Biomedical Literature Mining and Knowledge Discovery of Phenotyping Definitions

Indiana University-Purdue University Indianapolis (IUPUI)Phenotyping definitions are essential in cohort identification when conducting clinical research, but they become an obstacle when they are not readily available. Developing new definitions manually requires expert involvement that is labor-intensive, time-consuming, and unscalable. Moreover, automated approaches rely mostly on electronic health records’ data that suffer from bias, confounding, and incompleteness. Limited efforts established in utilizing text-mining and data-driven approaches to automate extraction and literature-based knowledge discovery of phenotyping definitions and to support their scalability. In this dissertation, we proposed a text-mining pipeline combining rule-based and machine-learning methods to automate retrieval, classification, and extraction of phenotyping definitions’ information from literature. To achieve this, we first developed an annotation guideline with ten dimensions to annotate sentences with evidence of phenotyping definitions' modalities, such as phenotypes and laboratories. Two annotators manually annotated a corpus of sentences (n=3,971) extracted from full-text observational studies’ methods sections (n=86). Percent and Kappa statistics showed high inter-annotator agreement on sentence-level annotations. Second, we constructed two validated text classifiers using our annotated corpora: abstract-level and full-text sentence-level. We applied the abstract-level classifier on a large-scale biomedical literature of over 20 million abstracts published between 1975 and 2018 to classify positive abstracts (n=459,406). After retrieving their full-texts (n=120,868), we extracted sentences from their methods sections and used the full-text sentence-level classifier to extract positive sentences (n=2,745,416). Third, we performed a literature-based discovery utilizing the positively classified sentences. Lexica-based methods were used to recognize medical concepts in these sentences (n=19,423). Co-occurrence and association methods were used to identify and rank phenotype candidates that are associated with a phenotype of interest. We derived 12,616,465 associations from our large-scale corpus. Our literature-based associations and large-scale corpus contribute in building new data-driven phenotyping definitions and expanding existing definitions with minimal expert involvement

Skills in Rheumatology

This Open Access book presents practical approaches to managing patients affected by various rheumatological diseases, allowing readers to gain a better understanding of the various clinical expressions and problems experienced by these patients. Discussing rheumatology from an organ systems perspective, it highlights the importance ofdetailed musculoskeletal examinations when treating patients affected by rheumatological diseases. The book first explores the latest diagnostic approaches and offers key tips for accurate musculoskeletal examinations before addressing the various treatment modalities, with a particular focus on the most common joints involved in rheumatoid arthritis: the wrists and the metacarpophalangeal joints (2nd and 3rd). Featuring easy-to-understand flow diagrams and explaining the common medical problems associated with rheumatic disease, such as shortness of breath and anemia, it is not only a valuable resource to rheumatologists, but will also appeal to medical students, junior residents, and primary healthcare physicians

Skills in Rheumatology

This Open Access book presents practical approaches to managing patients affected by various rheumatological diseases, allowing readers to gain a better understanding of the various clinical expressions and problems experienced by these patients. Discussing rheumatology from an organ systems perspective, it highlights the importance ofdetailed musculoskeletal examinations when treating patients affected by rheumatological diseases. The book first explores the latest diagnostic approaches and offers key tips for accurate musculoskeletal examinations before addressing the various treatment modalities, with a particular focus on the most common joints involved in rheumatoid arthritis: the wrists and the metacarpophalangeal joints (2nd and 3rd). Featuring easy-to-understand flow diagrams and explaining the common medical problems associated with rheumatic disease, such as shortness of breath and anemia, it is not only a valuable resource to rheumatologists, but will also appeal to medical students, junior residents, and primary healthcare physicians

Dyslipidemia

Dyslipidemia has a complex pathophysiology consisting of various genetic, lifestyle, and environmental factors. It has many adverse health impacts, notably in the development of chronic non-communicable diseases. Significant ethnic differences exist due to the prevalence and types of lipid disorders. While elevated serum total- and LDL-cholesterol are the main concern in Western populations, in other countries hypertriglyceridemia and low HDL-cholesterol are more prevalent. The latter types of lipid disorders are considered as components of the metabolic syndrome. The escalating trend of obesity, as well as changes in lifestyle and environmental factors will make dyslipidemia a global medical and public health threat, not only for adults but for the pediatric age group as well. Several experimental and clinical studies are still being conducted regarding the underlying mechanisms and treatment of dyslipidemia. The current book is providing a general overview of dyslipidemia from diverse aspects of pathophysiology, ethnic differences, prevention, health hazards, and treatment

