BAYESIAN STATISTICAL METHODS IN GENE-ENVIRONMENT AND GENE-GENE INTERACTION STUDIES

Complex diseases such as cancer result from multiple genetic changes and environmental exposures. Due to the rapid development of genotyping and sequencing technologies, we are now able to more accurately assess causal effects of many genetic and environmental factors. Genome-wide association studies have been able to localize many causal genetic variants predisposing to certain diseases. However, these studies only explain a small portion of variations in the heritability of diseases. More advanced statistical models are urgently needed to identify and characterize some additional genetic and environmental factors and their interactions, which will enable us to better understand the causes of complex diseases. In the past decade, thanks to the increasing computational capabilities and novel statistical developments, Bayesian methods have been widely applied in the genetics/genomics researches and demonstrating superiority over some regular approaches in certain research areas. Gene-environment and gene-gene interaction studies are among the areas where Bayesian methods may fully exert its functionalities and advantages. This dissertation focuses on developing new Bayesian statistical methods for data analysis with complex gene-environment and gene-gene interactions, as well as extending some existing methods for gene-environment interactions to other related areas. It includes three sections: (1) Deriving the Bayesian variable selection framework for the hierarchical gene-environment and gene-gene interactions; (2) Developing the Bayesian Natural and Orthogonal Interaction (NOIA) models for gene-environment interactions; and (3) extending the applications of two Bayesian statistical methods which were developed for gene-environment interaction studies, to other related types of studies such as adaptive borrowing historical data. We propose a Bayesian hierarchical mixture model framework that allows us to investigate the genetic and environmental effects, gene by gene interactions (epistasis) and gene by environment interactions in the same model. It is well known that, in many practical situations, there exists a natural hierarchical structure between the main effects and interactions in the linear model. Here we propose a model that incorporates this hierarchical structure into the Bayesian mixture model, such that the irrelevant interaction effects can be removed more efficiently, resulting in more robust, parsimonious and powerful models. We evaluate both of the 'strong hierarchical' and 'weak hierarchical' models, which specify that both or one of the main effects between interacting factors must be present for the interactions to be included in the model. The extensive simulation results show that the proposed strong and weak hierarchical mixture models control the proportion of false positive discoveries and yield a powerful approach to identify the predisposing main effects and interactions in the studies with complex gene-environment and gene-gene interactions. We also compare these two models with the 'independent' model that does not impose this hierarchical constraint and observe their superior performances in most of the considered situations. The proposed models are implemented in the real data analysis of gene and environment interactions in the cases of lung cancer and cutaneous melanoma case-control studies. The Bayesian statistical models enjoy the properties of being allowed to incorporate useful prior information in the modeling process. Moreover, the Bayesian mixture model outperforms the multivariate logistic model in terms of the performances on the parameter estimation and variable selection in most cases. Our proposed models hold the hierarchical constraints, that further improve the Bayesian mixture model by reducing the proportion of false positive findings among the identified interactions and successfully identifying the reported associations. This is practically appealing for the study of investigating the causal factors from a moderate number of candidate genetic and environmental factors along with a relatively large number of interactions. The natural and orthogonal interaction (NOIA) models of genetic effects have previously been developed to provide an analysis framework, by which the estimates of effects for a quantitative trait are statistically orthogonal regardless of the existence of Hardy-Weinberg Equilibrium (HWE) within loci. Ma et al. (2012) recently developed a NOIA model for the gene-environment interaction studies and have shown the advantages of using the model for detecting the true main effects and interactions, compared with the usual functional model. In this project, we propose a novel Bayesian statistical model that combines the Bayesian hierarchical mixture model with the NOIA statistical model and the usual functional model. The proposed Bayesian NOIA model demonstrates more power at detecting the non-null effects with higher marginal posterior probabilities. Also, we review two Bayesian statistical models (Bayesian empirical shrinkage-type estimator and Bayesian model averaging), which were developed for the gene-environment interaction studies. Inspired by these Bayesian models, we develop two novel statistical methods that are able to handle the related problems such as borrowing data from historical studies. The proposed methods are analogous to the methods for the gene-environment interactions on behalf of the success on balancing the statistical efficiency and bias in a unified model. By extensive simulation studies, we compare the operating characteristics of the proposed models with the existing models including the hierarchical meta-analysis model. The results show that the proposed approaches adaptively borrow the historical data in a data-driven way. These novel models may have a broad range of statistical applications in both of genetic/genomic and clinical studies.

