Functional Magnetic Resonance Imaging as an Assessment Tool in Critically Ill Patients

Little is known about whether residual cognitive function occurs in the earliest stages of brain injury. The overarching goal of the work presented in this dissertation was to elucidate the role of functional neuroimaging in assessing brain activity in critically ill patients. The overall objective was addressed in the following four empirical chapters: In Chapter 2, three versions of a hierarchically-designed auditory task were developed and their ability to detect various levels of auditory language processing was assessed in individual healthy participants. The same procedure was then applied in two acutely comatose patients. In Chapter 3, a hierarchical auditory task was employed in a heterogeneous cohort of acutely comatose patients. The results revealed that the level of auditory processing in coma may be predictive of subsequent functional recovery. In Chapter 4, two mental imagery paradigms were utilized to assess covert command-following in coma. The findings demonstrate, for the first time, preserved awareness in an acutely comatose patient. In Chapter 5, functional neuroimaging techniques were used for covert communication with two completely locked-in, critically ill patients. The results suggest that this methodology could be used as an augmentative communication tool to allow patients to be involved in their own medical decision-making. Taken together, the proceeding chapters of this work demonstrate that functional neuroimaging can detect preserved cognitive functions in some acutely comatose patients, which has both diagnostic and prognostic relevance. Moreover, these techniques may be extended even further to be used as a communication tool in critically ill patients

Design and Analysis of Randomized and Non-randomized Studies: Improving Validity and Reliability

The aim of the thesis is to investigate how to optimize the design and analysis of randomized and non-randomized therapeutic studies, in order to increase the validity and reliability of causal treatment effect estimates, specifically in heterogeneous diseases. The following research questions will be addressed: __1)__ What are the benefits of more advanced statistical analyses to estimate treatment effects from RTCs in heterogeneous diseases? a. What is the heterogeneity in acute neurological diseases with regard to baseline severity and further course of the disease? b. What is the potential gain in efficiency of covariate adjustment and proportional odds analysis in RCTs in Guillain-Barré syndrome (GBS)? __2)__ What is the validity and reliability of the RD design compared to an RCT to estimate causal treatment effects? a. What are threats to the validity of the RD design to estimate treatment effects compared to an RCT? b. How efficient is the RD design to estimate treatment effects compared to an RCT? c. What are the potential benefits of an alternative assignment approach in an RD design

A Predictive Model for Guillain-Barré Syndrome Based on Single Learning Algorithms

Background. Guillain-Barré Syndrome (GBS) is a potentially fatal autoimmune neurological disorder. The severity varies among the four main subtypes, named as Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Acute Motor Axonal Neuropathy (AMAN), Acute Motor Sensory Axonal Neuropathy (AMSAN), and Miller-Fisher Syndrome (MF). A proper subtype identification may help to promptly carry out adequate treatment in patients. Method. We perform experiments with 15 single classifiers in two scenarios: four subtypes’ classification and One versus All (OvA) classification. We used a dataset with the 16 relevant features identified in a previous phase. Performance evaluation is made by 10-fold cross validation (10-FCV). Typical classification performance measures are used. A statistical test is conducted in order to identify the top five classifiers for each case. Results. In four GBS subtypes’ classification, half of the classifiers investigated in this study obtained an average accuracy above 0.90. In OvA classification, the two subtypes with the largest number of instances resulted in the best classification results. Conclusions. This study represents a comprehensive effort on creating a predictive model for Guillain-Barré Syndrome subtypes. Also, the analysis performed in this work provides insight about the best single classifiers for each classification case

Forecasting Dengue, Chikungunya and Zika cases in Recife, Brazil: a spatio-temporal approach based on climate conditions, health notifications and machine learning

Dengue has become a challenge for many countries. Arboviruses transmitted by Aedes aegypti spread rapidly over the last decades. The emergence chikungunya fever and zika in South America poses new challenges to vector monitoring and control. This situation got worse from 2015 and 2016, with the rapid spread of chikungunya, causing fever and muscle weakness, and Zika virus, related to cases of microcephaly in newborns and the occurrence of Guillain-Barret syndrome, an autoimmune disease that affects the nervous system. The objective of this work was to construct a tool to forecast the distribution of arboviruses transmitted by the mosquito Aedes aegypti by implementing dengue, zika and chikungunya transmission predictors based on machine learning, focused on multilayer perceptrons neural networks, support vector machines and linear regression models. As a case study, we investigated forecasting models to predict the spatio-temporal distribution of cases from primary health notification data and climate variables (wind velocity, temperature and pluviometry) from Recife, Brazil, from 2013 to 2016, including 2015’s outbreak. The use of spatio-temporal analysis over multilayer perceptrons and support vector machines results proved to be very effective in predicting the distribution of arbovirus cases. The models indicate that the southern and western regions of Recife were very susceptible to outbreaks in the period under investigation. The proposed approach could be useful to support health managers and epidemiologists to prevent outbreaks of arboviruses transmitted by Aedes aegypti and promote public policies for health promotion and sanitation

