Feature Fusion and Detection in Alzheimer’s Disease Using a Novel Genetic Multi-Kernel SVM Based on MRI Imaging and Gene Data

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Voxel-based morphometry provides an opportunity to study Alzheimer’s disease (AD) at a subtle level. Therefore, identifying the important brain voxels that can classify AD, early mild cognitive impairment (EMCI) and healthy control (HC) and studying the role of these voxels in AD will be crucial to improve our understanding of the neurobiological mechanism of AD. Combining magnetic resonance imaging (MRI) imaging and gene information, we proposed a novel feature construction method and a novel genetic multi-kernel support vector machine (SVM) method to mine important features for AD detection. Specifically, to amplify the differences among AD, EMCI and HC groups, we used the eigenvalues of the top 24 Single Nucleotide Polymorphisms (SNPs) in a p-value matrix of 24 genes associated with AD for feature construction. Furthermore, a genetic multi-kernel SVM was established with the resulting features. The genetic algorithm was used to detect the optimal weights of 3 kernels and the multi-kernel SVM was used after training to explore the significant features. By analyzing the significance of the features, we identified some brain regions affected by AD, such as the right superior frontal gyrus, right inferior temporal gyrus and right superior temporal gyrus. The findings proved the good performance and generalization of the proposed model. Particularly, significant susceptibility genes associated with AD were identified, such as CSMD1, RBFOX1, PTPRD, CDH13 and WWOX. Some significant pathways were further explored, such as the calcium signaling pathway (corrected p-value = 1.35 × 10−6) and cell adhesion molecules (corrected p-value = 5.44 × 10−4). The findings offer new candidate abnormal brain features and demonstrate the contribution of these features to AD.Peer reviewedFinal Published versio

A Triple-Network Dynamic Connection Study in Alzheimer's Disease

© 2022 Meng, Wu, Liang, Zhang, Xu, Yang and Meng. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/Alzheimer's disease (AD) was associated with abnormal organization and function of large-scale brain networks. We applied group independent component analysis (Group ICA) to construct the triple-network consisting of the saliency network (SN), the central executive network (CEN), and the default mode network (DMN) in 25 AD, 60 mild cognitive impairment (MCI) and 60 cognitively normal (CN) subjects. To explore the dynamic functional network connectivity (dFNC), we investigated dynamic time-varying triple-network interactions in subjects using Group ICA analysis based on k-means clustering (GDA-k-means). The mean of brain state-specific network interaction indices (meanNII) in the three groups (AD, MCI, CN) showed significant differences by ANOVA analysis. To verify the robustness of the findings, a support vector machine (SVM) was taken meanNII, gender and age as features to classify. This method obtained accuracy values of 95, 94, and 77% when classifying AD vs. CN, AD vs. MCI, and MCI vs. CN, respectively. In our work, the findings demonstrated that the dynamic characteristics of functional interactions of the triple-networks contributed to studying the underlying pathophysiology of AD. It provided strong evidence for dysregulation of brain dynamics of AD.Peer reviewedFinal Published versio

Integrative network analysis of rifampinregulated miRNAs and their functions in human hepatocytes

Rifampin is an important drug used in the treatment of tuberculosis, and it increases the drug metabolism in human hepatocytes. Previous studies have shown that rifampin can indirectly influence drug deposition through the regulation of molecular interactions of miRNA, PXR and other genes. The potential functions of miRNAs associated with rifampin- induced drug disposition are poorly understood. In this study, significantly differentially expressed miRNAs (SDEM) were extracted and used to predict the miRNA-regulated co-expression target genes (MCeTG). Additionally, a miRNA-regulated co-expressed protein interaction network (MCePIN) was constructed for SDEM by extending from the protein interaction network (PIN). The functioning of the miRNAs were analyzed using GO analysis and KEGG pathway enrichment analysis. A total of 20 miRNAs belonging to SDEM were identified, and 632 miRNA-regulated genes were predicted. The MCePIN was constructed by extending from PIN, and 10 miRNAs and 33 genes that are relevant to 7 functions, including response to wounding, wound healing, response to drug, defense response, inflammatory response, liver development and drug metabolism, were discerned. The results provided by this study offer valuable insights into the effect of rifampin on miRNAs, genes and protein levels

