O mapeamento genético e a genética funcional de doenças são de grande importância na pesquisa médica e genômica. Para estas finalidades o estudo de associação entre fatores de risco genéticos e doença tem ganhado destaque na literatura. Neste trabalho disserta-se sobre a análise de associação aplicada ao mapeamento genético de doenças, caracterizando diferentes possibilidades de planejamentos experimentais e de utilização de modelos estatísticos de análise de dados. As formalizações estatísticas, como o tipo de delineamento experimental, a inclusão ou não de dados familiares, bem como a escolha do método estatístico de análise, que são decisivos na avaliação do poder dos testes obtidos e na sua aplicabilidade ao mapeamento genético, também são discutidas. Além disso, considera-se a análise de associação por meio de modelos de regressão logística em que, as análises de dados genéticos são abordadas via dados no nível genotípico e cromossômico. Finalmente, os conceitos supracitados são aplicados a conjuntos de dados reais, fornecidos pelo Laboratório de Cardiologia e Genética Molecular do InCor/USP, com o objetivo de ilustrar o problema teórico tratado e motivar a aplicação das metodologias estatísticas envolvidas. / The genetic mapping and functional genetics have great importance in the genomics research. In order to conduct these researches the study of the association between genetic risk factors and disease has been becoming an important role in the literature. In this work we consider the association analyses applied to the genetic diseases mapping, charactering different possibilities of experimental designs and the use of statistical models to analyze data sets. The statistical concepts, as the kind of experimental design, the inclusion of familiar records or not, as well as the choice of the statistical analyze method, which are very important to the evaluation of the power of the tests obtained and to their applicability in the genetic mapping, are also discussed. Furthermore, we consider the association analysis at person level and chromosome data set. Finally, the latter concepts are applied to a real data set, provided by the Molecular Genetic and Cardiology Laboratory of InCor/USP, in order to illustrate the theoretical problem treated in this work and to motive the use of the involved statistical methodologies.

<div> <div> <div> <p>Organizations today collect and aggregate huge amounts of data from individuals under various scenarios and for different purposes. Such aggregation of individuals’ data when combined with techniques of data analytics allows organizations to make informed decisions and predictions. But in many situations, different portions of the data associated with individuals are collected and curated by different organizations. To derive more accurate conclusions and predictions, those organization may want to conduct the analysis based on their joint data, which cannot be simply accomplished by each organization exchanging its own data with other organizations due to the sensitive nature of data. Developing approaches for collaborative privacy-preserving data analytics, however, is a nontrivial task. At least two major challenges have to be addressed. The first challenge is that the security of the data possessed by each organization should always be properly protected during and after the collaborative analysis process, whereas the second challenge is the high computational complexity usually accompanied by cryptographic primitives used to build such privacy-preserving protocols. </p><p><br></p><p> </p><div> <div> <div> <p>In this dissertation, based on widely adopted primitives in cryptography, we address the aforementioned challenges by developing techniques for data analytics that not only allow multiple mutually distrustful parties to perform data analysis on their joint data in a privacy-preserving manner, but also reduce the time required to complete the analysis. More specifically, using three common data analytics tasks as concrete examples, we show how to construct the respective privacy-preserving protocols under two different scenarios: (1) the protocols are executed by a collaborative process only involving the participating parties; (2) the protocols are outsourced to some service providers in the cloud. Two types of optimization for improving the efficiency of those protocols are also investigated. The first type allows each participating party access to a statistically controlled leakage so as to reduce the amount of required computation, while the second type utilizes the parallelism that could be incorporated into the task and pushes some computation to the offline phase to reduce the time needed for each participating party without any additional leakage. Extensive experiments are also conducted on real-world datasets to demonstrate the effectiveness of our proposed techniques.<br></p> <p> </p> </div> </div> </div> </div> </div> </div>