Mitochondrial and autophagic alterations in human-derived cell models of Parkinson's disease related to LRRK2 (G2019S) and GBA (N370S) mutations

[eng] Parkinson's disease (PD) is the second most common neurodegenerative disease, and the most common movement disorder in the world population. In most cases its aetiology is still unknown, however, mitochondrial alterations and autophagy deregulations are some of the molecular mechanisms that are altered in this disease. These molecular alterations of PD are not limited only to the destruction of dopaminergic neurons in the substantia nigra pars compacta, but they have also been described in the peripheral nervous system and the organs that it innervates. There is also evidence of the presence of other molecular alterations in diverse tissues, such as dysfunction of Complex I of the mitochondrial respiratory chain and accumulation of alpha synuclein in fibroblasts of patients with PD. One of the great difficulties the research and understanding of the mechanisms that lead to PD is the inaccessibility of the target tissue of the disease. In the best of cases, autopsy tissue from patients with advanced PD is available, leaving a question mark about the molecular processes of prodromal and early stages of the disease. Animal models have helped to unravel some questions, but the development of accessible and replicable cell models, preferably at low cost, is much needed. It is in this context that the cellular models obtained from PD patients and from asymptomatic carriers of genes associated with the disease are of great importance and require validation. The present thesis consists of the study of two cell models obtained from patients with PD associated with the LRRK2 mutation (G2019S), asymptomatic carriers of LRRK2 (G2019S) and homozygous and heterozygous carriers of GBA (N370S); which are the genes most frequently associated with familial PD and the most important genetic risk factor for PD, respectively. First, the mitochondrial and autophagic profile of fibroblasts derived from the skin of asymptomatic carriers of the LRRK2 (G2019S) mutation and with PD were analysed. The analysis was carried out under two conditions, keeping the fibroblasts in a standard culture medium (DMEM with 25mM glucose) and after subjecting them to a mitochondrial challenge for 24 hours (DMEM with 10mM galactose), in order to simulate the oxidative environment of neurons. dopaminergic. In this study, a genotype-phenotype correlation was confirmed in fibroblasts obtained from asymptomatic carriers of the LRRK2 (G2029S) mutation and patients with PD linked to this same mutation, and it was demonstrated that a mitochondrial and autophagic function profile allows to differentiate between groups. The second study explored the genotype-phenotype correlation in a cellular model characterized by neurospheres, a conglomerate of cells obtained from the dedifferentiation of human adipocytes into neuronal stem cells, and its relationship with the onset of macroautophagy in subjects carrying the mutation GBA (N370S). The main finding of this study is that mitochondrial dysfunction preceded alterations of macroautogphagic flux in subjects carrying the GBA (N370S) mutation. In conclusion, the study of asymptomatic subjects carrying mutations associated with PD represents a relevant study method that shows initial molecular alterations and the presence of compensatory mechanisms that can be studied for the development of preventive strategies and treatments in early stages of the disease.[spa] La enfermedad de Parkinson (EP) es el trastorno de movimiento más frecuente en la población mundial. Considerada mayoritariamente idiopática y multifactorial, alteraciones mitocondriales y en la regulación autofagica son algunos de los mecanismos moleculares que se han encontrado alterados en la etiopatología de la enfermedad. El descubrimiento de genes relacionados a formas familiares de EP, del cual LRRK2 es el más frecuente, y los genes que aumentan el riesgo de padecer la enfermedad, como GBA, han abierto un campo de estudio en el cual se pueden analizar los mecanismos moleculares que llevan a la neurodegeneración en formas genéticas de la EP. La presente tesis consiste en el estudio de dos modelos celulares obtenidos a partir de portadores asintomáticos de LRRK2(G2019S) (NMLRRK2(G2019S)), pacientes con EP asociada a la mutación LRRK2(G2019S) (PDLRRK2(G2019S)), así como de portadores homozigotos y heterozigotos de GBA(N370S). El primer estudio analizó el perfil mitocondrial y autofágico de fibroblastos NMLRRK2(G2019S) y PDLRRK2(G2019S). El análisis se realizó en dos condiciones, en un medio de cultivo estándar (DMEM, glucosa 25mM) y tras someterlos 24 horas a un reto mitocondrial (DMEM, galactosa 10mM), simulando el ambiente oxidativo de las neuronas dopaminérgicas. En este estudio se confirmó una correlación genotipo-fenotipo en fibroblastos obtenidos de ambos grupos y una función mitocondrial y autofágica que permite diferenciarlos entre ellos. El segundo estudio exploró la correlación genotipo-fenotipo en un modelo celular caracterizado por neuroesferas, un conglomerado de células obtenido a partir de la desdiferenciación de adipocitos humanos en células madres neuronales, y su relación con el inicio de la macroautofagia en sujetos portadores de la mutación GBA(N370S). El hallazgo principal de este segundo estudio es que la disfunción mitocondrial precede a las alteraciones del flujo macroautofágico en sujetos portadores de la mutación GBA(N370S). El estudio de sujetos asintomáticos portadores de mutaciones asociadas a PD representa un relevante método de estudio que evidencia alteraciones moleculares iniciales y la presencia de mecanismos compensatorios que pueden ser estudiados para el desarrollo de estrategias preventivas y tratamientos en lateabas tempranas de la enfermedad