Time-Frequency based Feature Selection for Discrimination of non stationary Biosignals.

This research proposes a generic methodology for dimensionality reduction upon time-frequency representations applied to the classification of different types of biosignals. The methodology directly deals with the highly redundant and irrelevant data contained in these representations, combining a first stage of irrelevant data removal by variable selection, with a second stage of redundancy reduction using methods based on linear transformations. The study addresses two techniques that provided a similar performance: the first one is based on the selection of a set of the most relevant time?frequency points, whereas the second one selects the most relevant frequency bands. The first methodology needs a lower quantity of components, leading to a lower feature space; but the second improves the capture of the time-varying dynamics of the signal, and therefore provides a more stable performance. In order to evaluate the generalization capabilities of the methodology proposed it has been applied to two types of biosignals with different kinds of non-stationary behaviors: electroencephalographic and phonocardiographic biosignals. Even when these two databases contain samples with different degrees of complexity and a wide variety of characterizing patterns, the results demonstrate a good accuracy for the detection of pathologies, over 98%.The results open the possibility to extrapolate the methodology to the study of other biosignals.

Regularized model learning in EDAs for continuous and multi-objective optimization

Probabilistic modeling is the de�ning characteristic of estimation of distribution algorithms (EDAs) which determines their behavior and performance in optimization. Regularization is a well-known statistical technique used for obtaining an improved model by reducing the generalization error of estimation, especially in high-dimensional problems. `1-regularization is a type of this technique with the appealing variable selection property which results in sparse model estimations. In this thesis, we study the use of regularization techniques for model learning in EDAs. Several methods for regularized model estimation in continuous domains based on a Gaussian distribution assumption are presented, and analyzed from di�erent aspects when used for optimization in a high-dimensional setting, where the population size of EDA has a logarithmic scale with respect to the number of variables. The optimization results obtained for a number of continuous problems with an increasing number of variables show that the proposed EDA based on regularized model estimation performs a more robust optimization, and is able to achieve signi�cantly better results for larger dimensions than other Gaussian-based EDAs. We also propose a method for learning a marginally factorized Gaussian Markov random �eld model using regularization techniques and a clustering algorithm. The experimental results show notable optimization performance on continuous additively decomposable problems when using this model estimation method. Our study also covers multi-objective optimization and we propose joint probabilistic modeling of variables and objectives in EDAs based on Bayesian networks, speci�cally models inspired from multi-dimensional Bayesian network classi�ers. It is shown that with this approach to modeling, two new types of relationships are encoded in the estimated models in addition to the variable relationships captured in other EDAs: objectivevariable and objective-objective relationships. An extensive experimental study shows the e�ectiveness of this approach for multi- and many-objective optimization. With the proposed joint variable-objective modeling, in addition to the Pareto set approximation, the algorithm is also able to obtain an estimation of the multi-objective problem structure. Finally, the study of multi-objective optimization based on joint probabilistic modeling is extended to noisy domains, where the noise in objective values is represented by intervals. A new version of the Pareto dominance relation for ordering the solutions in these problems, namely �-degree Pareto dominance, is introduced and its properties are analyzed. We show that the ranking methods based on this dominance relation can result in competitive performance of EDAs with respect to the quality of the approximated Pareto sets. This dominance relation is then used together with a method for joint probabilistic modeling based on `1-regularization for multi-objective feature subset selection in classi�cation, where six di�erent measures of accuracy are considered as objectives with interval values. The individual assessment of the proposed joint probabilistic modeling and solution ranking methods on datasets with small-medium dimensionality, when using two di�erent Bayesian classi�ers, shows that comparable or better Pareto sets of feature subsets are approximated in comparison to standard methods.

