Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Infinite Dimensional Slow Modulations In A Delayed Model For Orthogonal Cutting Vibrations

We apply the method of multiple scales (MMS) to a well known model of regenerative cutting vibrations in the large delay regime. By ``large'' we mean the delay is much larger than the time scale of typical cutting tool oscillations. The MMS upto second order for such systems has been developed recently, and is applied here to study tool dynamics in the large delay regime. The second order analysis is found to be much more accurate than first order analysis. Numerical integration of the MMS slow flow is much faster than for the original equation, yet shows excellent accuracy. The main advantage of the present analysis is that infinite dimensional dynamics is retained in the slow flow, while the more usual center manifold reduction gives a planar phase space. Lower-dimensional dynamical features, such as Hopf bifurcations and families of periodic solutions, are also captured by the MMS. Finally, the strong sensitivity of the dynamics to small changes in parameter values is seen clearly.

Efficient Output-Sensitive Construction of Reeb Graphs

The Reeb graph tracks topology changes in level sets of a scalar function and finds applications in scientific visualization and geometric modeling. This paper describes a near-optimal two-step algorithm that constructs the Reeb graph of a Morse function defined over manifolds in any dimension. The algorithm first identifies the critical points of the input manifold, and then connects these critical points in the second step to obtain the Reeb graph. A simplification mechanism based on topological persistence aids in the removal of noise and unimportant features. A radial layout scheme results in a feature-directed drawing of the Reeb graph. Experimental results demonstrate the efficiency of the Reeb graph construction in practice and its applications.

NMR-Studies of Octahedral Dicyano-(2,2' Bipyridine) and Tetracyano-(2,2'-Bipyridine) Iron(ii) Complexes

Coordination compounds of the polypyridines, 2,2 ' -bipyridine (bipy) and 1,10-penanthroline (phen) have offered renewed interest on account of their manifold applications and from the point of view of understanding their structure-reactivity relationships.1 Iron(II) reacts with them to form tris-complexes possessing spin-paired ground states. Cyanide ion greatly enhances the rate of displacement of bipy or phen to form the Schilt class of compounds. Fe(bipy)2(CN)2 and Fe(phen)2(CN)2. They display varying colours in solution depending upon the nature of the solvent and react reversibly with acids to form diprotonated species.2 Magnetic circular dichroism studies have been reported to describe their lowest electronic excitation.

Smooth stabilisation of nonholonomic robots subject to disturbances

In this paper, we address the problem of stabilisation of robots subject to nonholonommic constraints and external disturbances using port-Hamiltonian theory and smooth time-invariant control laws. This should be contrasted with the commonly used switched or time-varying laws. We propose a control design that provides asymptotic stability of an manifold (also called relative equilibria)-due to the Brockett condition this is the only type of stabilisation possible using smooth time-invariant control laws. The equilibrium manifold can be shaped to certain extent to satisfy specific control objectives. The proposed control law also incorporates integral action, and thus the closed-loop system is robust to unknown constant disturbances. A key step in the proposed design is a change of coordinates not only in the momentum, but also in the position vector, which differs from coordinate transformations previously proposed in the literature for the control of nonholonomic systems. The theoretical properties of the control law are verified via numerical simulation based on a robotic ground vehicle model with differential traction wheels and non co-axial centre of mass and point of contact.

A unified approach to the gauging of space-time and internal symmetries

The properties of the manifold of a Lie groupG, fibered by the cosets of a sub-groupH, are exploited to obtain a geometrical description of gauge theories in space-timeG/H. Gauge potentials and matter fields are pullbacks of equivariant fields onG. Our concept of a connection is more restricted than that in the similar scheme of Ne'eman and Regge, so that its degrees of freedom are just those of a set of gauge potentials forG, onG/H, with no redundant components. The ldquotranslationalrdquo gauge potentials give rise in a natural way to a nonsingular tetrad onG/H. The underlying groupG to be gauged is the groupG of left translations on the manifoldG and is associated with a ldquotrivialrdquo connection, namely the Maurer-Cartan form. Gauge transformations are all those diffeomorphisms onG that preserve the fiber-bundle structure.

On The Topology Of Manifolds With Positive Isotropic Curvature

We show that a closed orientable Riemannian n-manifold, n >= 5, with positive isotropic curvature and free fundamental group is homeomorphic to the connected sum of copies of Sn-1 x S-1.

