A Small World Perspective on Urban Systems

The theory of small-world networks as initiated by Watts and Strogatz (1998) has drawn new insights in spatial analysis as well as systems theory. The theoryâeuro?s concepts and methods are particularly relevant to geography, where spatial interaction is mainstream and where interactions can be described and studied using large numbers of exchanges or similarity matrices. Networks are organized through direct links or by indirect paths, inducing topological proximities that simultaneously involve spatial, social, cultural or organizational dimensions. Network synergies build over similarities and are fed by complementarities between or inside cities, with the two effects potentially amplifying each other according to the âeurooepreferential attachmentâeuro hypothesis that has been explored in a number of different scientific fields (Barabási, Albert 1999; Barabási A-L 2002; Newman M, Watts D, Barabàsi A-L). In fact, according to Barabási and Albert (1999), the high level of hierarchy observed in âeurooescale-free networksâeuro results from âeurooepreferential attachmentâeuro, which characterizes the development of networks: new connections appear preferentially close to nodes that already have the largest number of connections because in this way, the improvement in the network accessibility of the new connection will likely be greater. However, at the same time, network regions gathering dense and numerous weak links (Granovetter, 1985) or network entities acting as bridges between several components (Burt 2005) offer a higher capacity for urban communities to benefit from opportunities and create future synergies. Several methodologies have been suggested to identify such denser and more coherent regions (also called communities or clusters) in terms of links (Watts, Strogatz 1998; Watts 1999; Barabási, Albert 1999; Barabási 2002; Auber 2003; Newman 2006). These communities not only possess a high level of dependency among their member entities but also show a low level of âeurooevulnerabilityâeuro, allowing for numerous redundancies (Burt 2000; Burt 2005). The SPANGEO project 2005âeuro"2008 (SPAtial Networks in GEOgraphy), gathering a team of geographers and computer scientists, has included empirical studies to survey concepts and measures developed in other related fields, such as physics, sociology and communication science. The relevancy and potential interpretation of weighted or non-weighted measures on edges and nodes were examined and analyzed at different scales (intra-urban, inter-urban or both). New classification and clustering schemes based on the relative local density of subgraphs were developed. The present article describes how these notions and methods contribute on a conceptual level, in terms of measures, delineations, explanatory analyses and visualization of geographical phenomena.

Combining bone resorption markers and heel quantitative ultrasound to discriminate between fracture cases and controls.

This nested case-control analysis of a Swiss ambulatory cohort of elderly women assessed the discriminatory power of urinary markers of bone resorption and heel quantitative ultrasound for non-vertebral fractures. The tests all discriminated between cases and controls, but combining the two strategies yielded no additional relevant information. INTRODUCTION: Data are limited regarding the combination of bone resorption markers and heel quantitative bone ultrasound (QUS) in the detection of women at risk for fracture. METHODS: In a nested case-control analysis, we studied 368 women (mean age 76.2 +/- 3.2 years), 195 with low-trauma non-vertebral fractures and 173 without, matched for age, BMI, medical center, and follow-up duration, from a prospective study designed to predict fractures. Urinary total pyridinolines (PYD) and deoxypyridinolines (DPD) were measured by high performance liquid chromatography. All women underwent bone evaluations using Achilles+ and Sahara heel QUS. RESULTS: Areas under the receiver operating-characteristic curve (AUC) for discriminative models of the fracture group, with 95% confidence intervals, were 0.62 (0.56-0.68) and 0.59 (0.53-0.65) for PYD and DPD, and 0.64 (0.58-0.69) and 0.65 (0.59-0.71) for Achilles+ and Sahara QUS, respectively. The combination of resorption markers and QUS added no significant discriminatory information to either measurement alone with an AUC of 0.66 (0.60-0.71) for Achilles+ with PYD and 0.68 (0.62-0.73) for Sahara with PYD. CONCLUSIONS: Urinary bone resorption markers and QUS are equally discriminatory between non-vertebral fracture patients and controls. However, the combination of bone resorption markers and QUS is not better than either test used alone.