Bayesian model selection of structural explanatory models: Application to road accident data

Using the Bayesian approach as the model selection criteria, the main purpose in this study is to establish a practical road accident model that can provide a better interpretation and prediction performance. For this purpose we are using a structural explanatory model with autoregressive error term. The model estimation is carried out through Bayesian inference and the best model is selected based on the goodness of fit measures. To cross validate the model estimation further prediction analysis were done. As the road safety measures the number of fatal accidents in Spain, during 2000-2011 were employed. The results of the variable selection process show that the factors explaining fatal road accidents are mainly exposure, economic factors, and surveillance and legislative measures. The model selection shows that the impact of economic factors on fatal accidents during the period under study has been higher compared to surveillance and legislative measures.

Expert systems for vendor selection

The survival of organisations, especially SMEs, depends, to the greatest extent, on those who supply them with the required material input. This is because if the supplier fails to deliver the right materials at the right time and place, and at the right price, then the recipient organisation is bound to fail in its obligations to satisfy the needs of its customers, and to stay in business. Hence, the task of choosing a supplier(s) from a list of vendors, that an organisation will trust with its very existence, is not an easy one. This project investigated how purchasing personnel in organisations solve the problem of vendor selection. The investigation went further to ascertain whether an Expert Systems model could be developed and used as a plausible solution to the problem. An extensive literature review indicated that very scanty research has been conducted in the area of Expert Systems for Vendor Selection, whereas many research theories in expert systems and in purchasing and supply management chain, respectively, had been reported. A survey questionnaire was designed and circulated to people in the industries who actually perform the vendor selection tasks. Analysis of the collected data confirmed the various factors which are considered during the selection process, and established the order in which those factors are ranked. Five of the factors, namely, Production Methods Used, Vendors Financial Background, Manufacturing Capacity, Size of Vendor Organisations, and Suppliers Position in the Industry; appeared to have similar patterns in the way organisations ranked them. These patterns suggested that the bigger the organisation, the more importantly they regarded the above factors. Further investigations revealed that respondents agreed that the most important factors were: Product Quality, Product Price and Delivery Date. The most apparent pattern was observed for the Vendors Financial Background. This generated curiosity which led to the design and development of a prototype expert system for assessing the financial profile of a potential supplier(s). This prototype was called ESfNS. It determines whether a prospective supplier(s) has good financial background or not. ESNS was tested by the potential users who then confirmed that expert systems have great prospects and commercial viability in the domain for solving vendor selection problems.

Stock selection with full-scale optimization and differential evolution

When composing stock portfolios, managers frequently choose among hundreds of stocks. The stocks' risk properties are analyzed with statistical tools, and managers try to combine these to meet the investors' risk profiles. A recently developed tool for performing such optimization is called full-scale optimization (FSO). This methodology is very flexible for investor preferences, but because of computational limitations it has until now been infeasible to use when many stocks are considered. We apply the artificial intelligence technique of differential evolution to solve FSO-type stock selection problems of 97 assets. Differential evolution finds the optimal solutions by self-learning from randomly drawn candidate solutions. We show that this search technique makes large scale problem computationally feasible and that the solutions retrieved are stable. The study also gives further merit to the FSO technique, as it shows that the solutions suit investor risk profiles better than portfolios retrieved from traditional methods.