Efficient algorithms for computing Reeb graphs

The Reeb graph tracks topology changes in level sets of a scalar function and finds applications in scientific visualization and geometric modeling. We describe an algorithm that constructs the Reeb graph of a Morse function defined on a 3-manifold. Our algorithm maintains connected components of the two dimensional levels sets as a dynamic graph and constructs the Reeb graph in O(nlogn+nlogg(loglogg)3) time, where n is the number of triangles in the tetrahedral mesh representing the 3-manifold and g is the maximum genus over all level sets of the function. We extend this algorithm to construct Reeb graphs of d-manifolds in O(nlogn(loglogn)3) time, where n is the number of triangles in the simplicial complex that represents the d-manifold. Our result is a significant improvement over the previously known O(n2) algorithm. Finally, we present experimental results of our implementation and demonstrate that our algorithm for 3-manifolds performs efficiently in practice.

Oireista puhuminen lääkärin vastaanotolla : Keskustelunanalyyttinen tutkimus lääkärin kysymyksistä

Talking about symptoms during medical consultation. A conversation analytical study of doctors questions This linguistically oriented conversation analytic study investigates doctors questions and patients answers during medical consultation. The focus is on 1) the syntactic constructions of the doctors questions concerning the patients symptoms, 2) the function of different types of syntactic constructions, and 3) the sequential placement of the questions. The data used in the study consist of 57 videotaped doctor patient encounters in Finnish primary health care. The study shows that the traditional division between open and closed questions is vague and needs to be examined further. Open wh-questions and closed yes/no questions form heterogeneous classes: some of the closed questions can be treated as open and vice versa. Wh-questions which occur during the physical examination are often constructed to elicit short answers. These questions can consist of one word (e.g. milloin when ) which does not move to a new topic but supports the unfinished activity of palpation. During the verbal examination, wh-questions are formulated to elicit long descriptions as answers. For example, by asking mites + X ( what about + X), the doctor can open up a new topic and simultaneously give the patient the opportunity to discuss the topic from his/her perspective. Almost half of the yes/no questions project longer than just a minimal answer (e.g. a short confirmation or rejection). In these questions, the doctors use verbal elements which show that more than just a minimal answer is required. They can, for example, add an indefinite element (joku some or mitään any ) to a yes/no question, add a conjunctive vai ( or ) to the end of the question and thus open a space for various types of answers, or add a suggested answer to the question. In addition, the results show that declarative questions not only check understanding, but display the doctor s diagnosing process, check whether the doctor can move on to the next topic or action, and display implicitly the doctor s idea of what is connected and what is relevant. One aim of the study is to describe how different syntactic structures work together. A typical question chain consists of two or three questions. The first question is an open wh-question that elicits a new topic and creates different types of presuppositions. Contingent questions are constructed as yes/no questions that seek an affirmative answer or as declarative sentences that seek confirmation. Contingent questions can function as repair initiators and thus support achieving mutual understanding. Therefore, they are tools for the doctor to construct a description of the medical problem collaboratively with the patient. The results add to the results of previous studies on questions in medical consultation, but also suggest some corrections. They provide additional evidence for the idea that different types of syntactic constructions are useful in different types of settings. However, they also show that the variety of questions that doctors use is more manifold and diverse than the variety introduced in earlier studies and textbooks.

Scheffleriläinen rationaalisuus ja kasvatustodellisuuden monikerroksisuus : Jännitteitä ja ratkaisuja Israel Schefflerin kasvatusfilosofiassa

The study is a philosophical analysis of Israel Scheffler’s philosophy of education, focusing on three crucial conceptions in his philosophy: the conception of rationality, the conception of human nature, and the conception of reality. The interrelations of these three concepts as well as their relations to educational theorizing are analysed and elaborated. A conceptual problem concerning Scheffler’s ideal of rationality derives from Scheffler’s supposition of the strong analogy between science education and moral education in terms of the ideal of rationality. This analogy is argued to be conceptually problematic, since the interconnections of rationality, objectivity, and truth, appear to differ from each other in the realms of ethics and science, given the presuppositions of ontological realism and ethical naturalism, to which Scheffler explicitly subscribes. This study considers two philosophical alternatives for solving this problem. The first alternative relates the analogy to the normative concept of personhood deriving from the teleological understanding of human nature. Nevertheless, this position turns out to be problematic for Scheffler, since he rejects all teleological thinking in his philosophy. The problem can be solved, as it is argued, by limiting Scheffler’s rejection of teleology – in light of his philosophical outlook on the whole – in a manner that allows a modest version of a teleological conception of human nature. The second alternative, based especially on Scheffler’s later contributions, is to suggest that reality is actually more complex and manifold than it appears to be in light of a contemporary naturalist worldview. This idea of plurealism – Scheffler’s synthesis of pluralism and realism – is represented especially in Scheffler’s contributions related to his debate with Nelson Goodman dealing with both constructivism and realism. The idea of plurealism is not only related to the ethics-science-distinction, but is more widely related to the relationship between ontological realism and the incommensurable systems of description in diverse realms of human understanding. The Scheffler-Goodman debate is also analysed in relation to the contemporary constructivism-realism debate in educational philosophy. In terms of educational questions, Scheffler’s plurealism is argued as offering a fruitful perspective. Scheffler’s philosophy of education can be interpreted as searching for solutions to the problems deriving from the tension between the tradition of analytical philosophy and the complexity and multiplicity of educational reality. The complexity of reality combined with the supposition of the limitedness of human knowledge does not lead Scheffler to relativism or particularism, but, in contrast, Schefflerian formulations of rationality and objectivity preserve the possibility for critical inquiry in all realms of educational reality. In light of this study, Scheffler’s philosophy of education provides an exceptional example of combining ontological realism, epistemological fallibilism, and the defence of the ideal of rationality, combined with a wide-ranging understanding of educational reality.