Examination of Heterogeneous Crossing Sequences Between Toner and Rollerball Pen Strokes by Digital Microscopy and 3-D Laser Profilometry

The determination of line crossing sequences between rollerball pens and laser printers presents difficulties that may not be overcome using traditional techniques. This research aimed to study the potential of digital microscopy and 3-D laser profilometry to determine line crossing sequences between a toner and an aqueous ink line. Different paper types, rollerball pens, and writing pressure were tested. Correct opinions of the sequence were given for all case scenarios, using both techniques. When the toner was printed before the ink, a light reflection was observed in all crossing specimens, while this was never observed in the other sequence types. The 3-D laser profilometry, more time-consuming, presented the main advantage of providing quantitative results. The findings confirm the potential of the 3-D laser profilometry and demonstrate the efficiency of digital microscopy as a new technique for determining the sequence of line crossings involving rollerball pen ink and toner. With the mass marketing of laser printers and the popularity of rollerball pens, the determination of line crossing sequences between such instruments is encountered by forensic document examiners. This type of crossing presents difficulties with optical microscopic line crossing techniques involving ballpoint pens or gel pens and toner (1-4). Indeed, the rollerball's aqueous ink penetrates through the toner and is absorbed by the fibers of the paper, leaving the examiner with the impression that the toner is above the ink even when it is not (5). Novotny and Westwood (3) investigated the possibility of determining aqueous ink and toner crossing sequences by microscopic observation of the intersection before and after toner removal. A major disadvantage of their study resides in destruction of the sample by scraping off the toner line to see what was underneath. The aim of this research was to investigate the ways to overcome these difficulties through digital microscopy and three-dimensional (3-D) laser profilometry. The former was used as a technique for the determination of sequences between gel pen and toner printing strokes, but provided less conclusive results than that of an optical stereomicroscope (4). 3-D laser profilometry, which allows one to observe and measure the topography of a surface, has been the subject of a number of recent studies in this area. Berx and De Kinder (6) and Schirripa Spagnolo (7,8) have tested the application of laser profilometry to determine the sequence of intersections of several lines. The results obtained in these studies overcome disadvantages of other methods applied in this area, such as scanning electron microscope or the atomic force microscope. The main advantages of 3-D laser profilometry include the ease of implementation of the technique and its nondestructive nature, which does not require sample preparation (8-10). Moreover, the technique is reproducible and presents a high degree of freedom in the vertical axes (up to 1000 μm). However, when the paper surface presents a given roughness, if the pen impressions alter the paper with a depth similar to the roughness of medium, the results are not always conclusive (8). It becomes difficult in this case to distinguish which characteristics can be imputed to the pen impressions or the quality of the paper surface. This important limitation is assessed by testing different types of paper of variable quality (of different grammage and finishing) and the writing pressure. The authors will therefore assess the limits of 3-D laser profilometry technique and determine whether the method can overcome such constraints. Second, the authors will investigate the use of digital microscopy because it presents a number of advantages: it is efficient, user-friendly, and provides an objective evaluation and interpretation.

Perception and Interpretation of Advance Warning Signs on County Roads, HR-256, 1984

This research consisted of five laboratory experiments designed to address the following two objectives in an integrated analysis: (1) To discriminate between the symbol Stop Ahead warning sign and a small set of other signs (which included the word-legend Stop Ahead sign); and (2) To analyze sign detection, recognizability, and processing characteristics by drivers. A set of 16 signs was used in each of three experiments. A tachistoscope was used to display each sign image to a respondent for a brief interval in a controlled viewing experiment. The first experiment was designed to test detection of a sign in the driver's visual field; the second experiment was designed to test the driver's ability to recognize a given sign in the visual field; and the third experiment was designed to test the speed and accuracy of a driver's response to each sign as a command to perform a driving action. A fourth experiment tested the meanings drivers associated with an eight-sign subset of the 16 signs used in the first three experiments. A fifth experiment required all persons to select which (if any) signs they considered to be appropriate for use on two scale model county road intersections. The conclusions are that word-legend Stop Ahead signs are more effective driver communication devices than symbol stop-ahead signs; that it is helpful to drivers to have a word plate supplementing the symbol sign if a symbol sign is used; and that the guidance in the Manual on Uniform Traffic Control Devices on the placement of advance warning signs should not supplant engineering judgment in providing proper sign communication at an intersection.

