Unified Cox model based multifactor dimensionality reduction method for gene-gene interaction analysis of the survival phenotype

BioData Mining

Seungyeoun Lee¹  Donghee Son¹  Yongkang Kim²  Taesung Park²  Wenbao Yu³ 

[1] Department of Mathematics and Statistics, Sejong University;Department of Statistics, Seoul National University;Division of Oncology and Centre for Childhood Cancer Research, Children’s Hospital of Philadelphia;

关键词: Survival time;    Cox model;    Multifactor dimensionality reduction method;    Gene-gene interaction;    Unified model based method;   

DOI  :  10.1186/s13040-018-0189-1

来源: DOAJ

【 摘 要 】

Abstract Background One strategy for addressing missing heritability in genome-wide association study is gene-gene interaction analysis, which, unlike a single gene approach, involves high-dimensionality. The multifactor dimensionality reduction method (MDR) has been widely applied to reduce multi-levels of genotypes into high or low risk groups. The Cox-MDR method has been proposed to detect gene-gene interactions associated with the survival phenotype by using the martingale residuals from a Cox model. However, this method requires a cross-validation procedure to find the best SNP pair among all possible pairs and the permutation procedure should be followed for the significance of gene-gene interactions. Recently, the unified model based multifactor dimensionality reduction method (UM-MDR) has been proposed to unify the significance testing with the MDR algorithm within the regression model framework, in which neither cross-validation nor permutation testing are needed. In this paper, we proposed a simple approach, called Cox UM-MDR, which combines Cox-MDR with the key procedure of UM-MDR to identify gene-gene interactions associated with the survival phenotype. Results The simulation study was performed to compare Cox UM-MDR with Cox-MDR with and without the marginal effects of SNPs. We found that Cox UM-MDR has similar power to Cox-MDR without marginal effects, whereas it outperforms Cox-MDR with marginal effects and more robust to heavy censoring. We also applied Cox UM-MDR to a dataset of leukemia patients and detected gene-gene interactions with regard to the survival time. Conclusion Cox UM-MDR is easily implemented by combining Cox-MDR with UM-MDR to detect the significant gene-gene interactions associated with the survival time without cross-validation and permutation testing. The simulation results are shown to demonstrate the utility of the proposed method, which achieves at least the same power as Cox-MDR in most scenarios, and outperforms Cox-MDR when some SNPs having only marginal effects might mask the detection of the causal epistasis.

【 授权许可】

Unknown