Exploring changes in lipid metabolism is helpful for providing unique insight into hepatocellular carcinoma (HCC) pathogenesis mechanisms and early hepatocarcinogenesis. However, lipid metabolism involves different omics molecular interactions by means of both linear and nonlinear forms. Thus, we proposed a novel network construction method based on molecular pair evaluation from linear and nonlinear viewpoints (PELN) for clinical studies. In PELN, molecular relationships were explored in depth by horizontal comparison (linear relationship) and vertical comparison (nonlinear relationship) to reflect disease development for biomarker discovery. In the score calculated by PELN, case ratios and case frequencies were used to comprehensively measure the discriminative ability of the molecular pairs, which can reduce the influence of sampling variability resulting from different subjects. HCC genomics and metabolomics datasets related to lipid metabolism were analyzed by PELN, and the selected network warning signals were shown to effectively predict cancer onset. The experimental results showed that compared with other network methods, including DMNC, DNB-HC, ATSD-DN and MN-PCC, PELN was more robust and precise for distinguishing HCC samples from non-HCC samples. Further analysis using statistical methods demonstrated that studying changes in lipid metabolism using PELN based on multiomics data can help to further understand the pathological mechanisms associated with HCC development, contributing to early diagnosis and affecting clinical prognosis.

MicroRNAs (miRNAs) play important roles in the occurrence and development of diseases. However, it is still challenging to identify the effective miRNA biomarkers for improving the disease diagnosis and prognosis. In this study, we proposed the miRNA data analysis method based on multi-view miRNA networks and reinforcement learning, miRMarker, to define the potential miRNA disease biomarkers. miRMarker constructs the cooperative regulation network and functional similarity network based on the expression data and known miRNA-disease relations, respectively. The cooperative regulation of miRNAs was evaluated by measuring the changes of relative expression. Natural language processing was introduced for calculating the miRNA functional similarity. Then, miRMarker integrates the multi-view miRNA networks and defines the informative miRNA modules through a reinforcement learning strategy. We compared miRMarker with eight efficient data analysis methods on nine transcriptomics datasets to show its superiority in disease sample discrimination. The comparison results suggested that miRMarker outperformed other data analysis methods in receiver operating characteristic analysis. Furthermore, the defined miRNA modules of miRMarker on colorectal cancer data not only show the excellent performance of cancer sample discrimination but also play significant roles in the cancer-related pathway disturbances. The experimental results indicate that miRMarker can build the robust miRNA interaction network by integrating the multi-view networks. Besides, exploring the miRNA interaction network using reinforcement learning favors defining the important miRNA modules. In summary, miRMarker can be a hopeful tool in biomarker identification for human diseases.

During the development of complex diseases, there is a critical transition from one status to another at a tipping point, which can be an early indicator of disease deterioration. To effectively enhance the performance of early risk identification, a novel dynamic network construction algorithm for identifying early warning signals based on a data-driven approach (EWS-DDA) was proposed. In EWS-DDA, the shrunken centroid was introduced to measure dynamic expression changes in assumed pathway reactions during the progression of complex disease for network construction and to define early warning signals by means of a data-driven approach. We applied EWS-DDA to perform a comprehensive analysis of gene expression profiles of gastric cancer (GC) from The Cancer Genome Atlas database and the Gene Expression Omnibus database. Six crucial genes were selected as potential biomarkers for the early diagnosis of GC. The experimental results of statistical analysis and biological analysis suggested that the six genes play important roles in GC occurrence and development. Then, EWS-DDA was compared with other state-of-the-art network methods to validate its performance. The theoretical analysis and comparison results suggested that EWS-DDA has great potential for a more complete presentation of disease deterioration and effective extraction of early warning information.

BACKGROUND: Biomedical event extraction is a fundamental task in biomedical text mining, which provides inspiration for medicine research and disease prevention. Biomedical events include simple events and complex events. Existing biomedical event extraction methods usually deal with simple events and complex events uniformly, and the performance of complex event extraction is relatively low. RESULTS: In this paper, we propose a fine-grained Bidirectional Long Short Term Memory method for biomedical event extraction, which designs different argument detection models for simple and complex events respectively. In addition, multi-level attention is designed to improve the performance of complex event extraction, and sentence embeddings are integrated to obtain sentence level information which can resolve the ambiguities for some types of events. Our method achieves state-of-the-art performance on the commonly used dataset Multi-Level Event Extraction. CONCLUSIONS: The sentence embeddings enrich the global sentence-level information. The fine-grained argument detection model improves the performance of complex biomedical event extraction. Furthermore, the multi-level attention mechanism enhances the interactions among relevant arguments. The experimental results demonstrate the effectiveness of the proposed method for biomedical event extraction.

Different biomarker patterns, such as those of molecular biomarkers and ratio biomarkers, have their own merits in clinical applications. In this study, a novel machine learning method used in biomedical data analysis for constructing classification models by combining different biomarker patterns (CDBP)is proposed. CDBP uses relative expression reversals to measure the discriminative ability of different biomarker patterns, and selects the pattern with the higher score for classifier construction. The decision boundary of CDBP can be characterized in simple and biologically meaningful manners. The CDBP method was compared with eight state-of-the-art methods on eight gene expression datasets to test its performance. CDBP, with fewer features or ratio features, had the highest classification performance. Subsequently, CDBP was employed to extract crucial diagnostic information from a rat hepatocarcinogenesis metabolomics dataset. The potential biomarkers selected by CDBP provided better classification of hepatocellular carcinoma (HCC)and non-HCC stages than previous works in the animal model. The statistical analyses of these potential biomarkers in an independent human dataset confirmed their discriminative abilities of different liver diseases. These experimental results highlight the potential of CDBP for biomarker identification from high-dimensional biomedical datasets and demonstrate that it can be a useful tool for disease classification.

Analyzing the disease data from the view of combinatorial features may better characterize the disease phenotype. In this study, a novel method is proposed to construct feature combinations and a classification model (CFC-CM) by mining key feature relationships. CFC-CM iteratively tests for differences in the feature relationship between different groups. To do this, it uses a modified $k$k-top-scoring pair (M-$k$k-TSP) algorithm and then selects the most discriminative feature pairs in the current feature set to infer the combinatorial features and build the classification model. Compared with support vector machines, random forests, least absolute shrinkage and selection operator, elastic net, and M-$k$k-TSP, the superior performance of CFC-CM on nine public gene expression datasets validates its potential for more precise identification of complex diseases. Subsequently, CFC-CM was applied to two metabolomics datasets, it obtained accuracy rates of $88.73\pm 2.06\%$88.73±2.06% and $79.11\pm 2.70\%$79.11±2.70% in distinguishing between hepatocellular carcinoma and hepatic cirrhosis groups and between acute kidney injury (AKI) and non-AKI samples, results superior to those of the other five methods. In summary, the better results of CFC-CM show that in contrast to molecules and combinations constituted by just two features, the combinations inferred by appropriate number of features could better identify the complex diseases.