This thesis provides novel methodology for statistical analysis of paired high-dimensional genomic data, with the aimto identify gene interactions specific to each group of samples as well as the gene connections that change between the two classes of observations. An example of such groups can be patients under two medical conditions, in which the estimation of gene interaction networks is relevant to biologists as part of discerning gene regulatory mechanisms that control a disease process like, for instance, cancer. We construct these interaction networks fromdata by considering the non-zero structure of correlationmatrices, which measure linear dependence between random variables, and their inversematrices, which are commonly known as precision matrices and determine linear conditional dependence instead. In this regard, we study three statistical problems related to the testing, single estimation and joint estimation of (conditional) dependence structures. Firstly, we develop hypothesis testingmethods to assess the equality of two correlation matrices, and also two correlation sub-matrices, corresponding to two classes of samples, and hence the equality of the underlying gene interaction networks. We consider statistics based on the average of squares, maximum and sum of exceedances of sample correlations, which are suitable for both independent and paired observations. We derive the limiting distributions for the test statistics where possible and, for practical needs, we present a permuted samples based approach to find their corresponding non-parametric distributions. Cases where such hypothesis testing presents enough evidence against the null hypothesis of equality of two correlation matrices give rise to the problem of estimating two correlation (or precision) matrices. However, before that we address the statistical problem of estimating conditional dependence between random variables in a single class of samples when data are high-dimensional, which is the second topic of the thesis. We study the graphical lasso method which employs an L1 penalized likelihood expression to estimate the precision matrix and its underlying non-zero graph structure. The lasso penalization termis given by the L1 normof the precisionmatrix elements scaled by a regularization parameter, which determines the trade-off between sparsity of the graph and fit to the data, and its selection is our main focus of investigation. We propose several procedures to select the regularization parameter in the graphical lasso optimization problem that rely on network characteristics such as clustering or connectivity of the graph. Thirdly, we address the more general problem of estimating two precision matrices that are expected to be similar, when datasets are dependent, focusing on the particular case of paired observations. We propose a new method to estimate these precision matrices simultaneously, a weighted fused graphical lasso estimator. The analogous joint estimation method concerning two regression coefficient matrices, which we call weighted fused regression lasso, is also developed in this thesis under the same paired and high-dimensional setting. The two joint estimators maximize penalized marginal log likelihood functions, which encourage both sparsity and similarity in the estimated matrices, and that are solved using an alternating direction method of multipliers (ADMM) algorithm. Sparsity and similarity of thematrices are determined by two tuning parameters and we propose to choose them by controlling the corresponding average error rates related to the expected number of false positive edges in the estimated conditional dependence networks. These testing and estimation methods are implemented within the R package ldstatsHD, and are applied to a comprehensive range of simulated data sets as well as to high-dimensional real case studies of genomic data. We employ testing approaches with the purpose of discovering pathway lists of genes that present significantly different correlation matrices on healthy and unhealthy (e.g., tumor) samples. Besides, we use hypothesis testing problems on correlation sub-matrices to reduce the number of genes for estimation. The proposed joint estimation methods are then considered to find gene interactions that are common between medical conditions as well as interactions that vary in the presence of unhealthy tissues.

Today's high-throughput data collection devices, e.g. spectrometers and gene chips, create information in abundance. However, this poses serious statistical challenges, as the number of features is usually much larger than the number of observed units.  Further, in this high-dimensional setting, only a small fraction of the features are likely to be informative for any specific project. In this thesis, three different approaches to the two-class supervised classification in this high-dimensional, low sample setting are considered. There are classifiers that are known to mitigate the issues of high-dimensionality, e.g. distance-based classifiers such as Naive Bayes. However, these classifiers are often computationally intensive and therefore less time-consuming for discrete data. Hence, continuous features are often transformed into discrete features. In the first paper, a discretization algorithm suitable for high-dimensional data is suggested and compared with other discretization approaches. Further, the effect of discretization on misclassification probability in high-dimensional setting is evaluated.   Linear classifiers are more stable which motivate adjusting the linear discriminant procedure to high-dimensional setting. In the second paper, a two-stage estimation procedure of the inverse covariance matrix, applying Lasso-based regularization and Cuthill-McKee ordering is suggested. The estimation gives a block-diagonal approximation of the covariance matrix which in turn leads to an additive classifier. In the third paper, an asymptotic framework that represents sparse and weak block models is derived and a technique for block-wise feature selection is proposed.      