A seleção genômica (Genomic Selection - GS) permite identificar indivíduos superiores com base no seu método genômico e apresenta a possibilidade de incorporação do melhoramento quantitativo à genética molecular. O melhor preditor linear não viesado (Best Linear Unbiased Prediction - BLUP) é um método de predição dos efeitos aleatórios do modelo com base nos componentes de variância obtidos por meio do método máxima verossimilhança restrita (Restricted maximum likelihood - REML). A eficiência do REML\\BLUP pode ser incrementada por meio da incorporação de matrizes de parentesco genômico nos modelos de seleção genômica, uma vez que os efeitos genéticos genômicos aditivos dos indivíduos avaliados constituem os componentes aleatórios dos modelos mistos abordados. Dentre os algoritmos disponíveis para estimá-las, a partir de dados de polimorfismo de nucleotídeo único (Single-nucleotide polymorphism - SNP\'s) há as matrizes de Vanraden (2008) Astle e Balding (2009) e as de Yang et al. (2010) (matriz de parentesco unificado e matriz de parentesco unificado ajustado). Adicionalmente ao método de estimação da matriz de parentesco, a acurácia da GS depende da densidade de marcadores e da extensão e padrão de desequilíbrio de ligação (Linkage desequilibrium - LD) que existe no painel. Com isto, os objetivos foram: i) investigar o efeito da redução nas densidades de marcadores SNP\'s, por meio do LD, na estimativa do parentesco genético dos indivíduos e, consequentemente, na acurácia preditiva da GS; ii) estudar o efeito do uso de diferentes tipos de matrizes de parentesco genômico na acurácia da seleção genômica para linhagens e híbridos de milho tropical. Para isso, foram considerados dois painéis distintos de milho tropical: uma composta por 64 linhagens endogâmicas e a outra, por 452 híbridos. Estas foram avaliadas para o caráter produtividade de grãos, em oito e cinco ambientes, respectivamente. As linhagens e os híbridos foram genotipados com a plataforma Affymetrix&reg; Axiom&reg; Maize Genotyping Array, com cerca de 600 mil marcadores. Foram construídos diferentes cenários de GS quanto ao tipo de painel (linhagens e híbridos), densidade de marcadores (400k, 60k, 9586 e 1304 para linhagens e 50k, 4458 e 495, para híbridos) e tipos de matrizes de parentesco (citadas acima). Em cada um destes cenários foi estimada a herdabilidade, acurácia, capacidade preditiva e a coincidência de seleção. A partir dos resultados conclui-se que: tanto para híbridos como para linhagens, a densidade de marcas pode ser reduzida significativamente por meio do LD existente entre os SNP\'s, sem gerar prejuízos quanto à acurácia da GS, mas reduzindo os custos com genotipagem e a demanda computacional. Para predição genômica das linhagens, a matriz de Vanraden (2008) apresenta o melhor custo benefício, pois tem menor demanda computacional e proporciona resultados satisfatórios quanto à acurácia e coincidência de seleção. Para a predição genômica de híbridos, as matrizes de Yang et al. (2010) são superiores em relação às demais testadas, quanto à acurácia preditiva e coincidência de seleção. / The efficiency of the Best Linear Unbiased Prediction (BLUP), along with the Restricted maximum likelihood (REML) methods, can be increased by incorporating genomic kinship matrices to Genomic Selection models (GS). Among the available algorithms to estimate these matrices from single-nucleotide polymorphism (SNP) data there are Vanraden (2008), Astle e Balding (2009) and Yang et al. (2010) (unified relationship matrix and adjusted unified relationship matrix). In addition to the estimation method of the relationship matrix, the accuracy of GS depends on the density of markers and the extent and pattern of linkage disequilibrium (LD) that there is in the panel. Thus, the aims were: i) assess the effect of marker density reduction, based on LD, on the estimative of the genetic relationship of individuals and, consequently, on the predictive accuracy of GS; ii) study the effects of types of genomic relationship matrices on the accuracy of genomic selection for tropical maize lines and hybrids. In order to achieve there, two distinct panel of tropical maize were used: the first consisting of 64 inbred lines and latter of 452 hybrids. These panels were evaluated in field trials for grain yield in eight and five environments, respectively. The lines and hybrids were genotyped by the Affymetrix&reg; Axiom&reg; Maize Genotyping Array platform with 612 thousand markers. Distinct scenarios of GS were comprised considering panel type (lines and hybrids), marker density (400k, 60k, 9586 and 1304 for lines and, 50k, 4458 and 495 for hybrids) and, types of kinship matrices cited aboved. In each of these scenarios heritability, accuracy, predictive capacity and the selection coincidence were estimated. From the results it was concluded that: for both, hybrids and lines, marker density can be significantly reduced based on LD between SNP\'s without affecting the accuracy. Furthermore, this reduction also decreases genotyping costs and computational requirements. For genomic prediction of lines, Vanraden (2008) matrix shows the best cost-benefit, because it demands less computer resources and provides satisfactory results in terms of accuracy and selection coincidence. On the other hand, for genomic prediction of hybrids, the matrices of Yang et al. (2010) yielded higher predictive accuracies and selection coincidences.

