Genome-wide microarray technology has facilitated the systematic discovery of diagnostic biomarkers of cancers and other pathologies. However, meta-analyses of published arrays using melanoma as a test cancer has uncovered significant inconsistences that hinder advances in clinical practice. In this study a computational model for the integrated analysis of microarray datasets is proposed in order to provide a robust ranking of genes in terms of their relative significance; both genome-wide relative significance (GWRS) and genome-wide global significance (GWGS). When applied to five melanoma microarray datasets published between 2000 and 2011, a new 12-gene diagnostic biomarker signature for melanoma was defined (i.e., EGFR, FGFR2, FGFR3, IL8, PTPRF, TNC, CXCL13, COL11A1, CHP2, SHC4, PPP2R2C, and WNT4). Of these, CXCL13, COL11A1, PTPRF and SHC4 are components of the MAPK pathway and were validated by immunocyto- and immunohisto-chemistry. These proteins were found to be overexpressed in metastatic and primary melanoma cells in vitro and in melanoma tissue in situ compared to melanocytes cultured from healthy skin epidermis and normal healthy human skin. One challenge for the integrated analysis of microarray data is that the microarray data are produced using different platforms and bio-samples, e.g. including both cell line- and biopsy-based microarray datasets. In order to address these challenges, the computational model was further enhanced the stratification of datasets into either biopsy or cell line derived datasets, and via the weighting of microarray data based on quality criteria of data. The methods enhancement was applied to 14 microarray datasets of three cancers (breast, prostate, and melanoma) based on classification accuracy and on the capability to identify predictive biomarkers. Four novel measures for evaluating the capability to identify predictive biomarkers are proposed: (1) classifying independent testing data using wrapper feature selection with machine leaning, (2) assessing the number of common genes with the genes retrieved in independent testing data, (3) assessing the number of common genes with the genes retrieved in across multiple training datasets, (4) assessing the number of common genes with the genes validated in the literature. This enhancement of computational approach (i) achieved reliable classification performance across multiple datasets, (ii) recognized more significant genes into the top-ranked genes as compared to the genes detected by the independent test data, and (iii) detected more meaningful genes than were validated in previous melanoma studies in the literature.

Master of Science / Department of Agronomy / Allan Fritz / Fusarium head blight (FHB) is one of the most devastative diseases in wheat. Growing resistant cultivars is one of the most effective strategies to minimize the disease damage. Huangcandou (HCD) is a Chinese wheat landrace showing a high level of resistance to FHB spread within a spike (type II). To identify quantitative traits loci (QTL) for resistance in HCD, a population of 190 recombinant inbred lines (RILs) were developed from a cross between HCD and Jagger, a susceptible hard winter wheat (HWW) released in Kansas. The population was evaluated for type II resistance at the greenhouses of Kansas State University. After initial marker screening, 261 polymorphic simple-sequence repeats (SSR) between parents were used for analysis of the RIL population. Among three QTL identified, two from HCD were mapped on the short arms of chromosomes 3B (3BS) and 3A (3AS). The QTL on the distal end of 3BS showed a major effect on type II resistance in all three experiments. This QTL coincides with a previously reported Fhb1, and explained 28.3% of phenotypic variation. The QTL on 3AS explained 9.7% of phenotypic variation for mean PSS over three experiments. The third QTL from chromosome 2D of Jagger explained 6.5% of phenotypic variation. Allelic substitution using the closest marker to each QTL revealed that substitution of Jagger alleles of two QTL on 3AS and 3BS with those from HCD significantly reduced the PSS. HCD containing both QTL on 3AS and 3BS with a large effect on type II resistance can be an alternative source of FHB resistance for improving FHB type II resistance in wheat. Besides, meta-analyses were used to estimate 95% confidence intervals (CIs) of 24 mapped QTL in five previously mapped populations derived from Chinese landraces: Wangshuibai (WSB), Haiyanzhong (HYZ), Huangfangzhu (HFZ), Baishanyuehuang (BSYH) and Huangcandou (HCD). Nineteen QTL for FHB type II resistance were projected to 10 QTL clusters. Five QTL on chromosomes 1A, 5A, 7A, and 3BS (2) were identified as confirmed QTL that have stable and consistent effects on FHB resistance and markers in these meta-QTL regions should be useful for marker-assisted breeding.