Kehittävän kuntoutuksen mahdollisuudet. : Tutkimus Aslak -kuntoutuksen työkytkennän ja asiakkuuden rakentumisesta.

The possibilities of developmental rehabilitation. A study on the construction of work relatedness and the customer in Aslak rehabilitation The challenge of work-related rehabilitation is to anticipate the factors threatening work ability and to affect them. The purpose of this study was to analyze how work-related rehabilitation is constructed in practice and what are the challenges and, at the same time, the possibilities of an innovative transformation of rehabilitation when trying to achive this goal. The theoretical basis is cultural-historical activity theory and developmental work research. Based on a historical analysis, I studied rehabilitation activity empirically using the data gathered from one Aslak programme (Aslak = occupationally oriented medical rehabilitation) over two years. I described and analysed the construction of Aslak using ethnographic data and interviews. The data includes audio- and video-recordings of the Aslak course, fieldnotes, documents and other materials used in the course. The study aimed to reveal rehabilitation practices from different perspectives carried out by different stakeholders and participants in the Aslak course. It focused on the Aslak trajectory produced by a multiorganizational subject. I analyzed the rehabilitation activity using the method of ethnographic analysis of infrastructure. The method of analyzing the construction of the object of rehabilititation the customer was a membership categorization analysis (MCD) based on the ethnomethodological research tradition. I analyzed the meanings denoting customers given by different parties during one Aslak process and the relations between the meanings. Based on this analysis, I studied the disturbances, ruptures, and innovations in the rehabilitation activity. The results of the study show that the infrastructure of Aslak has different basic ideas. Aslak is constructed most explicitly on the infrastructure of medical rehabilitation. The second layer has been provided with some tools of identifying and preventing well-defined occupation-specific load factors. However, it has failed to perform a new structure, as Aslak has encountered, at the same time, rapid changes in working life. The study identified some promising markers representing new kinds of work-related rehabilitation ideas, but they proved to be incomplete and fragile. As a consequence of the multilayered infrastructure, the contents of the Aslak course were split into fragmented phases and disconnected themes, which were blocked in by the master idea of medical orientation. Its relationship to work remained weak and obscure. The categorizations of customers in Aslak were manifold and contradictory. According to the results, the possibilities for transforming work-related rehabilitation lie both in changing the orientation to the customer to be more relevant to changing working life and forging the infrastructural innovations related to this change. The results showed that a new work-relatedeness would be difficult but possible to construct. What is needed is the construction of an infrastructure that will support a coherent master idea of work-related rehabilitation over the entire trajectory of a process. A shared idea of a rehabilitation object must be constructed in close collaboration between different stakeholders, such as Kela (the Social Insurance Institution of Finland), occupational health services, work organizations, and rehabilitation institutes. Key words: Aslak rehabilitation, work-related rehabilitation, development of rehabilitation, customer of rehabilitation, developmental work research, analysis of infrastructure, membership category analysis

