Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.
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2014-06
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Abstract
Background
Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.Methods
A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.Results
All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.Conclusions
Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.Type
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Markunas, Christina A, Eric Lock, Karen Soldano, Heidi Cope, Chien-Kuang C Ding, David S Enterline, Gerald Grant, Herbert Fuchs, et al. (2014). Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics. BMC medical genomics, 7(1). p. 39. 10.1186/1755-8794-7-39 Retrieved from https://hdl.handle.net/10161/25905.
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Scholars@Duke
Gerald Arthur Grant
Herbert Edgar Fuchs
Clinical neuro-oncology research including collaborations studying molecular genetics of childhood brain tumors.
Potential role of the free electron laser in surgery of pediatric brain tumors. Current work includes animal models with human brain tumor xenografts in preclinical studies.
Collaboration with the neurooncology laboratory of Dr. Darell Bigner in preclinical studies of new therapeutic agents.
Allison Elizabeth Ashley-Koch
My work focuses on the dissection of human traits using multi-omic technologies (genetics, epigenetics, metabolomics and proteomics). I am investigating the basis of several neurological and psychiatric conditions such as neural tube defects and post-traumatic stress disorder. I also study modifiers of sickle cell disease.
Simon Gray Gregory
Dr. Gregory is the Margaret Harris and David Silverman Distinguished Professor and Director of the Brain Tumor Omics Program in the Duke Department of Neurosurgery, the Vice Chair of Research in the Department of Neurology, and Director of the Molecular Genomics Core at the Duke Molecular Physiology Institute.
As a neurogenomicist, Dr. Gregory applies the experience gained from leading the sequencing of chromosome 1 for the Human Genome Project to elucidating the mechanisms underlying multi-factorial diseases using genetic, genomic, and epigenetic approaches. Dr. Gregory’s primary areas of research involve understanding the molecular processes associated with disease development and progression in brain tumors and Alzheimer’s disease, drug induced white matter injury repair in multiple sclerosis, and the characterization of lesion microenvironmental changes in MS.
He is broadly regarded across Duke as a leader in the development of novel single cell and spatial molecular technologies towards understanding the pathogenic mechanisms of disease development. Dr. Gregory is also the Section Chair of Genomics and Epigenetics at the DMPI and Director of the Duke Center of Autoimmunity and MS in the Department of Neurology.
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