De acordo com a Aprendizagem Motora, os golpes de Judô podem ser classificados como habilidades seriadas - implicam a realização de uma sequência de movimentos (componentes) que resulta no desequilíbrio (kuzushi), encaixe (tsukuri) e finalização (kake) do oponente - e abertas - o oponente se movimenta constantemente durante a luta. Tradicionalmente, as técnicas são ensinadas por meio do uchi komi que se caracteriza pela repetição de golpes sem a sua finalização e praticado com pouca ou nenhuma reação do oponente. Considerando a classificação dos golpes, o ensino por meio do uchi komi apresenta limitações por não levar em consideração o contexto da luta que é de natureza dual e dinâmica. Na área de estudos da Aprendizagem Motora, o problema de contexto tem sido investigado por meio da manipulação de dois tipos de meta: a da tarefa e a de aprendizagem. Aplicando-se esses dois tipos de meta à aprendizagem dos golpes de Judô tem-se que a meta da tarefa corresponde à meta do golpe em si e a meta de aprendizagem adiciona a essa meta a situação em que este golpe será utilizado, por exemplo, de shiai ou randori. Isto posto, o presente estudo investigou o efeito da meta de aprendizagem na aquisição do golpe o soto gari do Judô. Foi delineado um experimento constituído por 7 sessões de prática, divididas em: a) pré-teste, que ocorreu na 1ª sessão e objetivou a formação dos grupos experimentais; b) fase de aquisição, da 2ª à 6ª sessões, de prática do golpe o soto gari; c) teste de transferência imediato (TRi) na 6ª sessão realizado imediatamente após a última sessão de prática; d) teste de transferência atrasado (TRa), realizado 7 dias após a 6ª sessão. Os testes de transferência foram constituídos por uma situação de luta controlada. Os participantes (n=24) foram distribuídos em dois grupos experimentais (n=12): Grupo Meta da Tarefa (GMT) e Grupo Meta de Aprendizagem (GMA). Ambos os grupos receberam antes das sessões de prática instrução sobre a meta da tarefa. O GMA foi adicionalmente instruído que ao final das sessões de prática haveria uma luta na qual deveria projetar o oponente utilizando o golpe o soto gari. Na fase de aquisição, em cada bloco das sessões de prática, os participantes assistiram a 3 formas diferentes de executar o golpe o soto gari. Os praticantes foram livres para escolher dentre as 3 formas do golpe uma que iria praticar durante o bloco todo. As escolhas de cada participante foram registradas. Como medidas de desempenho nos testes de transferência foram consideradas: a) a quantidade de tentativas do golpe realizadas; b) em caso de sucesso na execução do golpe, esta foi avaliada seguindo os critérios estabelecidos pela Federação Internacional de Judô para pontuação. Os resultados mostraram que o GMA, ao receber a meta da aprendizagem, elaborou estratégias na escolha das formas de execução do golpe, apresentou superioridade em relação ao GMT na quantidade de tentativas do golpe e, no quesito pontuação, obteve melhora no TRa em comparação ao TRi / According to Motor Learning, Judo techniques can be classified as serial skills - they imply the execution of a sequence of movements (components), resulting in unbalance (kuzushi), preparation (tsukuri) and finishing (kake) of the opponent - and open - the opponent constantly moves during the fight. Traditionally, those techniques are taught through the uchi komi, which is characterized by movement repetition that neglects the finishing phase of the throw and is practiced with little or no reaction from the opponent. Considering the classification of techniques, teaching through the uchi komi presents limitations by not taking into account the context of the fight which is dual and dynamic in nature. In the field of Motor Learning, the context problem has been investigated through the manipulation of two types of goals: task and learning goals. Applying these two types of goals to the learning of Judo technique, the task goal corresponds to the goal of the technique itself and the learning goal adds to this the situation in which this technique will be used, for example, shiai or randori. Thus, the present study investigated the effect of the learning goal on the acquisition of o soto gari Judo technique. An