Scalable Feature Selection Applications for Genome-Wide Association Studies of Complex Diseases

Personalized medicine will revolutionize our capabilities to combat disease. Working toward this goal, a fundamental task is the deciphering of geneticvariants that are predictive of complex diseases. Modern studies, in the formof genome-wide association studies (GWAS) have afforded researchers with the opportunity to reveal new genotype-phenotype relationships through the extensive scanning of genetic variants. These studies typically contain over half a million genetic features for thousands of individuals. Examining this with methods other than univariate statistics is a challenging task requiring advanced algorithms that are scalable to the genome-wide level. In the future, next-generation sequencing studies (NGS) will contain an even larger number of common and rare variants. Machine learning-based feature selection algorithms have been shown to have the ability to effectively create predictive models for various genotype-phenotype relationships. This work explores the problem of selecting genetic variant subsets that are the most predictive of complex disease phenotypes through various feature selection methodologies, including filter, wrapper and embedded algorithms. The examined machine learning algorithms were demonstrated to not only be effective at predicting the disease phenotypes, but also doing so efficiently through the use of computational shortcuts. While much of the work was able to be run on high-end desktops, some work was further extended so that it could be implemented on parallel computers helping to assure that they will also scale to the NGS data sets. Further, these studies analyzed the relationships between various feature selection methods and demonstrated the need for careful testing when selecting an algorithm. It was shown that there is no universally optimal algorithm for variant selection in GWAS, but rather methodologies need to be selected based on the desired outcome, such as the number of features to be included in the prediction model. It was also demonstrated that without proper model validation, for example using nested cross-validation, the models can result in overly-optimistic prediction accuracies and decreased generalization ability. It is through the implementation and application of machine learning methods that one can extract predictive genotype–phenotype relationships and biological insights from genetic data sets.

Fiber-reinforced composite fixed dental prostheses: Studies of the materials used as pontics

Fiber-reinforced composite fixed dental prostheses – Studies of the materials used as pontics University of Turku, Faculty of Medicine, Institute of Dentistry, Department of Biomaterials Science, Finnish Doctoral Program in Oral Sciences – FINDOS, Annales Universitatis Turkuensis, Turku, Finland 2015 Fiber-reinforced composites (FRC), a non-metallic biomaterial, represent a suitable alternative in prosthetic dentistry when used as a component of fixed dental prostheses (FDPs). Some drawbacks have been identified in the clinical performance of FRC restorations, such as delamination of the veneering material and fracture of the pontic. Therefore, the current series of studies were performed to investigate the possibilities of enhancing the mechanical and physical properties of FRC FDPs by improving the materials used as pontics, to then heighten their longevity. Four experiments showed the importance of the pontic design and surface treatment in the performance of FRC FDPs. In the first, the load-bearing capacities of inlay-retained FRC FDPs with pontics of various materials and thicknesses were evaluated. Three different pontic materials were assessed with different FRC framework vertical positioning. Thicker pontics showed increased load-bearing capacities, especially ceramic pontics. A second study was completed investigating the influence of the chemical conditioning of the ridge-lap surface of acrylic resin denture teeth on their bonding to a composite resin. Increased shear bond strength demonstrated the positive influence of the pretreatment of the acrylic surfaces, indicating dissolution of the denture surfaces, and suggesting potential penetration of the monomer systems into the surface of denture teeth. A third study analyzed the penetration depth of different monomer systems on the acrylic resin denture teeth surfaces. The possibility of establishing a durable bond between acrylic pontics and FRC frameworks was demonstrated by the ability of monomers to penetrate the surface of acrylic resin denture teeth, measured by a confocal scanning type microscope. A fourth study was designed to evaluate the load-bearing capacities of FRC FDPs using the findings of the previous three studies. In this case, the performance of pre-shaped acrylic resin denture teeth used as pontics with different composite resins as filling materials was evaluated. The filling material influenced the load-bearing capacities, providing more durable FRC FDPs. It can be concluded that the mechanical and physical properties of FRC FDPs can be improved as has been shown in the development of this thesis. The improvements reported then might provide long lasting prosthetic solutions of this kind, positioning them as potentially permanent rehabilitation treatments. Key words: fiber-reinforced composite, fixed dental prostheses, inlay-retained bridges, adhesion, acrylic resin denture teeth, dental material.