Made available in DSpace on 2016-04-27T18:12:34Z (GMT). No. of bitstreams: 1 Juliana Chica Lopes.pdf: 324667 bytes, checksum: acdc8765b5b888b850c24b2aae9db4b1 (MD5) Previous issue date: 2008-05-28 / Starting from Berenstein s (2001) definition about linkage as an "unconscious structure that connects one or more subjects (...) based on a relationship on presence", the objective of this research was to understand the configuration of linkages in therapeutic group process. It leaded us to reflect about how the linkage can be relevant for phonoaudiological work. We filmed two therapeutic groups formed by 4 and 3 adolescents respectively, once per month, during 5 months, bringing up 10 shots. The films were analyzed from its regular spelling transcript, added to the registration of scene information. The results showed that linkages were formed through: elements acting as group connectors, in our case: games and topics of common knowledge; roles assumed by the participants of the group; sharing common experiences about groups external to the therapy context; the bringing up of a shared vital project. We concluded that the linkage process within therapy is also a development process both of sociocultural attitudes as language / Partindo da definição de Berenstein (2001) que entende vínculo como uma estrutura inconsciente que une um ou mais sujeitos (...) em base a uma relação de presença , o objetivo da presente pesquisa foi o de compreender a configuração de vínculos no processo terapêutico grupal, para, a partir daí, refletir sobre como o vínculo pode ser relevante no trabalho fonoaudiológico. Foram filmados dois grupos terapêuticos formados por 4 e 3 adolescentes respectivamente, uma vez por mês, durante um período de 5 meses, perfazendo um total de 10 filmagens. Os filmes foram analisados a partir da sua transcrição em ortografia regular somada ao registro de informações sobre a cena. Os resultados mostraram que os vínculos se configuraram a partir: de elementos que funcionam como conectores do grupo, no nosso caso jogos e temas de conhecimento comum; de papéis assumidos pelos participantes do grupo; do compartilhamento de vivências comuns experimentadas nos grupos externos ao da terapia; da ascensão de um projeto vital compartilhado. Concluiu-se que o processo de configuração de vínculo no âmbito terapêutico é também um processo de desenvolvimento tanto de atitudes socioculturais como de linguagem

Myelination of axons in the central and peripheral nervous system (CNS and PNS) is required for saltatory propagation of nerve impulses. Myelinated axons are organized in functionally distinct membrane domains and the correct formation and maintenance of these domains is fundamental for the correct propagation of the electrical impulse; however, the underlying mechanisms by which these domains are specified are just starting to be unravelled. The paranodal junctions (PNJs) have been shown to contribute to node formation in the CNS and to domain maintenance both in the CNS and PNS. In this thesis I have studied the function of the linkage of the PNJs to the axonal cytoskeleton in regulating these processes by using a combination of knock out and transgenic rescue strategies. Further, I have initiated studies on the live imaging of node assembly. I have shown that the link between the PNJ and the axonal cytoskeleton is required for both the correct timing of oligodendrocyte process migration and for clustering nodal proteins at heminodes, before nodes of Ranvier are formed. Failure to correctly regulate these events during development results in shorter internodes in adults. Further, I have shown the importance of the axonal paranodal cytoskeleton in the maintenance of the node of Ranvier, both in CNS and PNS. In the absence of a link between the PNJ and the axonal cytoskeleton, paranodes disassemble, which causes disruption of both nodal and juxtaparanodal domains. Electron microscopy shows that, despite paranodal disruption, transverse bands are preserved when the anchorage of the PNJ to the axonal cytoskeleton is removed. Surprisingly, the preservation of these structures is associated with the amelioration of the neurological defects seen in mice lacking PNJs. In order to study nodal assembly, I have initiated studies on the transport of the nodal proteins Neurofascin186 and β1Nav tagged with fluorescent tags in transgenic mice, in order to analyse axonal transport during development. I have exploited the triangularis muscle explant preparation and have analysed transport of nodal proteins in young and adult mice. I have shown that transport speeds decrease with age and that the two proteins are transported at different speeds in young animals, but these differences do not persist in adults. This suggests that during myelination these proteins are transported in different vesicles and that this may change during development.

