ABSTRACT
A novel application of Hidden Markov Models is used to help research intended to test the immunuregulatory effects of mesenchymal stem cells in a cynomolgus monkey model of islet transplantation. The Hidden Markov Model, an unsupervised learning data mining technique, is used to automatically determine the postoperative day (POD) corresponding to a decrease of graft function, a possible sign of transplant rejection, on nonhuman primates after isolated islet cell transplant. Currently, decrease of graft function is being determined solely on experts' judgment. Further, information gathered from the evaluation of construted Hidden Markov Models is used as part of a clustering method to aggregate the nonhuman subjects into groups or clusters with the objective of finding similarities that could potentially help predict the health outcome of subjects undergoing postoperative care. Results on expert labeled data show the HMM to be accurate 60% of the time. Clusters based on the HMMs further suggest a possible correspondence between donor haplotypes matching and loss of function outcomes.
ABSTRACT
Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.
