Eugenics or empowered choice? Community issues arising from prenatal testing

The prevention of inherited disabilities is viewed in two contrasting ways – either as enhancing reproductive choice and improving population health, or as discriminating against disabled community members. We argue that modern clinical genetics, including preimplantation genetic diagnosis (PGD), reflects a persistent and defensible desire by the community to prevent disability, rather than as increasing discrimination or threatening to produce a 'new eugenic' society. Screening should be presented as a distinct issue for decision-making about the prevention or acceptance of disability, rather than as a routinely accepted component of antenatal care. The community must improve its understanding of the experiences of those who manage disability, and continue to debate the issues of discrimination, selective genetic prevention and enhancement, reproductive freedom, and eugenics.

Testing the link between the latitudinal gradient in species richness and rates of molecular evolution

Numerous hypotheses have been proposed to explain latitudinal gradients in species richness, but all are subject to ongoing debate. Here we examine Rohde's (1978, 1992) hypothesis, which proposes that climatic conditions at low latitudes lead to elevated rates of speciation. This hypothesis predicts that rates of molecular evolution should increase towards lower latitudes, but this prediction has never been tested. We discuss potential links between rates of molecular evolution and latitudinal diversity gradients, and present the first test of latitudinal variation in rates of molecular evolution. Using 45 phylogenetically independent, latitudinally separated pairs of bird species and higher taxa, we compare rates of evolution of two mitochondrial genes and DNA-DNA hybridization distances. We find no support for an effect of latitude on rate of molecular evolution. This result casts doubt on the generality of a key component of Rohde's hypothesis linking climate and speciation.

Mismatch negativity in childhood temporal lobe epilepsy: a proposed paradigm for testing central auditory processing

Background: Temporal lobe epilepsy (TLE) is a neurological disorder that directly affects cortical areas responsible for auditory processing. The resulting abnormalities can be assessed using event-related potentials (ERP), which have high temporal resolution. However, little is known about TLE in terms of dysfunction of early sensory memory encoding or possible correlations between EEGs, linguistic deficits, and seizures. Mismatch negativity (MMN) is an ERP component – elicited by introducing a deviant stimulus while the subject is attending to a repetitive behavioural task – which reflects pre-attentive sensory memory function and reflects neuronal auditory discrimination and perceptional accuracy. Hypothesis: We propose an MMN protocol for future clinical application and research based on the hypothesis that children with TLE may have abnormal MMN for speech and non-speech stimuli. The MMN can be elicited with a passive auditory oddball paradigm, and the abnormalities might be associated with the location and frequency of epileptic seizures. Significance: The suggested protocol might contribute to a better understanding of the neuropsychophysiological basis of MMN. We suggest that in TLE central sound representation may be decreased for speech and non-speech stimuli. Discussion: MMN arises from a difference to speech and non-speech stimuli across electrode sites. TLE in childhood might be a good model for studying topographic and functional auditory processing and its neurodevelopment, pointing to MMN as a possible clinical tool for prognosis, evaluation, follow-up, and rehabilitation for TLE.

Specification and testing of multiplicative time-varying GARCH models with applications

In this article, we develop a specification technique for building multiplicative time-varying GARCH models of Amado and Teräsvirta (2008, 2013). The variance is decomposed into an unconditional and a conditional component such that the unconditional variance component is allowed to evolve smoothly over time. This nonstationary component is defined as a linear combination of logistic transition functions with time as the transition variable. The appropriate number of transition functions is determined by a sequence of specification tests. For that purpose, a coherent modelling strategy based on statistical inference is presented. It is heavily dependent on Lagrange multiplier type misspecification tests. The tests are easily implemented as they are entirely based on auxiliary regressions. Finite-sample properties of the strategy and tests are examined by simulation. The modelling strategy is illustrated in practice with two real examples: an empirical application to daily exchange rate returns and another one to daily coffee futures returns.

