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VADEr: Vision Transformer-Inspired Framework for Polygenic Risk Reveals Underlying Genetic Heterogeneity in Prostate Cancer.

作者信息

Talwar James V, Klie Adam, Pagadala Meghana S, Pasternak Gil, Rose Brent, Seibert Tyler M, Gymrek Melissa, Carter Hannah

机构信息

Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA 92093, USA.

Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA.

出版信息

medRxiv. 2025 May 18:2025.05.16.25327672. doi: 10.1101/2025.05.16.25327672.


DOI:10.1101/2025.05.16.25327672
PMID:40463543
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12132116/
Abstract

Polygenic risk scores (PRSs) serve as quantitative metrics of genetic liability for various conditions. Traditionally calculated as an effect size weighted genotype summation, this formulation assumes conditional feature independence and overlooks the potential for complex interactions among genetic variants. Transformers, a class of deep learning architectures known for capturing dependencies between features, have demonstrated remarkable predictive power across domains. In this work, we introduce VADEr, a Vision Transformer (ViT)-inspired architecture that combines techniques from both natural language processing and computer vision to capture properties exhibited by genetic data and model local and global interactions for genotype-to-phenotype prediction. Evaluating VADEr's performance in predicting prostate cancer (PCa) risk, we found that across a range of metrics, including accuracy, average precision, and Matthews correlation coefficient, VADEr outperformed all benchmark methods, demonstrating its effectiveness in the context of complex disease risk prediction. To illuminate identified drivers of disease risk by VADEr, we formulated DARTH scores, an attention-based attribution metric, to capture the personalized contribution of each genomic region. These scores revealed distinct genetic heterogeneity captured by VADEr, with drivers of predicted risk identified in key PCa risk regions including the , , and loci. DARTH scores also revealed germline predispositions for particular PCa molecular subtypes, including an association between the locus and the subtype, both implicated in the regulation of androgen receptor activity. Overall, by effectively capturing dependencies among genetic variants and providing interpretable insights, VADEr and DARTH scores offer a promising direction for advancing genotype-to-phenotype prediction, particularly in complex disease.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf91/12132116/3c10b59e46c8/nihpp-2025.05.16.25327672v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf91/12132116/8e4d72e5a9ef/nihpp-2025.05.16.25327672v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf91/12132116/1bfeea42f8a5/nihpp-2025.05.16.25327672v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf91/12132116/3c10b59e46c8/nihpp-2025.05.16.25327672v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf91/12132116/8e4d72e5a9ef/nihpp-2025.05.16.25327672v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf91/12132116/1bfeea42f8a5/nihpp-2025.05.16.25327672v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf91/12132116/3c10b59e46c8/nihpp-2025.05.16.25327672v1-f0003.jpg

相似文献

[1]
VADEr: Vision Transformer-Inspired Framework for Polygenic Risk Reveals Underlying Genetic Heterogeneity in Prostate Cancer.

medRxiv. 2025-5-18

[2]
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[3]
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[4]
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[5]
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[6]
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J Imaging Inform Med. 2025-1-27

[7]
Precision Medicine in Cardiovascular Disease Prevention: Clinical Validation of Multi-Ancestry Polygenic Risk Scores in a U.S. Cohort.

Nutrients. 2025-3-6

[8]
Polygenic Risk and Rare Variants in Endotypes of Idiopathic Pulmonary Fibrosis.

medRxiv. 2025-6-4

[9]
Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study.

Elife. 2023-3-27

[10]
Skin Cancer Segmentation and Classification Using Vision Transformer for Automatic Analysis in Dermatoscopy-Based Noninvasive Digital System.

Int J Biomed Imaging. 2024-2-3

本文引用的文献

[1]
Nucleotide Transformer: building and evaluating robust foundation models for human genomics.

Nat Methods. 2025-2

[2]
Modeling gene interactions in polygenic prediction via geometric deep learning.

Genome Res. 2025-1-22

[3]
Histopathologic and Molecular Characterization of IDH-Mutant Prostatic Adenocarcinoma.

Mod Pathol. 2025-1

[4]
DeepRisk: A deep learning approach for genome-wide assessment of common disease risk.

Fundam Res. 2024-3-19

[5]
GRIEVOUS: your command-line general for resolving cross-dataset genotype inconsistencies.

Bioinformatics. 2024-8-2

[6]
Inferring disease architecture and predictive ability with LDpred2-auto.

Am J Hum Genet. 2023-12-7

[7]
Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response.

Nat Commun. 2023-5-12

[8]
Deep learning-based polygenic risk analysis for Alzheimer's disease prediction.

Commun Med (Lond). 2023-4-6

[9]
PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry.

BMC Cancer. 2022-12-9

[10]
Markers of kidney function, genetic variation related to cognitive function, and cognitive performance in the UK Biobank.

BMC Nephrol. 2022-4-27

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