Worldly Saints : Social Interaction of Dominican Penitent Women in Italy, 1200-1500

Doctoral dissertation, University of Turku

Avian Evolutionary Genomics: Studies of Ficedula Flycatchers

In this thesis, different genetic tools are used to investigate both natural variation and speciation in the Ficedula flycatcher system: pied (Ficedula hypoleuca) and collared (F. albicollis) flycatchers. The molecular evolution of a gene involved in postnatal body growth, GH, has shown high degree of conservation at the mature protein between birds and mammals, whereas the variation observed in its signal peptide seems to be adaptive in pied flycatcher (I & II). Speciation is the process by which reproductive barriers to gene flow evolve between populations, and understanding the mechanisms involved in pre- and post-zygotic isolation have been investigated in Ficedula flycatchers. The Z chromosome have been suggested to be the hotspot for genes involved in speciation, thus sequencing of 13 Z-linked coding genes from the two species in allopatry and sympatry have been conducted (III). Surprisingly, the majority of Z-linked genes seemed to be highly conserved, suggesting instead a potential involvement of regulatory regions. Previous studies have shown that genes involved in hybrid fitness, female preferences and male plumage colouration are sex-linked. Hence, three pigmentation genes have been investigated: MC1R, AGRP, and TYRP1. Of these three genes, TYRP1 was identified as a strong candidate to be associated with black-brown plumage variation in sympatric populations, and hence is a strong candidate for a gene contributing to pre-zygotic isolation (IV). In sympatric areas, where pied and collared flycatchers have overlapping breeding areas, hybridization sometimes occurs leading to the production of unfit hybrids. By using a proteomic approach a novel expression pattern in hybrids was revealed compared to the parental species (V) and differentially expressed proteins subsequently identified by sequence similarity (VI). In conclusion, the Z chromosome appears to play an important role in flycatcher speciation, but probably not at the coding level. In addition the novel expression patterns might give new insights into the maladaptive hybrids.

Validation Studies of Thermal-hydraulic Code for Safety Analysis of Nuclear Power Plants

This thesis gives an overview of the validation process for thermal hydraulic system codes and it presents in more detail the assessment and validation of the French code CATHARE for VVER calculations. Three assessment cases are presented: loop seal clearing, core reflooding and flow in a horizontal steam generator. The experience gained during these assessment and validation calculations has been used to analyze the behavior of the horizontal steam generator and the natural circulation in the geometry of the Loviisa nuclear power plant. The cases presented are not exhaustive, but they give a good overview of the work performed by the personnel of Lappeenranta University of Technology (LUT). Large part of the work has been performed in co-operation with the CATHARE-team in Grenoble, France. The design of a Russian type pressurized water reactor, VVER, differs from that of a Western-type PWR. Most of thermal-hydraulic system codes are validated only for the Western-type PWRs. Thus, the codes should be assessed and validated also for VVER design in order to establish any weaknesses in the models. This information is needed before codes can be used for the safety analysis. Theresults of the assessment and validation calculations presented here show that the CATHARE code can be used also for the thermal-hydraulic safety studies for VVER type plants. However, some areas have been indicated which need to be reassessed after further experimental data become available. These areas are mostly connected to the horizontal stem generators, like condensation and phase separation in primary side tubes. The work presented in this thesis covers a large numberof the phenomena included in the CSNI code validation matrices for small and intermediate leaks and for transients. Also some of the phenomena included in the matrix for large break LOCAs are covered. The matrices for code validation for VVER applications should be used when future experimental programs are planned for code validation.