The Pathogenesis and Clinical Management of Dengue

Dengue is an arboviral disease that exerts a significant public health burden on the tropical world. Currently there is no available vaccine or specific therapeutic. My reviews show that our understanding of dengue pathogenesis, transmission dynamics and optimal case management is incomplete. The work presented in this thesis is a compilation of expert reviews/perspectives and primary research that addresses some of these knowledge gaps. Understanding dengue pathogenesis and in particular, risk factors for progression to severe dengue, is an important priority to reduce morbidity and mortality, especially in young children. Genetic variants of the MICB and PLCE genes have been shown to be associated with severe dengue. I tested the hypothesis that these variants are also associated with less severe dengue infection and with higher early viraemia levels in two studies involving the genotyping of 3961 and 2742 dengue cases respectively. My studies showed that these genetic variants are associated with less severe but clinically apparent dengue infection but showed no evidence of an association with higher viraemia levels. The functional basis of these susceptibility mutations remains unclear. Dengue transmission dynamics are shaped by the prevalence of the permissive vectors, Aedes aegypti and Aedes albopictus. My research hypothesis was that susceptibility and transmission of dengue might differ between the two species. I conducted a clinical study that compared the susceptibility of Ae. aegypti and Ae. albopictus to both initial and disseminated dengue after direct blood feeding experiments on viraemic patients. This work showed that both mosquito types were equally susceptible to initial infection with dengue but that Ae. albopictus was less likely to develop salivary infection, and, thus, an infectious phenotype. These results have important implications for the development of dengue transmission models, especially in areas of dengue emergence where the influence of Ae. albopictus is thought to be greatest. In addition, the results confirm the central importance of patient plasma viraemia in causing successful DENV transmission, suggesting that reducing this through the use of antivirals could potentially reduce transmission. Clinical management of dengue patients remains an enormous challenge. Statins are rational candidate drugs for dengue because of their previously identified positive influence on vascular endothelial function. I conducted a clinical trial of lovastatin therapy in adult dengue patients. The trial showed that lovastatin was safe and well tolerated in dengue patients but it did not show any positive effects on the kinetics of viraemia or on any of the pre-specified clinical or laboratory features. I conducted a survey of platelet management in 20 countries and found a wide variety of approaches to the use of platelets in dengue underscoring the need for prospective clinical trials to inform evidence in this area. To reduce the large sample size normally required for the development of dengue therapeutics, I considered the use of a human dengue infection model in dengue drug development. This model has the potential to a game-changer in drug development and in the design of future trials

Interplay between lipoproteins, the complement system and blood cells in atherosclerosis

Er is toenemend bewijs dat het niet noodzakelijk is om cholesterol en vetzuren in nuchtere toestand te meten, maar dat een niet-nuchtere meting in de meeste gevallen ook kan volstaan. De ontwikkeling van aderverkalking is complex en gaat veel verder dan alleen het cholesterolgehalte in het bloed. Aderverkalking, vet- en cholesterolstofwisseling en het immuunsysteem inclusief rode bloedcellen zijn nauw met elkaar verbonden. Hierbij lijkt het immuunsysteem zowel schadelijk als beschermend tegen de ontwikkeling van aderverkalking te kunnen werken. Vitamine D kan deels de schadelijke activatie van witte bloedcellen na vetinname voorkomen en heeft een gunstig effect op de elasticiteit van de slagaders. Rode bloedcellen kunnen juist een beschermend effect uitoefenen op de vaatwand door middel van transport van schadelijke cholesterolpakketjes. Dit transportmechanisme kan mogelijk plaatsvinden door middel van het niet-specifieke immuunsysteem met de complement receptor 1 danwel op basis van de ABO bloedgroep of een combinatie van beideUBL - phd migration 201