Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Procurement in Project Implementation

Tutkimus keskittyy hankintatoimen kehittämiseen osana laitosprojektien toteutusta. Työ pohjautuu empiiriseltä taustaltaan Pöyry Oyj:n projektiliiketoimintaan ja työn tarkastelunäkökulmaksi onvalittu projektihallinnosta vastaavan yrityksen näkökulma. Tutkimus on hyvin käytännönläheinen ¿ se lähtee hankinnan ja sen seurannan ongelmista ja pyrkii tarjoamaan niihin uudenlaisia ratkaisuja. Pohjimmiltaan tutkimus kuuluu teollisuustalouden piiriin, vaikka tietojärjestelmätieteellä on vahva tukirooli. Työn tavoitteet ja tulokset liittyvät teollisuustaloudelle ominaisesti yrityksen toiminnan kehittämiseen, käytetyt välineet ja ratkaisut puolestaan hyödyntävät tietojärjestelmätieteen antamia mahdollisuuksia. Tutkimuksessa on käytetty konstruktiivista tutkimusotetta, jonka mukaisesti on luotu innovatiivisia konstruktioita ratkaisemaan aitoja reaalimaailman ongelmia ja tätä kautta tuotettu kontribuutioita teollisuustaloudelle. Tavoitteena oli järjestää hankintatoimi ja sen seuranta suurissa laitosprojekteissa tehokkaammin. Tätä varten uudistettiin ensin projektihallinnon ja hankintatoimen toimintaohjeet vastaamaan paremmin nykyajan vaatimuksia. Toimintaohjeiden perusteella ryhdyttiin toteuttamaan hankintaohjelmistoa, joka pystyisi kattamaan kaikki toimintaohjeissa kuvatut piirteet. Lopulta hankintaohjelmisto toi mukanaan uusia piirteitä projektihallintoon ja hankintatoimeen ja nämä sisällytettiin toimintaohjeisiin. Tähän kehitystyöhön ryhdyttiin, jotta laitosprojektien projektihallinto ja hankintatoimi toimisivat paremmin, eli pienemmin kustannuksin tuottaen projekteissa tarvittavat tulokset nopeammin, tarkemmin ja laadukkaammin. Tutkimuksella on kolmenlaisia tuloksia: hankintatoimen parannetut metodit, hankintaohjelmiston pohjana olevat toiminta- ja laskentamallit sekä implementaationa hankintasovellus. Uudistetut projekti- ja hankintaohjeet kuvaavat hankintatoiminnan parannettuja metodeja. Hankintaohjelmistoasuunnitellessa ja kehitettäessä tehdyt kuvaukset sisältävät uusia malleja niin hankintaprosessille kuin hankinnan seuraamiseksi suurissa laitosprojekteissa. Itse ohjelmisto on tuloksena implementaatio, joka perustuu parannettuihin hankintametodeihin ja uusiin toiminta- ja laskentamalleihin. Uudistetut projekti- ja hankintaohjeet ovat olleet käytössä Pöyry Oyj:ssä vuodesta 1991. Vuosien varrella nämä toimintaohjeet ovat auttaneet ja tukeneet satojen laitosprojektientoteutusta ja ylläpitäneet Pöyry Oyj:n kilpailukykyä kansainvälisenä projektitalona. Hankintasovellus puolestaan on ollut käytössä useissa projekteissa ja sen on havaittu pienentävän hankintatoimen suoria työkustannuksia laitosprojekteissa. Sovelluksen katsotaan myös tuovan epäsuoria kustannussäästöjä parempien hankintapäätösten muodossa, mutta näiden säästöjen suuruutta ei pystytä luotettavasti arvioimaan.