Validity and reliability of the Spanish version of the DN4 (Douleur Neuropathique 4 questions) questionnaire for differential diagnosis of pain syndromes associated to a neuropathic or somatic component

BACKGROUND This study assesses the validity and reliability of the Spanish version of DN4 questionnaire as a tool for differential diagnosis of pain syndromes associated to a neuropathic (NP) or somatic component (non-neuropathic pain, NNP). METHODS A study was conducted consisting of two phases: cultural adaptation into the Spanish language by means of conceptual equivalence, including forward and backward translations in duplicate and cognitive debriefing, and testing of psychometric properties in patients with NP (peripheral, central and mixed) and NNP. The analysis of psychometric properties included reliability (internal consistency, inter-rater agreement and test-retest reliability) and validity (ROC curve analysis, agreement with the reference diagnosis and determination of sensitivity, specificity, and positive and negative predictive values in different subsamples according to type of NP). RESULTS A sample of 164 subjects (99 women, 60.4%; age: 60.4 +/- 16.0 years), 94 (57.3%) with NP (36 with peripheral, 32 with central, and 26 with mixed pain) and 70 with NNP was enrolled. The questionnaire was reliable [Cronbach's alpha coefficient: 0.71, inter-rater agreement coefficient: 0.80 (0.71-0.89), and test-retest intra-class correlation coefficient: 0.95 (0.92-0.97)] and valid for a cut-off value > or = 4 points, which was the best value to discriminate between NP and NNP subjects. DISCUSSION This study, representing the first validation of the DN4 questionnaire into another language different than the original, not only supported its high discriminatory value for identification of neuropathic pain, but also provided supplemental psychometric validation (i.e. test-retest reliability, influence of educational level and pain intensity) and showed its validity in mixed pain syndromes.

Exact and approximate stepdown methods for multiple hypothesis testing

Consider the problem of testing k hypotheses simultaneously. In this paper,we discuss finite and large sample theory of stepdown methods that providecontrol of the familywise error rate (FWE). In order to improve upon theBonferroni method or Holm's (1979) stepdown method, Westfall and Young(1993) make eective use of resampling to construct stepdown methods thatimplicitly estimate the dependence structure of the test statistics. However,their methods depend on an assumption called subset pivotality. The goalof this paper is to construct general stepdown methods that do not requiresuch an assumption. In order to accomplish this, we take a close look atwhat makes stepdown procedures work, and a key component is a monotonicityrequirement of critical values. By imposing such monotonicity on estimatedcritical values (which is not an assumption on the model but an assumptionon the method), it is demonstrated that the problem of constructing a validmultiple test procedure which controls the FWE can be reduced to the problemof contructing a single test which controls the usual probability of a Type 1error. This reduction allows us to draw upon an enormous resamplingliterature as a general means of test contruction.

Development of a Database for Drilled Shaft Foundation Testing (DSHAFT), June 2012

Drilled shafts have been used in the US for more than 100 years in bridges and buildings as a deep foundation alternative. For many of these applications, the drilled shafts were designed using the Working Stress Design (WSD) approach. Even though WSD has been used successfully in the past, a move toward Load Resistance Factor Design (LRFD) for foundation applications began when the Federal Highway Administration (FHWA) issued a policy memorandum on June 28, 2000.The policy memorandum requires all new bridges initiated after October 1, 2007, to be designed according to the LRFD approach. This ensures compatibility between the superstructure and substructure designs, and provides a means of consistently incorporating sources of uncertainty into each load and resistance component. Regionally-calibrated LRFD resistance factors are permitted by the American Association of State Highway and Transportation Officials (AASHTO) to improve the economy and competitiveness of drilled shafts. To achieve this goal, a database for Drilled SHAft Foundation Testing (DSHAFT) has been developed. DSHAFT is aimed at assimilating high quality drilled shaft test data from Iowa and the surrounding regions, and identifying the need for further tests in suitable soil profiles. This report introduces DSHAFT and demonstrates its features and capabilities, such as an easy-to-use storage and sharing tool for providing access to key information (e.g., soil classification details and cross-hole sonic logging reports). DSHAFT embodies a model for effective, regional LRFD calibration procedures consistent with PIle LOad Test (PILOT) database, which contains driven pile load tests accumulated from the state of Iowa. PILOT is now available for broader use at the project website: http://srg.cce.iastate.edu/lrfd/. DSHAFT, available in electronic form at http://srg.cce.iastate.edu/dshaft/, is currently comprised of 32 separate load tests provided by Illinois, Iowa, Minnesota, Missouri and Nebraska state departments of transportation and/or department of roads. In addition to serving as a manual for DSHAFT and providing a summary of the available data, this report provides a preliminary analysis of the load test data from Iowa, and will open up opportunities for others to share their data through this quality–assured process, thereby providing a platform to improve LRFD approach to drilled shafts, especially in the Midwest region.