Agency theory problems behind the fall of shopping centers

The present article assesses agency theory related problems contributing to the fall of shopping centers. The negative effects of the financial and economic downturn started in 2008 were accentuated in emerging markets like Romania. Several shopping centers were closed or sold through bankruptcy proceedings or forced execution. These failed shopping centers, 10 in number, were selected in order to assess agency theory problems contributing to the failure of shopping centers; as research method qualitative multiple cases-studies is used. Results suggest, that in all of the cases the risk adverse behavior of the External Investor- Principal, lead to risk sharing problems and subsequently to the fall of the shopping centers. In some of the cases Moral Hazard (lack of Developer-Agent’s know-how and experience) as well as Adverse Selection problems could be identified. The novelty of the topic for the shopping center industry and the empirical evidences confer a significant academic and practical value to the present article.

Exact Combinatorial Optimization with Graph Convolutional Neural Networks

Combinatorial optimization problems are typically tackled by the branch-and-bound paradigm. We propose to learn a variable selection policy for branch-and-bound in mixed-integer linear programming, by imitation learning on a diversified variant of the strong branching expert rule. We encode states as bipartite graphs and parameterize the policy as a graph convolutional neural network. Experiments on a series of synthetic problems demonstrate that our approach produces policies that can improve upon expert-designed branching rules on large problems, and generalize to instances significantly larger than seen during training.

Práticas de alimentação complementar no primeiro ano de vida e fatores associados

OBJETIVO: Investigar a prevalência de consumo de alimentos complementares e os fatores associados à alimentação complementar oportuna em menores de um ano. MÉTODOS: Participaram do estudo 1 176 crianças, durante a Campanha Nacional de Vacinação de 2003, em São Bernardo do Campo (SP), cujos acompanhantes responderam questionário que incluiu questões sobre a alimentação da criança nas 24 horas precedentes. A estimativa da prevalência de consumo dos alimentos complementares foi realizada por um modelo de regressão logística ajustado por idade; as medianas de introdução de alimentos por análise de sobrevida e os fatores associados à alimentação complementar oportuna por regressão de Poisson com ajuste robusto de variância e seleção hierarquizada de variáveis. RESULTADOS: Observou-se introdução precoce de alimentos complementares: no quarto mês, cerca de um terço das crianças recebiam suco de fruta e um quarto das crianças recebiam mingau, fruta ou sopa, ao passo que a probabilidade de consumir a comida da família aos oito meses foi baixa (48%). A mediana de idade para o consumo de frutas foi de 266 dias (IC95% 256-275), de papa de legumes foi 258 dias (IC95% 250-264) e comida da família, 292 dias (IC 95% 287-303). Os fatores associados ao consumo de alimentos sólidos antes dos seis meses de idade foram: sistema de assistência à saúde; idade materna; trabalho materno e uso de chupeta. CONCLUSÃO: O consumo precoce de alimentos sólidos, um risco potencial para a saúde infantil e para o desenvolvimento de doenças crônicas na idade adulta, evidenciam a necessidade de ações programáticas para reversão deste quadro.

Comparison of univariate and multivariate calibration for the determination of micronutrients in pellets of plant materials by laser induced breakdown spectrometry

The application of laser induced breakdown spectrometry (LIBS) aiming the direct analysis of plant materials is a great challenge that still needs efforts for its development and validation. In this way, a series of experimental approaches has been carried out in order to show that LIBS can be used as an alternative method to wet acid digestions based methods for analysis of agricultural and environmental samples. The large amount of information provided by LIBS spectra for these complex samples increases the difficulties for selecting the most appropriated wavelengths for each analyte. Some applications have suggested that improvements in both accuracy and precision can be achieved by the application of multivariate calibration in LIBS data when compared to the univariate regression developed with line emission intensities. In the present work, the performance of univariate and multivariate calibration, based on partial least squares regression (PLSR), was compared for analysis of pellets of plant materials made from an appropriate mixture of cryogenically ground samples with cellulose as the binding agent. The development of a specific PLSR model for each analyte and the selection of spectral regions containing only lines of the analyte of interest were the best conditions for the analysis. In this particular application, these models showed a similar performance. but PLSR seemed to be more robust due to a lower occurrence of outliers in comparison to the univariate method. Data suggests that efforts dealing with sample presentation and fitness of standards for LIBS analysis must be done in order to fulfill the boundary conditions for matrix independent development and validation. (C) 2009 Elsevier B.V. All rights reserved.

