Guiying Yan

LncRNADisease: a database for long-non-coding RNA-associated diseases

In this article, we describe a long-non-coding RNA (lncRNA) and disease association database (LncRNADisease), which is publicly accessible at http://cmbi.bjmu.edu.cn/lncrnadisease. In recent years, a large number of lncRNAs have been identified and increasing evidence shows that lncRNAs play critical roles in various biological processes. Therefore, the dysfunctions of lncRNAs are associated with a wide range of diseases. It thus becomes important to understand lncRNAs’ roles in diseases and to identify candidate lncRNAs for disease diagnosis, treatment and prognosis. For this purpose, a high-quality lncRNA–disease association database would be extremely beneficial. Here, we describe the LncRNADisease database that collected and curated approximately 480 entries of experimentally supported lncRNA–disease associations, including 166 diseases. LncRNADisease also curated 478 entries of lncRNA interacting partners at various molecular levels, including protein, RNA, miRNA and DNA. Moreover, we annotated lncRNA–disease associations with genomic information, sequences, references and species. We normalized the disease name and the type of lncRNA dysfunction and provided a detailed description for each entry. Finally, we developed a bioinformatic method to predict novel lncRNA–disease associations and integrated the method and the predicted associated diseases of 1564 human lncRNAs into the database.

Semi-supervised learning for potential human microRNA-disease associations inference.

MicroRNAs play critical role in the development and progression of various diseases. Predicting potential miRNA-disease associations from vast amount of biological data is an important problem in the biomedical research. Considering the limitations in previous methods, we developed Regularized Least Squares for MiRNA-Disease Association (RLSMDA) to uncover the relationship between diseases and miRNAs. RLSMDA can work for diseases without known related miRNAs. Furthermore, it is a semi-supervised (does not need negative samples) and global method (prioritize associations for all the diseases simultaneously). Based on leave-one-out cross validation, reliable AUC have demonstrated the reliable performance of RLSMDA. We also applied RLSMDA to Hepatocellular cancer and Lung cancer and implemented global prediction for all the diseases simultaneously. As a result, 80% (Hepatocellular cancer) and 84% (Lung cancer) of top 50 predicted miRNAs and 75% of top 20 potential associations based on global prediction have been confirmed by biological experiments. We also applied RLSMDA to diseases without known related miRNAs in golden standard dataset. As a result, in the top 3 potential related miRNA list predicted by RLSMDA for 32 diseases, 34 disease-miRNA associations were successfully confirmed by experiments. It is anticipated that RLSMDA would be a useful bioinformatics resource for biomedical researches.

Novel human lncRNA–disease association inference based on lncRNA expression profiles

MOTIVATION More and more evidences have indicated that long-non-coding RNAs (lncRNAs) play critical roles in many important biological processes. Therefore, mutations and dysregulations of these lncRNAs would contribute to the development of various complex diseases. Developing powerful computational models for potential disease-related lncRNAs identification would benefit biomarker identification and drug discovery for human disease diagnosis, treatment, prognosis and prevention. RESULTS In this article, we proposed the assumption that similar diseases tend to be associated with functionally similar lncRNAs. Then, we further developed the method of Laplacian Regularized Least Squares for LncRNA-Disease Association (LRLSLDA) in the semisupervised learning framework. Although known disease-lncRNA associations in the database are rare, LRLSLDA still obtained an AUC of 0.7760 in the leave-one-out cross validation, significantly improving the performance of previous methods. We also illustrated the performance of LRLSLDA is not sensitive (even robust) to the parameters selection and it can obtain a reliable performance in all the test classes. Plenty of potential disease-lncRNA associations were publicly released and some of them have been confirmed by recent results in biological experiments. It is anticipated that LRLSLDA could be an effective and important biological tool for biomedical research. AVAILABILITY The code of LRLSLDA is freely available at http://asdcd.amss.ac.cn/Software/Details/2.

