Application of Multidimensional Selective Item Response Regression Model for Studying Multiple Gene Methylation in...

Alteration of gene methylation patterns has been reported to be involved in the early onsets of many human malignancies. Many exogenous risk factors, such as cigarette smoke, dietary additives, chemical exposures, radiation, and biologic agents including viral infection, are involved in the methylation pathways of cancers. We propose a multidimensional selective item response regression model to describe and test how a risk factor may alter molecular pathways involving aberrant methylation of multiple genes in oncogenesis. Our modeling framework is built on an item response model for multivariate dichotomous responses of high dimension, such as aberrant methylation of multiple tumor-suppressor genes, but we allow risk factors such as SV40 viral infection to alter the distribution of the latent factors that subsequently affect the outcome of cancer. We postulate empirical identification conditions under our model formulation. Moreover, we do not prespecify the links between the multiple dichotomous methylation responses and the latent factors, but rather conduct specification searches with a genetic algorithm to discover the links. Parameter estimation through maximum likelihood and specification searches in models with multidimensional latent factors for multivariate binary responses have become practical only recently, due to modern statistical computing development. We illustrate our proposal with the biological finding that simultaneous methylation of multiple tumor-suppressor genes is associated with the presence of SV40 viral sequences and with the cancer status of lymphoma/leukemia.We are able to test whether the data are consistent with the causal hypothesis that SV40 induces aberrant methylation of multiple genes in its oncogenic pathways. At the same time, we are able to evaluate the role of SV40 in the methylation pathway and to determine whether the methylation pathway is responsible for the development of leukemia/lymphoma.