Dataset Information

Non-parametric combination analysis of multiple data types enables detection of novel regulatory mechanisms in T cells of multiple sclerosis patients.

ABSTRACT: Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system with prominent neurodegenerative components. The triggering and progression of MS is associated with transcriptional and epigenetic alterations in several tissues, including peripheral blood. The combined influence of transcriptional and epigenetic changes associated with MS has not been assessed in the same individuals. Here we generated paired transcriptomic (RNA-seq) and DNA methylation (Illumina 450?K array) profiles of CD4+ and CD8+ T cells (CD4, CD8), using clinically accessible blood from healthy donors and MS patients in the initial relapsing-remitting and subsequent secondary-progressive stage. By integrating the output of a differential expression test with a permutation-based non-parametric combination methodology, we identified 149 differentially expressed (DE) genes in both CD4 and CD8 cells collected from MS patients. Moreover, by leveraging the methylation-dependent regulation of gene expression, we identified the gene SH3YL1, which displayed significant correlated expression and methylation changes in MS patients. Importantly, silencing of SH3YL1 in primary human CD4 cells demonstrated its influence on T cell activation. Collectively, our strategy based on paired sampling of several cell-types provides a novel approach to increase sensitivity for identifying shared mechanisms altered in CD4 and CD8 cells of relevance in MS in small sized clinical materials.

SUBMITTER: Fernandes SJ

PROVIDER: S-EPMC6700160 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Non-parametric combination analysis of multiple data types enables detection of novel regulatory mechanisms in T cells of multiple sclerosis patients.

Fernandes Sunjay Jude SJ Morikawa Hiromasa H Ewing Ewoud E Ruhrmann Sabrina S Joshi Rubin Narayan RN Lagani Vincenzo V Karathanasis Nestoras N Khademi Mohsen M Planell Nuria N Schmidt Angelika A Tsamardinos Ioannis I Olsson Tomas T Piehl Fredrik F Kockum Ingrid I Jagodic Maja M Tegnér Jesper J Gomez-Cabrero David D

Scientific reports 20190819 1

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system with prominent neurodegenerative components. The triggering and progression of MS is associated with transcriptional and epigenetic alterations in several tissues, including peripheral blood. The combined influence of transcriptional and epigenetic changes associated with MS has not been assessed in the same individuals. Here we generated paired transcriptomic (RNA-seq) and DNA methylation (Illumina 450 K array) profi ...[more]

PMID: 31427643

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Project description:One third of patients with medically refractory focal epilepsy have normal-appearing MRI scans. This poses a problem as identification of the epileptogenic region is required for surgical treatment. This study performs a multimodal voxel-based analysis (VBA) to identify brain abnormalities in MRI-negative focal epilepsy. Data was collected from 69 focal epilepsy patients (42 with discrete lesions on MRI scans, 27 with no visible findings on scans), and 62 healthy controls. MR images comprised T1-weighted, fluid-attenuated inversion recovery (FLAIR), fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging, and neurite density index (NDI) from neurite orientation dispersion and density imaging. These multimodal images were coregistered to T1-weighted scans, normalized to a standard space, and smoothed with 8 mm FWHM. Initial analysis performed voxel-wise one-tailed t-tests separately on grey matter concentration (GMC), FLAIR, FA, MD, and NDI, comparing patients with epilepsy to controls. A multimodal non-parametric combination (NPC) analysis was also performed simultaneously on FLAIR, FA, MD, and NDI. Resulting p-maps were family-wise error rate corrected, threshold-free cluster enhanced, and thresholded at p < 0.05. Sensitivity was established through visual comparison of results to manually drawn lesion masks or seizure onset zone (SOZ) from stereoelectroencephalography. A leave-one-out cross-validation with the same analysis protocols was performed on controls to determine specificity. NDI was the best performing individual modality, detecting focal abnormalities in 38% of patients with normal MRI and conclusive SOZ. GMC demonstrated the lowest sensitivity at 19%. NPC provided superior performance to univariate analyses with 50% sensitivity. Specificity in controls ranged between 96 and 100% for all analyses. This study demonstrated the utility of a multimodal VBA utilizing NPC for detecting epileptogenic lesions in MRI-negative focal epilepsy. Future work will apply this approach to datasets from other centres and will experiment with different combinations of MR sequences.

Dataset Information

Non-parametric combination analysis of multiple data types enables detection of novel regulatory mechanisms in T cells of multiple sclerosis patients.

Publications

Non-parametric combination analysis of multiple data types enables detection of novel regulatory mechanisms in T cells of multiple sclerosis patients.

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