A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine

There is a need for more efficient methods giving insight into the complex mechanisms of neurotoxicity. Testing strategies including in vitro methods have been proposed to comply with this requirement. With the present study we aimed to develop a novel in vitro approach which mimics in vivo complexity, detects neurotoxicity comprehensively, and provides mechanistic insight. For this purpose we combined rat primary re-aggregating brain cell cultures with a mass spectrometry (MS)-based metabolomics approach. For the proof of principle we treated developing re-aggregating brain cell cultures for 48h with the neurotoxicant methyl mercury chloride (0.1-100muM) and the brain stimulant caffeine (1-100muM) and acquired cellular metabolic profiles. To detect toxicant-induced metabolic alterations the profiles were analysed using commercial software which revealed patterns in the multi-parametric dataset by principal component analyses (PCA), and recognised the most significantly altered metabolites. PCA revealed concentration-dependent cluster formations for methyl mercury chloride (0.1-1muM), and treatment-dependent cluster formations for caffeine (1-100muM) at sub-cytotoxic concentrations. Four relevant metabolites responsible for the concentration-dependent alterations following methyl mercury chloride treatment could be identified using MS-MS fragmentation analysis. These were gamma-aminobutyric acid, choline, glutamine, creatine and spermine. Their respective mass ion intensities demonstrated metabolic alterations in line with the literature and suggest that the metabolites could be biomarkers for mechanisms of neurotoxicity or neuroprotection. In addition, we evaluated whether the approach could identify neurotoxic potential by testing eight compounds which have target organ toxicity in the liver, kidney or brain at sub-cytotoxic concentrations. PCA revealed cluster formations largely dependent on target organ toxicity indicating possible potential for the development of a neurotoxicity prediction model. With such results it could be useful to perform a validation study to determine the reliability, relevance and applicability of this approach to neurotoxicity screening. Thus, for the first time we show the benefits and utility of in vitro metabolomics to comprehensively detect neurotoxicity and to discover new biomarkers.

