Identification of genetic biomarkers, drug targets and agents for respiratory diseases utilising integrated bioinformatics approaches.

Respiratory diseases (RD) are significant public health burdens and malignant diseases worldwide. However, the RD-related biological information and interconnection still need to be better understood. Thus, this study aims to detect common differential genes and potential hub genes (HubGs), emphasizing their actions, signaling pathways, regulatory biomarkers for diagnosing RD and candidate drugs for treating RD. In this paper we used integrated bioinformatics approaches (such as, gene ontology (GO) and KEGG pathway enrichment analysis, molecular docking, molecular dynamic simulation and network-based molecular interaction analysis). We discovered 73 common DEGs (CDEGs) and ten HubGs (ATAD2B, PPP1CB, FOXO1, AKT3, BCR, PDE4D, ITGB1, PCBP2, CD44 and SMARCA2). Several significant functions and signaling pathways were strongly related to RD. We recognized six transcription factor (TF) proteins (FOXC1, GATA2, FOXL1, YY1, POU2F2 and HINFP) and five microRNAs (hsa-mir-218-5p, hsa-mir-335-5p, hsa-mir-16-5p, hsa-mir-106b-5p and hsa-mir-15b-5p) as the important transcription and post-transcription regulators of RD. Ten HubGs and six major TF proteins were considered drug-specific receptors. Their binding energy analysis study was carried out with the 63 drug agents detected from network analysis. Finally, the five complexes (the PDE4D-benzo[a]pyrene, SMARCA2-benzo[a]pyrene, HINFP-benzo[a]pyrene, CD44-ketotifen and ATAD2B-ponatinib) were selected for RD based on their strong binding affinity scores and stable performance as the most probable repurposable protein-drug complexes. We believe our findings will give readers, wet-lab scientists, and pharmaceuticals a thorough grasp of the biology behind RD.

A classification of MRI brain tumor based on two stage feature level ensemble of deep CNN models.

The brain tumor is one of the deadliest cancerous diseases and its severity has turned it to the leading cause of cancer related mortality. The treatment procedure of the brain tumor depends on the type, location and size of the tumor. Relying solely on human inspection for precise categorization can lead to inevitably dangerous situation. This manual diagnosis process can be improved and accelerated through an automated Computer Aided Diagnosis (CADx) system. In this article, a novel approach using two-stage feature ensemble of deep Convolutional Neural Networks (CNN) is proposed for precise and automatic classification of brain tumors. Three unique Magnetic Resonance Imaging (MRI) datasets and a dataset merging all the unique datasets are considered. The datasets contain three types of brain tumor (meningioma, glioma, pituitary) and normal brain images. From five pre-trained models and a proposed CNN model, the best models are chosen and concatenated in two stages for feature extraction. The best classifier is also chosen among five different classifiers based on accuracy. From the extracted features, most substantial features are selected using Principal Component Analysis (PCA) and fed into the classifier. The robustness of the proposed two stage ensemble model is analyzed using several performance metrics and three different experiments. Through the prominent performance, the proposed model is able to outperform other existing models attaining an average accuracy of 99.13% by optimization of the developed algorithms. Here, the individual accuracy for Dataset 1, Dataset 2, Dataset 3, and Merged Dataset is 99.67%, 98.16%, 99.76%, and 98.96% respectively. Finally a User Interface (UI) is created using the proposed model for real time validation.

Network based systems biology approach to identify diseasome and comorbidity associations of Systemic Sclerosis with cancers.

