Efficient estimation algorithms for large and complex data sets

The recent world-wide surge in available data allows the investigation of many new and sophisticated questions that were inconceivable just a few years ago. However, two types of data sets often complicate the subsequent analysis: Data that is simple in structure but large in size, and data that is small in size but complex in structure. These two kinds of problems also apply to biological data. For example, data sets acquired from family studies, where the data can be visualized as pedigrees, are small in size but, because of the dependencies within families, they are complex in structure. By comparison, next-generation sequencing data, such as data from chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq), is simple in structure but large in size. Even though the available computational power is increasing steadily, it often cannot keep up with the massive amounts of new data that are being acquired. In these situations, ordinary methods are no longer applicable or scale badly with increasing sample size. The challenge in today’s environment is then to adapt common algorithms for modern data sets. This dissertation considers the challenge of performing inference on modern data sets, and approaches the problem in two parts: first using a problem in the field of genetics, and then using one from molecular biology. In the first part, we focus on data of a complex nature. Specifically, we analyze data from a family study on colorectal cancer (CRC). To model familial clusters of increased cancer risk, we assume inheritable but latent variables for a risk factor that increases the hazard rate for the occurrence of CRC. During parameter estimation, the inheritability of this latent variable necessitates a marginalization of the likelihood that is costly in time for large families. We first approached this problem by implementing computational accelerations that reduced the time for an optimization by the Nelder-Mead method to about 10% of a naive implementation. In a next step, we developed an expectation-maximization (EM) algorithm that works on data obtained from pedigrees. To achieve this, we used factor graphs to factorize the likelihood into a product of “local” functions, which enabled us to apply the sum-product algorithm in the E-step, reducing the computational complexity from exponential to linear. Our algorithm thus enables parameter estimation for family studies in a feasible amount of time. In the second part, we turn to ChIP-Seq data. Previously, practitioners were required to assemble a set of tools based on different statistical assumptions and dedicated to specific applications such as calling protein occupancy peaks or testing for differential occupancies between experimental conditions. In order to remove these restrictions and create a unified framework for ChIP-Seq analysis, we developed GenoGAM (Genome-wide Generalized Additive Model), which extends generalized additive models to efficiently work on data spread over a long x axis by reducing the scaling from cubic to linear and by employing a data parallelism strategy. Our software makes the well-established and flexible GAM framework available for a number of genomic applications. Furthermore, the statistical framework allows for significance testing for differential occupancy. In conclusion, I show how developing algorithms of lower complexity can open the door for analyses that were previously intractable. On this basis, it is recommended to focus subsequent research efforts on lowering the complexity of existing algorithms and design new, lower-complexity algorithms

Building catalogues of genetic variation in Poplar

La tesi descrive l\u2019analisi della variazione genetica a livello di sequenza in due specie di pioppo (Populus nigra e Populus detoides) con l\u2019utilizzo di tecnologie di sequenziamento di nuova generazione e di analisi bioinformatiche. \uc8 stata analizzata sia la variazione a livello di singolo nucleotide in un numero ristretto di geni ma in un campione molto esteso di individui, sia la variazione strutturale nell\u2019intero genoma in un campione limitato di individu

A Novel Adaptive Method for the Analysis of Next-Generation Sequencing Data to Detect Complex Trait Associations with Rare Variants Due to Gene Main Effects and Interactions

There is solid evidence that rare variants contribute to complex disease etiology. Next-generation sequencing technologies make it possible to uncover rare variants within candidate genes, exomes, and genomes. Working in a novel framework, the kernel-based adaptive cluster (KBAC) was developed to perform powerful gene/locus based rare variant association testing. The KBAC combines variant classification and association testing in a coherent framework. Covariates can also be incorporated in the analysis to control for potential confounders including age, sex, and population substructure. To evaluate the power of KBAC: 1) variant data was simulated using rigorous population genetic models for both Europeans and Africans, with parameters estimated from sequence data, and 2) phenotypes were generated using models motivated by complex diseases including breast cancer and Hirschsprung's disease. It is demonstrated that the KBAC has superior power compared to other rare variant analysis methods, such as the combined multivariate and collapsing and weight sum statistic. In the presence of variant misclassification and gene interaction, association testing using KBAC is particularly advantageous. The KBAC method was also applied to test for associations, using sequence data from the Dallas Heart Study, between energy metabolism traits and rare variants in ANGPTL 3,4,5 and 6 genes. A number of novel associations were identified, including the associations of high density lipoprotein and very low density lipoprotein with ANGPTL4. The KBAC method is implemented in a user-friendly R package

Exploiting natural selection to study adaptive behavior

The research presented in this dissertation explores different computational and modeling techniques that combined with predictions from evolution by natural selection leads to the analysis of the adaptive behavior of populations under selective pressure. For this thesis three computational methods were developed: EXPLoRA, EVORhA and SSA-ME. EXPLoRA finds genomic regions associated with a trait of interests (QTL) by explicitly modeling the expected linkage disequilibrium of a population of sergeants under selection. Data from BSA experiments was analyzed to find genomic loci associated with ethanol tolerance. EVORhA explores the interplay between driving and hitchhiking mutations during evolution to reconstruct the subpopulation structure of clonal bacterial populations based on deep sequencing data. Data from mixed infections and evolution experiments of E. Coli was used and their population structure reconstructed. SSA-ME uses mutual exclusivity in cancer to prioritize cancer driver genes. TCGA data of breast cancer tumor samples were analyzed.status: publishe

An efficient discrete artificial bee colony algorithm for the blocking flow shop problem with total flowtime minimization

This paper presents a high performing Discrete Artificial Bee Colony algorithm for the blocking flow shop problem with flow time criterion. To develop the proposed algorithm, we considered four strategies for the food source phase and two strategies for each of the three remaining phases (employed bees, onlookers and scouts). One of the strategies tested in the food source phase and one implemented in the employed bees phase are new. Both have been proved to be very effective for the problem at hand. The initialization scheme named HPF2(¿, µ) in particular, which is used to construct the initial food sources, is shown in the computational evaluation to be one of the main procedures that allow the DABC_RCT to obtain good solutions for this problem. To find the best configuration of the algorithm, we used design of experiments (DOE). This technique has been used extensively in the literature to calibrate the parameters of the algorithms but not to select its configuration. Comparing it with other algorithms proposed for this problem in the literature demonstrates the effectiveness and superiority of the DABC_RCTPeer ReviewedPostprint (author’s final draft

Statistical methods for transcriptomics: From microarrays to RNA-seq

La transcriptómica estudia el nivel de expresión de los genes en distintas condiciones experimentales para tratar de identificar los genes asociados a un fenotipo dado así como las relaciones de regulación entre distintos genes. Los datos ómicos se caracterizan por contener información de miles de variables en una muestra con pocas observaciones. Las tecnologías de alto rendimiento más comunes para medir el nivel de expresión de miles de genes simultáneamente son los microarrays y, más recientemente, la secuenciación de RNA (RNA-seq). Este trabajo de tesis versará sobre la evaluación, adaptación y desarrollo de modelos estadísticos para el análisis de datos de expresión génica, tanto si ha sido estimada mediante microarrays o bien con RNA-seq. El estudio se abordará con herramientas univariantes y multivariantes, así como con métodos tanto univariantes como multivariantes.Tarazona Campos, S. (2014). Statistical methods for transcriptomics: From microarrays to RNA-seq [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/48485TESISPremios Extraordinarios de tesis doctorale