The effect of information and communication technology on global paper consumption

The objective of this thesis is to find out how information and communication technology affects the global consumption of printing and writing papers. Another objective is to find out, whether there are differences between paper grades in these effects. The empirical analysis is conducted by linear regression analysis using three sets of country-level panel data from 1990-2006. Data set of newsprint contains 95 countries, data set of uncoated woodfree paper 61 countries and data set of coated mechanical paper 42 countries. The material is based on paper consumption data of RISI’s Industry Statistics Database and on the information and communication technology data of GMID-database. Results indicate that number of Internet users has statistically significant negative effect on the consumption of newsprint and on the consumption of coated mechanical paper and number of mobile telephone users has positive effect on the consumptions of these papers. Results also indicate that information and communication technologies have only small effect on consumption of uncoated woodfree paper or no significant effect at all, but these results are more uncertain to some extent.

Reproducibility of Vertebral Fracture Assessment Readings From Dual-energy X-ray Absorptiometry in Both a Population-based and Clinical Cohort: Cohen's and Uniform Kappa.

Vertebral fracture assessments (VFAs) using dual-energy X-ray absorptiometry increase vertebral fracture detection in clinical practice and are highly reproducible. Measures of reproducibility are dependent on the frequency and distribution of the event. The aim of this study was to compare 2 reproducibility measures, reliability and agreement, in VFA readings in both a population-based and a clinical cohort. We measured agreement and reliability by uniform kappa and Cohen's kappa for vertebral reading and fracture identification: 360 VFAs from a population-based cohort and 85 from a clinical cohort. In the population-based cohort, 12% of vertebrae were unreadable. Vertebral fracture prevalence ranged from 3% to 4%. Inter-reader and intrareader reliability with Cohen's kappa was fair to good (0.35-0.71 and 0.36-0.74, respectively), with good inter-reader and intrareader agreement by uniform kappa (0.74-0.98 and 0.76-0.99, respectively). In the clinical cohort, 15% of vertebrae were unreadable, and vertebral fracture prevalence ranged from 7.6% to 8.1%. Inter-reader reliability was moderate to good (0.43-0.71), and the agreement was good (0.68-0.91). In clinical situations, the levels of reproducibility measured by the 2 kappa statistics are concordant, so that either could be used to measure agreement and reliability. However, if events are rare, as in a population-based cohort, we recommend evaluating reproducibility using the uniform kappa, as Cohen's kappa may be less accurate.

Paperikoneen viira- ja puristinosan mitoituslaskennan ohjeistaminen

Työssä laadittiin viira- ja puristinosan rungoston mitoituslaskentaa varten ohjeet FE-analysointiin. Työ suoritettiin keräämällä aluksi eri yksiköissä Valmetilla käytössä olevat mitoituslaskentaohjeet, aihetta käsittelevät muistiot ja diplomityöt sekä sekä keskustelemalla muiden viira- ja puristinosastolla laskentaa suorittavien suunnittelijoiden kanssa. Tämän jälkeen ohjeista koottiin ja täydennettiin yksi yhteinen ohjeisto, joka on jatkossa kaikkien laskijoiden käytössä. Valmiit ohjeet koottiin Valmetin Rautpohjan osastoiden yhteiseen Notes- järjestelmään. Ohjekannasta tehtiin sellainen, että siihen on helppo myöhemmin lisätä muiden rakenneryhmien ohjeita. Ohjeet jaettiin viiteen ryhmään ohjeiden lukemisen ja päivityksen helpottamiseksi. Mitoituslaskentaohjeiden käyttöä testattiin laskemalla yhden todellisen projektin puristinosan runkolaskelmat ohjeiden avulla. Yhteisen ohjeistuksen avulla yhtenäistettiin mallinnus- ja laskentatapoja niin Valmetin sisällä kuin mitoituslaskentaa tekevien alihankkijoiden keskuudessa.

Clean development mechanism and joint implementation in China and Russia as related to industrial energy projects

Being highly discussed the problem of climate change and global warming has been keeping importance for several of decades. As a response to the world’s need in solution for climate change disasters, the United Nations Framework Convention on Climate Change was adopted in 1992 and supplemented with the Kyoto protocol in 1997. This work is aimed to give better understanding of the Convention, Kyoto Protocol with its mechanisms and their function, related to energy projects in such case countries, as Russia and China, in order to assist evaluation of projects cost-effectiveness. It provides basic information about the Convention and the Protocol with their regulations, overview of present situation and future post-Kyoto forecasts, while the most attention is concentrated on the clean development mechanism and joint implementation step-by-step project cycles and specific regulations in given countries. The current study disclosed that CDM and JI project cycles are resulting in a complicated process. By the moment it requires step-by-step following of a number of methodologies, spending time and finance to particular project development. Uncertainties about post-Kyoto period bring additional risk to the projects and complicate any business decision concerning Kyoto Protocol.

