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Machine learning models identify ferroptosis-related genes as potential diagnostic biomarkers for Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a complex, and multifactorial neurodegenerative disease. Previous studies have revealed that oxidative stress, synaptic toxicity, autophagy, and neuroinflammation play crucial roles in the progress of AD, however, its pathogenesis is still unclear. Recent researches have indicated that ferroptosis, an iron-dependent programmed cell death, might be involved in the pathogenesis of AD. Therefore, we aim to screen correlative ferroptosis-related genes (FRGs) in the progress of AD to clarify insights into the diagnostic value. Interestingly, we identified eight FRGs were significantly differentially expressed in AD patients. 10,044 differentially expressed genes (DEGs) were finally identified by differential expression analysis. The following step was investigating the function of DEGs using gene set enrichment analysis (GSEA). Weight gene correlation analysis was performed to explore ten modules and 104 hub genes. Subsequently, based on machine learning algorithms, we constructed diagnostic classifiers to select characteristic genes. Through the multivariable logistic regression analysis, five features (RAF1, NFKBIA, MOV10L1, IQGAP1, FOXO1) were then validated, which composed a diagnostic model of AD. Thus, our findings not only developed genetic diagnostics strategy, but set a direction for further study of the disease pathogenesis and therapy targets.

SUBMITTER: Deng Y

PROVIDER: S-EPMC9575464 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Machine learning models identify ferroptosis-related genes as potential diagnostic biomarkers for Alzheimer's disease.

Deng Yanyao Y Feng Yanjin Y Lv Zhicheng Z He Jinli J Chen Xun X Wang Chen C Yuan Mingyang M Xu Ting T Gao Wenzhe W Chen Dongjie D Zhu Hongwei H Hou Deren D

Frontiers in aging neuroscience 20220928

Alzheimer's disease (AD) is a complex, and multifactorial neurodegenerative disease. Previous studies have revealed that oxidative stress, synaptic toxicity, autophagy, and neuroinflammation play crucial roles in the progress of AD, however, its pathogenesis is still unclear. Recent researches have indicated that ferroptosis, an iron-dependent programmed cell death, might be involved in the pathogenesis of AD. Therefore, we aim to screen correlative ferroptosis-related genes (FRGs) in the progre ...[more]

PMID: 36262887

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Project description:BackgroundAlzheimer's disease (AD) involves complex alterations in biological pathways, making comprehensive blood biomarkers crucial for accurate and earlier diagnosis. However, the cost-effectiveness and operational complexity of method using blood-based biomarkers significantly limit its availability in clinical practice.MethodsWe developed low-cost, convenient machine learning-based with digital biomarkers (MLDB) using plasma spectra data to detect AD or mild cognitive impairment (MCI) from healthy controls (HCs) and discriminate AD from different types of neurodegenerative diseases. Retrospective data were gathered for 1324 individuals, including 293 with amyloid beta positive AD, 151 with mild cognitive impairment (MCI), 106 with Lewy body dementia (DLB), 106 with frontotemporal dementia (FTD), 135 with progressive supranuclear palsy (PSP) and 533 healthy controls (HCs) between July 2017 and August 2023.FindingsRandom forest classifier and feature selection procedures were used to select digital biomarkers. MLDB achieved area under the curves (AUCs) of 0.92 (AD vs. HC, Sensitivity 88.2%, specificity 84.1%), 0.89 (MCI vs. HC, Sensitivity 88.8%, specificity 86.4%), 0.83 (AD vs. DLB, Sensitivity 77.2%, specificity 74.6%), 0.80 (AD vs. FTD, sensitivity 74.2%, specificity 72.4%), and 0.93 (AD vs. PSP, sensitivity 76.1%, specificity 75.7%). Digital biomarkers distinguishing AD from HC were negatively correlated with plasma p-tau217 (r = -0.22, p < 0.05) and glial fibrillary acidic protein (GFAP) (r = -0.09, p < 0.05).InterpretationThe ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared) plasma spectra features can identify AD-related pathological changes. These spectral features serve as digital biomarkers, providing valuable support in the early screening and diagnosis of AD.FundingThe National Natural Science Foundation of China, STI2030-Major Projects, National Key R&D Program of China, Outstanding Youth Fund of Hunan Provincial Natural Science Foundation, Hunan Health Commission Grant, Science and Technology Major Project of Hunan Province, Hunan Innovative Province Construction Project, Grant of National Clinical Research Center for Geriatric Disorders, Xiangya Hospital and Postdoctoral Fellowship Program of CPSF.