Regional Approach to Landslide Interpretation and Repair, TR-430, 2001

The objective of this report is to provide Iowa county engineers and highway maintenance personnel with procedures that will allow them to efficiently and effectively interpret and repair or avoid landslides. The research provides an overview of basic slope stability analyses that can be used to diagnose the cause and effect associated with a slope failure. Field evidence for identifying active or potential slope stability problems is outlined. A survey of county engineers provided data for presenting a slope stability risk map for the state of Iowa. Areas of high risk are along the western border and southeastern portion of the state. These regions contain deep to moderately deep loess. The central portion of the state is a low risk area where the surficial soils are glacial till or thin loess over till. In this region, the landslides appear to occur predominately in backslopes along deeply incised major rivers, such as the Des Moines River, or in foreslopes. The south-central portion of the state is an area of medium risk where failures are associated with steep backslopes and improperly compacted foreslopes. Soil shear strength data compiled from the Iowa DOT and consulting engineers files are correlated with geologic parent materials and mean values of shear strength parameters and unit weights were computed for glacial till, friable loess, plastic loess and local alluvium. Statistical tests demonstrate that friction angles and unit weights differ significantly but in some cases effective stress cohesion intercept and undrained shear strength data do not. Moreover, effective stress cohesion intercept and undrained shear strength data show a high degree of variability. The shear strength and unit weight data are used in slope stability analyses for both drained and undrained conditions to generate curves that can be used for a preliminary evaluation of the relative stability of slopes within the four materials. Reconnaissance trips to over fifty active and repaired landslides in Iowa suggest that, in general, landslides in Iowa are relatively shallow [i.e., failure surfaces less than 6 ft (2 m) deep] and are either translational or shallow rational. Two foreslope and two backslope failure case histories provide additional insights into slope stability problems and repair in Iowa. These include the observation that embankment soils compacted to less than 95% relative density show a marked strength decrease from soils at or above that density. Foreslopes constructed of soils derived from shale exhibit loss of strength as a result of weathering. In some situations, multiple causes of instability can be discerned from back analyses with the slope stability program XSTABL. In areas where the stratigraphy consists of loess over till or till over bedrock, the geologic contracts act as surfaces of groundwater accumulation that contribute to slope instability.

Addendum to Perception and Interpretation of Advance Warning Signs on County Roads, HR-256, 1985

This contract extension was granted to analyze data obtained in the original contract period at a level of detail not called for in the original contract nor permitted by the time constraints of the original contract schedule. These further analyses focused on two primary questions: I. What sources of variation can be isolated within the overall pattern of driver recognition errors reported previously for the 16 signs tested in Project HR-256? 2. Were there systematic relations among data on the placement of signs in a simulated signing exercise and data on the respondents' ability to detect the presence of a sign in a visual field or their ability to recognize quickly and correctly a sign shown them or the speed with which these same persons can respond to a sign for a driver decision?

Quantitative X-Ray Diffraction Measurements by Fast Scanning, HR-111

Two goals were pursued in this research: first, to evaluate statistically some effects of sample preparation and instrument geometry on reproducibility of X-ray diffraction intensity data; and second, to develop a procedure for finding minimum peak and background counting times for a desired level of accuracy. The ratio of calcite to dolomite in limestones was determined in trials. Ultra-fine wet grinding of the limestone in porcelain impact type ball mill gave most consistent X-ray results, but caused considerable line broadening, and peaks were best measured on an area count basis. Sample spinning reduced variance about one third, and a coarse beam-medium detector slit arrangement was found to be best. An equation is developed relating coefficient of variation of a count ratio to peak and background counts. By use of the equation or graphs the minimum coefficient of variation is predicted from one fast scan, and the number and optimum arrangement of additional counting periods to reduce variation to a desired limit may be obtained. The calculated coefficient is the maximum which may be attributed to the counting statistic but does not include experimental deviations.