Assessment in CLIL

The aim of this talk is to explore assessment in higher education and support for learners during their academic education. It investigates the assessment methods that provide success for universities and learners. Universities which implement CLIL should assess learners who would like to attend a programme in English without taking account of their English language qualifications. This assessment should be done in writing, listening and comprehension, speaking and reading and comprehension. In the literature, formative and summative assessments are considered. Formative assessment is ongoing, 'more complex as its intention is to be directly diagnostics with a view to immediately impacting on learner's next steps' (Coyle et al, 2010). Summative assessment occurs at the end of the term or course. McKay, 2006 divides assessment into three phases: design, operationalization and administration phase. If these three phases can't be embedded in the classroom as they are, they can be introduced as a set of questions; why?, how? and what?

Supplier's position in project marketing networks

The present study explores relationships between project marketers and their customers in project marketing context. The purpose of the study is to increase the understanding on supplier’s position in project marketing networks. Project marketing is representing a high volume in the international business, and the industrial network approach and the project marketing research cannot fully explain a supplier’s position in project marketing networks. Increased knowledge on project networks can also contribute to industrial marketing research more generally. Data for the present study was collected firstly during the pilot case study from project buyers in the paper and the steel industry in interviews. Secondly an entire project marketing case concerning a steel industry case was used as a data source. The data included interviews, correspondence between the supplier and the buyer, and project documents. The data of the pilot case was analysed with contents analysis, and in the case a deeper analysis based on the developed Stage Dimension framework was used. Supplier’s position in project marketing networks is a hierarchical and dynamic concept including a supplier’s position on the highest level. The dimensions of the position concept are the intermediate level, and the dimensions are based on the underlying components. Supplier’s position is composed from four organization related dimensions, and two individual actor related dimensions. The composition of the supplier’s position varies during the project marketing process, and consequently the relative importance of the dimensions is changing over the process. Supplier’s position in project marketing networks is shaped by incremental and radical changes. Radical changes are initiated by critical events. The study contributes to the research of industrial networks and project marketing. The theoretical contribution of the study is threefold: firstly it proposes a structure of the position concept in project marketing networks, secondly it proposes the Position Stage Dimension Component (PSDC) model for the development of supplier’s position during the project marketing process, and thirdly the study widens the critical event concept to cover the project marketing process both on the organizational and individual level. In addition to the theoretical contributions there are several managerial implications for planning and implementing marketing strategies in the project context.

Factors of customer project profitability in an engineering industrial enterprise

The purpose of the study is to find factors affecting projects' profitability in project business. The issue is approached from customer profitability and project management point of view. The study has been made for a big Finnish company acting in a global market place. The research method is quantitative. Research hypotheses are based on the literature. The used database is originated from the company's ERP- (enterprise resource planning) and project financial follow-up —system. The findings of the study supported the hypotheses weakly. Obviously profitability fluctuated depending on a customer and a project manager. The reasons could not be justified with the variables used in the research.

Enhancement of R&D project management system

Stora Enso has research centres in Finland, Sweden and Germany. The research centres use PIMS as a research project invoicing and monitoring system. Possible reorganization and new financing model for R&D functions have been considered and the project management system should be developed to support the new operation model. The objective of this thesis is to find a model for R&D project management, and to present the project management system of Stora Enso, and to discuss if the current system could be developed to respond to the new needs or should it be replaced with another system. The theoretical part of the study describes challenges in R&D project management, and presents different project characteristics, and methods for managing R&D project portfolio. It is also described how the project management system can support project monitoring and controlling, and how inter-project learning can be enhanced. The empirical part of the study presents the current project management system of Stora Enso and how the system should be developed to support Stora Enso’s R&D functions better. In conclusion, it is stated that there is no relevant reason to replace PIMS with another system, because PIMS can be developed to support R&D project management better with a hybrid system. It is also suggested that the new financing model should not be implemented before more comprehensive analysis of its effects is conducted.