The publication of a draft equine genome sequence and the release by Illumina of a 50,000 marker single-nucleotide polymorphism (SNP) genotyping chip has provided equine researchers with the opportunity to use new approaches to study the relationships between genotype and phenotype. In particular, it is hoped that the use of high-density markers applied to population samples will enable progress to be made with regard to more complex diseases. The first objective of this thesis is to explore the potential for the equine SNP chip to enable such studies to be performed in the horse. The second objective is to investigate the genetic background of osteochondrosis (OC) in the horse. These objectives have been tackled using 348 Thoroughbreds from the US, divided into cases and controls, and a further 836 UK Thoroughbreds, the majority with no phenotype data. All horses had been genotyped with the Illumina Equine SNP50 BeadChip. Linkage disequilibrium (LD) is the non-random association of alleles at neighbouring loci. The reliance of many genomic methodologies on LD between neutral markers and causal variants makes it an important characteristic of genome structure. In this thesis, the genomic data has been used to study the extent of LD in the Thoroughbred and the results considered in terms of genome coverage. Results suggest that the SNP chip offers good coverage of the genome. Published theoretical relationships between LD and historical effective population size (Ne) were exploited to enable accuracy predictions for genome-wide evaluation (GWE) to be made. A subsequent in-depth exploration of this theory cast some doubt on the reliability of this approach in the estimation of Ne, but the general conclusion that the Thoroughbred population has a small Ne which should enable GWE to be carried out efficiently in this population, remains valid. In the course of these studies, possible errors embedded within the current sequence assembly were identified using empirical approaches. Osteochondrosis is a developmental orthopaedic disease which affects the joints of young horses. Osteochondrosis is considered multifactorial in origin with a variety of environmental factors and heredity having been implicated. In this thesis, a genome-wide association study was carried out to identify quantitative trait loci (QTL) associated with OC. A single SNP was found to be significantly associated with OC. The low heritability of OC combined with the apparent lack of major QTL suggests GWE as an alternative approach to tackle this disease. A GWE analysis was carried out on the same dataset but the resulting genomic breeding values had no predictive ability for OC status. This, combined with the small number of significant QTL, indicates a lack of power which could be addressed in the future by increasing sample size. An alternative to genotyping more horses for the 50K SNP chip would be to use a low-density SNP panel and impute remaining genotypes. The final chapter of this thesis examines the feasibility of this approach in the Thoroughbred. Results suggest that genotyping only a subset of samples at high density and the remainder at lower density could be an effective strategy to enable greater progress to be made in the arena of equine genomics. Finally, this thesis provides an outlook on the future for genomics in the horse.

O mapeamento genético e a genética funcional de doenças são de grande importância na pesquisa médica e genômica. Para estas finalidades o estudo de associação entre fatores de risco genéticos e doença tem ganhado destaque na literatura. Neste trabalho disserta-se sobre a análise de associação aplicada ao mapeamento genético de doenças, caracterizando diferentes possibilidades de planejamentos experimentais e de utilização de modelos estatísticos de análise de dados. As formalizações estatísticas, como o tipo de delineamento experimental, a inclusão ou não de dados familiares, bem como a escolha do método estatístico de análise, que são decisivos na avaliação do poder dos testes obtidos e na sua aplicabilidade ao mapeamento genético, também são discutidas. Além disso, considera-se a análise de associação por meio de modelos de regressão logística em que, as análises de dados genéticos são abordadas via dados no nível genotípico e cromossômico. Finalmente, os conceitos supracitados são aplicados a conjuntos de dados reais, fornecidos pelo Laboratório de Cardiologia e Genética Molecular do InCor/USP, com o objetivo de ilustrar o problema teórico tratado e motivar a aplicação das metodologias estatísticas envolvidas. / The genetic mapping and functional genetics have great importance in the genomics research. In order to conduct these researches the study of the association between genetic risk factors and disease has been becoming an important role in the literature. In this work we consider the association analyses applied to the genetic diseases mapping, charactering different possibilities of experimental designs and the use of statistical models to analyze data sets. The statistical concepts, as the kind of experimental design, the inclusion of familiar records or not, as well as the choice of the statistical analyze method, which are very important to the evaluation of the power of the tests obtained and to their applicability in the genetic mapping, are also discussed. Furthermore, we consider the association analysis at person level and chromosome data set. Finally, the latter concepts are applied to a real data set, provided by the Molecular Genetic and Cardiology Laboratory of InCor/USP, in order to illustrate the theoretical problem treated in this work and to motive the use of the involved statistical methodologies.

