THREE METHODS TO INCREASE THE LIKELY TO IDENTIFY GENE INVOLVED IN COMPLEX DISEASE

The large part of human pathology is composed by complex disease, such as heart disease, obesity, cancer, diabetes, and many common psychiatric and neurological conditions. The common feature of all these conditions is the multifactorial etiology that involves both genetic and environmental factors. The common disease-common variant (CDCV) hypothesis posits that common, interacting alleles underlie most common diseases, in association with environmental factors. Furthermore, according to the thrift genotype, such alleles have been subjected to selective pressure, mainly those involved in metabolic disease such as T2DM and obesity. Although the concept of gene-environment interaction is central to ecogenetics, and has long been recognized by geneticists (Haldane 1946), there are relatively few detailed descriptions of gene–environment interaction in biomedical literature. This lacking may be explained by difficulties in collecting environmental information of enough quality and by great difficulties in analyze them. Indeed, when the number of factors to analyze is large, become overwhelming the course of dimensionality and the multiple testing problems. In the present thesis the hypothesis that knowledge-driven approaches may improve the ability to identify genes involved in complex disease was checked. Three approaches have been presented, each of them leading to the identification of a factor or of a interaction of factors. As the study a complex disease is composed by three steps: (1) selection of candidate genes, (2) collecting of genetic and non-genetic information and (3) statistical analysis of data, it is showed that each of these steps may be improved by consideration of the biological background. The first study, regarded the possibility to exploit evolutionary information to identify genes involved in type 2 diabetes. This hypothesis was based on the thrifty genotype hypothesis. A gene was identified, ACO1, and was successfully associated to the disease. In the second study, we analyses the case of a gene, PPAGγ that have been inconsistency associated with obesity. We hypothesized that the inconsistence of association may be due to its relationship with environment. Then we jointly analyzed the genotype of the gene and comprehensive nutritional information about a cohort and proved an interaction. The genotype of PPARγ modulated the response to the diet. Ala-carriers gained more weight than ProPro individuals when had the same caloric intake. In the third study, we implemented a software tool to create simulated populations based on gene-environment interactions. The system was based on genetic information to simulate realistic populations. We used these simulated populations to collect information on statistical methods more frequently used to study case-controls samples. Afterward, we built an ensemble of these methods and applied it to a real sample. We showed that ensemble had better performances of each single methods in condition of small sample size

VI Workshop on Computational Data Analysis and Numerical Methods: Book of Abstracts

The VI Workshop on Computational Data Analysis and Numerical Methods (WCDANM) is going to be held on June 27-29, 2019, in the Department of Mathematics of the University of Beira Interior (UBI), Covilhã, Portugal and it is a unique opportunity to disseminate scientific research related to the areas of Mathematics in general, with particular relevance to the areas of Computational Data Analysis and Numerical Methods in theoretical and/or practical field, using new techniques, giving especial emphasis to applications in Medicine, Biology, Biotechnology, Engineering, Industry, Environmental Sciences, Finance, Insurance, Management and Administration. The meeting will provide a forum for discussion and debate of ideas with interest to the scientific community in general. With this meeting new scientific collaborations among colleagues, namely new collaborations in Masters and PhD projects are expected. The event is open to the entire scientific community (with or without communication/poster)

Decision Support Based on Bio-PEPA Modeling and Decision Tree Induction: A New Approach, Applied to a Tuberculosis Case Study

The problem of selecting determinant features generating appropriate model structure is a challenge in epidemiological modelling. Disease spread is highly complex, and experts develop their understanding of its dynamic over years. There is an increasing variety and volume of epidemiological data which adds to the potential confusion. We propose here to make use of that data to better understand disease systems. Decision tree techniques have been extensively used to extract pertinent information and improve decision making. In this paper, we propose an innovative structured approach combining decision tree induction with Bio-PEPA computational modelling, and illustrate the approach through application to tuberculosis. By using decision tree induction, the enhanced Bio-PEPA model shows considerable improvement over the initial model with regard to the simulated results matching observed data. The key finding is that the developer expresses a realistic predictive model using relevant features, thus considering this approach as decision support, empowers the epidemiologist in his policy decision making

ACE2 diversity in placental mammals reveals the evolutionary strategy of SARS-CoV-2