Matka koulun kestävän kehittämisen maisemassa

A Journey in the Landscape of Sustainable School Development “A Journey in the Landscape of Sustainable School Development” is a story of the Sorrila School development process. This research deals with a school development project as a process, and as a part of international projects on Education for Sustainable Development, with ENSI (Environment and School Initiatives) being the most important. The main purpose of the study was to analyze the change process as a general phenomenon as well as the learning connected to it. The research describes the development period 2001–2008 at the Sorrila Primary school. The research questions are as follows: 1. What did pupils learn during the research and development period? 2. How did the coordinating teacher develop personally? 3. How were the ENSI targets and other closely linked projects reached? 4. What was the feedback from the pupils, their parents and other teachers at the school? 5. How did the developing process proceed in 2001–2008? The method used was integrating action research, which also had ethnographical elements. Narrative was the form of the data as well as the manner of reporting. The method as a whole was integrating, ethnographical action research as a story. The research data consisted mostly of Knowledge Forum notes written by the teacher-researcher. Knowledge Forum is an Internetbased collaborative knowledge-building programme. Pupils’, parents’ and other teachers’ feedback, newspaper articles and students’ writings complied the data, which consists of material from seven years. Sustainable development was the basis of the school improvement. The targets of the United Nations Decade of Education for Sustainable Development (2005–2014) were part of the development projects. According to the research results the school was seen as part of complex systems where manifold and interactive learning took place. The learning of pupils, teachers and the school as a community can be characterised socioculturally. The school was able to reach a level of collaborative transformative learning. As well as several concrete projects, such as Comenius school project, school development consisted of networking at many levels. Along with the projects and networking, the school was able to apply the pedagogy of connection, by carrying out integrative and cross-disciplinary themes and using various learning and teaching methods. International cooperation was a natural part of the work. A figure of Aunt Green, the role model of the teacher researcher, was an innovation which resembled a change agent. The other role of the teacherresearcher as a coordinator, was important for her own professional development. According to the results the change process, which relied on sustainable school development, led the school along a road of positive renewals. It was not a series of projects but an ongoing process. The objectives of the international projects were accomplished to a great extent during the research period. According to the principles of action research, the main results were put forward in order to help others to develop their schools. Frictions and problems as well as positive experiences and rejecting dualities were seen as change forces. Keywords: education for sustainable development (ESD), sustainable school development, teacher professional development, integrating, pedagogy of connection, transformative learning

An elementary approach to gap theorems

Using elementary comparison geometry, we prove: Let (M, g) be a simply-connected complete Riemannian manifold of dimension >= 3. Suppose that the sectional curvature K satisfies -1-s(r) <= K <= -1, where r denotes distance to a fixed point in M. If lim(r ->infinity) e(2r) s(r) = 0, then (M, g) has to be isometric to H-n.The same proof also yields that if K satisfies -s(r) <= K <= 0 where lim(r ->infinity) r(2) s(r) = 0, then (M, g) is isometric to R-n, a result due to Greene and Wu.Our second result is a local one: Let (M, g) be any Riemannian manifold. For a E R, if K < a on a geodesic ball Bp (R) in M and K = a on partial derivative B-p (R), then K = a on B-p (R).

Rapid typing of P multocida

Fowl cholera, caused by P. multocida, is a serious disease of poultry with sudden surges in mortality and an emerging disease of the free ranged poultry industries. This project will develop a more rapid and cost effective screening method for P. multocida. The impacts of this new method are manifold: It will lead to an improved understanding of the epidemiology of fowl cholera and the possible sources of entry onto the farm leading to improved biosecurity measures and control programs. Another impact is improved serotyping, which will ensure more effective and targeted vaccination programs. Improving prevention and control programs and decreasing the reliance on antibiotics will enhance the sustainability and profitability of the industry.

Genome-wide association studies of quantitative traits with related individuals: Little (power) lost but much to be gained

For complex disease genetics research in human populations, remarkable progress has been made in recent times with the publication of a number of genome-wide association scans (GWAS) and subsequent statistical replications. These studies have identified new genes and pathways implicated in disease, many of which were not known before. Given these early successes, more GWAS are being conducted and planned, both for disease and quantitative phenotypes. Many researchers and clinicians have DNA samples available on collections of families, including both cases and controls. Twin registries around the world have facilitated the collection of large numbers of families, with DNA and multiple quantitative phenotypes collected on twin pairs and their relatives. In the design of a new GWAS with a fixed budget for the number of chips, the question arises whether to include or exclude related individuals. It is commonly believed to be preferable to use unrelated individuals in the first stage of a GWAS because relatives are 'over-matched' for genotypes. In this study, we quantify that for GWAS of a quantitative phenotype, relative to a sample of unrelated individuals surprisingly little power is lost when using relatives. The advantages of using relatives are manifold, including the ability to perform more quality control, the choice to perform within-family tests of association that are robust to population stratification, and the ability to perform joint linkage and association analysis. Therefore, the advantages of using relatives in GWAS for quantitative traits may well outweigh the small disadvantage in terms of statistical power.