experiment was designed consisting of 7 sessions, divided into: a) pre-test, occurred in the 1st session aimed at the formation of experimental groups; b) acquisition phase, from the 2nd to the 6th practice sessions of the o soto gari; c) immediate transfer test performed immediately after the 6th practice session; d) late transfer test, 7 days after the 6th session. The transfer tests consisted of a controlled fighting situation. Participants (n = 24) were divided into two experimental groups (n = 12): Task Goal Group (GMT) and Learning Goal Group (GMA). Both groups received before the practice sessions instruction about the goal of the task. GMA was instructed additionally that at the end of practice sessions there would be a fight in which participants should project the opponent using the technique o soto gari. In the acquisition phase, in each block of the practice sessions, the participants watched 3 different ways of executing the technique o soto gari. The participants were free to choose among the 3 forms one that would practice during the whole block. The choices of each participant were recorded. As performance measures in the transfer tests the following were considered: a) the number of attempts of the technique made by participants; b) if successful in the execution of the technique (projection), it was evaluated applying the criteria established by the International Judo Federation for scoring. The results showed that GMA elaborated strategies in the choice of the execution forms of o soto gari, presented superiority in relation to GMT in the number of attempts and in relation to scoring an improvement in the TRa in comparison to the TRi

A degradação da qualidade de água no Brasil é um problema sério que afeta grande parte dos rios e lagos. O objetivo desse trabalho é discutir quais mecanismos podem ser usados para a melhora da qualidade das águas tendo em vista a garantia dos seus usos. A legislação brasileira prevê que o sistema de gestão de recursos hídricos deve definir os usos pretendidos para as águas das bacias hidrográficas. Nos casos em que a qualidade das águas precisa ser melhorada para garantir os usos pretendidos, o sistema de gestão de recursos hídricos deve estabelecer etapas progressivas, em que, para cada etapa, são definidas metas de qualidade de água específicas. Utilizando como exemplo o sistema de gestão de qualidade de água de diferentes países, essa dissertação analisa o sistema brasileiro, a definição de metas e a sua relação com o sistema de gestão de recursos hídricos, conforme as definições previstas na Resolução CONAMA 357/05, e identifica os desafios e estratégias para superá-los. Também demonstra que, para que haja mudanças efetivas no cenário de qualidade das águas, será necessário para o país um planejamento estratégico, com prioridades definidas de acordo com as especificidades locais, os investimentos necessários e os aspectos econômicos, enfatizando-se o planejamento e o controle dos serviços de saneamento. / Water quality degradation is a serious problem that affects large extensions of rivers and lakes. The purpose of this thesis is to discuss which mechanism can be used to improve water quality in order to guarantee designated uses. The Brazilian water law establishes that the water resource management system must define the designated uses for the watershed. In cases where water quality must be improved to guarantee such uses, the water resource management system establishes a step-by-step system in which, for each step, specific water quality targets are defined. Using as an example the water quality management system of different countries, this thesis analyses the Brazilian system, the target definitions and its relations with the water resource management system, as defined by CONAMA Resolution 357/05, and identifies the challenges and the strategic seams to surpass them. It also demonstrates that, in order to get an effective change in the water quality scenario, it will be necessary for the country to work on strategic planning, with priorities based not only on specific local characteristics, but also on financial needs and economical aspects, with special emphasis on regulation and control of wastewater systems.

