sequences produces more accurate features. On two benchmark datasets, CeFra-Seq and RNALocate, the performance of NN-RNALoc is compared to powerful predictive models proposed in previous works (mRNALoc, RNATracker, mLoc-mRNA, DM3Loc, iLoc-mRNA, and EL-RMLocNet), and a ground neural (DNN5-mer) network. Compared to the previous methods, NN-RNALoc significantly reduces computation time and also outperforms them in terms of accuracy. This study's source code and datasets are freely accessible at https://github.com/NeginBabaiha/NN-RNALoc.

Removing the association of random gene sets and survival time in cancers with positive random bias using fixed-point gene set.

Cancer research aims to identify genes that cause or control disease progression. Although a wide range of gene sets have been published, they are usually in poor agreement with one another. Furthermore, recent findings from a gene-expression cohort of different cancer types, known as positive random bias, showed that sets of genes chosen randomly are significantly associated with survival time much higher than expected. In this study, we propose a method based on Brouwer's fixed-point theorem that employs significantly survival-associated random gene sets and reveals a small fixed-point gene set for cancers with a positive random bias property. These sets significantly correspond to cancer-related pathways with biological relevance for the progression and metastasis of the cancer types they represent. Our findings show that our proposed significant gene sets are biologically related to each cancer type available in the cancer genome atlas with the positive random bias property, and by using these sets, positive random bias is significantly more reduced in comparison with state-of-the-art methods in this field. The random bias property is removed in 8 of these 17 cancer types, and the number of random sets of genes associated with survival time is significantly reduced in the remaining 9 cancers.

wpLogicNet: logic gate and structure inference in gene regulatory networks.

MOTIVATION: The gene regulatory process resembles a logic system in which a target gene is regulated by a logic gate among its regulators. While various computational techniques are developed for a gene regulatory network (GRN) reconstruction, the study of logical relationships has received little attention. Here, we propose a novel tool called wpLogicNet that simultaneously infers both the directed GRN structures and logic gates among genes or transcription factors (TFs) that regulate their target genes, based on continuous steady-state gene expressions. RESULTS: wpLogicNet proposes a framework to infer the logic gates among any number of regulators, with a low time-complexity. This distinguishes wpLogicNet from the existing logic-based models that are limited to inferring the gate between two genes or TFs. Our method applies a Bayesian mixture model to estimate the likelihood of the target gene profile and to infer the logic gate a posteriori. Furthermore, in structure-aware mode, wpLogicNet reconstructs the logic gates in TF-gene or gene-gene interaction networks with known structures. The predicted logic gates are validated on simulated datasets of TF-gene interaction networks from Escherichia coli. For the directed-edge inference, the method is validated on datasets from E.coli and DREAM project. The results show that compared to other well-known methods, wpLogicNet is more precise in reconstructing the network and logical relationships among genes. AVAILABILITY AND IMPLEMENTATION: The datasets and R package of wpLogicNet are available in the github repository, https://github.com/CompBioIPM/wpLogicNet. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Using informative features in machine learning based method for COVID-19 drug repurposing.

Coronavirus disease 2019 (COVID-19) is caused by a novel virus named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This virus induced a large number of deaths and millions of confirmed cases worldwide, creating a serious danger to public health. However, there are no specific therapies or drugs available for COVID-19 treatment. While new drug discovery is a long process, repurposing available drugs for COVID-19 can help recognize treatments with known clinical profiles. Computational drug repurposing methods can reduce the cost, time, and risk of drug toxicity. In this work, we build a graph as a COVID-19 related biological network. This network is related to virus targets or their associated biological processes. We select essential proteins in the constructed biological network that lead to a major disruption in the network. Our method from these essential proteins chooses 93 proteins related to COVID-19 pathology. Then, we propose multiple informative features based on drug-target and protein-protein interaction information. Through these informative features, we find five appropriate clusters of drugs that contain some candidates as potential COVID-19 treatments. To evaluate our results, we provide statistical and clinical evidence for our candidate drugs. From our proposed candidate drugs, 80% of them were studied in other studies and clinical trials.

A neural network-based method for polypharmacy side effects prediction.