Exploration of the social dimension of corporate responsibility in a welfare state

This study focuses on corporate social responsibility (or CSR)as the latest dimension to emerge in the corporate responsibility and sustainability agenda, which in the recent past has rapidly risen to the top of the list of concerns for civil societies worldwide. Despite the continuing debates and discussions about the scope, benefits, and impacts of CSR to business and community in various sectors, levels, and types of society, many companies have moved forward to confront the opportunities and challenges of CSR. Thus, this study is about those proactive companies with a focus on the importance of CSR and its management inside and outside the company. It is an exploration and learning from the experience of Finnish companies, as well as other actors interested or involved in shaping the course of CSR, locally and globally. It also looks closely at how national culture affects the views, thinking, and management of CSR in a welfare state. This dissertation primarily draws on the analyses of information collected from a series of qualitative interviews and the existing literature in the area. This is complemented by an analysis of written and published documents on CSR from various sources. The results of the study give insightful information and detailed descriptions of a roadmap useful in learning and understanding CSR in Finnish companies. Despite the varying conceptual connotations, essential roadmap indicators point to the importance of framing CSR within the corporate responsibility concept, Finnish development and the welfare state system, globalization, stakeholders, and the pursuit of sustainable development as the main drivers of CSR, the remarkable progress of CSR in companies, and identification of key management areas and practices relevant to CSR. Similarly,the study reveals the importance of culture as essential in understanding and learning CSR. Finnish culture has a positive influence on the views, thinking, and management practices of CSR issues. Such a positive influence of culture, therefore, makes it easy for business people to discuss and understand CSR, because those CSR issues are already considered common and taken-for-granted by Finns and are implicit in the welfare state provisions. The experience of Finnish companies in implementing CSR policies in the supply chain is a concrete proactive step in advancing the message of CSR, that is, to bring companies and suppliers together to work on improving and strengthening relationships towards socially responsible practices worldwide. Such a forward step to deal with CSR issues in the supply chain reflects the companies' commitments and belief that CSR can be managed with the suppliers and gain positive benefits. Despite the problems and complexities, particularly in the global supply chain, managing CSR for Finnish companies presents new opportunities and challenges that are expected to intensify in the near future. The focus on CSR policy implementation inthe supply chain points to the importance of companies taking initiatives and forging cooperation with suppliers with the aim of addressing and improving CSR questions in the supply chains. The proactive stance of Finnish companies toward CSR is complemented by the active supporting role of important societalactors such as the government and NGOs. These actors carry out various promotional efforts and campaigns, thus bringing CSR into the mainstream of Finnish companies and strengthening the synergistic learning about CSR within the Finnish business and civil circles. The efforts of the government and NGOs to promote CSR are indicative of the importance of multipartite involvement and the emergence of better civil regulations. Likewise, their drive to learn from each other, exchange experiences, and contribute in CSR debates facilitated the evolution of CSRnetworks in the country. The results of this study add to the mounting evidence that CSR, in general, has created a new dimension in managing corporate sustainability. This study provides compelling empirical evidence and some direct quotations about CSR in the Finnish context. This information can be used to learn and gain new useful insights, approaches, and concepts for managing CSR.

Fiber-reinforced Composite as Oral Implant Material. Experimental studies of glass fiber and bioactive glass in vitro and in vivo

Fiber-reinforced composite as oral implant material: Experimental studies of glass fiber and bioactive glass in vitro and in vivo Department of Prosthetic Dentistry and Biomaterials Science, Institute of Dentistry, University of Turku, Turku, Finland 2008. Biocompatibility and mechanical properties are important variables that need to be determined when new materials are considered for medical implants. Special emphasis was placed on these characteristics in the present work, which aimed to investigate the potential of fiber-reinforced composite (FRC) material as an oral implant. Furthermore, the purpose of this study was to explore the effect of bioactive glass (BAG) on osseointegration of FRC implants. The biocompatibility and mechanical properties of FRC implants were studied both in vitro and in vivo. The mechanical properties of the bulk FRC implant were tested with a cantilever bending test, torsional test and push-out test. The biocompatibility was first evaluated with osteoblast cells cultured on FRC substrates. Bone bonding was determined with the mechanical push-out test and histological as well as histomorplanimetric evaluation. Implant surface was characterized with SEM and EDS analysis. The results of these studies showed that FRC implants can withstand the static load values comparably to titanium. Threaded FRC implants had significantly higher push-out strength than the threaded titanium implants. Cell culture study revealed no cytotoxic effect of FRC materials on the osteoblast-like-cells. Addition of BAG particles enhanced cell proliferation and mineralization of the FRC substrates The in vivo study showed that FRC implants can withstand static loading until failure without fracture. The results also suggest that the FRC implant is biocompatible in bone. The biological behavior of FRC was comparable to that of titanium after 4 and 12 weeks of implantation. Furthermore, addition of BAG to FRC implant increases peri-implant osteogenesis and bone maturation.