Project description:BackgroundUlcerative colitis (UC) is an idiopathic, chronic disorder characterized by inflammation, injury, and disruption of the colonic mucosa. However, there are still many difficulties in the diagnosis and differential diagnosis of UC. An increasing amount of research has shown a connection between ferroptosis and the etiology of UC. Therefore, our study aimed to identify the key genes related to ferroptosis in UC to provide new ideas for diagnosis UC.MethodsGene expression profiles of normal and UC samples were extracted from the Gene Expression Omnibus (GEO) database. By combining differentially expressed genes (DEGs), Weighted correlation network analysis (WGCNA) genes, and ferroptosis-related genes, hub genes were identified and then screened using Lasso regression. Based on the key genes, gene ontology (GO) and gene set enrichment analysis (GSEA) analyses were performed. We used NaiveBeyas, Logistic, IBk, and RandomForest algorithms to build a disease diagnosis model using the hub genes. The model was validated using GSE87473 as the validation set.ResultsGene expression matrices of GSE87466 and GSE75214 were downloaded from the GEO database, including 184 UC patients and 43 control samples. A total of 699 DEGs were obtained. From FerrDb, 565 genes related to ferroptosis were identified. The 1,513 genes with the highest absolute correlation coefficient value in the MEblue module were obtained from WGCNA analysis. Five hub genes (LCN2, MUC1, PARP8, PLIN2, and TIMP1) were identified using the Lasso regression algorithm based on the overlapped DEGs, WGCNA-identified genes, and ferroptosis-related genes. GO and GSEA analyses revealed that 5 hub genes were identified as being involved in the negative regulation of transcription by competitive promoter binding, cellular response to citrate cycle_tca_cycle, cytosolic_dna_sensing pathway, UV-A, and beta-alanine metabolism. The logistic algorithm's values of the area under the curve (AUC)were 1.000 and 0.995 for training and validation cohorts, and sensitivity is 0.962, specificity is 1.000, respectively, as determined by comparing various methods.ConclusionsThe previously described hub genes were identified as being intimately related to ferroptosis in UC and capable of distinguishing UC patients from controls. By detecting the expression of several genes, this model may aid in diagnosing UC and understanding the etiology and treatment of the disease.

Project description:BackgroundAlzheimer's disease (AD) is the most prevalent form of dementia, and is becoming one of the most burdening and lethal diseases. More useful biomarkers for diagnosing AD and reflecting the disease progression are in need and of significance.MethodsThe integrated bioinformatic analysis combined with machine-learning strategies was applied for exploring crucial functional pathways and identifying diagnostic biomarkers of AD. Four datasets (GSE5281, GSE131617, GSE48350, and GSE84422) with samples of AD frontal cortex are integrated as experimental datasets, and another two datasets (GSE33000 and GSE44772) with samples of AD frontal cortex were used to perform validation analyses. Functional Correlation enrichment analyses were conducted based on Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Reactome database to reveal AD-associated biological functions and key pathways. Four models were employed to screen the potential diagnostic biomarkers, including one bioinformatic analysis of Weighted gene co-expression network analysis (WGCNA)and three machine-learning algorithms: Least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) analysis. The correlation analysis was performed to explore the correlation between the identified biomarkers with CDR scores and Braak staging.ResultsThe pathways of the immune response and oxidative stress were identified as playing a crucial role during AD. Thioredoxin interacting protein (TXNIP), early growth response 1 (EGR1), and insulin-like growth factor binding protein 5 (IGFBP5) were screened as diagnostic markers of AD. The diagnostic efficacy of TXNIP, EGR1, and IGFBP5 was validated with corresponding AUCs of 0.857, 0.888, and 0.856 in dataset GSE33000, 0.867, 0.909, and 0.841 in dataset GSE44770. And the AUCs of the combination of these three biomarkers as a diagnostic tool for AD were 0.954 and 0.938 in the two verification datasets.ConclusionThe pathways of immune response and oxidative stress can play a crucial role in the pathogenesis of AD. TXNIP, EGR1, and IGFBP5 are useful biomarkers for diagnosing AD and their mRNA level may reflect the development of the disease by correlation with the CDR scores and Breaking staging.

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Machine learning models identify ferroptosis-related genes as potential diagnostic biomarkers for Alzheimer's disease.

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Machine learning models identify ferroptosis-related genes as potential diagnostic biomarkers for Alzheimer's disease.

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