BACKGROUND: Polypharmacy is a type of treatment that involves the concurrent use of multiple medications. Drugs may interact when they are used simultaneously. So, understanding and mitigating polypharmacy side effects are critical for patient safety and health. Since the known polypharmacy side effects are rare and they are not detected in clinical trials, computational methods are developed to model polypharmacy side effects. RESULTS: We propose a neural network-based method for polypharmacy side effects prediction (NNPS) by using novel feature vectors based on mono side effects, and drug-protein interaction information. The proposed method is fast and efficient which allows the investigation of large numbers of polypharmacy side effects. Our novelty is defining new feature vectors for drugs and combining them with a neural network architecture to apply for the context of polypharmacy side effects prediction. We compare NNPS on a benchmark dataset to predict 964 polypharmacy side effects against 5 well-established methods and show that NNPS achieves better results than the results of all 5 methods in terms of accuracy, complexity, and running time speed. NNPS outperforms about 9.2% in Area Under the Receiver-Operating Characteristic, 12.8% in Area Under the Precision-Recall Curve, 8.6% in F-score, 10.3% in Accuracy, and 18.7% in Matthews Correlation Coefficient with 5-fold cross-validation against the best algorithm among other well-established methods (Decagon method). Also, the running time of the Decagon method which is 15 days for one fold of cross-validation is reduced to 8 h by the NNPS method. CONCLUSIONS: The performance of NNPS is benchmarked against 5 well-known methods, Decagon, Concatenated drug features, Deep Walk, DEDICOM, and RESCAL, for 964 polypharmacy side effects. We adopt the 5-fold cross-validation for 50 iterations and use the average of the results to assess the performance of the NNPS method. The evaluation of the NNPS against five well-known methods, in terms of accuracy, complexity, and running time speed shows the performance of the presented method for an essential and challenging problem in pharmacology. Datasets and code for NNPS algorithm are freely accessible at https://github.com/raziyehmasumshah/NNPS .

A SARS-CoV-2 (COVID-19) biological network to find targets for drug repurposing.

The Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus needs a fast recognition of effective drugs to save lives. In the COVID-19 situation, finding targets for drug repurposing can be an effective way to present new fast treatments. We have designed a two-step solution to address this approach. In the first step, we identify essential proteins from virus targets or their associated modules in human cells as possible drug target candidates. For this purpose, we apply two different algorithms to detect some candidate sets of proteins with a minimum size that drive a significant disruption in the COVID-19 related biological networks. We evaluate the resulted candidate proteins sets with three groups of drugs namely Covid-Drug, Clinical-Drug, and All-Drug. The obtained candidate proteins sets approve 16 drugs out of 18 in the Covid-Drug, 273 drugs out of 328 in the Clinical-Drug, and a large number of drugs in the All-Drug. In the second step, we study COVID-19 associated proteins sets and recognize proteins that are essential to disease pathology. This analysis is performed using DAVID to show and compare essential proteins that are contributed between the COVID-19 comorbidities. Our results for shared proteins show significant enrichment for cardiovascular-related, hypertension, diabetes type 2, kidney-related and lung-related diseases.

An order independent algorithm for inferring gene regulatory network using quantile value for conditional independence tests.

In recent years, due to the difficulty and inefficiency of experimental methods, numerous computational methods have been introduced for inferring the structure of Gene Regulatory Networks (GRNs). The Path Consistency (PC) algorithm is one of the popular methods to infer the structure of GRNs. However, this group of methods still has limitations and there is a potential for improvements in this field. For example, the PC-based algorithms are still sensitive to the ordering of nodes i.e. different node orders results in different network structures. The second is that the networks inferred by these methods are highly dependent on the threshold used for independence testing. Also, it is still a challenge to select the set of conditional genes in an optimal way, which affects the performance and computation complexity of the PC-based algorithm. We introduce a novel algorithm, namely Order Independent PC-based algorithm using Quantile value (OIPCQ), which improves the accuracy of the learning process of GRNs and solves the order dependency issue. The quantile-based thresholds are considered for different orders of CMI tests. For conditional gene selection, we consider the paths between genes with length equal or greater than 2 while other well-known PC-based methods only consider the paths of length 2. We applied OIPCQ on the various networks of the DREAM3 and DREAM4 in silico challenges. As a real-world case study, we used OIPCQ to reconstruct SOS DNA network obtained from Escherichia coli and GRN for acute myeloid leukemia based on the RNA sequencing data from The Cancer Genome Atlas. The results show that OIPCQ produces the same network structure for all the permutations of the genes and improves the resulted GRN through accurately quantifying the causal regulation strength in comparison with other well-known PC-based methods. According to the GRN constructed by OIPCQ, for acute myeloid leukemia, two regulators BCLAF1 and NRSF reported previously are significantly important. However, the highest degree nodes in this GRN are ZBTB7A and PU1 which play a significant role in cancer, especially in leukemia. OIPCQ is freely accessible at https://github.com/haammim/OIPCQ-and-OIPCQ2 .