HGIMDA: Heterogeneous graph inference for miRNA-disease association prediction

Recently, microRNAs (miRNAs) have drawn more and more attentions because accumulating experimental studies have indicated miRNA could play critical roles in multiple biological processes as well as the development and progression of human complex diseases. Using the huge number of known heterogeneous biological datasets to predict potential associations between miRNAs and diseases is an important topic in the field of biology, medicine, and bioinformatics. In this study, considering the limitations in the previous computational methods, we developed the computational model of Heterogeneous Graph Inference for MiRNA-Disease Association prediction (HGIMDA) to uncover potential miRNA-disease associations by integrating miRNA functional similarity, disease semantic similarity, Gaussian interaction profile kernel similarity, and experimentally verified miRNA-disease associations into a heterogeneous graph. HGIMDA obtained AUCs of 0.8781 and 0.8077 based on global and local leave-one-out cross validation, respectively. Furthermore, HGIMDA was applied to three important human cancers for performance evaluation. As a result, 90% (Colon Neoplasms), 88% (Esophageal Neoplasms) and 88% (Kidney Neoplasms) of top 50 predicted miRNAs are confirmed by recent experiment reports. Furthermore, HGIMDA could be effectively applied to new diseases and new miRNAs without any known associations, which overcome the important limitations of many previous computational models.

PBMDA: A novel and effective path-based computational model for miRNA-disease association prediction

In the recent few years, an increasing number of studies have shown that microRNAs (miRNAs) play critical roles in many fundamental and important biological processes. As one of pathogenetic factors, the molecular mechanisms underlying human complex diseases still have not been completely understood from the perspective of miRNA. Predicting potential miRNA-disease associations makes important contributions to understanding the pathogenesis of diseases, developing new drugs, and formulating individualized diagnosis and treatment for diverse human complex diseases. Instead of only depending on expensive and time-consuming biological experiments, computational prediction models are effective by predicting potential miRNA-disease associations, prioritizing candidate miRNAs for the investigated diseases, and selecting those miRNAs with higher association probabilities for further experimental validation. In this study, Path-Based MiRNA-Disease Association (PBMDA) prediction model was proposed by integrating known human miRNA-disease associations, miRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity for miRNAs and diseases. This model constructed a heterogeneous graph consisting of three interlinked sub-graphs and further adopted depth-first search algorithm to infer potential miRNA-disease associations. As a result, PBMDA achieved reliable performance in the frameworks of both local and global LOOCV (AUCs of 0.8341 and 0.9169, respectively) and 5-fold cross validation (average AUC of 0.9172). In the cases studies of three important human diseases, 88% (Esophageal Neoplasms), 88% (Kidney Neoplasms) and 90% (Colon Neoplasms) of top-50 predicted miRNAs have been manually confirmed by previous experimental reports from literatures. Through the comparison performance between PBMDA and other previous models in case studies, the reliable performance also demonstrates that PBMDA could serve as a powerful computational tool to accelerate the identification of disease-miRNA associations.

IRWRLDA: improved random walk with restart for lncRNA-disease association prediction

In recent years, accumulating evidences have shown that the dysregulations of lncRNAs are associated with a wide range of human diseases. It is necessary and feasible to analyze known lncRNA-disease associations, predict potential lncRNA-disease associations, and provide the most possible lncRNA-disease pairs for experimental validation. Considering the limitations of traditional Random Walk with Restart (RWR), the model of Improved Random Walk with Restart for LncRNA-Disease Association prediction (IRWRLDA) was developed to predict novel lncRNA-disease associations by integrating known lncRNA-disease associations, disease semantic similarity, and various lncRNA similarity measures. The novelty of IRWRLDA lies in the incorporation of lncRNA expression similarity and disease semantic similarity to set the initial probability vector of the RWR. Therefore, IRWRLDA could be applied to diseases without any known related lncRNAs. IRWRLDA significantly improved previous classical models with reliable AUCs of 0.7242 and 0.7872 in two known lncRNA-disease association datasets downloaded from the lncRNADisease database, respectively. Further case studies of colon cancer and leukemia were implemented for IRWRLDA and 60% of lncRNAs in the top 10 prediction lists have been confirmed by recent experimental reports.

An O ( n log n ) algorithm for obstacle-avoiding routing tree construction in the λ-geometry plane

Routing is one of the important phases in VLSI/ULSI physical design. The obstacle-avoiding rectilinear Steiner minimal tree (OARSMT) construction is an essential part of routing since macro cells, IP blocks, and pre-routed nets are often regarded as obstacles in the routing phase. Efficient OARSMT algorithms can be employed in practical routers iteratively. Recently, IC routing and related researches have been extended from Manhattan architecture (λ2-geometry) to Y- / X-architecture (λ3- / λ4-geometry) to improve the chip performance. This paper presents an O(nlogn) heuristic, λ-OASMT, for obstacle-avoiding Steiner minimal tree construction in the λ-geometry plane. Based on obstacle-avoiding constrained Delaunay triangulation, a full connected tree is constructed and then embedded into λ-OASMT by a novel method called zonal combination. To the best of our knowledge, this is the first work addressing the λ-OASMT problem. Compared with two most recent works on OARSMT problem, λ-OASMT obtains up to 30Kx speedup with an even better quality solution. We have tested randomly generated cases with up to 1K terminals and 10K rectilinear obstacles within 3 seconds on a Sun V880 workstation (755MHz CPU and 4GB memory). The high efficiency and accuracy of λ-OASMT make it extremely practical and useful in the routing phase, as well as interconnect estimation in the process of floorplanning and placement.