Thesis advisor: Lisa Barrett / Researchers have wondered how the brain creates emotions since the early days of psychological science. With the advent of neuroimaging techniques in the early 1990's and a surge of studies in affective neuroscience in recent years, scientists are now poised to answer this question. In this paper, I present the most up-to-date and statistically advanced meta-analytic summary of the human neuroimaging literature on emotion. I compare the locationist approach (i.e., that emotion categories consistently and specifically correspond to distinct brain regions) with the psychological construction approach (i.e., that emotions are constructed of more general brain networks not specific to emotions) to better understand the brain basis of emotion. I begin by outlining the set of brain regions consistently activated across all studies of emotion experience and perception. I next report findings from two sets of analyses probing the brain basis of discrete emotion categories. The first types of analysis demonstrates the brain regions that are consistently associated with the experience and perception of anger, disgust, fear, happiness and sadness across studies. The second type of analysis demonstrates the mental states (e.g., emotion experience or perception, cognitive load, locus of attention, mental response to methods, etc.) that are consistently associated with activity in given brain locations across studies. Overall, there was little evidence that discrete emotion categories can be localized consistently and specifically to individual brain regions. Instead, I found evidence that is consistent with a psychological construction approach to the mind: a set of common processes corresponding to interacting brain networks constitute emotion experience and perception across a range of emotion categories. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

Schistosomiasis is a water-borne parasitic disease of great public health importance mainly in sub-Saharan African countries. The majority of current control programmes use the antihelminthic drug praziquantel to reduce disease burden in endemic areas. Praziquantel treatment has been reported to accelerate the development of protective immunity against re-infection that otherwise takes years to develop. To date, there is no licensed vaccine for schistosomiasis in humans but an attenuated schistosome parasite vaccine has been tested in animal models. Employing systematic review and meta-analysis approaches, my PhD research has four main objectives relating to attenuated schistosome vaccine and praziquantel treatment: 1) to identify predictors that determine protection levels after treatment with attenuated Schistosoma mansoni vaccines in the mouse model, 2) to quantify the influence of host and schistosome parasite species on attenuated parasite vaccine efficacy, 3) to explore the direction of change (increase/decrease) in schistosome parasite-specific antibody isotypes after praziquantel treatment in humans, 4) to identify predictors of praziquantel efficacy in humans. My analyses revealed three factors that have an influence on the protection levels provided by attenuated schistosome parasite vaccines: increasing numbers of immunizing parasites had a positive effect on the levels of protection whereas increasing the radiation dose and the time to challenge infection had negative effects. Analyses showed that the attenuated schistosome vaccine has the potential to achieve protection levels as high as 79% after a single dose in mice. Alongside this, baboon studies consistently reported protective effects of attenuated schistosome vaccines against re-infection. These results show there is a high potential for an attenuated schistosome parasite vaccine to be effective in humans. A meta-analysis of the influence of praziquantel treatment on the direction of change in schistosome-specific antibody isotypes was conducted. The analysis revealed considerable variability in the antibodies’ direction of change among populations. The results also demonstrated an increase of anti-worm IgA and IgE in the majority of studies. These antibodies have been reported to have a protective effect against re-infection. The combination of age and infection intensity, and the number of days after treatment were identified as influential predictors for some antibody isotypes, but there was no single predictor that consistently affected all antibody isotypes in the same way. Praziquantel efficacy levels in humans were investigated and the analyses revealed that cure rates for schistosomiasis increase with praziquantel dose, and were affected by the identity of the schistosome parasite species (S. mansoni vs. S. haematobium) and the age of the participants (children: 0-19 years old vs. adults: ≥ 20 years old). There has been no clear efficacy level reduction over the treatment years (1979-2013) suggesting that praziquantel is still effective in the treatment of schistosomiasis despite concerns about possible resistance. The development of a schistosome vaccine will benefit from a closer investigation into the mechanisms through which protection is acquired in attenuated schistosome parasite vaccine studies showing high potential efficacy in animal models. Nevertheless, it will take time to develop a schistosome vaccine for human use. The uptake of the vaccine will be made even more challenging by the lack of adequate infrastructure in schistosomiasis endemic areas. In the meantime, close monitoring of praziquantel efficacy levels is necessary to confirm the effectiveness of schistosomiasis control in endemic areas.