Valoriser le géopatrimoine par la médiation indirecte et la visualisation des objets géomorphologiques

Résumé: Valoriser le géopatrimoine par la médiation indirecte et la visualisation des objets géomorphologiques Le géopatrimoine regroupe des objets géologiques lato sensu auxquels certaines valeurs sont attribuées, en fonction de leur intérêt pour la science, de leur rareté, de leurs particularités culturelles ou écologiques, etc. Valoriser le géopatrimoine signifie avant tout faire partager cette approche aux non-spécialistes, en expliquant ce qui fait la valeur de ces objets. Cette valorisation peut s'effectuer, entre autres, sous la forme d'une activité touristique et contribuer ainsi au développement régional. Faire comprendre l'origine, la singularité et la valeur des formes du relief implique le recours à une communication éducative, désignée par le terme de médiation. Les implications de la dimension éducative du processus, comme la prise en compte des connaissances et attentes du public, la création d'un environnement favorable à l'apprentissage ou l'attractivité du contenu, sont souvent négligées. Du point de vue conceptuel, un modèle de la médiation indirecte (c'est-à-dire au moyen de supports médiatiques) a été proposé et appliqué au développement empirique de produits de médiation et à leur évaluation. Ce modèle ne garantit pas la réussite de la communication éducative, mais contribue à créer un cadre favorable au processus. De plus, plusieurs lignes directrices pour le choix du type de média et sa mise en forme ont été définies sur la base d'une compilation de résultats de la psychologie cognitive sur l'usage des médias pour l'apprentissage. Des méthodes qualitatives et quantitatives variées ont été mobilisées : enquêtes par questionnaire ex situ et in situ, auprès des visiteurs de géomorphosites de montagne, réalisation de médias interactifs testés ensuite auprès de divers publics (parcours enregistré, pré- et post-questionnaires) et entretiens collectifs. Les résultats obtenus éclairent divers aspects de la problématique. L'étude du public a montré, par exemple, que le géotourisme possède un réel public parmi les visiteurs des sites de montagnes : trois-quarts d'entre eux expriment de l'intérêt pour des explications sur la géologie et l'évolution du paysage. Cette thèse a exploré ces aspects liés au processus d'apprentissage en se focalisant sur les médias visuels, surtout interactifs. La plupart des médias visuels couramment utilisés en géomorphologie ont été considérés. Le développement de versions interactives de ces médias sous forme d'applications web a fourni un aperçu concret des possibilités des nouvelles technologies. Les utilisateurs apprécient en particulier a richesse du contenu, le haut degré d'interactivité et la variété de ces applications. De tels médias incitent à visiter le site naturel et semblent aussi répondre aux intérêts de publics variés. Abstract: Geoheritage promotion through non-personal interpretation and visualisation of geomorphological features Geoheritage concerns all geological features lato sensu to which some values are attributed, according to their scientific interest, their rarity, their cultural or ecological dimensions, etc. Geoheritage promotion implies sharing this point of view with non-specialists, explaining what gives value to those objects. Geotourism is one of the many ways to achieve geoheritage promotion, while contributing also to regional development. In order to make non-specialists understand the origin, the specificity and the value of landforms, educational communication is needed, that is called interpretation (French: médiation). This education dimension has several, and often neglected, implications, like taking into account public's knowledge and expectations, creating a favourable learning environment, attractive design, etc. From the conceptual point of view, a model for non-personal interpretation has been proposed and applied for the empirical development and for the assessment of interpretive products. This model does not guarantee success of educational communication, but help creating a favourable environment for this process. Moreover, some guidelines were defined from a compilation of several results of cognitive psychology on media use for learning. They guide the choice of the kind of media and its design. Several qualitative and quantitative methods were applied: survey questionnaires ex situ and in situ by mountain geomorphosites visitors, interactive medias developed and then tested by different kinds of users (with usertracking, pre- and post-survey questionnaires), group interviews. The results answered different aspects of the research questions. Visitor surveys revealed for example that geotourism could attract many visitors of mountain areas: three quarters of them say they are interested in getting explanations about geology and