Success factors of customer and supplier master data system

Especially in global enterprises, key data is fragmented in multiple Enterprise Resource Planning (ERP) systems. Thus the data is inconsistent, fragmented and redundant across the various systems. Master Data Management (MDM) is a concept, which creates cross-references between customers, suppliers and business units, and enables corporate hierarchies and structures. The overall goal for MDM is the ability to create an enterprise-wide consistent data model, which enables analyzing and reporting customer and supplier data. The goal of the study was defining the properties and success factors of a master data system. The theoretical background was based on literature and the case consisted of enterprise specific needs and demands. The theoretical part presents the concept, background, and principles of MDM and then the phases of system planning and implementation project. Case consists of background, definition of as is situation, definition of project, evaluation criterions and concludes the key results of the thesis. In the end chapter Conclusions combines common principles with the results of the case. The case part ended up dividing important factors of the system in success factors, technical requirements and business benefits. To clarify the project and find funding for the project, business benefits have to be defined and the realization has to be monitored. The thesis found out six success factors for the MDM system: Well defined business case, data management and monitoring, data models and structures defined and maintained, customer and supplier data governance, delivery and quality, commitment, and continuous communication with business. Technical requirements emerged several times during the thesis and therefore those can’t be ignored in the project. Conclusions chapter goes through these factors on a general level. The success factors and technical requirements are related to the essentials of MDM: Governance, Action and Quality. This chapter could be used as guidance in a master data management project.

