Statistical Analysis of the TSAD Interactome in Multiple Sclerosis: Multiple Testing, High Dimensional Regression and Interactions

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System (CNS). The presence of Oligoclonal Band (OCB) in Cerebrospinal Fluid (CSF) is an important diagnostic tool in MS. The main aim of this study was to determine SNPs and SNPs-SNPs interactions in the genomic TSAD (T-Cell Specific Adaptor Proteins) region which explain the difference between two MS conditions: OCB positive vs. OCB negative in sampled Norwegian patients. The data to this study was obtained from the MS Registry Ulleval University Hospital, Oslo, Norway. Of 899 patients, 802 were OCB positive and 97 OCB negative, each has 923 SNPs at specific position in their chromosome measure. The study incorporated two different statistical methods to our data analysis. First, we apply variable selection based on Lasso method, here we discuss Lasso for Logistic Regression Analysis and see interaction effect for the Lasso selected SNPs. In the second section, we analyze variable selection based on test of association. Here, we used Chi-Square and Fisher’s exact test of association to see association between the statuses of OCB to each SNP. We found out that the Chi-Square test of association selected 34 significant SNPs and the association test for Fisher’s exact test selected 38 significant SNPs at significance level of 0.05. Then we used Boferroni and False Discovery Rate to statistically significant SNPs for the multiple testing corrections. Finally, we looked for interaction effects to some selected SNPs from test of association and we have determined SNPs and SNP-SNP interactions which appear to have significant associated to the OCB subpopulation of MS patients, based on our study of the Norwegian cohort. These are selected SNPs which have been selected by any of the methods that we used (various hypothesis testing and regressions). This is the SNPs that we think should be studied further and validated on a new dataset. Of particular importance are the seven SNP-SNP interactions which we found. It is the first time a SNP-SNP study has been performed on these data, and the finding will be communicated to the Norwegian molecular biologists to be followed up. Keywords: Multiple Sclerosis, OCB, TSAD, Multiple Testing, High Dimensional Regressions, LASSO DOI : 10.7176/JMPB/61-01 Publication date: November 30 th 2019