Computational Techniques for Haplotype Inference and for Local Alignment Significance

This thesis which consists of an introduction and four peer-reviewed original publications studies the problems of haplotype inference (haplotyping) and local alignment significance. The problems studied here belong to the broad area of bioinformatics and computational biology. The presented solutions are computationally fast and accurate, which makes them practical in high-throughput sequence data analysis. Haplotype inference is a computational problem where the goal is to estimate haplotypes from a sample of genotypes as accurately as possible. This problem is important as the direct measurement of haplotypes is difficult, whereas the genotypes are easier to quantify. Haplotypes are the key-players when studying for example the genetic causes of diseases. In this thesis, three methods are presented for the haplotype inference problem referred to as HaploParser, HIT, and BACH. HaploParser is based on a combinatorial mosaic model and hierarchical parsing that together mimic recombinations and point-mutations in a biologically plausible way. In this mosaic model, the current population is assumed to be evolved from a small founder population. Thus, the haplotypes of the current population are recombinations of the (implicit) founder haplotypes with some point--mutations. HIT (Haplotype Inference Technique) uses a hidden Markov model for haplotypes and efficient algorithms are presented to learn this model from genotype data. The model structure of HIT is analogous to the mosaic model of HaploParser with founder haplotypes. Therefore, it can be seen as a probabilistic model of recombinations and point-mutations. BACH (Bayesian Context-based Haplotyping) utilizes a context tree weighting algorithm to efficiently sum over all variable-length Markov chains to evaluate the posterior probability of a haplotype configuration. Algorithms are presented that find haplotype configurations with high posterior probability. BACH is the most accurate method presented in this thesis and has comparable performance to the best available software for haplotype inference. Local alignment significance is a computational problem where one is interested in whether the local similarities in two sequences are due to the fact that the sequences are related or just by chance. Similarity of sequences is measured by their best local alignment score and from that, a p-value is computed. This p-value is the probability of picking two sequences from the null model that have as good or better best local alignment score. Local alignment significance is used routinely for example in homology searches. In this thesis, a general framework is sketched that allows one to compute a tight upper bound for the p-value of a local pairwise alignment score. Unlike the previous methods, the presented framework is not affeced by so-called edge-effects and can handle gaps (deletions and insertions) without troublesome sampling and curve fitting.

Computationally Efficient Methods for MDL-Optimal Density Estimation and Data Clustering

The Minimum Description Length (MDL) principle is a general, well-founded theoretical formalization of statistical modeling. The most important notion of MDL is the stochastic complexity, which can be interpreted as the shortest description length of a given sample of data relative to a model class. The exact definition of the stochastic complexity has gone through several evolutionary steps. The latest instantation is based on the so-called Normalized Maximum Likelihood (NML) distribution which has been shown to possess several important theoretical properties. However, the applications of this modern version of the MDL have been quite rare because of computational complexity problems, i.e., for discrete data, the definition of NML involves an exponential sum, and in the case of continuous data, a multi-dimensional integral usually infeasible to evaluate or even approximate accurately. In this doctoral dissertation, we present mathematical techniques for computing NML efficiently for some model families involving discrete data. We also show how these techniques can be used to apply MDL in two practical applications: histogram density estimation and clustering of multi-dimensional data.

Harmonic Analysis of Advanced Bus-Clamping PWM Techniques

Special switching sequences can be employed in space-vector-based generation of pulsewidth-modulated (PWM) waveforms for voltage-source inverters. These sequences involve switching a phase twice, switching the second phase once, and clamping the third phase in a subcycle. Advanced bus-clamping PWM (ABCPWM) techniques have been proposed recently that employ such switching sequences. This letter studies the spectral properties of the waveforms produced by these PWM techniques. Further, analytical closed-form expressions are derived for the total rms harmonic distortion due to these techniques. It is shown that the ABCPWM techniques lead to lower distortion than conventional space vector PWM and discontinuous PWM at higher modulation indexes. The findings are validated on a 2.2-kW constant $V/f$ induction motor drive and also on a 100-kW motor drive.

Feature selection and the concept of immediate neighborhood in the context of clustering techniques

The concept of feature selection in a nonparametric unsupervised learning environment is practically undeveloped because no true measure for the effectiveness of a feature exists in such an environment. The lack of a feature selection phase preceding the clustering process seriously affects the reliability of such learning. New concepts such as significant features, level of significance of features, and immediate neighborhood are introduced which result in meeting implicitly the need for feature slection in the context of clustering techniques.