Epidemiological studies of childhood and adolescence headache

The main purpose of this study was to examine the changes in the prevalence, incidence, and characteristics of headache in childhood and adolescence. In addition, the predictors of the change in the occurrence of childhood headache and the association between adolescent headache and behavior were studied. The occurrence and characteristics of headache were investigated as part of a prospective follow-up study, where 6-year-old children and their families (n=1132) were followed to the age of 12-years (n=1126). The study design entailed both a cohort and case-control group. The incidence of headache and the association between headache and behavior were studied in another cohort, consisting of 11-year-old twins (n=5393), who were followed to the age of 17 (n=4159). The prevalence rates of headache increased during the follow-up, especially in boys whose mothers suffered from frequent headache. The incidence rates of frequent headache changed the most in girls between ages of 11 and 14. Early-onset migraine and tension-type headache were equal predictors of migraine at age 12. The age-related changes observed in pain localization, concurrent symptoms and triggers were considerable. Headache frequency was significantly associated with externalizing and internalizing problem behaviors and adaptive behaviors as rated by parents, but only with externalizing problem behaviors as rated by teachers. Headache both in children and adolescents is characterized by its changing nature. Its prevention and treatment should take familial, environmental and psychosocial aspects into account.

Surface Studies of Thiolate Adsorbates on Some Metals

The results and discussions in this thesis are based on my studies about selfassembled thiol layers on gold, platinum, silver and copper surfaces. These kinds of layers are two-dimensional, one molecule thick and covalently organized at the surface. They are an easy way to modify surface properties. Self-assembly is today an intensive research field because of the promise it holds for producing new technology at nanoscale, the scale of atoms and molecules. These kinds of films have applications for example, in the fields of physics, biology, engineering, chemistry and computer science. Compared to the extensive literature concerning self-assembled monolayers (SAMs) on gold, little is known about the structure and properties of thiolbased SAMs on other metals. In this thesis I have focused on thiol layers on gold, platinum, silver and copper substrates. These studies can be regarded as a basic study of SAMs. Nevertheless, an understanding of the physical and chemical nature of SAMs allows the correlation between atomic structure and macroscopic properties. The results can be used as a starting point for many practical applications. X-ray photoelectron spectroscopy (XPS) and synchrotron radiation excited high resolution photoelectron spectroscopy (HR-XPS) together with time-offlight secondary ion mass spectrometry (ToF-SIMS) were applied to investigate thin organic films formed by the spontaneous adsorption of molecules on metal surfaces. Photoelectron spectroscopy was the main method used in these studies. In photoelectron spectroscopy, the sample is irradiated with photons and emitted photoelectrons are energy-analyzed. The obtained spectra give information about the atomic composition of the surface and about the chemical state of the detected elements. It is widely used in the study of thin layers and is a very powerful tool for this purpose. Some XPS results were complemented with ToF-SIMS measurements. It provides information on the chemical composition and molecular structure of the samples. Thiol (1-Dodecanethiol, CH3(CH2)11SH) solution was used to create SAMs on metal substrates. Uniform layers were formed on most of the studied metal surfaces. On platinum, surface aligned molecules were also detected in investigations by XPS and ToF-SIMS. The influence of radiation on the layer structure was studied, leading to the conclusion that parts of the hydrocarbon chains break off due to radiation and the rest of the layer is deformed. The results obtained showed differences depending on the substrate material. The influence of oxygen on layer formation was also studied. Thiol molecules were found to replace some of the oxygen from the metal surfaces.