Component Architecture for Context-Aware Applications

Mobiililaitteisiin tehdyt sovellukset ovat nykyään laajassa käytössä. Mobiilisovellukset tarjoavat käyttäjälleen usein tietyn ennalta määritellyn toiminnallisuuden eivätkä ne pysty mukautumaan vaihtelevaan käyttöympäristöönsä. Jos sovellus olisi tietoinen käyttöympäristöstään ja sen muutoksista, se voisi tarjota käyttäjälleen tilanteeseen sopivia ominaisuuksia. Käyttöympäristöstään tietoiset hajautetut sovellukset tarvitsevat kuitenkin huomattavasti perinteisiä sovelluksia monimutkaisemman arkkitehtuurin toimiakseen. Tässä työssä esitellään hajautetuille ja kontekstitietoisille sovelluksille tarkoitettu ohjelmistoarkkitehtuuri. Työ perustuu Oulun yliopiston CAPNET-tutkimusprojektissa kehitettyyn, mobiilisovelluksille tarkoitettuun arkkitehtuuriin. Tämän työn tarkoituksena on tarjota ratkaisuja niihin puutteisiin, jotka tulivat esille CAPNET-arkkitehtuurin kehitys- ja testausvaiheessa. Esimerkiksi arkkitehtuurin komponenttien määrittelyä tulisi tarkentaa ja ne tulisi jakaa horisontaalisiin kerroksiin niiden ominaisuuksien ja alustariippuvuuden mukaisesti. Työssä luodaan katsaus olemassa oleviin teknologioihin jotka tukevat hajautettujen ja kontekstitietoisten järjestelmien kehittämistä. Myös niiden soveltumista CAPNET-arkkitehtuuriin analysoidaan. Työssä esitellään CAPNET-arkkitehtuuri ja ehdotetaan uutta arkkitehtuuria ja komponenttien kerrosjaottelua. Ehdotuksessa arkkitehtuurin komponentit ja järjestelmän rakenne määritellään ja mallinnetaan UML-menetelmällä. Työn tuloksena on arkkitehtuurimäärittely, joka jakaa nykyisen arkkitehtuurin komponentit kerroksiin. Komponenttien rajapinnat on määritelty selkeästi ja tarkasti. Työ tarjoaa myös projektiryhmälle hyvän lähtökohdan uuden arkkitehtuurin suunnittelulle ja toteuttamiselle.

Model-based testing of software systems : functionality and performance

Software is a key component in many of our devices and products that we use every day. Most customers demand not only that their devices should function as expected but also that the software should be of high quality, reliable, fault tolerant, efficient, etc. In short, it is not enough that a calculator gives the correct result of a calculation, we want the result instantly, in the right form, with minimal use of battery, etc. One of the key aspects for succeeding in today's industry is delivering high quality. In most software development projects, high-quality software is achieved by rigorous testing and good quality assurance practices. However, today, customers are asking for these high quality software products at an ever-increasing pace. This leaves the companies with less time for development. Software testing is an expensive activity, because it requires much manual work. Testing, debugging, and verification are estimated to consume 50 to 75 per cent of the total development cost of complex software projects. Further, the most expensive software defects are those which have to be fixed after the product is released. One of the main challenges in software development is reducing the associated cost and time of software testing without sacrificing the quality of the developed software. It is often not enough to only demonstrate that a piece of software is functioning correctly. Usually, many other aspects of the software, such as performance, security, scalability, usability, etc., need also to be verified. Testing these aspects of the software is traditionally referred to as nonfunctional testing. One of the major challenges with non-functional testing is that it is usually carried out at the end of the software development process when most of the functionality is implemented. This is due to the fact that non-functional aspects, such as performance or security, apply to the software as a whole. In this thesis, we study the use of model-based testing. We present approaches to automatically generate tests from behavioral models for solving some of these challenges. We show that model-based testing is not only applicable to functional testing but also to non-functional testing. In its simplest form, performance testing is performed by executing multiple test sequences at once while observing the software in terms of responsiveness and stability, rather than the output. The main contribution of the thesis is a coherent model-based testing approach for testing functional and performance related issues in software systems. We show how we go from system models, expressed in the Unified Modeling Language, to test cases and back to models again. The system requirements are traced throughout the entire testing process. Requirements traceability facilitates finding faults in the design and implementation of the software. In the research field of model-based testing, many new proposed approaches suffer from poor or the lack of tool support. Therefore, the second contribution of this thesis is proper tool support for the proposed approach that is integrated with leading industry tools. We o er independent tools, tools that are integrated with other industry leading tools, and complete tool-chains when necessary. Many model-based testing approaches proposed by the research community suffer from poor empirical validation in an industrial context. In order to demonstrate the applicability of our proposed approach, we apply our research to several systems, including industrial ones.