Introdução: A Estimulação Transcraniana por Corrente Contínua (ETCC) é uma intervenção não farmacológica com resultados discordantes quanto à sua eficácia para o tratamento do Episódio Depressivo Maior (EDM). Possivelmente devido a heterogeneidade dos estudos, as três meta-análises publicadas até agora sobre o assunto apontam para uma pequena vantagem a favor da técnica, dependendo da variável de desfecho analisada (melhora de depressão ou resposta). Todas essas meta-análises utilizaram dados agregados. Focamo-nos, no presente estudo, na realização de uma revisão sistemática da literatura e de uma meta-análise baseada em dados individuais de pacientes (MA-DIP) com Depressão Maior (DM) submetidos à ETCC na fase aguda. Este tipo de análise é mais preciso na avaliação da eficácia de uma intervenção e na obtenção dos preditores de respostas de tratamento, já que as características individuais de cada sujeito são consideradas ao invés das médias e frequências, como nas meta-análises de dados agregados. Objetivos: (1) avaliar a eficácia da ETCC na fase aguda da DM, (2) identificar preditores de resposta, remissão e melhora da depressão específicos e (3) avaliar a aceitabilidade da intervenção. Resultados: Os dados foram colecionados de 6 ensaios clínicos randomizados placebo controlados, totalizando 289 sujeitos. A ETCC ativa foi estatisticamente superior à estimulação simulada em relação à resposta (34% vs. 19%, respectivamente; RC=2,44, IC 95% = 1,38-4,32, NNT=7), remissão (23,1% vs. 12,7%, respectivamente; RC= 2,38, IC 95% = 1,22 - 4,64, NNT=9) e melhora da depressão (coeficiente = 0,35, IC 95% =0,12 0,57). Demonstrou-se que após ajustes para outros preditores e confundidores, depressão resistente a tratamento e doses mais altas de ETCC foram, respectivamente, inversa e diretamente associadas com a eficácia da ETCC. Conclusões: O tamanho de efeito do tratamento com ETCC foi comparável àqueles reportados, em outros estudos, para a Estimulação Magnética Transcraniana repetitiva (EMTr) e para o tratamento farmacológico (com antidepressivos tricíclicos e inibidores seletivos de recaptação de serotonina) na atenção primária para depressão. Os parâmetros mais importantes para otimização em ensaios clínicos futuros são a refratariedade da depressão e a dose da ETCC / Introduction: Transcranial direct current stimulation (tDCS) is a nonpharmacological intervention for depression. Randomised, sham-controlled clinical trials (RCTs) conducted hitherto have presented mixed results regarding its efficacy. Although recent meta-analyses suggest some efficacy when measuring depression symptoms using a continuous outcome, these meta-analyses were limited in their results as they used an aggregate data approach. We aimed therefore to perform an individual patient data (IPD) meta-analysis. In contrast to an aggregate data meta-analysis, an IPD approach uses the raw data of each participant within a study. IPD is more accurate in estimating the efficacy of an intervention since aggregate data meta-analyses present only summary estimates of efficacy. IPD meta-analysis is also superior to the aggregate data approach for obtaining predictors of treatment outcome, as the characteristics of each patient are assessed instead of the mean and frequency values obtained in the traditional aggregate data meta-analysis. Objectives (a) To provide precise estimates of tDCS efficacy based on continuous (depression improvement) and categorical (response and remission rates) outcomes, (b) to identify variables associated with tDCS efficacy and (c) to estimate the treatment acceptability. Results: Data were gathered from six randomised sham-controlled trials, enrolling 289 patients. Active tDCS was significantly superior to sham for response (34% v. 19%, respectively, odds ratio (OR) = 2.44, 95% CI 1.384.32, number needed to treat (NNT) = 7), remission (23.1% v. 12.7%, respectively, OR = 2.38, 95% CI 1.224.64, NNT = 9) and depression improvement ( coefficient 0.35, 95% CI 0.120.57). Mixed effects models showed that, after adjustment for other predictors and confounders, treatment-resistant depression and higher tDCS doses were, respectively, negatively and positively associated with tDCS efficacy. Conclusions: The effect size of tDCS treatment was comparable with those reported for repetitive transcranial magnetic stimulation (rTMS) and antidepressant drug treatment in primary care. The most important parameters for optimisation in future trials are depression refractoriness and tDCS dose