Made available in DSpace on 2017-07-10T17:37:17Z (GMT). No. of bitstreams: 1 Elcio_Friske.pdf: 2134254 bytes, checksum: a68baa9abb11f51692fe7500a517561f (MD5) Previous issue date: 2016-02-29 / Fundação Araucária / The aim of this work was to evaluate the genetic diversity and map genomic regions associated with grains maturation in common corn lineages. The phenotypic attributes of 81 elite inbred lines of corn were assessed in field experiment implanted in square lattice design with three repetitions. The variance and multivariate analysis were carried out considering complete randomized blocks due to its equivalence with the estimation for the lattice efficiency. For the mapping by linkage disequilibrium, 72 elite inbred lines have been genotyped for SNP markers at platform 650K (Affymetrix®) and associated with the genotypic values of the traits related to maturation: number of days for the male flowering (DFM) and female (DFF), and the grain moisture loss, determined by the area below the moisture curve (AACUM). The results of the variance analysis pointed out the existence of genetic diversity in the germplasm for all the assessed traits, detecting a wide variability for DFM, DFF and AACUM. Weak genetic correlations between yield and maturation components indicated the possibility of selection for earliness without compromising the grain yield. The genetic diversity quantified by the distances of Mahalanobis enabled the suggestion of hybrid combinations of higher heterotic effect for earliness and grain yield. There were similarities in the Tocher and UPGMA grouping, which were efficient to classify the genetic variability. By the mixed linear model (MLM) it was possible to detect associations among days for male and female flourishing with SNP markers in all chromosomes, with predominance of chromosomes 1 and 3 and for the loss of moisture in the chromosomes 5 and 6. With of multiple regression analysis of stepwise for DFM, DFF and AACUM, the complete models explained 79%, 93% and 56% of the variation for the genotypic values, respectively, being found predominantly significant markers in the chromosomes 1 and 3. The detection of similar and also different genomic regions for these traits, which are highly correlated, makes possible to raise the hypothesis of the importance of the genetic linkage and pleiotropy to explain the maturation of grains in corn inbred lines. The results obtained are promising and the genomic regions associated with DFM, DFF and AACUM, will be evaluated in validation experiments, which will be useful in selection programs of genotypes with the maturity sought by the breeder / O trabalho teve como objetivos avaliar a diversidade genética e mapear regiões genômicas associadas com maturação de grãos em linhagens de milho comum. Os atributos fenotípicos de 81 linhagens elites de milho foram avaliados em experimento de campo implantado em delineamento de látice quadrado com três repetições. Procedeu-se a análise de variância e multivariada considerando blocos completos casualizados devido a sua equivalência com a estimação para eficiência do látice. Para o mapeamento por desequilíbrio de ligação, 72 linhagens elites foram genotipadas para marcadores SNP na plataforma 650K (Affymetrix®) e associados aos valores genotípicos dos caracteres relacionados à maturação: número de dias para o florescimento masculino (DFM) e feminino (DFF), e perda de umidade dos grãos, determinada pela área abaixo da curva de umidade (AACUM). Os resultados da análise de variância indicaram a existência de diversidade genética no germoplasma para todos os caracteres avaliados, detectando-se ampla variabilidade para DFM, DFF e AACUM. Correlações genéticas fracas entre os componentes de rendimento e de maturação indicaram a possibilidade de seleção para precocidade sem comprometer a produtividade. A diversidade genética quantificada pelas distâncias de Mahalanobis permitiu sugerir combinações hibridas de maior efeito heterótico para precocidade e produtividade. Houve semelhanças no agrupamento de Tocher e UPGMA, que foram eficientes para classificar a variabilidade genética. Pelo modelo linear misto (MLM) foi possível detectar associações entre dias para o florescimento masculino e feminino com marcadores SNP em todos os cromossomos, com predominância nos cromossomos 1 e 3, e para perda de umidade nos cromossomos 5 e 6. Com a análise de regressão múltipla de stepwise para DFM, DFF e AACUM, os modelos completos explicaram 79%, 93% e 56% da variação para os valores genotípicos, respectivamente, encontrando-se predominantemente marcadores significativos nos cromossomos 1 e 3. A detecção de regiões genômicas semelhantes e também distintas para esses caracteres, que são altamente correlacionados, torna possível levantar a hipótese da importância de ligação gênica e de pleiotropia para explicar a maturação de grãos em linhagens de milho. Os resultados obtidos são promissores e as regiões genômicas associadas com DFM, DFF e AACUM, serão avaliadas em experimentos de validação, que poderão ser úteis em programa para seleção de genótipos com a maturidade buscada pelo melhorista