Ethics in a Technological World : Framing the Questions and Three Approaches

This study addresses the following question: How to think about ethics in a technological world? The question is treated first thematically by framing central issues in the relationship between ethics and technology. This relationship has three distinct facets: i) technological advance poses new challenges for ethics, ii) traditional ethics may become poorly applicable in a technologically transformed world, and iii) the progress in science and technology has altered the concept of rationality in ways that undermine ethical thinking itself. The thematic treatment is followed by the description and analysis of three approaches to the questions framed. First, Hans Jonas s thinking on the ontology of life and the imperative of responsibility is studied. In Jonas s analysis modern culture is found to be nihilistic because it is unable to understand organic life, to find meaning in reality, and to justify morals. At the root of nihilism Jonas finds dualism, the traditional Western way of seeing consciousness as radically separate from the material world. Jonas attempts to create a metaphysical grounding for an ethic that would take the technologically increased human powers into account and make the responsibility for future generations meaningful and justified. The second approach is Albert Borgmann s philosophy of technology that mainly assesses the ways in which technological development has affected everyday life. Borgmann admits that modern technology has liberated humans from toil, disease, danger, and sickness. Furthermore, liberal democracy, possibilities for self-realization, and many of the freedoms we now enjoy would not be possible on a large scale without technology. Borgmann, however, argues that modern technology in itself does not provide a whole and meaningful life. In fact, technological conditions are often detrimental to the good life. Integrity in life, according to him, is to be sought among things and practices that evade technoscientific objectification and commodification. Larry Hickman s Deweyan philosophy of technology is the third approach under scrutiny. Central in Hickman s thinking is a broad definition of technology that is nearly equal to Deweyan inquiry. Inquiry refers to the reflective and experiential way humans adapt to their environment by modifying their habits and beliefs. In Hickman s work, technology consists of all kinds of activities that through experimentation and/or reflection aim at improving human techniques and habits. Thus, in addition to research and development, many arts and political reforms are technological for Hickman. He argues for recasting such distinctions as fact/value, poiesis/praxis/theoria, and individual/society. Finally, Hickman does not admit a categorical difference between ethics and technology: moral values and norms need to be submitted to experiential inquiry as well as all the other notions. This study mainly argues for an interdisciplinary approach to the ethics of technology. This approach should make use of the potentialities of the research traditions in applied ethics, the philosophy of technology, and the social studies on science and technology and attempt to overcome their limitations. This study also advocates an endorsement of mid-level ethics that concentrate on the practices, institutions, and policies of temporal human life. Mid-level describes the realm between the instantaneous and individualistic micro-level and the universal and global macro level.

Living Poetically in the Modern Age : The Situational Aspects of Kierkegaard's Thought

How did Søren Kierkegaard (1813 1855) situate the human subject into historical and social actuality? How did he take into consideration his own situatedness? As key for understanding these questions the research takes the ideal of living poetically that Kierkegaard outlined in his dissertation. In The Concept of Irony (1841) Kierkegaard took up this ideal of the Romantic ironists and made it into an ethical-religious ideal. For him the ideal of living poetically came to mean 1) becoming brought up by God, while 2) assuming ethical-religiously one s role and place in the historical actuality. Through an exegesis of Kierkegaard s texts from 1843 to 1851 it is shown how this ideal governed Kierkegaard s thought and action throughout his work. The analysis of Kierkegaard s ideal of living poetically not only a) shows how the Kierkegaardian subject is situated in its historical context. It also b) sheds light on Kierkegaard s social and political thought, c) helps to understand Kierkegaard s character as a religious thinker, and d) pits his ethical-religious orientation in life against its scientific and commonsense alternatives. The research evaluates the rationality of the way of life championed by Kierkegaard by comparing it with ways of life dominated by reflection and reasoning. It uses Kierkegaard s ideal of living poetically in trying to understand the tensions between religious and unreligious ways of life.

Optimal maintenance policy for equipment subject to random deterioration and random failure A modern control theory approach.