The recent emergence of SARS-CoV-2 is responsible for the current pandemic of COVID-19, which uses the human membrane protein ACE2 as a gateway to the host-cell infection. We perform comparative genomic analysis of 70 ACE2 placental mammal orthologues to identify variations and contribute to the understanding of evolutionary dynamics behind this successful adaptation to infect humans. Our results reveal that 4% of the ACE2 sites are under positive selection, all located in the catalytic domain, suggesting possibly taxon-specific adaptations related to the ACE2 function, such as cardiovascular physiology. Considering all variable sites, we selected 30 of them located at the critical ACE2 binding sites to the SARS-CoV-like viruses to analyze in more detail. Our results reveal a relatively high diversity of ACE2 between placental mammal species while showing no polymorphism within human populations, at least considering the 30 inter-species variable sites. A perfect scenario for natural selection favored this opportunistic new coronavirus in its trajectory of infecting humans. We suggest that SARS-CoV-2 became a specialist coronavirus for human hosts. Differences in the rate of infection and mortality could be related to the innate immune responses, other unknown genetic factors, as well as non-biological factors

Doctor of Philosophy

dissertationThe purpose of this dissertation is to investigate the heterogeneity in patterns of aging and the factors throughout the life course that shape them. By focusing on variability within the population we are able to advance our knowledge of how circumstances throughout the life course affect the way individuals age. We find that the paths to disease and longevity are diverse and that the social environment plays an important role in shaping these patterns. Our results support a wide body of literature showing that morbidity is not an inevitable consequence of aging, even in the oldest old population. Health status and longevity are shaped by the historical circumstances and social environments that we live in. This study offers three innovative and significant contributions to the understanding of biological and environmental determinants of aging by (1) disentangling the biological and temporal sources of trends in cancer incidence among the elderly, (2) investigating the possible social and physiological effects of fertility history on comorbidity trajectories after age 65, and (3) studying heterogeneity in the heritable contributions to variation in longevity across early life family and social environments

Sex Differences in Middle Mortality

This work presents a new mathematical expression for middle and old age mortality as an alternative to the classic Gompertz-Makeham model. Whereas old age mortality is driven by biological aging, middle mortality is mainly caused by behavior. To test the model, sex differences in life expectancy and mortality in Europe from the mid-nineteenth century until recent periods are investigated. The here presented mortality model shows that the female advantage in life expectancy and its dynamics are mainly caused by male risky life style

Statistical advances and challenges for analyzing correlated high dimensional SNP data in genomic study for complex diseases

Recent advances of information technology in biomedical sciences and other applied areas have created numerous large diverse data sets with a high dimensional feature space, which provide us a tremendous amount of information and new opportunities for improving the quality of human life. Meanwhile, great challenges are also created driven by the continuous arrival of new data that requires researchers to convert these raw data into scientific knowledge in order to benefit from it. Association studies of complex diseases using SNP data have become more and more popular in biomedical research in recent years. In this paper, we present a review of recent statistical advances and challenges for analyzing correlated high dimensional SNP data in genomic association studies for complex diseases. The review includes both general feature reduction approaches for high dimensional correlated data and more specific approaches for SNPs data, which include unsupervised haplotype mapping, tag SNP selection, and supervised SNPs selection using statistical testing/scoring, statistical modeling and machine learning methods with an emphasis on how to identify interacting loci.Comment: Published in at http://dx.doi.org/10.1214/07-SS026 the Statistics Surveys (http://www.i-journals.org/ss/) by the Institute of Mathematical Statistics (http://www.imstat.org

COVID-19 Outbreak Prediction with Machine Learning

Abstract: Several outbreak prediction models for COVID-19 are being used by officials around the world to make informed decisions and enforce relevant control measures. Among the standard models for COVID-19 global pandemic prediction, simple epidemiological and statistical models have received more attention by authorities, and these models are popular in the media. Due to a high Level of uncertainty and lack of essential data, standard models have shown low accuracy for long-term prediction. Although the literature includes several attempts to address this issue, the essential generalization and robustness abilities of existing models need to be improved. This paper presents a comparative analysis ofmachine learning and soft computingmodels to predict the COVID-19 outbreak as an alternative to susceptible–infected–recovered (SIR) and susceptible-exposed-infectious-removed (SEIR) models. Among a wide range of machine learning models investigated, two models showed promising results (i.e., multi-layered perceptron, MLP; and adaptive network-based fuzzy inference system, ANFIS). Based on the results reported here, and due to the highly complex nature of the COVID-19 outbreak and variation in its behavior across nations, this study suggests machine Learning as an effective tool to model the outbreak. This paper provides an initial benchmarking to demonstrate the potential of machine learning for future research. This paper further suggests that a genuine novelty in outbreak prediction can be realized by integrating machine learning and SEIR models.publishedVersio