Ontologies for the study of neurological disease

We have begun work on two separate but related ontologies for the study of neurological diseases. The first, the Neurological Disease Ontology (ND), is intended to provide a set of controlled, logically connected classes to describe the range of neurological diseases and their associated signs and symptoms, assessments, diagnoses, and interventions that are encountered in the course of clinical practice. ND is built as an extension of the Ontology for General Medical Sciences — a high-level candidate OBO Foundry ontology that provides a set of general classes that can be used to describe general aspects of medical science. ND is being built with classes utilizing both textual and axiomatized definitions that describe and formalize the relations between instances of other classes within the ontology itself as well as to external ontologies such as the Gene Ontology, Cell Ontology, Protein Ontology, and Chemical Entities of Biological Interest. In addition, references to similar or associated terms in external ontologies, vocabularies and terminologies are included when possible. Initial work on ND is focused on the areas of Alzheimer’s and other diseases associated with dementia, multiple sclerosis, and stroke and cerebrovascular disease. Extensions to additional groups of neurological diseases are planned. The second ontology, the Neuro-Psychological Testing Ontology (NPT), is intended to provide a set of classes for the annotation of neuropsychological testing data. The intention of this ontology is to allow for the integration of results from a variety of neuropsychological tests that assay similar measures of cognitive functioning. Neuro-psychological testing is an important component in developing the clinical picture used in the diagnosis of patients with a range of neurological diseases, such as Alzheimer’s disease and multiple sclerosis, and following stroke or traumatic brain injury. NPT is being developed as an extension to the Ontology for Biomedical Investigations

Developmental hypomyelination in Wolfram syndrome: New insights from neuroimaging and gene expression analyses

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration

High Throughput Neurological Phenotyping with MetaMap

The phenotyping of neurological patients involves the conversion of signs and symptoms into machine readable codes selected from an appropriate ontology. The phenotyping of neurological patients is manual and laborious. MetaMap is used for high throughput mapping of the medical literature to concepts in the Unified Medical Language System Metathesaurus (UMLS). MetaMap was evaluated as a tool for the high throughput phenotyping of neurological patients. Based on 15 patient histories from electronic health records, 30 patient histories from neurology textbooks, and 20 clinical summaries from the Online Mendelian Inheritance in Man repository, MetaMap showed a recall of 61-89%, a precision of 84-93%, and an accuracy of 56-84% for the identification of phenotype concepts. The most common cause of false negatives (failure to recognize a phenotype concept) was an inability of MetaMap to find concepts that were represented as a description or a definition of the concept. The most common cause of false positives (incorrect identification of a concept in the text) was a failure to recognize that a concept was negated. MetaMap shows potential for high throughput phenotyping of neurological patients if the problems of false negatives and false positives can be solved

Subsumption is a Novel Feature Reduction Strategy for High Dimensionality Datasets

High dataset dimensionality poses challenges for machine learning classifiers because of high computational costs and the adverse consequences of redundant features. Feature reduction is an attractive remedy to high dimensionality. Three different feature reduction strategies (subsumption, Relief F, and principal component analysis) were evaluated using four machine learning classifiers on a high dimension dataset with 474 unique features, 20 diagnoses, and 364 instances. All three feature reduction strategies proved capable of significant feature reduction while maintaining classification accuracy. At high levels of feature reduction, the principal components strategy outperformed Relief F and subsumption. Subsumption is a novel strategy for feature reduction if features are organized in a hierarchical ontology

Development of learning objectives for neurology in a veterinary curriculum: part I: undergraduates

Background With an increasing caseload of veterinary neurology patients in first opinion practice, there is a requirement to establish relevant learning objectives for veterinary neurology encompassing knowledge, skills and attitudes for veterinary undergraduate students in Europe. With help of experts in veterinary neurology from the European College of Veterinary Neurology (ECVN) and the European Society of Veterinary Neurology (ESVN) a survey of veterinary neurologic learning objectives using a modified Delphi method was conducted. The first phase comprised the development of a draft job description and learning objectives by a working group established by the ECVN. In the second phase, a quantitative questionnaire (multiple choice, Likert scale and free text) covering 140 learning objectives and subdivided into 8 categories was sent to 341 ESVN and ECVN members and a return rate of 62% (n = 213/341) was achieved. Results Of these 140 learning objectives ECVN Diplomates and ESVN members considered 42 (30%) objectives as not necessary for standard clinical veterinary neurology training, 94 (67%) were graded to be learned at a beginner level and 4 (3%) at an advanced level. The following objectives were interpreted as the most important day one skills: interpret laboratory tests, perform a neurological examination and establish a neuroanatomical localization. In this survey the three most important diseases of the central nervous system included epilepsy, intervertebral disc disease and inflammatory diseases. The three most important diseases of the peripheral nervous system included polyradiculoneuritis, myasthenia gravis and toxic neuropathies. Conclusions The results of this study should help to reform the veterinary curriculum regarding neurology and may reduce the phenomenon of “Neurophobia”.</p

Zika virus infection reprograms global transcription of host cells to allow sustained infection.

Zika virus (ZIKV) is an emerging virus causally linked to neurological disorders, including congenital microcephaly and Guillain-Barré syndrome. There are currently no targeted therapies for ZIKV infection. To identify novel antiviral targets and to elucidate the mechanisms by which ZIKV exploits the host cell machinery to support sustained replication, we analyzed the transcriptomic landscape of human microglia, fibroblast, embryonic kidney and monocyte-derived macrophage cell lines before and after ZIKV infection. The four cell types differed in their susceptibility to ZIKV infection, consistent with differences in their expression of viral response genes before infection. Clustering and network analyses of genes differentially expressed after ZIKV infection revealed changes related to the adaptive immune system, angiogenesis and host metabolic processes that are conducive to sustained viral production. Genes related to the adaptive immune response were downregulated in microglia cells, suggesting that ZIKV effectively evades the immune response after reaching the central nervous system. Like other viruses, ZIKV diverts host cell resources and reprograms the metabolic machinery to support RNA metabolism, ATP production and glycolysis. Consistent with these transcriptomic analyses, nucleoside metabolic inhibitors abrogated ZIKV replication in microglia cells

The unreasonable effectiveness of mathematics: Cartesian linguistics, the mind-body problem and pragmatic evolution

Victor Gomez-Pin highlighted succincty one object of the second Congress on Ontology held in San Sebastián and Barcelona in March of 1996 -by raising two questions due to Husserl about Descartes, namely: is there a persistent value to Descarte's most basic ideas? And if so, can they stimulete new, powerful ideas in our era? Indeed, one of the most interesting and fundamental puzzles that Descartes was the first to face with any success is the nature of the connections between mind and body, and the relevance of mathematics to both. It was the physicist Eugene Wigner, however, who called it the "unreasonable" elfectiveness of mathematics, by which he had in mind above all the powerful applications of mathematics to physics, which have proven crucial for the advance of modem science.1 The Greeks showed and early interest in these most basic questions of ontology and eplstemology, and from the answers given by such ligures as the Pythagoreans and Plato in antiquity, it is clear that mathematics played a fundamental part in their analysis and understanding of nature