Uncovering driver genes in breast cancer through an innovative machine learning mutational analysis method.

Breast cancer has become a severe public health concern and one of the leading causes of cancer-related death in women worldwide. Several genes and mutations in these genes linked to breast cancer have been identified using sophisticated techniques, despite the fact that the exact cause of breast cancer is still unknown. A commonly used feature for identifying driver mutations is the recurrence of a mutation in patients. Nevertheless, some mutations are more likely to occur than others for various reasons. Sequencing analysis has shown that cancer-driving genes operate across complex networks, often with mutations appearing in a modular pattern. In this work, as a retrospective study, we used TCGA data, which is gathered from breast cancer patients. We introduced a new machine-learning approach to examine gene functionality in networks derived from mutation associations, gene-gene interactions, and graph clustering for breast cancer analysis. These networks have uncovered crucial biological components in critical pathways, particularly those that exhibit low-frequency mutations. The statistical strength of the clinical study is significantly boosted by evaluating the network as a whole instead of just single gene effects. Our method successfully identified essential driver genes with diverse mutation frequencies. We then explored the functions of these potential driver genes and their related pathways. By uncovering low-frequency genes, we shed light on understudied pathways associated with breast cancer. Additionally, we present a novel Monte Carlo-based algorithm to identify driver modules in breast cancer. Our findings highlight the significance and role of these modules in critical signaling pathways in breast cancer, providing a comprehensive understanding of breast cancer development. Materials and implementations are available at: [https://github.com/MahnazHabibi/BreastCancer].

Identification of essential genes associated with SARS-CoV-2 infection as potential drug target candidates with machine learning algorithms.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the fast discovery of effective treatments to fight this worldwide concern. Several genes associated with the SARS-CoV-2, which are essential for its functionality, pathogenesis, and survival, have been identified. These genes, which play crucial roles in SARS-CoV-2 infection, are considered potential therapeutic targets. Developing drugs against these essential genes to inhibit their regular functions could be a good approach for COVID-19 treatment. Artificial intelligence and machine learning methods provide powerful infrastructures for interpreting and understanding the available data and can assist in finding fast explanations and cures. We propose a method to highlight the essential genes that play crucial roles in SARS-CoV-2 pathogenesis. For this purpose, we define eleven informative topological and biological features for the biological and PPI networks constructed on gene sets that correspond to COVID-19. Then, we use three different unsupervised learning algorithms with different approaches to rank the important genes with respect to our defined informative features. Finally, we present a set of 18 important genes related to COVID-19. Materials and implementations are available at: https://github.com/MahnazHabibi/Gene_analysis .

A new machine learning method for cancer mutation analysis.

It is complicated to identify cancer-causing mutations. The recurrence of a mutation in patients remains one of the most reliable features of mutation driver status. However, some mutations are more likely to happen than others for various reasons. Different sequencing analysis has revealed that cancer driver genes operate across complex pathways and networks, with mutations often arising in a mutually exclusive pattern. Genes with low-frequency mutations are understudied as cancer-related genes, especially in the context of networks. Here we propose a machine learning method to study the functionality of mutually exclusive genes in the networks derived from mutation associations, gene-gene interactions, and graph clustering. These networks have indicated critical biological components in the essential pathways, especially those mutated at low frequency. Studying the network and not just the impact of a single gene significantly increases the statistical power of clinical analysis. The proposed method identified important driver genes with different frequencies. We studied the function and the associated pathways in which the candidate driver genes participate. By introducing lower-frequency genes, we recognized less studied cancer-related pathways. We also proposed a novel clustering method to specify driver modules. We evaluated each driver module with different criteria, including the terms of biological processes and the number of simultaneous mutations in each cancer. Materials and implementations are available at: https://github.com/MahnazHabibi/MutationAnalysis.

Comprehensive analysis of pathways in Coronavirus 2019 (COVID-19) using an unsupervised machine learning method.

The World Health Organization (WHO) introduced "Coronavirus disease 19" or "COVID-19" as a novel coronavirus in March 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the fast discovery of effective treatments to fight this worldwide crisis. Artificial intelligence and bioinformatics analysis pipelines can assist with finding biomarkers, explanations, and cures. Artificial intelligence and machine learning methods provide powerful infrastructures for interpreting and understanding the available data. On the other hand, pathway enrichment analysis, as a dominant tool, could help researchers discover potential key targets present in biological pathways of host cells that are targeted by SARS-CoV-2. In this work, we propose a two-stage machine learning approach for pathway analysis. During the first stage, four informative gene sets that can represent important COVID-19 related pathways are selected. These "representative genes" are associated with the COVID-19 pathology. Then, two distinctive networks were constructed for COVID-19 related signaling and disease pathways. In the second stage, the pathways of each network are ranked with respect to some unsupervised scorning method based on our defined informative features. Finally, we present a comprehensive analysis of the top important pathways in both networks. Materials and implementations are available at: https://github.com/MahnazHabibi/Pathway.

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.

Topological network based drug repurposing for coronavirus 2019.

