Big data in sleep medicine: prospects and pitfalls in phenotyping

Clinical polysomnography (PSG) databases are a rich resource in the era of “big data” analytics. We explore the uses and potential pitfalls of clinical data mining of PSG using statistical principles and analysis of clinical data from our sleep center. We performed retrospective analysis of self-reported and objective PSG data from adults who underwent overnight PSG (diagnostic tests, n=1835). Self-reported symptoms overlapped markedly between the two most common categories, insomnia and sleep apnea, with the majority reporting symptoms of both disorders. Standard clinical metrics routinely reported on objective data were analyzed for basic properties (missing values, distributions), pairwise correlations, and descriptive phenotyping. Of 41 continuous variables, including clinical and PSG derived, none passed testing for normality. Objective findings of sleep apnea and periodic limb movements were common, with 51% having an apnea–hypopnea index (AHI) >5 per hour and 25% having a leg movement index >15 per hour. Different visualization methods are shown for common variables to explore population distributions. Phenotyping methods based on clinical databases are discussed for sleep architecture, sleep apnea, and insomnia. Inferential pitfalls are discussed using the current dataset and case examples from the literature. The increasing availability of clinical databases for large-scale analytics holds important promise in sleep medicine, especially as it becomes increasingly important to demonstrate the utility of clinical testing methods in management of sleep disorders. Awareness of the strengths, as well as caution regarding the limitations, will maximize the productive use of big data analytics in sleep medicine

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

AbstractMany individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.</jats:p

Dopamine homeostasis and environmental risk factors in Parkinson's Disease model

The neurotransmitter dopamine (DA) is an important factor in the regulation of many biological processes, from pleasure and addiction to balance and locomotion. Therefore, understanding and defining the mechanisms and factors that are required for proper DA homeostasis is an integral component in managing and elucidating the causes of DA related diseases. Among these diseases, Parkinson's disease (PD) is the most notable and remains one of the most researched yet puzzling motor system associated neurological disorders. PD is characterized by a preferential loss of DA neurons in the substantia nigra. Though the cause and exact mechanism of this disease remains undefined, numerous environmental factors such as metals and pesticides have been associated with the etiology of the disease process. In the following studies, the genetic components of DA homeostasis and environmental risk factors in a Drosophila model of PD are investigated. The implication of metals as a component in the pathology of PD is examined in relationship to zinc toxicity. Catecholamines's up (Catsup), which plays a crucial role in regulating DA homeostasis and is proposed to be a member of the mammalian KE4 ZIP transporter family, demonstrates zinc sensitivity, with the proposed underlying factors being a dysregulation of DA synthesis and DA transport. The findings of this report demonstrate that loss of dopamine transporter (DAT) function, results in a more robust sensitivity to zinc than that seen in Catsup mutants. In addition exogenous DA increases sensitivity of wild type flies to zinc, similar to that which is seen Catsup mutants. Interestingly, LiCl ameliorates the toxic effects of zinc. The results also demonstrate a functional relationship between paraquat toxicity and DAT, which affects DA transport. To determine the consequences of early exposure to paraquat on lifespan and mobility, the effect of a one time exposure to young adult flies was observed. The results of this experiment show that a brief exposure to paraquat illicts long term detrimental affects on survival as well as parkinsonian type phenotypes. (Published By University of Alabama Libraries

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations