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Genetic Epidemiology
Article . 2025 . Peer-reviewed
License: CC BY
Data sources: Crossref
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PubMed Central
Article . 2025
License: CC BY
Data sources: PubMed Central
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Exploring Random Forest in Genetic Risk Score Construction

Authors: Vaishnavi Venkat; Kaylyn Clark; X. Jessie Jeng; Tsung‐Chieh Yao; Hui‐Ju Tsai; Tzu‐Pin Lu; Tzu‐Hung Hsiao; +8 Authors

Exploring Random Forest in Genetic Risk Score Construction

Abstract

ABSTRACT Genetic risk scores (GRS) are crucial tools for estimating an individual's genetic liability to various traits and diseases, computed as a weighted sum of trait‐associated allele counts. Traditionally, GRS models assume additive, linear effects of risk variants. However, complex traits often involve nonadditive interactions, such as epistasis, which are not captured by these conventional methods. In this study, we investigate the use of random forest (RF) models as a model‐free approach for constructing GRS, leveraging RF's capacity to capture complex, nonlinear interactions among genetic variants. Specifically, we introduce two new RF‐based GRS strategies to boost RF performance and to incorporate base data information if available, including (1) ctRF, which optimizes linkage disequilibrium (LD) clumping and p ‐value thresholds within RF; and (2) wRF, which adjusts the chance of SNP inclusion in tree nodes based on their association strength. Through simulation studies and real data applications of Alzheimer's disease, body mass index, and atopy, we find that ctRF consistently outperforms other RF‐based methods and classical additive models when traits exhibit complex genetic architectures. Additionally, incorporating informative base data into RF‐GRS construction can enhance predictive accuracy. Our findings suggest that RF‐based GRS can effectively capture intricate genetic interactions, and offer a robust alternative to traditional GRS methods, especially for complex traits with nonlinear genetic effects.

Keywords

Random Forest, Models, Genetic, Epistasis, Genetic, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Body Mass Index, Alzheimer Disease, Risk Factors, Humans, Genetic Predisposition to Disease, Computer Simulation, Research Article, Genome-Wide Association Study, Genetic Risk Score

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
2
Top 10%
Average
Average
Green
hybrid