Browsing by Subject "Linear regression"

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    Brain Connectivity-Informed Regularization Methods for Regression
    (Springer, 2017-12-06) Karas, Marta; Brzyski, Damian; Dzemidzic, Mario; Goñi, Joaquín; Kareken, David A.; Randolph, Timothy W.; Harezlak, Jaroslaw; Neurology, School of Medicine
    One of the challenging problems in brain imaging research is a principled incorporation of information from different imaging modalities. Frequently, each modality is analyzed separately using, for instance, dimensionality reduction techniques, which result in a loss of mutual information. We propose a novel regularization method to estimate the association between the brain structure features and a scalar outcome within the linear regression framework. Our regularization technique provides a principled approach to use external information from the structural brain connectivity and inform the estimation of the regression coefficients. Our proposal extends the classical Tikhonov regularization framework by defining a penalty term based on the structural connectivity-derived Laplacian matrix. Here, we address both theoretical and computational issues. The approach is first illustrated using simulated data and compared with other penalized regression methods. We then apply our regularization method to study the associations between the alcoholism phenotypes and brain cortical thickness using a diffusion imaging derived measure of structural connectivity. Using the proposed methodology in 148 young male subjects with a risk for alcoholism, we found a negative associations between cortical thickness and drinks per drinking day in bilateral caudal anterior cingulate cortex, left lateral OFC, and left precentral gyrus.
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    Roles of alternative splicing in modulating transcriptional regulation
    (BMC, 2017-10-03) Li, Jin; Wang, Yang; Rao, Xi; Wang, Yue; Feng, Weixing; Liang, Hong; Medical and Molecular Genetics, School of Medicine
    Background The ability of a transcription factor to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms. Alternative splicing can modulate gene function by adding or removing certain protein domains, and therefore affect the activity of protein. Reverse engineering of gene regulatory networks using gene expression profiles has proven valuable in dissecting the logical relationships among multiple proteins during the transcriptional regulation. However, it is unclear whether alternative splicing of certain proteins affects the activity of other transcription factors. Results In order to investigate the roles of alternative splicing during transcriptional regulation, we constructed a statistical model to infer whether the alternative splicing events of modulator proteins can affect the ability of key transcription factors in regulating the expression levels of their transcriptional targets. We tested our strategy in KIRC (Kidney Renal Clear Cell Carcinoma) using the RNA-seq data downloaded from TCGA (the Cancer Genomic Atlas). We identified 828of modulation relationships between the splicing levels of modulator proteins and activity levels of transcription factors. For instance, we found that the activity levels of GR (glucocorticoid receptor) protein, a key transcription factor in kidney, can be influenced by the splicing status of multiple proteins, including TP53, MDM2 (mouse double minute 2 homolog), RBM14 (RNA-binding protein 14) and SLK (STE20 like kinase). The influenced GR-targets are enriched by key cancer-related pathways, including p53 signaling pathway, TR/RXR activation, CAR/RXR activation, G1/S checkpoint regulation pathway, and G2/M DNA damage checkpoint regulation pathway. Conclusions Our analysis suggests, for the first time, that exon inclusion levels of certain regulatory proteins can affect the activities of many transcription factors. Such analysis can potentially unravel a novel mechanism of how splicing variation influences the cellular function and provide important insights for how dysregulation of splicing outcome can lead to various diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12918-017-0465-6) contains supplementary material, which is available to authorized users.