IDMIR: identification of dysregulated miRNAs associated with disease based on a miRNA-miRNA interaction network constructed through gene expression data.

Micro ribonucleic acids (miRNAs) play a pivotal role in governing the human transcriptome in various biological phenomena. Hence, the accumulation of miRNA expression dysregulation frequently assumes a noteworthy role in the initiation and progression of complex diseases. However, accurate identification of dysregulated miRNAs still faces challenges at the current stage. Several bioinformatics tools have recently emerged for forecasting the associations between miRNAs and diseases. Nonetheless, the existing reference tools mainly identify the miRNA-disease associations in a general state and fall short of pinpointing dysregulated miRNAs within a specific disease state. Additionally, no studies adequately consider miRNA-miRNA interactions (MMIs) when analyzing the miRNA-disease associations. Here, we introduced a systematic approach, called IDMIR, which enabled the identification of expression dysregulated miRNAs through an MMI network under the gene expression context, where the network's architecture was designed to implicitly connect miRNAs based on their shared biological functions within a particular disease context. The advantage of IDMIR is that it uses gene expression data for the identification of dysregulated miRNAs by analyzing variations in MMIs. We illustrated the excellent predictive power for dysregulated miRNAs of the IDMIR approach through data analysis on breast cancer and bladder urothelial cancer. IDMIR could surpass several existing miRNA-disease association prediction approaches through comparison. We believe the approach complements the deficiencies in predicting miRNA-disease association and may provide new insights and possibilities for diagnosing and treating diseases. The IDMIR approach is now available as a free R package on CRAN (https://CRAN.R-project.org/package=IDMIR).

PathwayTMB: A pathway-based tumor mutational burden analysis method for predicting the clinical outcome of cancer immunotherapy.

Immunotherapy has become one of the most promising therapy methods for cancer, but only a small number of patients are responsive to it, indicating that more effective biomarkers are urgently needed. This study developed a pathway analysis method, named PathwayTMB, to identify genomic mutation pathways that serve as potential biomarkers for predicting the clinical outcome of immunotherapy. PathwayTMB first calculates the patient-specific pathway-based tumor mutational burden (PTMB) to reflect the cumulative extent of mutations for each pathway. It then screens mutated survival benefit-related pathways to construct an immune-related prognostic signature based on PTMB (IPSP). In a melanoma training set, IPSP-high patients presented a longer overall survival and a higher response rate than IPSP-low patients. Moreover, the IPSP showed a superior predictive effect compared with TMB. In addition, the prognostic and predictive value of the IPSP was consistently validated in two independent validation sets. Finally, in a multi-cancer dataset, PathwayTMB also exhibited good performance. Our results indicate that PathwayTMB could identify the mutation pathways for predicting immunotherapeutic survival, and their combination may serve as a potential predictive biomarker for immune checkpoint inhibitor therapy.

DTSEA: A network-based drug target set enrichment analysis method for drug repurposing against COVID-19.

The Coronavirus Disease 2019 (COVID-19) pandemic is still wreaking havoc worldwide. Therefore, the urgent need for efficient treatments pushes researchers and clinicians into screening effective drugs. Drug repurposing may be a promising and time-saving strategy to identify potential drugs against this disease. Here, we developed a novel computational approach, named Drug Target Set Enrichment Analysis (DTSEA), to identify potent drugs against COVID-19. DTSEA first mapped the disease-related genes into a gene functional interaction network, and then it used a network propagation algorithm to rank all genes in the network by calculating the network proximity of genes to disease-related genes. Finally, an enrichment analysis was performed on drug target sets to prioritize disease-candidate drugs. It was shown that the top three drugs predicted by DTSEA, including Ataluren, Carfilzomib, and Aripiprazole, were significantly enriched in the immune response pathways indicating the potential for use as promising COVID-19 inhibitors. In addition to these drugs, DTSEA also identified several drugs (such as Remdesivir and Olumiant), which have obtained emergency use authorization (EUA) for COVID-19. These results indicated that DTSEA could effectively identify the candidate drugs for COVID-19, which will help to accelerate the development of drugs for COVID-19. We then performed several validations to ensure the reliability and validity of DTSEA, including topological analysis, robustness analysis, and prediction consistency. Collectively, DTSEA successfully predicted candidate drugs against COVID-19 with high accuracy and reliability, thus making it a formidable tool to identify potential drugs for a specific disease and facilitate further investigation.

DrugSim2DR: systematic prediction of drug functional similarities in the context of specific disease for drug repurposing.

BACKGROUND: Traditional approaches to drug development are costly and involve high risks. The drug repurposing approach can be a valuable alternative to traditional approaches and has therefore received considerable attention in recent years. FINDINGS: Herein, we develop a previously undescribed computational approach, called DrugSim2DR, which uses a network diffusion algorithm to identify candidate anticancer drugs based on a drug functional similarity network. The innovation of the approach lies in the drug-drug functional similarity network constructed in a manner that implicitly links drugs through their common biological functions in the context of a specific disease state, as the similarity relationships based on general states (e.g., network proximity or Jaccard index of drug targets) ignore disease-specific molecular characteristics. The drug functional similarity network may provide a reference for prediction of drug combinations. We describe and validate the DrugSim2DR approach through analysis of data on breast cancer and lung cancer. DrugSim2DR identified some US Food and Drug Administration-approved anticancer drugs, as well as some candidate drugs validated by previous studies in the literature. Moreover, DrugSim2DR showed excellent predictive performance, as evidenced by receiver operating characteristic analysis and multiapproach comparisons in various cancer datasets. CONCLUSIONS: DrugSim2DR could accurately assess drug-drug functional similarity within a specific disease context and may more effectively prioritize disease candidate drugs. To increase the usability of our approach, we have developed an R-based software package, DrugSim2DR, which is freely available on CRAN (https://CRAN.R-project.org/package=DrugSim2DR).