BioMed Research International

Volume 2016 (2016), Article ID 7460740, 9 pages

http://dx.doi.org/10.1155/2016/7460740

## A Meta-Path-Based Prediction Method for Human miRNA-Target Association

^{1}College of Information Science and Electronic Engineering & Collaboration and Innovation Center for Digital Chinese Medicine of 2011 Project of Colleges and Universities in Hunan Province, Hunan University, Changsha, Hunan 410082, China^{2}College of Information Science and Electronic Engineering, Hunan University, Changsha, Hunan 410082, China

Received 30 June 2016; Revised 14 August 2016; Accepted 21 August 2016

Academic Editor: Xing Chen

Copyright © 2016 Jiawei Luo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### Abstract

MicroRNAs (miRNAs) are short noncoding RNAs that play important roles in regulating gene expressing, and the perturbed miRNAs are often associated with development and tumorigenesis as they have effects on their target mRNA. Predicting potential miRNA-target associations from multiple types of genomic data is a considerable problem in the bioinformatics research. However, most of the existing methods did not fully use the experimentally validated miRNA-mRNA interactions. Here, we developed RMLM and RMLMSe to predict the relationship between miRNAs and their targets. RMLM and RMLMSe are global approaches as they can reconstruct the missing associations for all the miRNA-target simultaneously and RMLMSe demonstrates that the integration of sequence information can improve the performance of RMLM. In RMLM, we use RM measure to evaluate different relatedness between miRNA and its target based on different meta-paths; logistic regression and MLE method are employed to estimate the weight of different meta-paths. In RMLMSe, sequence information is utilized to improve the performance of RMLM. Here, we carry on fivefold cross validation and pathway enrichment analysis to prove the performance of our methods. The fivefold experiments show that our methods have higher AUC scores compared with other methods and the integration of sequence information can improve the performance of miRNA-target association prediction.

#### 1. Introduction

MicroRNAs (miRNAs) are important endogenous 21-22 nt RNAs that play important regulatory roles in gene expression. Several studies have shown that miRNAs participate in the regulation of amount cellular process, such as cell proliferation and differentiation [1], development [2], and disease [3, 4]. Considering the importance of miRNAs, it is critical to identify and decipher miRNA-target interactions at a genome level.

All the time, scientists and academics have made great efforts in uncovering the associations between miRNA and its targets by using biological experiments [5–8]. However, it is impossible to depict a complete picture of miRNA regulation mechanisms only relying on biological experiments due to the high expenses on time and cost [9]. Therefore, computational approaches must be designed to be a cost-effective choice to describe the complete mechanism of miRNA regulatory. Now, many computational approaches show great advantage in predicting putative miRNA targets [10–13].

Over the past decade, plenty of miRNA-mRNA pairs prediction approaches have been developed to identify miRNA targets by using sequence data, including TargetScanS/TargetScan [14, 15], miRanda [16], Pictar [17], DITAT-MicroT [18], and PITA [19]. The majority of these prediction algorithms were built on specific binding rules, including the degree of site conservation, thermodynamic stability, sequence complementarity, energy, target site context, secondary structure, and site accessibility. Because of the complex character of miRNA-target interactions, these sequence-based methods have relatively high false-positive rate [20]. Furthermore, those predictions methods were mostly only at static sequence level, leading to those exact interactions that are specific to certain conditions or diseases. More importantly, sequence-based methods do not support statistically significant predictions as the miRNA binding sites are small, causing the results by different methods to be inconsistent.

To identify condition-specific interactions, many methods integrating expression profiles information into sequence-based predictions have been proposed to study miRNA-mRNA regulatory mechanism. These methods are based on the assumption that gene has negative correlations with the miRNA because of the downregulation effect that miRNAs have on their targets. These methods can be divided into four categories including simple correlation analysis [21, 22], simple/regularized regression models [23–25], Bayesian inference [19, 26], and causally inference between miRNAs and their targets [27]. Pearson correlation, one of the typical simple correlation methods, is commonly used in computing the strength of the association between a pair of miRNA and mRNA. However, Pearson correlation has high false-positive rate as the simplicity of it. Furthermore, Pearson correlation is mainly used in predicting linear associations. Lasso regression [24, 25], one of the regression models, is a high-dimensional method used to extract more reliable association as they usually optimize the network provided by sequence-based method and retain the relatively reliable edges. GenMir++ [19], the first and well-cited Bayesian inference method, calculates the existence probabilities of the relationship between a miRNA and its target based on a Bayesian model. However, this method needs prior information, such as sequence information. In general, methods in Bayesian category assume different priors [28] and are difficult in learning parameters. MCMG (joint analysis of multiple cancer for MiRNA-gene interactions), based on empirical Bayesian model [29], identifies miRNA-target associations that are either specific to a cancer type or common to several cancers by jointly analyzed across cancers. Muniategui et al. use do-calculus to estimate the causal effects the miRNA have on all the target mRNAs. The four categories methods can improve prediction performance as they integrate expression profiles information into sequence-based prediction methods [30]. But, most of the existing approaches cannot effectively use the valuable experimentally validated information [31–34]. Besides, the lack of miRNA expression profile may cause the unreliability of the predicted miRNA-target associations.

On the whole, the limitations of existing methods are summarized as follows. Firstly, sequenced-based prediction algorithms suffer from a high false-positive rate; second, the methods integrating expression profile data can only analyse one cancer every time; third, some methods cannot effectively utilize validated knowledge. To solve these problems, we propose two network-based approaches, RMLM and RMLMSe, to identify miRNA-target interactions based on meta-path. Meta-path is a good measuring method to compute the relatedness between the same or different types of objects in heterogeneous information network, as it contains a certain sequence of different link types [35]. Different meta-paths have different semantic meaning corresponding to different relationships between connected objects. In RMLM, we first utilize RM (a meta-path related measure proposed by Cao et al. [36]) to evaluate the existence probability of a link between miRNA and its targets. As different meta-path corresponds to different relation graphs, we may improve the final performance when integrating these different graphs by appropriate weights corresponding to different meta-paths. Thus, we then employ logistic regression and maximum-likelihood estimation (MLE) method to estimate the weight of different meta-path. Here, the issue of relationship prediction can be regarded as a two-class classification problem by using Bayesian analysis and logistic regression and then the MLE method can be employed to estimate the parameter vector. In RMLMSe, sequence information is integrated to improve the performance of the RMLM. Furthermore, as global approaches, RMLM and RMLMSe can remodel the missing relationship for all the diseases-associated miRNAs at the same time. Fivefold cross validations, pathway enrichment analysis about global network, and three important diseases network show that our proposed methods work well in predicting the relationship between miRNA and its target.

#### 2. Problem Definition

In this part, we describe the concepts of Heterogeneous Information Network and meta-path used in this paper.

##### 2.1. Heterogeneous Information Network

A heterogeneous information network is an important type of information network with multiple types of nodes and multiple types of links [36–38]. It can be represented as . is the set of nodes, which involves types of nodes: , where is th node of type . is the set of links between the nodes in , which involves types of links.

Each type of links between source node of type and target node of type corresponds to a binary relation . More specifically, if (th nodes of type ) and (th nodes of type ) are connected by a link of type . For example, in Figure 1, the relation between miRNA and gene is “.” Particularly, equals 1 if th miRNA regulates th gene.