MAZIN, S. C.Metodos Bayesianos em Metanalise: Especicac~ao da Distribuic~ao a Priori para a Variabilidade entre os Estudos. 2009. 175f. Dissertac~ao (mestrado) - Faculdade de Medicina de Ribeir~ao Preto, Universidade de S~ao Paulo, Ribeir~ao Preto, 2009. Prossionais da saude, pesquisadores e outros responsaveis por polticas de saude s~ao frequentemente inundados com quantidades de informac~oes nem sempre manejaveis, o que torna a revis~ao sistematica uma maneira eciente de integrar o conhecimento existente gerando dados que auxiliem a tomada de decis~ao. Em uma revis~ao sistematica os dados dos diferentes estudos podem ser quantitativamente combinados por metodos estatsticos chamados metanalise. A metanalise e uma ferramenta estatstica utilizada para combinar ou integrar os resultados dos diversos estudos independentes, sobre o mesmo tema. Entre os estudos que comp~oem a metanalise pode existir uma variabilidade que n~ao e devida ao acaso, chamada heterogeneidade. A heterogeneidade e geralmente testada pelo teste Q ou quanticada pela estatstica I2. A investigac~ao da heterogeneidade na metanalise e de grande import^ancia pois a aus^encia ou a presenca indica o modelo estatstico mais adequado. Assim, na aus^encia desta variabilidade utilizamos um modelo estatstico de efeito xo e na presenca utilizamos um modelo de efeitos aleatorios que incorpora a variabilidade entre os estudos na metanalise. Muitas metanalises s~ao compostas por poucos estudos, e quando isso acontece, temos diculdades de estimar as medidas de efeito metanalticas atraves da teoria classica, pois esta e dependente de pressupostos assintoticos. Na abordagem bayesiana n~ao temos esse problema, mas devemos ter muito cuidado com a especicac~ao da distribuic~ao a priori. Uma vantagem da infer^encia bayesiana e a possibilidade de predizer um resultado para um estudo futuro. Neste trabalho, conduzimos um estudo sobre a especicac~ao da distribuic~ao a priori para o par^ametro que expressa a vari^ancia entre os estudos e constatamos que n~ao existe uma unica escolha que caracterize uma distribuic~ao a priori que possa ser considerada ~ao informativa\"em todas as situac~oes. A escolha de uma distribuic~ao a priori ~ao informativa\"depende da heterogeneidade entre os estudos na metanalise. Assim a distribuic~ao a priori deve ser escolhida com muito cuidado e seguida de uma analise de sensibilidade, especialmente quando o numero de estudos e pequeno. / MAZIN, S. C. Bayesian methods in meta-analysis: specication of prior distributions for the between-studies variability. 2009. 175s. Dissertation (master degree) - Faculty of Medicine of Ribeir~ao Preto, University of S~ao Paulo, Ribeir~ao Preto, 2009. Health professionals, researchers and others responsible for health policy are often overwhelmed by amounts of information that can not always be manageable, which makes the systematic review an ecient way to integrate existing knowledge generating information that may help decision making. In a systematic review, data from dierent studies can be quantitatively combined by statistical methods called meta-analysis. The meta-analysis is a statistical tool used to combine or integrate the results of several independent studies on the same topic. Among the studies that comprise the meta-analysis we have a variability that does not yield from the chance, called the heterogeneity. Heterogeneity is usually tested by Q or quantied by the statistic I2. The investigation of heterogeneity in meta-analysis has a great importance because the absence or presence indicates the most appropriate statistical model. In the absence of this variability we used a xed eect statistical model and a random eects model was used to incorporate the variability between studies in the meta-analysis. Many meta-analysis are composed of few studies, and in those cases, it is dicult to estimate the eect of meta-analytic measures by the classical theory because the asymptotic assumptions. In the Bayesian approach we do not have this problem, but we must be very careful about the specication of prior distribution. One advantage of Bayesian inference is the ability to predict an outcome for a future study. In this work, carried out a study about the specication of prior distribution for the parameter that expresses of the variance between studies and found that there is no single choice that features a prior distribution that would be considered uninformative at all times. The choice of a prior distribution uninformative depend heterogeneity among studies in the meta-analysis. Thus, the prior distribution should be examined very carefully and followed by a sensitivity analysis, especially when the number of studies is small.