Advances in computational methods for identifying cancer driver genes

Cancer driver genes (CDGs) are crucial in cancer prevention, diagnosis and treatment. This study employed computational methods for identifying CDGs, categorizing them into four groups. The major frameworks for each of these four categories were summarized. Additionally, we systematically gathered data from public databases and biological networks, and we elaborated on computational methods for identifying CDGs using the aforementioned databases. Further, we summarized the algorithms, mainly involving statistics and machine learning, used for identifying CDGs. Notably, the performances of nine typical identification methods for eight types of cancer were compared to analyze the applicability areas of these methods. Finally, we discussed the challenges and prospects associated with methods for identifying CDGs. The present study revealed that the network-based algorithms and machine learning-based methods demonstrated superior performance

Genome-wide association and interaction studies of CSF T-tau/Aβ42 ratio in ADNI cohort

The pathogenic relevance in Alzheimer’s disease (AD) presents a decrease of cerebrospinal fluid (CSF) amyloid-ß42 (Aß42) burden and an increase in CSF total-tau (T-tau) levels. In this work, we performed genome-wide association study (GWAS) and genome-wide interaction study (GWIS) of T-tau/Aß42 ratio as an AD imaging quantitative trait (QT) on 843 subjects and 563,980 single nucleotide polymorphisms (SNPs) in ADNI cohort. We aim to identify not only SNPs with significant main effects but also SNPs with interaction effects to help explain “missing heritability”. Linear regression method was used to detect SNP-SNP interactions among SNPs with uncorrected p-value≤0.01 from the GWAS. Age, gender and diagnosis were considered as covariates in both studies. The GWAS results replicated the previously reported AD-related genes APOE, APOC1 and TOMM40, as well as identified 14 novel genes, which showed genome-wide statistical significance. GWIS revealed 7 pairs of SNPs meeting the cell-size criteria and with bonferroni-corrected p-value≤0.05. As we expect, these interaction pairs all had marginal main effects but explained a relatively high-level variance of T-tau/Aß42, demonstrating their potential association with AD pathology

Hippocampal Subregion and Gene Detection in Alzheimer’s Disease Based on Genetic Clustering Random Forest

The distinguishable subregions that compose the hippocampus are differently involved in functions associated with Alzheimer's disease (AD). Thus, the identification of hippocampal subregions and genes that classify AD and healthy control (HC) groups with high accuracy is meaningful. In this study, by jointly analyzing the multimodal data, we propose a novel method to construct fusion features and a classification method based on the random forest for identifying the important features. Specifically, we construct the fusion features using the gene sequence and subregions correlation to reduce the diversity in same group. Moreover, samples and features are selected randomly to construct a random forest, and genetic algorithm and clustering evolutionary are used to amplify the difference in initial decision trees and evolve the trees. The features in resulting decision trees that reach the peak classification are the important "subregion gene pairs". The findings verify that our method outperforms well in classification performance and generalization. Particularly, we identified some significant subregions and genes, such as hippocampus amygdala transition area (HATA), fimbria, parasubiculum and genes included RYR3 and PRKCE. These discoveries provide some new candidate genes for AD and demonstrate the contribution of hippocampal subregions and genes to AD

Genome-wide Network-assisted Association and Enrichment Study of Amyloid Imaging Phenotype in Alzheimer's Disease

Background: The etiology of Alzheimer's disease remains poorly understood at the mechanistic level, and genome-wide network-based genetics have the potential to provide new insights into the disease mechanisms. Objective: The study aimed to explore the collective effects of multiple genetic association signals on an AV-45 PET measure, which is a well-known Alzheimer's disease biomarker, by employing a network assisted strategy. Methods: First, we took advantage of a dense module search algorithm to identify modules enriched by genetic association signals in a protein-protein interaction network. Next, we performed statistical evaluation to the modules identified by dense module search, including a normalization process to adjust the topological bias in the network, a replication test to ensure the modules were not found randomly , and a permutation test to evaluate unbiased associations between the modules and amyloid imaging phenotype. Finally, topological analysis, module similarity tests and functional enrichment analysis were performed for the identified modules. Results: We identified 24 consensus modules enriched by robust genetic signals in a genome-wide association analysis. The results not only validated several previously reported AD genes (APOE, APP, TOMM40, DDAH1, PARK2, ATP5C1, PVRL2, ELAVL1, ACTN1 and NRF1), but also nominated a few novel genes (ABL1, ABLIM2) that have not been studied in Alzheimer's disease but have shown associations with other neurodegenerative diseases. Conclusion: The identified genes, consensus modules and enriched pathways may provide important clues to future research on the neurobiology of Alzheimer's disease and suggest potential therapeutic targets