Prediction of disease-related interactions between microRNAs and environmental factors based on a semi-supervised classifier.

Accumulated evidence has shown that microRNAs (miRNAs) can functionally interact with a number of environmental factors (EFs) and their interactions critically affect phenotypes and diseases. Therefore, in-silico inference of disease-related miRNA-EF interactions is becoming crucial not only for the understanding of the mechanisms by which miRNAs and EFs contribute to disease, but also for disease diagnosis, treatment, and prognosis. In this paper, we analyzed the human miRNA-EF interaction data and revealed that miRNAs (EFs) with similar functions tend to interact with similar EFs (miRNAs) in the context of a given disease, which suggests a potential way to expand the current relation space of miRNAs, EFs, and diseases. Based on this observation, we further proposed a semi-supervised classifier based method (miREFScan) to predict novel disease-related interactions between miRNAs and EFs. As a result, the leave-one-out cross validation has shown that miREFScan obtained an AUC of 0.9564, indicating that miREFScan has a reliable performance. Moreover, we applied miREFScan to predict acute promyelocytic leukemia-related miRNA-EF interactions. The result shows that forty-nine of the top 1% predictions have been confirmed by experimental literature. In addition, using miREFScan we predicted and publicly released novel miRNA-EF interactions for 97 human diseases. Finally, we believe that miREFScan would be a useful bioinformatic resource for the research about the relationships among miRNAs, EFs, and human diseases.

NLLSS: Predicting Synergistic Drug Combinations Based on Semi-supervised Learning.

Fungal infection has become one of the leading causes of hospital-acquired infections with high mortality rates. Furthermore, drug resistance is common for fungus-causing diseases. Synergistic drug combinations could provide an effective strategy to overcome drug resistance. Meanwhile, synergistic drug combinations can increase treatment efficacy and decrease drug dosage to avoid toxicity. Therefore, computational prediction of synergistic drug combinations for fungus-causing diseases becomes attractive. In this study, we proposed similar nature of drug combinations: principal drugs which obtain synergistic effect with similar adjuvant drugs are often similar and vice versa. Furthermore, we developed a novel algorithm termed Network-based Laplacian regularized Least Square Synergistic drug combination prediction (NLLSS) to predict potential synergistic drug combinations by integrating different kinds of information such as known synergistic drug combinations, drug-target interactions, and drug chemical structures. We applied NLLSS to predict antifungal synergistic drug combinations and showed that it achieved excellent performance both in terms of cross validation and independent prediction. Finally, we performed biological experiments for fungal pathogen Candida albicans to confirm 7 out of 13 predicted antifungal synergistic drug combinations. NLLSS provides an efficient strategy to identify potential synergistic antifungal combinations.

A computational framework to infer human disease-associated long noncoding RNAs.

As a major class of noncoding RNAs, long noncoding RNAs (lncRNAs) have been implicated in various critical biological processes. Accumulating researches have linked dysregulations and mutations of lncRNAs to a variety of human disorders and diseases. However, to date, only a few human lncRNAs have been associated with diseases. Therefore, it is very important to develop a computational method to globally predict potential associated diseases for human lncRNAs. In this paper, we developed a computational framework to accomplish this by combining human lncRNA expression profiles, gene expression profiles, and human disease-associated gene data. Applying this framework to available human long intergenic noncoding RNAs (lincRNAs) expression data, we showed that the framework has reliable accuracy. As a result, for non-tissue-specific lincRNAs, the AUC of our algorithm is 0.7645, and the prediction accuracy is about 89%. This study will be helpful for identifying novel lncRNAs for human diseases, which will help in understanding the roles of lncRNAs in human diseases and facilitate treatment. The corresponding codes for our method and the predicted results are all available at http://asdcd.amss.ac.cn/MingXiLiu/lncRNA-disease.html.