Significant random signatures reveals new biomarker for breast cancer.

BACKGROUND: In 2012, Venet et al. proposed that at least in the case of breast cancer, most published signatures are not significantly more associated with outcome than randomly generated signatures. They suggested that nominal p-value is not a good estimator to show the significance of a signature. Therefore, one can reasonably postulate that some information might be present in such significant random signatures. METHODS: In this research, first we show that, using an empirical p-value, these published signatures are more significant than their nominal p-values. In other words, the proposed empirical p-value can be considered as a complimentary criterion for nominal p-value to distinguish random signatures from significant ones. Secondly, we develop a novel computational method to extract information that are embedded within significant random signatures. In our method, a score is assigned to each gene based on the number of times it appears in significant random signatures. Then, these scores are diffused through a protein-protein interaction network and a permutation procedure is used to determine the genes with significant scores. The genes with significant scores are considered as the set of significant genes. RESULTS: First, we applied our method on the breast cancer dataset NKI to achieve a set of significant genes in breast cancer considering significant random signatures. Secondly, prognostic performance of the computed set of significant genes is evaluated using DMFS and RFS datasets. We have observed that the top ranked genes from this set can successfully separate patients with poor prognosis from those with good prognosis. Finally, we investigated the expression pattern of TAT, the first gene reported in our set, in malignant breast cancer vs. adjacent normal tissue and mammospheres. CONCLUSION: Applying the method, we found a set of significant genes in breast cancer, including TAT, a gene that has never been reported as an important gene in breast cancer. Our results show that the expression of TAT is repressed in tumors suggesting that this gene could act as a tumor suppressor in breast cancer and could be used as a new biomarker.

The Ability of Different Imputation Methods to Preserve the Significant Genes and Pathways in Cancer.

Deciphering important genes and pathways from incomplete gene expression data could facilitate a better understanding of cancer. Different imputation methods can be applied to estimate the missing values. In our study, we evaluated various imputation methods for their performance in preserving significant genes and pathways. In the first step, 5% genes are considered in random for two types of ignorable and non-ignorable missingness mechanisms with various missing rates. Next, 10 well-known imputation methods were applied to the complete datasets. The significance analysis of microarrays (SAM) method was applied to detect the significant genes in rectal and lung cancers to showcase the utility of imputation approaches in preserving significant genes. To determine the impact of different imputation methods on the identification of important genes, the chi-squared test was used to compare the proportions of overlaps between significant genes detected from original data and those detected from the imputed datasets. Additionally, the significant genes are tested for their enrichment in important pathways, using the ConsensusPathDB. Our results showed that almost all the significant genes and pathways of the original dataset can be detected in all imputed datasets, indicating that there is no significant difference in the performance of various imputation methods tested. The source code and selected datasets are available on http://profiles.bs.ipm.ir/softwares/imputation_methods/.

LRC: A new algorithm for prediction of conformational B-cell epitopes using statistical approach and clustering method.

Identifying of B-cell epitopes from antigen is a challenging task in bioinformatics and applied in vaccine design and drug development. Recently, several methods have been presented to predict epitopes. The physicochemical or structural properties are used by these methods. In this paper, we propose a more appropriate epitope prediction method, LRC, that is based on a combination of physicochemical and structural properties. First, we construct a graph from the surface of antigen, then by using the logistic regression, we model the physicochemical and structural properties and weight each vertex of the graph. Finally, we utilize a clustering method, MCL, to cluster the graph. The effectiveness of the proposed method is benchmarked using several antibody-antigen PDB complexes. The results of LRC algorithm are compared with other methods (DiscoTope, SEPPA and Ellipro) in terms of sensitivity, specificity and other well-known measures. Results indicate that applying the LRC algorithm improves the precision of prediction epitopes in comparison with the mentioned methods. Our LRC program and supplementary material are freely available from http://bs.ipm.ir/softwares/LRC/.