Studies of Eu- and Yb-induced Reconstructions on the Si(100) Surface

This thesis presents experimental studies of rare earth (RE) metal induced structures on Si(100) surfaces. Two divalent RE metal adsorbates, Eu and Yb, are investigated on nominally flat Si(100) and on vicinal, stepped Si(100) substrates. Several experimental methods have been applied, including scanning tunneling microscopy/spectroscopy (STM/STS), low energy electron diffraction (LEED), synchrotron radiation photoelectron spectroscopy (SR-PES), Auger electron spectroscopy (AES), thermal desorption spectroscopy (TDS), and work function change measurements (Δφ). Two stages can be distinguished in the initial growth of the RE/Si interface: the formation of a two-dimensional (2D) adsorbed layer at submonolayer coverage and the growth of a three-dimensional (3D) silicide phase at higher coverage. The 2D phase is studied for both adsorbates in order to discover whether they produce common reconstructions or reconstructions common to the other RE metals. For studies of the 3D phase Yb is chosen due to its ability to crystallize in a hexagonal AlB2 type lattice, which is the structure of RE silicide nanowires, therefore allowing for the possibility of the growth of one-dimensional (1D) wires. It is found that despite their similar electronic configuration, Eu and Yb do not form similar 2D reconstructions on Si(100). Instead, a wealth of 2D structures is observed and atomic models are proposed for the 2×3-type reconstructions. In addition, adsorbate induced modifications on surface morphology and orientational symmetry are observed. The formation of the Yb silicide phase follows the Stranski-Krastanov growth mode. Nanowires with the hexagonal lattice are observed on the flat Si(100) substrate, and moreover, an unexpectedly large variety of growth directions are revealed. On the vicinal substrate the growth of the silicide phase as 3D islands and wires depends drastically on the growth conditions. The conditions under which wires with high aspect ratio and single orientation parallel to the step edges can be formed are demonstrated.

Offshore Sourcing in Software Development: Case Studies of Finnish-Russian Cooperation

The study examines international cooperation in product development in software development organisations. The software industry is known for its global nature and knowledge-intensity, which makes it an interesting setting to examine international cooperation in. Software development processes are increasingly distributed worldwide, but for small or even medium-sized enterprises, typical for the software industry, such distribution of operations is often possible only in association with crossing the company’s boundaries. The strategic decision-making of companies is likely to be affected by the characteristics of the industry, and this includes decisions about cooperation or sourcing. The objective of this thesis is to provide a holistic view on factors affecting decisions about offshore sourcing in software development. Offshore sourcing refers to a cooperative mode of offshoring, where a firm does not establish its own presence in a foreign country, but utilises a local supplier. The study examines product development activities that are distributed across organisational and geographical boundaries. The objective can be divided into two subtopics: general reasons for international cooperation in product development and particular reasons for cooperation between Finnish and Russian companies. The focus is on the strategic rationale at the company level, in particular in small and medium-sized enterprises. The theoretical discourse of the study builds upon the literature on international cooperation and networking, with particular focus on cooperation with foreign suppliers and within product development activities. The resource-based view is also discussed, as heterogeneity and interdependency of the resources possessed by different firms are seen as factors motivating international cooperation. Strategically, sourcing can be used to access resources possessed by an industrial network, to enhance the product development of a firm, or to optimise its cost structure. In order to investigate the issues raised by the theoretical review, two empirical studies on international cooperation in software product development have been conducted. The emphasis of the empirical part of the study is on cooperation between Finnish and Russian companies. The data has been gathered through four case studies on Finnish software development organisations and four case studies on Russian offshore suppliers. Based on the material from the case studies, a framework clarifying and grouping the factors that influence offshore sourcing decisions has been built. The findings indicate that decisions regarding offshore sourcing in software development are far more complex than generally assumed. The framework provides a holistic view on factors affecting decisions about offshore sourcing in software development, capturing the multidimensionality of motives for entering offshore cooperation. Four groups of factors emerged from the data: A) strategy-related aspects, B) aspects related to resources and capabilities, C) organisation-related aspects, and D) aspects related to the entrepreneur or management. By developing a holistic framework of decision factors, the research offers in-depth theoreticalunderstanding of offshore sourcing rationale in product development. From the managerial point of view, the proposed framework sums up the issues that a firm should pay attention to when contemplating product development cooperation with foreign suppliers. Understanding different components of sourcing decisions can lead to improved preconditions for strategising and engaging in offshore cooperation. A thorough decisionmaking process should consider all the possible benefits and risks of product development cooperation carefully.