Systemic Sclerosis (SSc) is an autoimmune disease associated with changes in the skin's structure in which the immune system attacks the body. A recent meta-analysis has reported a high incidence of cancer prognosis including lung cancer (LC), leukemia (LK), and lymphoma (LP) in patients with SSc as comorbidity but its underlying mechanistic details are yet to be revealed. To address this research gap, bioinformatics methodologies were developed to explore the comorbidity interactions between a pair of diseases. Firstly, appropriate gene expression datasets from different repositories on SSc and its comorbidities were collected. Then the interconnection between SSc and its cancer comorbidities was identified by applying the developed pipelines. The pipeline was designed as a generic workflow to demonstrate a premise comorbid condition that integrate regarding gene expression data, tissue/organ meta-data, Gene Ontology (GO), Molecular pathways, and other online resources, and analyze them with Gene Set Enrichment Analysis (GSEA), Pathway enrichment and Semantic Similarity (SS). The pipeline was implemented in R and can be accessed through our Github repository: https://github.com/hiddenntreasure/comorbidity. Our result suggests that SSc and its cancer comorbidities share differentially expressed genes, functional terms (gene ontology), and pathways. The findings have led to a better understanding of disease pathways and our developed methodologies may be applied to any set of diseases for finding any association between them. This research may be used by physicians, researchers, biologists, and others.

LungNet: A hybrid deep-CNN model for lung cancer diagnosis using CT and wearable sensor-based medical IoT data.

Lung cancer, also known as pulmonary cancer, is one of the deadliest cancers, but yet curable if detected at the early stage. At present, the ambiguous features of the lung cancer nodule make the computer-aided automatic diagnosis a challenging task. To alleviate this, we present LungNet, a novel hybrid deep-convolutional neural network-based model, trained with CT scan and wearable sensor-based medical IoT (MIoT) data. LungNet consists of a unique 22-layers Convolutional Neural Network (CNN), which combines latent features that are learned from CT scan images and MIoT data to enhance the diagnostic accuracy of the system. Operated from a centralized server, the network has been trained with a balanced dataset having 525,000 images that can classify lung cancer into five classes with high accuracy (96.81%) and low false positive rate (3.35%), outperforming similar CNN-based classifiers. Moreover, it classifies the stage-1 and stage-2 lung cancers into 1A, 1B, 2A and 2B sub-classes with 91.6% accuracy and false positive rate of 7.25%. High predictive capability accompanied with sub-stage classification renders LungNet as a promising prospect in developing CNN-based automatic lung cancer diagnosis systems.

Machine Learning Approaches to Identify Patient Comorbidities and Symptoms That Increased Risk of Mortality in COVID-19.

Providing appropriate care for people suffering from COVID-19, the disease caused by the pandemic SARS-CoV-2 virus, is a significant global challenge. Many individuals who become infected may have pre-existing conditions that may interact with COVID-19 to increase symptom severity and mortality risk. COVID-19 patient comorbidities are likely to be informative regarding the individual risk of severe illness and mortality. Determining the degree to which comorbidities are associated with severe symptoms and mortality would thus greatly assist in COVID-19 care planning and provision. To assess this we performed a meta-analysis of published global literature, and machine learning predictive analysis using an aggregated COVID-19 global dataset. Our meta-analysis suggested that chronic obstructive pulmonary disease (COPD), cerebrovascular disease (CEVD), cardiovascular disease (CVD), type 2 diabetes, malignancy, and hypertension as most significantly associated with COVID-19 severity in the current published literature. Machine learning classification using novel aggregated cohort data similarly found COPD, CVD, CKD, type 2 diabetes, malignancy, and hypertension, as well as asthma, as the most significant features for classifying those deceased versus those who survived COVID-19. While age and gender were the most significant predictors of mortality, in terms of symptom-comorbidity combinations, it was observed that Pneumonia-Hypertension, Pneumonia-Diabetes, and Acute Respiratory Distress Syndrome (ARDS)-Hypertension showed the most significant associations with COVID-19 mortality. These results highlight the patient cohorts most likely to be at risk of COVID-19-related severe morbidity and mortality, which have implications for prioritization of hospital resources.

Discovering novel cancer bio-markers in acquired lapatinib resistance using Bayesian methods.