Quantification of chlorpheniramine maleate enantiomers by ultraviolet spectroscopy and chemometric methods

Chlorpheniramine maleate (CLOR) enantiomers were quantified by ultraviolet spectroscopy and partial least squares regression. The CLOR enantiomers were prepared as inclusion complexes with beta-cyclodextrin and 1-butanol with mole fractions in the range from 50 to 100%. For the multivariate calibration the outliers were detected and excluded and variable selection was performed by interval partial least squares and a genetic algorithm. Figures of merit showed results for accuracy of 3.63 and 2.83% (S)-CLOR for root mean square errors of calibration and prediction, respectively. The ellipse confidence region included the point for the intercept and the slope of 1 and 0, respectively. Precision and analytical sensitivity were 0.57 and 0.50% (S)-CLOR, respectively. The sensitivity, selectivity, adjustment, and signal-to-noise ratio were also determined. The model was validated by a paired t test with the results obtained by high-performance liquid chromatography proposed by the European pharmacopoeia and circular dichroism spectroscopy. The results showed there was no significant difference between the methods at the 95% confidence level, indicating that the proposed method can be used as an alternative to standard procedures for chiral analysis.

QSAR modeling of antitubercular activity of diverse organic compounds

Tuberculosis (TB) is a worldwide infectious disease that has shown over time extremely high mortality levels. The urgent need to develop new antitubercular drugs is due to the increasing rate of appearance of multi-drug resistant strains to the commonly used drugs, and the longer durations of therapy and recovery, particularly in immuno-compromised patients. The major goal of the present study is the exploration of data from different families of compounds through the use of a variety of machine learning techniques so that robust QSAR-based models can be developed to further guide in the quest for new potent anti-TB compounds. Eight QSAR models were built using various types of descriptors (from ADRIANA.Code and Dragon software) with two publicly available structurally diverse data sets, including recent data deposited in PubChem. QSAR methodologies used Random Forests and Associative Neural Networks. Predictions for the external evaluation sets obtained accuracies in the range of 0.76-0.88 (for active/inactive classifications) and Q(2)=0.66-0.89 for regressions. Models developed in this study can be used to estimate the anti-TB activity of drug candidates at early stages of drug development (C) 2011 Elsevier B.V. All rights reserved.

Azorean Agriculture Efficiency by PAR

Copyright © 2013 Springer Netherlands.

Cluster analysis and segmentation of Global M&A transactions

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Finance from the NOVA – School of Business and Economics

Feature Nets: behavioural modelling of software product lines

Software product lines (SPL) are diverse systems that are developed using a dual engineering process: (a)family engineering defines the commonality and variability among all members of the SPL, and (b) application engineering derives specific products based on the common foundation combined with a variable selection of features. The number of derivable products in an SPL can thus be exponential in the number of features. This inherent complexity poses two main challenges when it comes to modelling: Firstly, the formalism used for modelling SPLs needs to be modular and scalable. Secondly, it should ensure that all products behave correctly by providing the ability to analyse and verify complex models efficiently. In this paper we propose to integrate an established modelling formalism (Petri nets) with the domain of software product line engineering. To this end we extend Petri nets to Feature Nets. While Petri nets provide a framework for formally modelling and verifying single software systems, Feature Nets offer the same sort of benefits for software product lines. We show how SPLs can be modelled in an incremental, modular fashion using Feature Nets, provide a Feature Nets variant that supports modelling dynamic SPLs, and propose an analysis method for SPL modelled as Feature Nets. By facilitating the construction of a single model that includes the various behaviours exhibited by the products in an SPL, we make a significant step towards efficient and practical quality assurance methods for software product lines.