CN: a consensus algorithm for inferring gene regulatory networks using the SORDER algorithm and conditional mutual information test.

Inferring Gene Regulatory Networks (GRNs) from gene expression data is a major challenge in systems biology. The Path Consistency (PC) algorithm is one of the popular methods in this field. However, as an order dependent algorithm, PC algorithm is not robust because it achieves different network topologies if gene orders are permuted. In addition, the performance of this algorithm depends on the threshold value used for independence tests. Consequently, selecting suitable sequential ordering of nodes and an appropriate threshold value for the inputs of PC algorithm are challenges to infer a good GRN. In this work, we propose a heuristic algorithm, namely SORDER, to find a suitable sequential ordering of nodes. Based on the SORDER algorithm and a suitable interval threshold for Conditional Mutual Information (CMI) tests, a network inference method, namely the Consensus Network (CN), has been developed. In the proposed method, for each edge of the complete graph, a weighted value is defined. This value is considered as the reliability value of dependency between two nodes. The final inferred network, obtained using the CN algorithm, contains edges with a reliability value of dependency of more than a defined threshold. The effectiveness of this method is benchmarked through several networks from the DREAM challenge and the widely used SOS DNA repair network in Escherichia coli. The results indicate that the CN algorithm is suitable for learning GRNs and it considerably improves the precision of network inference. The source of data sets and codes are available at .

IPCA-CMI: an algorithm for inferring gene regulatory networks based on a combination of PCA-CMI and MIT score.

Inferring gene regulatory networks (GRNs) is a major issue in systems biology, which explicitly characterizes regulatory processes in the cell. The Path Consistency Algorithm based on Conditional Mutual Information (PCA-CMI) is a well-known method in this field. In this study, we introduce a new algorithm (IPCA-CMI) and apply it to a number of gene expression data sets in order to evaluate the accuracy of the algorithm to infer GRNs. The IPCA-CMI can be categorized as a hybrid method, using the PCA-CMI and Hill-Climbing algorithm (based on MIT score). The conditional dependence between variables is determined by the conditional mutual information test which can take into account both linear and nonlinear genes relations. IPCA-CMI uses a score and search method and defines a selected set of variables which is adjacent to one of X or Y. This set is used to determine the dependency between X and Y. This method is compared with the method of evaluating dependency by PCA-CMI in which the set of variables adjacent to both X and Y, is selected. The merits of the IPCA-CMI are evaluated by applying this algorithm to the DREAM3 Challenge data sets with n variables and n samples (n = 10, 50, 100) and to experimental data from Escherichia coil containing 9 variables and 9 samples. Results indicate that applying the IPCA-CMI improves the precision of learning the structure of the GRNs in comparison with that of the PCA-CMI.

The structural properties of DNA regulate gene expression.

Regulatory sequences such as promoters not only contain cis-regulatory elements as switches of transcription, but also exhibit particular topological features. In this paper, we introduce a systematic genome scale approach to characterize the roles of structural conformation and stability profile of promoter sequence in gene expression. The average free energy of promoter dinucleotides stacking nearest neighbors are subjected to scrutiny by statistical hidden Markov models to reveal the function of constrains and properties of promoter structure in transcription. When applied for a 1000 bp 5' upstream sequence of genes, the proposed model via assessing free energy profile identified co-expressed genes of Arabidopsis thaliana in response to the auxin hormone. The applied perspective dynamic network which mediates transcription regulation provides a great hindrance to conceive how DNA conformation interacts with cis-regulatory elements, chromatin structure and many other factors. This study indeed drew the complexity of the promoter's regulatory behavior from sequence over the former studies and evokes a new hypothesis to be validated experimentally.

A clustering approach for estimating parameters of a profile hidden Markov model.

A Profile Hidden Markov Model (PHMM) is a standard form of a Hidden Markov Models used for modeling protein and DNA sequence families based on multiple alignment. In this paper, we implement Baum-Welch algorithm and the Bayesian Monte Carlo Markov Chain (BMCMC) method for estimating parameters of small artificial PHMM. In order to improve the prediction accuracy of the estimation of the parameters of the PHMM, we classify the training data using the weighted values of sequences in the PHMM then apply an algorithm for estimating parameters of the PHMM. The results show that the BMCMC method performs better than the Maximum Likelihood estimation.