Probabilistic classifiers have the advantage of providing the probability of membership in each class for new observations rather than simply assigning to a class. In the fourth paper, a method is developed for constructing a Bayesian predictive classifier. Given the block-diagonal covariance matrix, the resulting Bayesian predictive and marginal classifier provides an efficient solution to the high-dimensional problem by splitting it into smaller tractable problems. The relevance and benefits of the proposed methods are illustrated using both simulated and real data. / Med dagens teknik, till exempel spektrometer och genchips, alstras data i stora mängder. Detta överflöd av data är inte bara till fördel utan orsakar även vissa problem, vanligtvis är antalet variabler (p) betydligt fler än antalet observation (n). Detta ger så kallat högdimensionella data vilket kräver nya statistiska metoder, då de traditionella metoderna är utvecklade för den omvända situationen (p<n).  Dessutom är det vanligtvis väldigt få av alla dessa variabler som är relevanta för något givet projekt och styrkan på informationen hos de relevanta variablerna är ofta svag. Därav brukar denna typ av data benämnas som gles och svag (sparse and weak). Vanligtvis brukar identifiering av de relevanta variablerna liknas vid att hitta en nål i en höstack. Denna avhandling tar upp tre olika sätt att klassificera i denna typ av högdimensionella data.  Där klassificera innebär, att genom ha tillgång till ett dataset med både förklaringsvariabler och en utfallsvariabel, lära en funktion eller algoritm hur den skall kunna förutspå utfallsvariabeln baserat på endast förklaringsvariablerna. Den typ av riktiga data som används i avhandlingen är microarrays, det är cellprov som visar aktivitet hos generna i cellen. Målet med klassificeringen är att med hjälp av variationen i aktivitet hos de tusentals gener (förklaringsvariablerna) avgöra huruvida cellprovet kommer från cancervävnad eller normalvävnad (utfallsvariabeln). Det finns klassificeringsmetoder som kan hantera högdimensionella data men dessa är ofta beräkningsintensiva, därav fungera de ofta bättre för diskreta data. Genom att transformera kontinuerliga variabler till diskreta (diskretisera) kan beräkningstiden reduceras och göra klassificeringen mer effektiv. I avhandlingen studeras huruvida av diskretisering påverkar klassificeringens prediceringsnoggrannhet och en mycket effektiv diskretiseringsmetod för högdimensionella data föreslås. Linjära klassificeringsmetoder har fördelen att vara stabila. Nackdelen är att de kräver en inverterbar kovariansmatris och vilket kovariansmatrisen inte är för högdimensionella data. I avhandlingen föreslås ett sätt att skatta inversen för glesa kovariansmatriser med blockdiagonalmatris. Denna matris har dessutom fördelen att det leder till additiv klassificering vilket möjliggör att välja hela block av relevanta variabler. I avhandlingen presenteras även en metod för att identifiera och välja ut blocken. Det finns också probabilistiska klassificeringsmetoder som har fördelen att ge sannolikheten att tillhöra vardera av de möjliga utfallen för en observation, inte som de flesta andra klassificeringsmetoder som bara predicerar utfallet. I avhandlingen förslås en sådan Bayesiansk metod, givet den blockdiagonala matrisen och normalfördelade utfallsklasser. De i avhandlingen förslagna metodernas relevans och fördelar är visade genom att tillämpa dem på simulerade och riktiga högdimensionella data.

Gaussian graphical model has been a popular tool to investigate conditional dependency between random variables by estimating sparse precision matrices. The estimated precision matrices could be mapped into networks for visualization. For related but different classes, jointly estimating networks by taking advantage of common structure across classes can help us better estimate conditional dependencies among variables. Furthermore, there may exist multilevel structure among variables; some variables are considered as higher level variables and others are nested in these higher level variables, which are called lower level variables. In this dissertation, we made several contributions to the area of joint estimation of Gaussian graphical models across heterogeneous classes: the first is to propose a joint estimation method for estimating Gaussian graphical models across unbalanced multi-classes, whereas the second considers multilevel variable information during the joint estimation procedure and simultaneously estimates higher level network and lower level network. For the first project, we consider the problem of jointly estimating Gaussian graphical models across unbalanced multi-class. Most existing methods require equal or similar sample size among classes. However, many real applications do not have similar sample sizes. Hence, in this dissertation, we propose the joint adaptive graphical lasso, a weighted L1 penalized approach, for unbalanced multi-class problems. Our joint adaptive graphical lasso approach combines information across classes so that their common characteristics can be shared during the estimation process. We also introduce regularization into the adaptive term so that the unbalancedness of data is taken into account. Simulation studies show that our approach performs better than existing methods in terms of false positive rate, accuracy, Mathews correlation coefficient, and false discovery rate. We demonstrate the advantage of our approach using liver cancer data set. For the second one, we propose a method to jointly estimate the multilevel Gaussian graphical models across multiple classes. Currently, methods are still limited to investigate a single level conditional dependency structure when there exists the multilevel structure among variables. Due to the fact that higher level variables may work together to accomplish certain tasks, simultaneously exploring conditional dependency structures among higher level variables and among lower level variables are of our main interest. Given multilevel data from heterogeneous classes, our method assures that common structures in terms of the multilevel conditional dependency are shared during the estimation procedure, yet unique structures for each class are retained as well. Our proposed approach is achieved by first introducing a higher level variable factor within a class, and then common factors across classes. The performance of our approach is evaluated on several simulated networks. We also demonstrate the advantage of our approach using breast cancer patient data. / Ph. D.