A comparison of two computer-assisted remedial reading programs for adolescent unskilled readers : component reading skills and repeated reading

This study compared the relative effectiveness of two computerized remedial reading programs in improving the reading word recognition, rate, and comprehension of adolescent readers demonstrating significant and longstanding reading difficulties. One of the programs involved was Autoskill Component Reading Subskills Program, which provides instruction in isolated letters, syllables, and words, to a point of rapid automatic responding. This program also incorporates reading disability subtypes in its approach. The second program, Read It Again. Sam, delivers a repeated reading strategy. The study also examined the feasibility of using peer tutors in association with these two programs. Grade 9 students at a secondary vocational school who satisfied specific criteria with respect to cognitive and reading ability participated. Eighteen students were randomly assigned to three matched groups, based on prior screening on a battery of reading achievement tests. Two I I groups received training with one of the computer programs; the third group acted as a control and received the remedial reading program offered within the regular classroom. The groups met daily with a trained tutor for approximately 35 minutes, and were required to accumulate twenty hours of instruction. At the conclusion of the program, the pretest battery was repeated. No significant differences were found in the treatment effects of the two computer groups. Each of the two treatment groups was able to effect significantly improved reading word recognition and rate, relative to the control group. Comprehension gains were modest. The treatment groups demonstrated a significant gain, relative to the control group, on one of the three comprehension measures; only trends toward a gain were noted on the remaining two measures. The tutoring partnership appeared to be a viable alternative for the teacher seeking to provide individualized computerized remedial programs for adolescent unskilled readers. Both programs took advantage of computer technology in providing individualized drill and practice, instant feedback, and ongoing recordkeeping. With limited cautions, each of these programs was considered effective and practical for use with adolescent unskilled readers.

Dynamic whole system testing of combined renewable heating systems : the current state of the art

Objective: For the evaluation of the energetic performance of combined renewable heating systems that supply space heat and domestic hot water for single family houses, dynamic behaviour, component interactions, and control of the system play a crucial role and should be included in test methods. Methods: New dynamic whole system test methods were developed based on “hardware in the loop” concepts. Three similar approaches are described and their differences are discussed. The methods were applied for testing solar thermal systems in combination with fossil fuel boilers (heating oil and natural gas), biomass boilers, and/or heat pumps. Results: All three methods were able to show the performance of combined heating systems under transient operating conditions. The methods often detected unexpected behaviour of the tested system that cannot be detected based on steady state performance tests that are usually applied to single components. Conclusion: Further work will be needed to harmonize the different test methods in order to reach comparable results between the different laboratories. Practice implications: A harmonized approach for whole system tests may lead to new test standards and improve the accuracy of performance prediction as well as reduce the need for field tests.

Testing of combined heating systems for small houses: Improved procedures for whole system test methods : Deliverable 2.3

Dynamic system test methods for heating systems were developed and applied by the institutes SERC and SP from Sweden, INES from France and SPF from Switzerland already before the MacSheep project started. These test methods followed the same principle: a complete heating system – including heat generators, storage, control etc., is installed on the test rig; the test rig software and hardware simulates and emulates the heat load for space heating and domestic hot water of a single family house, while the unit under test has to act autonomously to cover the heat demand during a representative test cycle. Within the work package 2 of the MacSheep project these similar – but different – test methods were harmonized and improved. The work undertaken includes:  • Harmonization of the physical boundaries of the unit under test. • Harmonization of the boundary conditions of climate and load. • Definition of an approach to reach identical space heat load in combination with an autonomous control of the space heat distribution by the unit under test. • Derivation and validation of new six day and a twelve day test profiles for direct extrapolation of test results.   The new harmonized test method combines the advantages of the different methods that existed before the MacSheep project. The new method is a benchmark test, which means that the load for space heating and domestic hot water preparation will be identical for all tested systems, and that the result is representative for the performance of the system over a whole year. Thus, no modelling and simulation of the tested system is needed in order to obtain the benchmark results for a yearly cycle. The method is thus also applicable to products for which simulation models are not available yet. Some of the advantages of the new whole system test method and performance rating compared to the testing and energy rating of single components are:  • Interaction between the different components of a heating system, e.g. storage, solar collector circuit, heat pump, control, etc. are included and evaluated in this test. • Dynamic effects are included and influence the result just as they influence the annual performance in the field. • Heat losses are influencing the results in a more realistic way, since they are evaluated under "real installed" and representative part-load conditions rather than under single component steady state conditions.   The described method is also suited for the development process of new systems, where it replaces time-consuming and costly field testing with the advantage of a higher accuracy of the measured data (compared to the typically used measurement equipment in field tests) and identical, thus comparable boundary conditions. Thus, the method can be used for system optimization in the test bench under realistic operative conditions, i.e. under relevant operating environment in the lab.   This report describes the physical boundaries of the tested systems, as well as the test procedures and the requirements for both the unit under test and the test facility. The new six day and twelve day test profiles are also described as are the validation results.