Studies of Liquid-liquid Separation in Fibre Coalescer

This thesis focuses on fibre coalescers whose efficiency is based on the surface properties/characteristics. They have the ability to preferentially wet or interact with one or more of the fluids to be separated. Thus, the interfacial phenomena governing the separation efficiency of the coalescers is investigated depending on physical factors such as flowrates, phase ratios and coalescer packing density. Design of process equipment to produce and separate of the emulsions was carried out.The experimentation was carried out to test the separation efficiency of the coalescing medias, namely fibreglass, polyester I and polyester II. The performances of the coalescing medias were assessed via droplet size information. In conclusion, the objectives (design of process equipment and experimentation) were achieved. Fibre glass was the best coalescing media, next was polyester I and then finally polyester II. Droplets sizes increased with decreased flowrates and increased packing density of the coalescer. Phase ratio had effect on the droplet sizes of the feed but had no effect on the coalescence of droplets of the feed.

Understanding Neolithic Southern Levant: case studies of archaeological semiosis in action

I undersökningen tillämpas Charles Sanders Peirces semiotik för en kritisk granskning av arkeologiska tolkningsprocesser. Enligt Peirce bygger all betydelsegivning på tecken, som kan vara teckningar, föremål, ord, byggkonstruktioner eller egentligen vad som helst. Ett tecken är tredimensionellt: ”objekt”, ”tecken” och ”tolkning”. I sina tidiga skrifter definierar han tre grundtyper för tecknet, Index, Icon och Symbol. De grundläggande definitionerna i Peirces semiotik blir till ett slags lins. När den placeras på skrifter av en arkeolog som uttolkar tecken, framträder deras inre uppbyggnad, motiveringar och logiska konsekvens klart. Att beakta är, att denna bok är lika lite avsedd att utgöra en systematisk klarläggning av den arkeologiska semiotiken, som en omfattande beskrivning av symboliken i det neolitiska Mellanöstern. Analysen är deskriptiv och inte avsedd att utvärdera tolkningarnas riktighet, utan enbart att klarlägga hur arkeologen kommit fram till dessa. Som objekt har valts neolitiska södra Levanten, där viktiga fynd gällande denna i mänsklighetens kulturhistoria så betydelsefulla skede har gjorts. Förhistorien är intressant med tanke på arkeologisk semiosis, eftersom uttolkaren av en symbol inte kan stöda sig på textfynd, utan måste på annat sätt upptäcka vad ett föremål eller en byggnad betytt för sin upphovsman. Att upptäcka en trovärdig betydelse är ofta en mycket svår och understundom rentav omöjlig uppgift. Efter att förhållandet mellan semiotik och arkeologi dryftats analyseras i boken John Garstangs och Kathleen M. Kenyons grundläggande tolkningar i Jeriko, Denise-Schmandt Besserats jämförande analyser för uttolkningen av \'Ain Ghazalis kranium, Michele A. Millers kontextuella analys i Jarmuk samt David Lewis-Williams’ starkt strukturalistiska analys av betydelsen av fynden i \'Ain Ghazal. Peirces semiotik har använts som stöd för arkeologin i mycket mindre utsträckning än F. de Saussures lingvistiska ja strukturalistiska semiotik. I Mellanöstern har man hittills inte alls gjort det. Ingen av de forskare som behandlas i boken hänvisar själv till semiotik eller tecken. Logiken i uttolkningen av dessa undersökningar är mycket invecklad, och de av Peirce gestaltade processerna för betydelsegivning visar sig härvidlag utgöra en ytterst klargörande kritisk apparat.