The stochastic version of Pontryagin's maximum principle is applied to determine an optimal maintenance policy of equipment subject to random deterioration. The deterioration of the equipment with age is modelled as a random process. Next the model is generalized to include random catastrophic failure of the equipment. The optimal maintenance policy is derived for two special probability distributions of time to failure of the equipment, namely, exponential and Weibull distributions Both the salvage value and deterioration rate of the equipment are treated as state variables and the maintenance as a control variable. The result is illustrated by an example

Review of continuum, finite element and hybrid techniques in the analysis of stress concentrations in structures

When a uniform flow of any nature is interrupted, the readjustment of the flow results in concentrations and rare-factions, so that the peak value of the flow parameter will be higher than that which an elementary computation would suggest. When stress flow in a structure is interrupted, there are stress concentrations. These are generally localized and often large, in relation to the values indicated by simple equilibrium calculations. With the advent of the industrial revolution, dynamic and repeated loading of materials had become commonplace in engine parts and fast moving vehicles of locomotion. This led to serious fatigue failures arising from stress concentrations. Also, many metal forming processes, fabrication techniques and weak-link type safety systems benefit substantially from the intelligent use or avoidance, as appropriate, of stress concentrations. As a result, in the last 80 years, the study and and evaluation of stress concentrations has been a primary objective in the study of solid mechanics. Exact mathematical analysis of stress concentrations in finite bodies presents considerable difficulty for all but a few problems of infinite fields, concentric annuli and the like, treated under the presumption of small deformation, linear elasticity. A whole series of techniques have been developed to deal with different classes of shapes and domains, causes and sources of concentration, material behaviour, phenomenological formulation, etc. These include real and complex functions, conformal mapping, transform techniques, integral equations, finite differences and relaxation, and, more recently, the finite element methods. With the advent of large high speed computers, development of finite element concepts and a good understanding of functional analysis, it is now, in principle, possible to obtain with economy satisfactory solutions to a whole range of concentration problems by intelligently combining theory and computer application. An example is the hybridization of continuum concepts with computer based finite element formulations. This new situation also makes possible a more direct approach to the problem of design which is the primary purpose of most engineering analyses. The trend would appear to be clear: the computer will shape the theory, analysis and design.

Self-image (autoidolon) techniques for the realisation of optical computing type operations

Abstract is not available.

Assimilation of remote sensing and hydrological data using adaptive filtering techniques for watershed modelling

The knowledge of hydrological variables (e. g. soil moisture, evapotranspiration) are of pronounced importance in various applications including flood control, agricultural production and effective water resources management. These applications require the accurate prediction of hydrological variables spatially and temporally in watershed/basin. Though hydrological models can simulate these variables at desired resolution (spatial and temporal), often they are validated against the variables, which are either sparse in resolution (e. g. soil moisture) or averaged over large regions (e. g. runoff). A combination of the distributed hydrological model (DHM) and remote sensing (RS) has the potential to improve resolution. Data assimilation schemes can optimally combine DHM and RS. Retrieval of hydrological variables (e. g. soil moisture) from remote sensing and assimilating it in hydrological model requires validation of algorithms using field studies. Here we present a review of methodologies developed to assimilate RS in DHM and demonstrate the application for soil moisture in a small experimental watershed in south India.

Expression, Enzymatic Activities and Subcellular Localization of Hepatitis E Virus and Semliki Forest Virus Replicase Proteins

Viruses are submicroscopic, infectious agents that are obligate intracellular parasites. They adopt various types of strategies for their parasitic replication and proliferation in infected cells. The nucleic acid genome of a virus contains information that redirects molecular machinery of the cell to the replication and production of new virions. Viruses that replicate in the cytoplasm and are unable to use the nuclear transcription machinery of the host cell have developed their own transcription and capping systems. This thesis describes replication strategies of two distantly related viruses, hepatitis E virus (HEV) and Semliki Forest virus (SFV), which belong to the alphavirus-like superfamily of positive-strand RNA viruses. We have demonstrated that HEV and SFV share a unique cap formation pathway specific for alphavirus-like superfamily. The capping enzyme first acts as a methyltransferase, catalyzing the transfer of a methyl group from S-adenosylmethionine to GTP to yield m7GTP. It then transfers the methylated guanosine to the end of viral mRNA. Both reactions are virus-specific and differ from those described for the host cell. Therefore, these capping reactions offer attractive targets for the development of antiviral drugs. Additionally, it has been shown that replication of SFV and HEV takes place in association with cellular membranes. The origin of these membranes and the intracellular localization of the components of the replication complex were studied by modern microscopy techniques. It was demonstrated that SFV replicates in cytoplasmic membranes that are derived from endosomes and lysosomes. According to our studies, site for HEV replication seems to be the intermediate compartment which mediates the traffic between endoplasmic reticulum and the Golgi complex. As a result of this work, a unique mechanism of cap formation for hepatitis E virus replicase has been characterized. It represents a novel target for the development of specific inhibitors against viral replication.