Lukemisen ja kirjoittamisen käytännöt metodologisessa ristivalotuksessa

Kirjallisuusarvostelu

Skill Development in Music Reading. The Eye-Movement Approach

This dissertation examined skill development in music reading by focusing on the visual processing of music notation in different music-reading tasks. Each of the three experiments of this dissertation addressed one of the three types of music reading: (i) sight-reading, i.e. reading and performing completely unknown music, (ii) rehearsed reading, during which the performer is already familiar with the music being played, and (iii) silent reading with no performance requirements. The use of the eye-tracking methodology allowed the recording of the readers’ eye movements from the time of music reading with extreme precision. Due to the lack of coherence in the smallish amount of prior studies on eye movements in music reading, the dissertation also had a heavy methodological emphasis. The present dissertation thus aimed to promote two major issues: (1) it investigated the eye-movement indicators of skill and skill development in sight-reading, rehearsed reading and silent reading, and (2) developed and tested suitable methods that can be used by future studies on the topic. Experiment I focused on the eye-movement behaviour of adults during their first steps of learning to read music notation. The longitudinal experiment spanned a nine-month long music-training period, during which 49 participants (university students taking part in a compulsory music course) sight-read and performed a series of simple melodies in three measurement sessions. Participants with no musical background were entitled as “novices”, whereas “amateurs” had had musical training prior to the experiment. The main issue of interest was the changes in the novices’ eye movements and performances across the measurements while the amateurs offered a point of reference for the assessment of the novices’ development. The experiment showed that the novices tended to sight-read in a more stepwise fashion than the amateurs, the latter group manifesting more back-and-forth eye movements. The novices’ skill development was reflected by the faster identification of note symbols involved in larger melodic intervals. Across the measurements, the novices also began to show sensitivity to the melodies’ metrical structure, which the amateurs demonstrated from the very beginning. The stimulus melodies consisted of quarter notes, making the effects of meter and larger melodic intervals distinguishable from effects caused by, say, different rhythmic patterns. Experiment II explored the eye movements of 40 experienced musicians (music education students and music performance students) during temporally controlled rehearsed reading. This cross-sectional experiment focused on the eye-movement effects of one-bar-long melodic alterations placed within a familiar melody. The synchronizing of the performance and eye-movement recordings enabled the investigation of the eye-hand span, i.e., the temporal gap between a performed note and the point of gaze. The eye-hand span was typically found to remain around one second. Music performance students demonstrated increased professing efficiency by their shorter average fixation durations as well as in the two examined eye-hand span measures: these participants used larger eye-hand spans more frequently and inspected more of the musical score during the performance of one metrical beat than students of music education. Although all participants produced performances almost indistinguishable in terms of their auditory characteristics, the altered bars indeed affected the reading of the score: the general effects of expertise in terms of the two eye- hand span measures, demonstrated by the music performance students, disappeared in the face of the melodic alterations. Experiment III was a longitudinal experiment designed to examine the differences between adult novice and amateur musicians’ silent reading of music notation, as well as the changes the 49 participants manifested during a nine-month long music course. From a methodological perspective, an opening to research on eye movements in music reading was the inclusion of a verbal protocol in the research design: after viewing the musical image, the readers were asked to describe what they had seen. A two-way categorization for verbal descriptions was developed in order to assess the quality of extracted musical information. More extensive musical background was related to shorter average fixation duration, more linear scanning of the musical image, and more sophisticated verbal descriptions of the music in question. No apparent effects of skill development were observed for the novice music readers alone, but all participants improved their verbal descriptions towards the last measurement. Apart from the background-related differences between groups of participants, combining verbal and eye-movement data in a cluster analysis identified three styles of silent reading. The finding demonstrated individual differences in how the freely defined silent-reading task was approached. This dissertation is among the first presentations of a series of experiments systematically addressing the visual processing of music notation in various types of music-reading tasks and focusing especially on the eye-movement indicators of developing music-reading skill. Overall, the experiments demonstrate that the music-reading processes are affected not only by “top-down” factors, such as musical background, but also by the “bottom-up” effects of specific features of music notation, such as pitch heights, metrical division, rhythmic patterns and unexpected melodic events. From a methodological perspective, the experiments emphasize the importance of systematic stimulus design, temporal control during performance tasks, and the development of complementary methods, for easing the interpretation of the eye-movement data. To conclude, this dissertation suggests that advances in comprehending the cognitive aspects of music reading, the nature of expertise in this musical task, and the development of educational tools can be attained through the systematic application of the eye-tracking methodology also in this specific domain.

Improving Product Information Management in Global Project Based Manufacturing

The transition of project based manufacturing business, even more into global networks, sets up challenges for companies to manage their business in this new operating environment. One way to tackle these challenges is the successful management of product information through an extended product’s lifecycle. Thus, one objective of this research is to find ways how product information management in global project based manufacturing can be improved. Another objective is to find a solution how the target company can improve its product information management in the offer-to-procurement business process. Due to the nature of the topic, the study follows constructive research methodology with qualitative methods. By combining literature related to this topic a framework is created to improve product information management in global project based manufacturing. The improvement process in this framework is based on a systematic approach from the current state towards target state. A general aim for improvements should be the integrated product and project lifecycle information management through Lean approach. This introduced framework is applied to the target company through two case projects. Data for building view of current state and analysis is collected mostly by theme interviews and also utilizing other material from the target company. Used tools help to analyzing was the BPMN and the Trace matrix for business chains. Results of the improvement process are collected in a solution proposal which contain the strategic target state as well as long and short term objectives. The strategic target state is defined as controlled customization. Also during the improvement process are created the Information requirements chart in the offer-to-procurement business process, and the Project related initial information questionnaire to customer.

Controlling and Assessment Indirect Spend – Case Study from Beverage Industry

Over the past decades, companies’ interest in controlling indirect sourcing process has increased. New indirect procurement strategies developed for the companies are needed in order to manage their indirect costs. New cost management strategies allow companies to improve their core competences. The research methodology and used in this thesis is qualitative. The theory is based on scientific publications. Empirical data given by the case organization, and was collected in the company’s own systems and in project steering meetings. The purpose of the study was to select a new electronic system for the company and give options for the company to reduce case organization’s indirect costs. The result showed that the most effective indirect cost management strategy was adopting a new electronic procurement system.