title: Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.
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.
authors: Christina A
authors: CA
authors: Markunas
authors: Eric
authors: E
authors: Lock
authors: Karen
authors: K
authors: Soldano
authors: Heidi
authors: H
authors: Cope
authors: Chien-Kuang C
authors: CK
authors: Ding
authors: David S
authors: DS
authors: Enterline
authors: Gerald
authors: G
authors: Grant
authors: Herbert
authors: H
authors: Fuchs
authors: Allison E
authors: AE
authors: Ashley-Koch
authors: Duke Center for Human Genetics, Duke University Medical Center, Durham, NC, USA. simon.gregory@duke.edu.
authors: Simon G
authors: SG
authors: Gregory
mesh_terms: D001139:Arnold-Chiari Malformation / Q000235:genetics*; D002648:Child; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D025341:Principal Component Analysis; D060888:Real-Time Polymerase Chain Reaction; D012886:Skull / Q000002:abnormalities*