Immunoglobulin G N-glycan biomarkers for autoimmune diseases: Current state and a glycoinformatics perspective

The effective treatment of autoimmune disorders can greatly benefit from disease-specific biomarkers that are functionally involved in immune system regulation and can be collected through minimally invasive procedures. In this regard, human serum IgG N-glycans are promising for uncovering disease predisposition and monitoring progression, and for the identification of specific molecular targets for advanced therapies. In particular, the IgG N-glycome in diseased tissues is considered to be disease-dependent; thus, specific glycan structures may be involved in the pathophysiology of autoimmune diseases. This study provides a critical overview of the literature on human IgG N-glycomics, with a focus on the identification of disease-specific glycan alterations. In order to expedite the establishment of clinically-relevant N-glycan biomarkers, the employment of advanced computational tools for the interpretation of clinical data and their relationship with the underlying molecular mechanisms may be critical. Glycoinformatics tools, including artificial intelligence and systems glycobiology approaches, are reviewed for their potential to provide insight into patient stratification and disease etiology. Challenges in the integration of such glycoinformatics approaches in N-glycan biomarker research are critically discussed

Simultaneous analysis of plasma and CSF by NMR and hierarchical models fusion

Because cerebrospinal fluid (CSF) is the biofluid which interacts most closely with the central nervous system, it holds promise as a reporter of neurological disease, for example multiple sclerosis (MScl). To characterize the metabolomics profile of neuroinflammatory aspects of this disease we studied an animal model of MScl—experimental autoimmune/allergic encephalomyelitis (EAE). Because CSF also exchanges metabolites with blood via the blood–brain barrier, malfunctions occurring in the CNS may be reflected in the biochemical composition of blood plasma. The combination of blood plasma and CSF provides more complete information about the disease. Both biofluids can be studied by use of NMR spectroscopy. It is then necessary to perform combined analysis of the two different datasets. Mid-level data fusion was therefore applied to blood plasma and CSF datasets. First, relevant information was extracted from each biofluid dataset by use of linear support vector machine recursive feature elimination. The selected variables from each dataset were concatenated for joint analysis by partial least squares discriminant analysis (PLS-DA). The combined metabolomics information from plasma and CSF enables more efficient and reliable discrimination of the onset of EAE. Second, we introduced hierarchical models fusion, in which previously developed PLS-DA models are hierarchically combined. We show that this approach enables neuroinflamed rats (even on the day of onset) to be distinguished from either healthy or peripherally inflamed rats. Moreover, progression of EAE can be investigated because the model separates the onset and peak of the disease

A new integrated framework for the identification of potential virus–drug associations

IntroductionWith the increasingly serious problem of antiviral drug resistance, drug repurposing offers a time-efficient and cost-effective way to find potential therapeutic agents for disease. Computational models have the ability to quickly predict potential reusable drug candidates to treat diseases.MethodsIn this study, two matrix decomposition-based methods, i.e., Matrix Decomposition with Heterogeneous Graph Inference (MDHGI) and Bounded Nuclear Norm Regularization (BNNR), were integrated to predict anti-viral drugs. Moreover, global leave-one-out cross-validation (LOOCV), local LOOCV, and 5-fold cross-validation were implemented to evaluate the performance of the proposed model based on datasets of DrugVirus that consist of 933 known associations between 175 drugs and 95 viruses.ResultsThe results showed that the area under the receiver operating characteristics curve (AUC) of global LOOCV and local LOOCV are 0.9035 and 0.8786, respectively. The average AUC and the standard deviation of the 5-fold cross-validation for DrugVirus datasets are 0.8856 ± 0.0032. We further implemented cross-validation based on MDAD and aBiofilm, respectively, to evaluate the performance of the model. In particle, MDAD (aBiofilm) dataset contains 2,470 (2,884) known associations between 1,373 (1,470) drugs and 173 (140) microbes. In addition, two types of case studies were carried out further to verify the effectiveness of the model based on the DrugVirus and MDAD datasets. The results of the case studies supported the effectiveness of MHBVDA in identifying potential virus-drug associations as well as predicting potential drugs for new microbes