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become the current health concern and threat to the entire world. Thus, the world needs the fast recognition of appropriate drugs to restrict the spread of this disease. The global effort started to identify the best drug compounds to treat COVID-19, but going through a series of clinical trials and our lack of information about the details of the virus's performance has slowed down the time to reach this goal. In this work, we try to select the subset of human proteins as candidate sets that can bind to approved drugs. Our method is based on the information on human-virus protein interaction and their effect on the biological processes of the host cells. We also define some informative topological and statistical features for proteins in the protein-protein interaction network. We evaluate our selected sets with two groups of drugs. The first group contains the experimental unapproved treatments for COVID-19, and we show that from 17 drugs in this group, 15 drugs are approved by our selected sets. The second group contains the external clinical trials for COVID-19, and we show that 85% of drugs in this group, target at least one protein of our selected sets. We also study COVID-19 associated protein sets and identify proteins that are essential to disease pathology. For this analysis, we use DAVID tools to show and compare disease-associated genes that are contributed between the COVID-19 comorbidities. Our results for shared genes show significant enrichment for cardiovascular-related, hypertension, diabetes type 2, kidney-related and lung-related diseases. In the last part of this work, we recommend 56 potential effective drugs for further research and investigation for COVID-19 treatment. Materials and implementations are available at: https://github.com/MahnazHabibi/Drug-repurposing.

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.

Psychosocial Adjustment to Illness and Its Relationship with Spiritual Wellbeing in Iranian Cancer Patients.

BACKGROUND: The aim of this study was to investigate the psychosocial adjustment to illness and its relation with spiritual health in cancer patients. METHODS: This study was conducted in 2019 in Iran. It was a descriptive study with a sample of 124 cancer patients. Data were collected using two questionnaires of the psychosocial adjustment to illness scale (PAIS) with 46 questions and the Paloutzian and Ellison spiritual health scale with 20 questions. RESULTS: The mean age of the participants in this study was 52.4 ± 13.2 (range 18 to 87 years). The mean months of life with cancer were 16.5 months. The mean score of psychosocial adjustment to illness was 30.7 ± 15.5. The mean score of spiritual wellbeing in the studied patients was 71.4 ± 17.1. The results of the Pearson correlation test showed a significant inverse relationship between the mean score of psychosocial adjustment to illness and the mean score of spiritual wellbeing (p > 0.001, rr = -.355). CONCLUSION: Cancer patients in this study had relatively good psychosocial adjustment with their illness. Spiritual wellbeing can increase psychosocial adjustment to illness in this group of patients.

Disruption of Protein Complexes from Weighted Complex Networks.

Essential proteins are indispensable units for living organisms. Removing those leads to disruption of protein complexes and causing lethality. Recently, theoretical methods have been presented to detect essential proteins in protein interaction network. In these methods, an essential protein is predicted as a high-degree vertex of protein interaction network. However, interaction data are usually incomplete and an essential protein cannot have high-connection due to data deficiency. Then, it is critical to design informative networks from other biological data sources. In this paper, we defined a minimal set of proteins to disrupt the maximum number of protein complexes. We constructed a weighted graph using a set of given complexes. We proposed a more appropriate method based on betweenness values to diagnose a minimal set of proteins whose removal would generate the disruption of protein complexes. The effectiveness of the proposed method was benchmarked using given dataset of complexes. The results of our method were compared to the results of other methods in terms of the number of disrupted complexes. Also, results indicated significant superiority of the minimal set of proteins in the massive disruption of complexes. Finally, we investigated the performance of our method for yeast and human datasets and analyzed biological properties of the selected proteins. Our algorithm and some example are freely available from http://bs.ipm.ac.ir/softwares/DPC/DPC.zip.

Exploring candidate biomarkers for lung and prostate cancers using gene expression and flux variability analysis.

Genome-scale metabolic models have provided valuable resources for exploring changes in metabolism under normal and cancer conditions. However, metabolism itself is strongly linked to gene expression, so integration of gene expression data into metabolic models might improve the detection of genes involved in the control of tumor progression. Herein, we considered gene expression data as extra constraints to enhance the predictive powers of metabolic models. We reconstructed genome-scale metabolic models for lung and prostate, under normal and cancer conditions to detect the major genes associated with critical subsystems during tumor development. Furthermore, we utilized gene expression data in combination with an information theory-based approach to reconstruct co-expression networks of the human lung and prostate in both cohorts. Our results revealed 19 genes as candidate biomarkers for lung and prostate cancer cells. This study also revealed that the development of a complementary approach (integration of gene expression and metabolic profiles) could lead to proposing novel biomarkers and suggesting renovated cancer treatment strategies which have not been possible to detect using either of the methods alone.

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/.

Disruption of protein complexes.