Origami is a potentially elegant and powerful source of inspiration for many engineering designs. The viable shapes (fold states) of a single device allow it to perform multiple, seemingly contradictory, functions. The fold state is a large factor in the device's performance, but there are challenges in selecting and maintaining those fold states. In this thesis we analyze existing concepts for overcoming these challenges. Those concepts are compared with those that occur in origami-based devices. From this analysis fundamental gaps were identified, specifically, shortcoming in the terminology used to refer to (1) non-flat origami states and (2) sets of facets and creases. Likewise we found a need for a comprehensive categorization method of fold states. Fold states are divided into seven types based on the set of fold angles they contain: U, P, F, UP, UF, PF, and UPF. The origami-based devices are analyzed based on their functional fold states, showing an emphasis on P and PF fold states. The fold states and their functions are tabulated. We demonstrate the table as a tool in an origami-based design method. Selecting fold states for an application is just the first step for effective use of origami. Once selected, the origami fold state must be maintained during use to perform its functions. This thesis also outlines the Origami Stability Integration Method (OSIM) for integrating a wealth of stability techniques. These techniques are categorized and analyzed to assist designers in selecting a technique for a device's application. Both methods, the fold-state selection method and the OSIM, are demonstrated in designing an origami-based ballistic barrier. The barrier is designed to stow in a compact fold state and deploy to a partially folded state to provide protection during armed conflicts. Quick deployment and a stable structure make the barrier a valuable example of origami-based design, demonstrating these two methods in addressing some of origami's design challenges.

In this dissertation, the posterior probability of linkage (PPL) framework is extended to the analysis of case-control (CC) data and three new linkage disequilibrium (LD) statistics are introduced. These statistics measure the evidence for or against LD, rather than testing the null hypothesis of no LD, and they therefore avoid the need for multiple testing corrections. They are suitable not only for CC designs but also can be used in application to family data, ranging from trios to complex pedigrees, all under the same statistical framework, allowing for the unified analysis of these disparate data structures. They also provide the other core advantages of the PPL framework, including the use of sequential updating to accumulate LD evidence across potentially heterogeneous sets of subsets of data; parameterization in terms of a very general trait likelihood, which simultaneously considers dominant, recessive, and additive models; and a straightforward mechanism for modeling two-locus epistasis. Finally, being implemented within the PPL framework, the new statistics readily allow linkage information obtained from distinct data, to be incorporated into LD analyses in the form of a prior probability distribution. Performance of the proposed LD statistics is examined using simulated data. In addition, the effects of key modeling violations on performance are assessed. These statistics are also applied to a previously published type 1 diabetes (T1D) family dataset with a few candidate genes with previously reported weak associations, and another T1D CC dataset also previously published as a genome-wide association (GWA) study with some strong associations reported. The new LD statistics under the PPLD framework confirm most of the findings in the published work and also find some new SNPs suspected of being associated with T1D. Sequential updating between the family dataset and the CC dataset dramatically increased the association signal strength for a CTLA4 SNP genotyped in both studies. Linkage information gleaned from the family dataset is also combined into the LD analysis of the CC dataset to demonstrate the utility of this unique feature of the PPL framework, and specifically for the new LD statistics.