Intra-Host Co-Existing Strains of SARS-CoV-2 Reference Genome Uncovered by Exhaustive Computational Search.

The COVID-19 pandemic caused by SARS-CoV-2 has had a severe impact on people worldwide. The reference genome of the virus has been widely used as a template for designing mRNA vaccines to combat the disease. In this study, we present a computational method aimed at identifying co-existing intra-host strains of the virus from RNA-sequencing data of short reads that were used to assemble the original reference genome. Our method consisted of five key steps: extraction of relevant reads, error correction for the reads, identification of within-host diversity, phylogenetic study, and protein binding affinity analysis. Our study revealed that multiple strains of SARS-CoV-2 can coexist in both the viral sample used to produce the reference sequence and a wastewater sample from California. Additionally, our workflow demonstrated its capability to identify within-host diversity in foot-and-mouth disease virus (FMDV). Through our research, we were able to shed light on the binding affinity and phylogenetic relationships of these strains with the published SARS-CoV-2 reference genome, SARS-CoV, variants of concern (VOC) of SARS-CoV-2, and some closely related coronaviruses. These insights have important implications for future research efforts aimed at identifying within-host diversity, understanding the evolution and spread of these viruses, as well as the development of effective treatments and vaccines against them.

Review on predicting pairwise relationships between human microbes, drugs and diseases: from biological data to computational models.

In recent years, with the rapid development of techniques in bioinformatics and life science, a considerable quantity of biomedical data has been accumulated, based on which researchers have developed various computational approaches to discover potential associations between human microbes, drugs and diseases. This paper provides a comprehensive overview of recent advances in prediction of potential correlations between microbes, drugs and diseases from biological data to computational models. Firstly, we introduced the widely used datasets relevant to the identification of potential relationships between microbes, drugs and diseases in detail. And then, we divided a series of a lot of representative computing models into five major categories including network, matrix factorization, matrix completion, regularization and artificial neural network for in-depth discussion and comparison. Finally, we analysed possible challenges and opportunities in this research area, and at the same time we outlined some suggestions for further improvement of predictive performances as well.

Aberration-corrected ultrafine analysis of miRNA reads at single-base resolution: a k-mer lattice approach.

Raw sequencing reads of miRNAs contain machine-made substitution errors, or even insertions and deletions (indels). Although the error rate can be low at 0.1%, precise rectification of these errors is critically important because isoform variation analysis at single-base resolution such as novel isomiR discovery, editing events understanding, differential expression analysis, or tissue-specific isoform identification is very sensitive to base positions and copy counts of the reads. Existing error correction methods do not work for miRNA sequencing data attributed to miRNAs' length and per-read-coverage properties distinct from DNA or mRNA sequencing reads. We present a novel lattice structure combining kmers, (k - 1)mers and (k + 1)mers to address this problem. The method is particularly effective for the correction of indel errors. Extensive tests on datasets having known ground truth of errors demonstrate that the method is able to remove almost all of the errors, without introducing any new error, to improve the data quality from every-50-reads containing one error to every-1300-reads containing one error. Studies on experimental miRNA sequencing datasets show that the errors are often rectified at the 5' ends and the seed regions of the reads, and that there are remarkable changes after the correction in miRNA isoform abundance, volume of singleton reads, overall entropy, isomiR families, tissue-specific miRNAs, and rare-miRNA quantities.

A Novel Method for Predicting Disease-Associated LncRNA-MiRNA Pairs Based on the Higher-Order Orthogonal Iteration.

A lot of research studies have shown that many complex human diseases are associated not only with microRNAs (miRNAs) but also with long noncoding RNAs (lncRNAs). However, most of the current existing studies focus on the prediction of disease-related miRNAs or lncRNAs, and to our knowledge, until now, there are few literature studies reported to pay attention to the study of impact of miRNA-lncRNA pairs on diseases, although more and more studies have shown that both lncRNAs and miRNAs play important roles in cell proliferation and differentiation during the recent years. The identification of disease-related genes provides great insight into the underlying pathogenesis of diseases at a system level. In this study, a novel model called PADLMHOOI was proposed to predict potential associations between diseases and lncRNA-miRNA pairs based on the higher-order orthogonal iteration, and in order to evaluate its prediction performance, the global and local LOOCV were implemented, respectively, and simulation results demonstrated that PADLMHOOI could achieve reliable AUCs of 0.9545 and 0.8874 in global and local LOOCV separately. Moreover, case studies further demonstrated the effectiveness of PADLMHOOI to infer unknown disease-related lncRNA-miRNA pairs.

A Novel Method for LncRNA-Disease Association Prediction Based on an lncRNA-Disease Association Network.

An increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) play critical roles in many important biological processes. Predicting potential lncRNA-disease associations can improve our understanding of the molecular mechanisms of human diseases and aid in finding biomarkers for disease diagnosis, treatment, and prevention. In this paper, we constructed a bipartite network based on known lncRNA-disease associations; based on this work, we proposed a novel model for inferring potential lncRNA-disease associations. Specifically, we analyzed the properties of the bipartite network and found that it closely followed a power-law distribution. Moreover, to evaluate the performance of our model, a leave-one-out cross-validation (LOOCV) framework was implemented, and the simulation results showed that our computational model significantly outperformed previous state-of-the-art models, with AUCs of 0.8825, 0.9004, and 0.9292 for known lncRNA-disease associations obtained from the LncRNADisease database, Lnc2Cancer database, and MNDR database, respectively. Thus, our approach may be an excellent addition to the biomedical research field in the future.

A Novel Probability Model for LncRNA⁻Disease Association Prediction Based on the Naïve Bayesian Classifier.

An increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) play crucial roles in biological processes, complex disease diagnoses, prognoses, and treatments. However, experimentally validated associations between lncRNAs and diseases are still very limited. Recently, computational models have been developed to discover potential associations between lncRNAs and diseases by integrating multiple heterogeneous biological data; this has become a hot topic in biological research. In this article, we constructed a global tripartite network by integrating a variety of biological information including miRNA⁻disease, miRNA⁻lncRNA, and lncRNA⁻disease associations and interactions. Then, we constructed a global quadruple network by appending gene⁻lncRNA interaction, gene⁻disease association, and gene⁻miRNA interaction networks to the global tripartite network. Subsequently, based on these two global networks, a novel approach was proposed based on the naïve Bayesian classifier to predict potential lncRNA⁻disease associations (NBCLDA). Comparing with the state-of-the-art methods, our new method does not entirely rely on known lncRNA⁻disease associations, and can achieve a reliable performance with effective area under ROC curve (AUCs)in leave-one-out cross validation. Moreover, in order to further estimate the performance of NBCLDA, case studies of colorectal cancer, prostate cancer, and glioma were implemented in this paper, and the simulation results demonstrated that NBCLDA can be an excellent tool for biomedical research in the future.

A Novel Model for Predicting Associations between Diseases and LncRNA-miRNA Pairs Based on a Newly Constructed Bipartite Network.

MOTIVATION: Increasing studies have demonstrated that many human complex diseases are associated with not only microRNAs, but also long-noncoding RNAs (lncRNAs). LncRNAs and microRNA play significant roles in various biological processes. Therefore, developing effective computational models for predicting novel associations between diseases and lncRNA-miRNA pairs (LMPairs) will be beneficial to not only the understanding of disease mechanisms at lncRNA-miRNA level and the detection of disease biomarkers for disease diagnosis, treatment, prognosis, and prevention, but also the understanding of interactions between diseases and LMPairs at disease level. RESULTS: It is well known that genes with similar functions are often associated with similar diseases. In this article, a novel model named PADLMP for predicting associations between diseases and LMPairs is proposed. In this model, a Disease-LncRNA-miRNA (DLM) tripartite network was designed firstly by integrating the lncRNA-disease association network and miRNA-disease association network; then we constructed the disease-LMPairs bipartite association network based on the DLM network and lncRNA-miRNA association network; finally, we predicted potential associations between diseases and LMPairs based on the newly constructed disease-LMPair network. Simulation results show that PADLMP can achieve AUCs of 0.9318, 0.9090 ± 0.0264, and 0.8950 ± 0.0027 in the LOOCV, 2-fold, and 5-fold cross validation framework, respectively, which demonstrate the reliable prediction performance of PADLMP.

Prediction of microRNA-disease associations based on distance correlation set.

BACKGROUND: Recently, numerous laboratory studies have indicated that many microRNAs (miRNAs) are involved in and associated with human diseases and can serve as potential biomarkers and drug targets. Therefore, developing effective computational models for the prediction of novel associations between diseases and miRNAs could be beneficial for achieving an understanding of disease mechanisms at the miRNA level and the interactions between diseases and miRNAs at the disease level. Thus far, only a few miRNA-disease association pairs are known, and models analyzing miRNA-disease associations based on lncRNA are limited. RESULTS: In this study, a new computational method based on a distance correlation set is developed to predict miRNA-disease associations (DCSMDA) by integrating known lncRNA-disease associations, known miRNA-lncRNA associations, disease semantic similarity, and various lncRNA and disease similarity measures. The novelty of DCSMDA is due to the construction of a miRNA-lncRNA-disease network, which reveals that DCSMDA can be applied to predict potential lncRNA-disease associations without requiring any known miRNA-disease associations. Although the implementation of DCSMDA does not require known disease-miRNA associations, the area under curve is 0.8155 in the leave-one-out cross validation. Furthermore, DCSMDA was implemented in case studies of prostatic neoplasms, lung neoplasms and leukaemia, and of the top 10 predicted associations, 10, 9 and 9 associations, respectively, were separately verified in other independent studies and biological experimental studies. In addition, 10 of the 10 (100%) associations predicted by DCSMDA were supported by recent bioinformatical studies. CONCLUSIONS: According to the simulation results, DCSMDA can be a great addition to the biomedical research field.