Multivariate genome wide association and network analysis of subcortical imaging phenotypes in Alzheimer's disease

Background: Genome-wide association studies (GWAS) have identified many individual genes associated with brain imaging quantitative traits (QTs) in Alzheimer's disease (AD). However single marker level association discovery may not be able to address the underlying biological interactions with disease mechanism. Results: In this paper, we used the MGAS (Multivariate Gene-based Association test by extended Simes procedure) tool to perform multivariate GWAS on eight AD-relevant subcortical imaging measures. We conducted multiple iPINBPA (integrative Protein-Interaction-Network-Based Pathway Analysis) network analyses on MGAS findings using protein-protein interaction (PPI) data, and identified five Consensus Modules (CMs) from the PPI network. Functional annotation and network analysis were performed on the identified CMs. The MGAS yielded significant hits within APOE, TOMM40 and APOC1 genes, which were known AD risk factors, as well as a few new genes such as LAMA1, XYLB, HSD17B7P2, and NPEPL1. The identified five CMs were enriched by biological processes related to disorders such as Alzheimer's disease, Legionellosis, Pertussis, and Serotonergic synapse. Conclusions: The statistical power of coupling MGAS with iPINBPA was higher than traditional GWAS method, and yielded new findings that were missed by GWAS. This study provides novel insights into the molecular mechanism of Alzheimer's Disease and will be of value to novel gene discovery and functional genomic studies

Modulation of transcriptional activity in brain lower grade glioma by alternative splicing

Proteins that modify the activity of transcription factors (TFs) are often called modulators and play a vital role in gene transcriptional regulation. Alternative splicing is a critical step of gene processing, and differentially spliced isoforms may have different functions. Alternative splicing can modulate gene function by adding or removing certain protein domains and thereby influence the activity of a protein. The objective of this study is to investigate the role of alternative splicing in modulating the transcriptional regulation in brain lower grade glioma (LGG), especially transcription factor ELK1, which is closely related to various disorders, including Alzheimer’s disease and Down syndrome. The results showed that changes in the exon inclusion ratio of proteins APP and STK16 are associated with changes in the expression correlation between ELK1 and its targets. In addition, the structural features of the two modulators are strongly associated with the pathological impact of exon inclusion. The results of our analysis suggest that alternatively spliced proteins have different functions in modifying transcription factors and can thereby induce the dysregulation of multiple genes

Detection of Association Features Based on Gene Eigenvalues and MRI Imaging Using Genetic Weighted Random Forest

In the studies of Alzheimer’s disease (AD), jointly analyzing imaging data and genetic data provides an effective method to explore the potential biomarkers of AD. AD can be separated into healthy controls (HC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD. In the meantime, identifying the important biomarkers of AD progression, and analyzing these biomarkers in AD provide valuable insights into understanding the mechanism of AD. In this paper, we present a novel data fusion method and a genetic weighted random forest method to mine important features. Specifically, we amplify the difference among AD, LMCI, EMCI and HC by introducing eigenvalues calculated from the gene p-value matrix for feature fusion. Furthermore, we construct the genetic weighted random forest using the resulting fused features. Genetic evolution is used to increase the diversity among decision trees and the decision trees generated are weighted by weights. After training, the genetic weighted random forest is analyzed further to detect the significant fused features. The validation experiments highlight the performance and generalization of our proposed model. We analyze the biological significance of the results and identify some significant genes (CSMD1, CDH13, PTPRD, MACROD2 and WWOX). Furthermore, the calcium signaling pathway, arrhythmogenic right ventricular cardiomyopathy and the glutamatergic synapse pathway were identified. The investigational findings demonstrate that our proposed model presents an accurate and efficient approach to identifying significant biomarkers in AD