A vast amount of gene expression data is available to biological researchers. As of October 2010, the GEO database has 45,777 chips of publicly available gene expression pro ling data from the Affymetrix (HGU133v2) GeneChip platform, representing 2.5 billion numerical measurements. Given this wealth of data, `meta-analysis' methods allowing inferences to be made from combinations of samples from different experiments are critically important. This thesis explores the application of localized pattern-mining approaches, as exemplified by biclustering, for large-scale gene expression analysis. Biclustering methods are particularly attractive for the analysis of large compendia of gene expression data as they allow the extraction of relationships that occur only across subsets of genes and samples. Standard correlation methods, however, assume a single correlation relationship between two genes occurs across all samples in the data. There are a number of existing biclustering methods, but as these did not prove suitable for large scale analysis, a novel method named `IslandCluster' was developed. This method provided a framework for investigating the results of different approaches to biclustering meta-analysis. The biclustering methods used in this work involve preprocessing of gene expression data into a unified scale in order to assess the significance of expression patterns. A novel discretisation approach is shown to identify distinct classes of genes' expression values more appropriately than approaches reported in the literature. A Gene Expression State Transformation (`GESTr') introduced as the first reported modelling of the biological state of expression on a unified scale and is shown to facilitate effective meta-analysis. Localised co-dependency analysis is introduced, a paradigm for identifying transcriptional relationships from gene expression data. Tools implementing this analysis were developed and used to analyse specificity of transcriptional relationships, to distinguish related subsets within a set of transcription factor (TF) targets and to tease apart combinatorial regulation of a set of targets by multiple TFs. The state of pluripotency, from which a mammalian cell has the potential to differentiate into any cell from any of the three adult germ layers, is maintained by forced expression of Nanog and may be induced from a non-pluripotent state by the expression of Oct4, Sox2, Klf4 and cMyc. Analysis of cMyc regulatory targets shed light on a recent proposition that cMyc induces an `embryonic stem cell like' transcriptional signature outside embryonic stem (ES) cells, revealing a cMyc-responsive subset of the signature and identifying ES cell expressed targets with evidence of broad cMyc-induction. Regulatory targets through which cMyc, Oct4, Sox2 and Nanog may maintain or induce pluripotency were identified, offering insight into transcriptional mechanisms involved in the control of pluripotency and demonstrating the utility of the novel analysis approaches presented in this work.

Meta-analysis is a statistical technique that combines results from multiple independent studies to make inferences about parameters of interest. Although it is popular for parameter estimation and hypothesis testing, meta-analytic approaches that incorporate heterogeneous studies have not been fully developed. For heterogeneous studies, we do not expect all of the studies to have the same true underlying effect and the use of the fixed-effects model in a meta-analysis in this situation violates the assumption of homogeneity of effect size. Heterogeneity among studies can arise from multiple sources such as differences in populations by ancestry, differences in study designs, and different impacts of environmental exposures on the effect of the variable of interest. In this thesis, we introduce an analytic strategy and statistical models for meta-analysis of potentially heterogeneous studies. First, we propose a two-stage clustering approach to account for heterogeneity in trans-ethnic meta-analysis of genome-wide association studies (GWAS). Specifically, we cluster studies in the two-stage approach using cohort-specific genetic information prior to meta-analysis to account for between-cluster heterogeneity as well as to bolster within-cluster homogeneity. An extensive simulation study shows that this approach improves power and diminishes computational intensity compared to existing methods for trans-ethnic meta-analysis. Next, under a meta-regression framework, we develop a likelihood ratio test (LRT) statistic to accommodate multiple random effects. We allow multiple sources of heterogeneity in terms of study characteristics and model the heterogeneities as random effects. We show that the proposed LRT maintains a similar or higher power than other existing methods in a simulation study especially when heterogeneity exists. We apply this new approach to meta-analyze genome-wide association data. Lastly, we derive a score test in the same context as our proposed new LRT and show the substantial advantage of the score test in computational efficiency compared to the new LRT. The introduced strategy and methodologies can effectively and efficiently aggregate the evidence from potentially heterogeneous studies in statistical genetics and other research areas.