Signalling transduction pathways (STPs) are commonly hijacked by many cancers for their growth and malignancy, but demystifying their underlying mechanisms is difficult. Here, we developed methodologies with a fully Bayesian approach in discovering novel driver bio-markers in aberrant STPs given high-throughput gene expression (GE) data. This project, namely 'PathTurbEr' (Pathway Perturbation Driver) uses the GE dataset derived from the lapatinib (an EGFR/HER dual inhibitor) sensitive and resistant samples from breast cancer cell lines (SKBR3). Differential expression analysis revealed 512 differentially expressed genes (DEGs) and their pathway enrichment revealed 13 highly perturbed singalling pathways in lapatinib resistance, including PI3K-AKT, Chemokine, Hippo and TGF-$\beta $ singalling pathways. Next, the aberration in TGF-$\beta $ STP was modelled as a causal Bayesian network (BN) using three MCMC sampling methods, i.e. Neighbourhood sampler (NS) and Hit-and-Run (HAR) sampler that potentially yield robust inference with lower chances of getting stuck at local optima and faster convergence compared to other state-of-art methods. Next, we examined the structural features of the optimal BN as a statistical process that generates the global structure using $p_1$-model, a special class of Exponential Random Graph Models (ERGMs), and MCMC methods for their hyper-parameter sampling. This step enabled key drivers identification that drive the aberration within the perturbed BN structure of STP, and yielded 34, 34 and 23 perturbation driver genes out of 80 constituent genes of three perturbed STP models of TGF-$\beta $ signalling inferred by NS, HAR and MH sampling methods, respectively. Functional-relevance and disease-relevance analyses suggested their significant associations with breast cancer progression/resistance.

Bayesian model of signal rewiring reveals mechanisms of gene dysregulation in acquired drug resistance in breast cancer.

Small molecule inhibitors, such as lapatinib, are effective against breast cancer in clinical trials, but tumor cells ultimately acquire resistance to the drug. Maintaining sensitization to drug action is essential for durable growth inhibition. Recently, adaptive reprogramming of signaling circuitry has been identified as a major cause of acquired resistance. We developed a computational framework using a Bayesian statistical approach to model signal rewiring in acquired resistance. We used the p1-model to infer potential aberrant gene-pairs with differential posterior probabilities of appearing in resistant-vs-parental networks. Results were obtained using matched gene expression profiles under resistant and parental conditions. Using two lapatinib-treated ErbB2-positive breast cancer cell-lines: SKBR3 and BT474, our method identified similar dysregulated signaling pathways including EGFR-related pathways as well as other receptor-related pathways, many of which were reported previously as compensatory pathways of EGFR-inhibition via signaling cross-talk. A manual literature survey provided strong evidence that aberrant signaling activities in dysregulated pathways are closely related to acquired resistance in EGFR tyrosine kinase inhibitors. Our approach predicted literature-supported dysregulated pathways complementary to both node-centric (SPIA, DAVID, and GATHER) and edge-centric (ESEA and PAGI) methods. Moreover, by proposing a novel pattern of aberrant signaling called V-structures, we observed that genes were dysregulated in resistant-vs-sensitive conditions when they were involved in the switch of dependencies from targeted to bypass signaling events. A literature survey of some important V-structures suggested they play a role in breast cancer metastasis and/or acquired resistance to EGFR-TKIs, where the mRNA changes of TGFBR2, LEF1 and TP53 in resistant-vs-sensitive conditions were related to the dependency switch from targeted to bypass signaling links. Our results suggest many signaling pathway structures are compromised in acquired resistance, and V-structures of aberrant signaling within/among those pathways may provide further insights into the bypass mechanism of targeted inhibition.

Integrating Heterogeneous Datasets for Cancer Module Identification.

The availability of multiple heterogeneous high-throughput datasets provides an enabling resource for cancer systems biology. Types of data include: Gene expression (GE), copy number aberration (CNA), miRNA expression, methylation, and protein-protein Interactions (PPI). One important problem that can potentially be solved using such data is to determine which of the possible pair-wise interactions among genes contributes to a range of cancer-related events, from tumorigenesis to metastasis. It has been shown by various studies that applying integrated knowledge from multi-omics datasets elucidates such complex phenomena with higher statistical significance than using a single type of dataset individually. However, computational methods for processing multiple data types simultaneously are needed. This chapter reviews some of the computational methods that use integrated approaches to find cancer-related modules.

Prediction of signaling cross-talks contributing to acquired drug resistance in breast cancer cells by Bayesian statistical modeling.