A Common-feature approach for testing present-value restrictions with financial data

It is well known that cointegration between the level of two variables (labeled Yt and yt in this paper) is a necessary condition to assess the empirical validity of a present-value model (PV and PVM, respectively, hereafter) linking them. The work on cointegration has been so prevalent that it is often overlooked that another necessary condition for the PVM to hold is that the forecast error entailed by the model is orthogonal to the past. The basis of this result is the use of rational expectations in forecasting future values of variables in the PVM. If this condition fails, the present-value equation will not be valid, since it will contain an additional term capturing the (non-zero) conditional expected value of future error terms. Our article has a few novel contributions, but two stand out. First, in testing for PVMs, we advise to split the restrictions implied by PV relationships into orthogonality conditions (or reduced rank restrictions) before additional tests on the value of parameters. We show that PV relationships entail a weak-form common feature relationship as in Hecq, Palm, and Urbain (2006) and in Athanasopoulos, Guillén, Issler and Vahid (2011) and also a polynomial serial-correlation common feature relationship as in Cubadda and Hecq (2001), which represent restrictions on dynamic models which allow several tests for the existence of PV relationships to be used. Because these relationships occur mostly with nancial data, we propose tests based on generalized method of moment (GMM) estimates, where it is straightforward to propose robust tests in the presence of heteroskedasticity. We also propose a robust Wald test developed to investigate the presence of reduced rank models. Their performance is evaluated in a Monte-Carlo exercise. Second, in the context of asset pricing, we propose applying a permanent-transitory (PT) decomposition based on Beveridge and Nelson (1981), which focus on extracting the long-run component of asset prices, a key concept in modern nancial theory as discussed in Alvarez and Jermann (2005), Hansen and Scheinkman (2009), and Nieuwerburgh, Lustig, Verdelhan (2010). Here again we can exploit the results developed in the common cycle literature to easily extract permament and transitory components under both long and also short-run restrictions. The techniques discussed herein are applied to long span annual data on long- and short-term interest rates and on price and dividend for the U.S. economy. In both applications we do not reject the existence of a common cyclical feature vector linking these two series. Extracting the long-run component shows the usefulness of our approach and highlights the presence of asset-pricing bubbles.

Development and testing of anode-supported solid oxide fuel cells with slurry-coated electrolyte and cathode

A laboratory setup was designed and put into operation for the development of solid oxide fuel cells (SOFCs). The whole project consisted of the preparation of the component materials: anode, cathode and electrolyte, and the buildup of a hydrogen leaking-free sample chamber with platinum leads and current collectors for measuring the electrochemical properties of single SOFCs. Several anode-supported single SOFCs of the type (ZrO(2):Y(2)O(3)+NiO) thick anode/(ZrO(2):Y(2)O(3)) thin electrolyte/(La(0.65)Sr(0.35)MnO(3)+ZrO(2):Y(2)O(3)) thin cathode have been prepared and tested at 700 and 800 degrees C after in situ H(2) anode reduction. The main results show that the slurry-coating method resulted in single-cells with good reproducibility and reasonable performance, suggesting that this method can be considered for fabrication of SOFCs. (c) 2005 Elsevier B.V. All rights reserved.