Protein complexes are a cornerstone of many biological processes and, together, they form various types of molecular machinery that perform a vast array of biological functions. Different complexes perform different functions and, the same complex can perform very different functions that depend on a variety of factors. Thus disruption of protein complexes can be lethal to an organism. It is interesting to identify a minimal set of proteins whose removal would lead to a massive disruption of protein complexes and, to understand the biological properties of these proteins. A method is presented for identifying a minimum number of proteins from a given set of complexes so that a maximum number of these complexes are disrupted when these proteins are removed. The method is based on spectral bipartitioning. This method is applied to yeast protein complexes. The identified proteins participate in a large number of biological processes and functional modules. A large proportion of them are essential proteins. Moreover, removing these identified proteins causes a large number of the yeast protein complexes to break into two fragments of nearly equal size, which minimizes the chance of either fragment being functional. The method is also superior in these aspects to alternative methods based on proteins with high connection degree, proteins whose neighbors have high average degree, and proteins that connect to lots of proteins of high connection degree. Our spectral bipartitioning method is able to efficiently identify a biologically meaningful minimal set of proteins whose removal causes a massive disruption of protein complexes in an organism.

Constructing circular phylogenetic networks from weighted quartets using simulated annealing.

In this paper, we present a heuristic algorithm based on the simulated annealing, SAQ-Net, as a method for constructing phylogenetic networks from weighted quartets. Similar to QNet algorithm, SAQ-Net constructs a collection of circular weighted splits of the taxa set. This collection is represented by a split network. In order to show that SAQ-Net performs better than QNet, we apply these algorithm to both the simulated and actual data sets containing salmonella, Bees, Primates and Rubber data sets. Then we draw phylogenetic networks corresponding to outputs of these algorithms using SplitsTree4 and compare the results. We find that SAQ-Net produces a better circular ordering and phylogenetic networks than QNet in most cases. SAQ-Net has been implemented in Matlab and is available for download at http://bioinf.cs.ipm.ac.ir/softwares/saq.net.

Protein complex prediction based on k-connected subgraphs in protein interaction network.

BACKGROUND: Protein complexes play an important role in cellular mechanisms. Recently, several methods have been presented to predict protein complexes in a protein interaction network. In these methods, a protein complex is predicted as a dense subgraph of protein interactions. However, interactions data are incomplete and a protein complex does not have to be a complete or dense subgraph. RESULTS: We propose a more appropriate protein complex prediction method, CFA, that is based on connectivity number on subgraphs. We evaluate CFA using several protein interaction networks on reference protein complexes in two benchmark data sets (MIPS and Aloy), containing 1142 and 61 known complexes respectively. We compare CFA to some existing protein complex prediction methods (CMC, MCL, PCP and RNSC) in terms of recall and precision. We show that CFA predicts more complexes correctly at a competitive level of precision. CONCLUSIONS: Many real complexes with different connectivity level in protein interaction network can be predicted based on connectivity number. Our CFA program and results are freely available from http://www.bioinf.cs.ipm.ir/softwares/cfa/CFA.rar.

MC-Net: a method for the construction of phylogenetic networks based on the Monte-Carlo method.

BACKGROUND: A phylogenetic network is a generalization of phylogenetic trees that allows the representation of conflicting signals or alternative evolutionary histories in a single diagram. There are several methods for constructing these networks. Some of these methods are based on distances among taxa. In practice, the methods which are based on distance perform faster in comparison with other methods. The Neighbor-Net (N-Net) is a distance-based method. The N-Net produces a circular ordering from a distance matrix, then constructs a collection of weighted splits using circular ordering. The SplitsTree which is a program using these weighted splits makes a phylogenetic network. In general, finding an optimal circular ordering is an NP-hard problem. The N-Net is a heuristic algorithm to find the optimal circular ordering which is based on neighbor-joining algorithm. RESULTS: In this paper, we present a heuristic algorithm to find an optimal circular ordering based on the Monte-Carlo method, called MC-Net algorithm. In order to show that MC-Net performs better than N-Net, we apply both algorithms on different data sets. Then we draw phylogenetic networks corresponding to outputs of these algorithms using SplitsTree and compare the results. CONCLUSIONS: We find that the circular ordering produced by the MC-Net is closer to optimal circular ordering than the N-Net. Furthermore, the networks corresponding to outputs of MC-Net made by SplitsTree are simpler than N-Net.

PROSIGN: a method for protein secondary structure assignment based on three-dimensional coordinates of consecutive C(alpha) atoms.

The automatic assignment of secondary structure from three-dimensional atomic coordinates of proteins is an essential step for the analysis and modeling of protein structures. So different methods based on different criteria have been designed to perform this task. We introduce a new method for protein secondary structure assignment based solely on C(alpha) coordinates. We introduce four certain relations between C(alpha) three-dimensional coordinates of consecutive residues, each of which applies to one of the four regular secondary structure categories: alpha-helix, 3(10)-helix, pi-helix and beta-strand. In our approach, the deviation of the C(alpha) coordinates of each residue from each relation is calculated. Based on these deviation values, secondary structures are assigned to all residues of a protein. We show that our method agrees well with popular methods as DSSP, STRIDE and assignments in PDB files. It is shown that our method gives more information about helix geometry leading to more accurate secondary structure assignment.