BACKGROUND: Initial success of inhibitors targeting oncogenes is often followed by tumor relapse due to acquired resistance. In addition to mutations in targeted oncogenes, signaling cross-talks among pathways play a vital role in such drug inefficacy. These include activation of compensatory pathways and altered activities of key effectors in other cell survival and growth-associated pathways. RESULTS: We propose a computational framework using Bayesian modeling to systematically characterize potential cross-talks among breast cancer signaling pathways. We employed a fully Bayesian approach known as the p 1-model to infer posterior probabilities of gene-pairs in networks derived from the gene expression datasets of ErbB2-positive breast cancer cell-lines (parental, lapatinib-sensitive cell-line SKBR3 and the lapatinib-resistant cell-line SKBR3-R, derived from SKBR3). Using this computational framework, we searched for cross-talks between EGFR/ErbB and other signaling pathways from Reactome, KEGG and WikiPathway databases that contribute to lapatinib resistance. We identified 104, 188 and 299 gene-pairs as putative drug-resistant cross-talks, respectively, each comprised of a gene in the EGFR/ErbB signaling pathway and a gene from another signaling pathway, that appear to be interacting in resistant cells but not in parental cells. In 168 of these (distinct) gene-pairs, both of the interacting partners are up-regulated in resistant conditions relative to parental conditions. These gene-pairs are prime candidates for novel cross-talks contributing to lapatinib resistance. They associate EGFR/ErbB signaling with six other signaling pathways: Notch, Wnt, GPCR, hedgehog, insulin receptor/IGF1R and TGF- ß receptor signaling. We conducted a literature survey to validate these cross-talks, and found evidence supporting a role for many of them in contributing to drug resistance. We also analyzed an independent study of lapatinib resistance in the BT474 breast cancer cell-line and found the same signaling pathways making cross-talks with the EGFR/ErbB signaling pathway as in the primary dataset. CONCLUSIONS: Our results indicate that the activation of compensatory pathways can potentially cause up-regulation of EGFR/ErbB pathway genes (counteracting the inhibiting effect of lapatinib) via signaling cross-talk. Thus, the up-regulated members of these compensatory pathways along with the members of the EGFR/ErbB signaling pathway are interesting as potential targets for designing novel anti-cancer therapeutics.

Voting-based cancer module identification by combining topological and data-driven properties.

Recently, computational approaches integrating copy number aberrations (CNAs) and gene expression (GE) have been extensively studied to identify cancer-related genes and pathways. In this work, we integrate these two data sets with protein-protein interaction (PPI) information to find cancer-related functional modules. To integrate CNA and GE data, we first built a gene-gene relationship network from a set of seed genes by enumerating all types of pairwise correlations, e.g. GE-GE, CNA-GE, and CNA-CNA, over multiple patients. Next, we propose a voting-based cancer module identification algorithm by combining topological and data-driven properties (VToD algorithm) by using the gene-gene relationship network as a source of data-driven information, and the PPI data as topological information. We applied the VToD algorithm to 266 glioblastoma multiforme (GBM) and 96 ovarian carcinoma (OVC) samples that have both expression and copy number measurements, and identified 22 GBM modules and 23 OVC modules. Among 22 GBM modules, 15, 12, and 20 modules were significantly enriched with cancer-related KEGG, BioCarta pathways, and GO terms, respectively. Among 23 OVC modules, 19, 18, and 23 modules were significantly enriched with cancer-related KEGG, BioCarta pathways, and GO terms, respectively. Similarly, we also observed that 9 and 2 GBM modules and 15 and 18 OVC modules were enriched with cancer gene census (CGC) and specific cancer driver genes, respectively. Our proposed module-detection algorithm significantly outperformed other existing methods in terms of both functional and cancer gene set enrichments. Most of the cancer-related pathways from both cancer data sets found in our algorithm contained more than two types of gene-gene relationships, showing strong positive correlations between the number of different types of relationship and CGC enrichment [Formula: see text]-values (0.64 for GBM and 0.49 for OVC). This study suggests that identified modules containing both expression changes and CNAs can explain cancer-related activities with greater insights.