Serial Testing for Detection of Multilocus Genetic Interactions

• Main Author: Al-Khaledi, Zaid T.
• Format: Others
• Published: UKnowledge 2019
• Subjects: Multifactor dimensionality reduction; Cross Validation; Model selection; Continuous Trait; Continuous Phenotype; Ordered Combinatorial Partitioning; Applied Statistics; Biostatistics; Statistics and Probability
• Online Access: https://uknowledge.uky.edu/statistics_etds/37; https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1044&context=statistics_etds

A method to detect relationships between disease susceptibility and multilocus genetic interactions is the Multifactor-Dimensionality Reduction (MDR) technique pioneered by Ritchie et al. (2001). Since its introduction, many extensions have been pursued to deal with non-binary outcomes and/or account for multiple interactions simultaneously. Studying the effects of multilocus genetic interactions on continuous traits (blood pressure, weight, etc.) is one case that MDR does not handle. Culverhouse et al. (2004) and Gui et al. (2013) proposed two different methods to analyze such a case. In their research, Gui et al. (2013) introduced the Quantitative Multifactor-Dimensionality Reduction (QMDR) that uses the overall average of response variable to classify individuals into risk groups. The classification mechanism may not be efficient under some circumstances, especially when the overall mean is close to some multilocus means. To address such difficulties, we propose a new algorithm, the Ordered Combinatorial Quantitative Multifactor-Dimensionality Reduction (OQMDR), that uses a series of testings, based on ascending order of multilocus means, to identify best interactions of different orders with risk patterns that minimize the prediction error. Ten-fold cross-validation is used to choose from among the resulting models. Regular permutations testings are used to assess the significance of the selected model. The assessment procedure is also modified by utilizing the Generalized Extreme-Value distribution to enhance the efficiency of the evaluation process. We presented results from a simulation study to illustrate the performance of the algorithm. The proposed algorithm is also applied to a genetic data set associated with Alzheimer's Disease.