landscape (in particular its dynamic dimensions). This thesis examined those aspects with a focus on visual medias, both statics and interactive. Most of currently used medias in geomorphology were considered. Interactive versions of those medias were developed in web applications; they gave a concrete overview on the opportunities that new technologies offer. The content richness, the high interaction level and the diversity of the applications are the most liked aspects by the users. Such medias drive to visit the natural site and seem to correspond to the interests of various kinds of publics. Zusammenfassung: Aufwertung des erdwissenschaftlichen Erbes durch mediale Vermittlung und Visualisierung von geomorphologischen Objekten Das erdwissenschaftliche Erbe besteht aus geologischen Gegebenheiten lato sensu, denen entsprechend ihrer Bedeutung für die Wissenschaft, ihrer Seltenheit, ihrer kulturellen oder ökologischen Besonderheiten usw. bestimmte Werte zugeordnet werden. Das erdwissenschaftliche Erbe aufzuwerten bedeutet in erster Linie, diesen Ansatz Nichtspezialisten näher zu bringen, indem ihnen erklärt wird, was den Wert dieser Gegebenheiten ausmacht. Dies kann etwa im Rahmen eines touristischen Angebots geschehen und so die regionale Entwicklung unterstützen. Um Entstehung, Besonderheit und Wert von Geländeformen verständlich zu machen, wird eine pädagogische Kommunikationsform verwendet, die als mediale Vermittlung (franz. médiation) bezeichnet wird. Die Bedeutung der pädagogischen Dimension des Vermittlungsprozesses wie etwa der Einbezug des Wissens und der Erwartungen des Publikums, die Gestaltung eines positiven Lernklimas oder die Attraktivität des Inhalts wird oft vernachlässigt. Auf konzeptueller Ebene wurde ein Modell der indirekten Interpretation erarbeitet (d. h. anhand von Medien), das bei der empirischen Entwicklung der Interpretationsprodukte und ihrer Evaluation Anwendung fand. Dieses Modell garantiert zwar nicht den Erfolg der pädagogischen Kommunikation. Es trägt aber dazu bei, einen für den Prozess günstigen Kontext zu schaffen. Des Weiteren wurden mehrere Richtlinien für die Wahl des Medientyps und dessen Ausgestaltung anhand einer Zusammenstellung von Resultaten der kognitiven Psychologie über den Gebrauch von Medien in Lernprozessen definiert. Es wurden verschiedene qualitative und quantitative Methoden eingesetzt: Befragung mittels Fragebogen der Besucher von geomorphologischen Geotopen im Gebirge - ex situ und in situ -, Erarbeitung von interaktiven Medien, die anschliessend anhand verschiedener Zielgruppen gestestet wurden (Aufnahme des Besuchparcours, Vor- und Nachfragebögen) sowie kollektive Interviews. Die Ergebnisse geben Aufschluss zu verschiedenen Aspekten der Fragestellung. Die Befragung des Publikums hat zum Beispiel deutlich gemacht, dass der Geotourismus unter den Besuchern von Berggebieten tatsächlich auf eine Nachfrage stösst: drei Viertel von ihnen zeigen ein Interesse für Erläuterungen zur Geologie und der Landschaftsentwicklung. Die vorliegende Doktorarbeit hat die genannten Aspekte der Lernprozesse untersucht, wobei der Fokus auf visuellen, insbesondere interaktiven Medien lag. Die meisten gängigen visuellen Medien der Geomorphologie wurden berücksichtigt. Die Entwicklung von interaktiven Versionen dieser Medien in Form von Web-Anwendungen hat die Möglichkeiten der neuen Technologien veranschaulicht. Die Benutzer schätzten insbesondere die Vielfalt des Inhalts, die hohe Interaktivität und die Diversität dieser Anwendungen. Solche Medien laden dazu ein, ein Naturgebiet zu besuchen und scheinen den Interessen der verschiedenen Publikumsgruppen entgegenzukommen.

Effect of supplementation with vitamin D3 and calcium on quantitative ultrasound of bone in elderly institutionalized women: a longitudinal study.

Supplementation of elderly institutionalized women with vitamin D and calcium decreased hip fractures and increased hip bone mineral density. Quantitative ultrasound (QUS) measurements can be performed in nursing homes, and easily repeated for follow-up. However, the effect of the correction of vitamin D deficiency on QUS parameters is not known. Therefore, 248 institutionalized women aged 62-98 years were included in a 2-year open controlled study. They were randomized into a treated group (n = 124), receiving 440 IU of vitamin D3 combined with 500 mg calcium (1250 mg calcium carbonate, Novartis) twice daily, and a control group (n = 124). One hundred and three women (42%), aged 84.5 +/- 7.5 years, completed the study: 50 in the treated group, 53 in the controls. QUS of the calcaneus, which measures BUA (broadband ultrasound attenuation) and SOS (speed of sound), and biochemical analysis were performed before and after 1 and 2 years of treatment. Only the results of the women with a complete follow-up were taken into account. Both groups had low initial mean serum 25-hydroxyvitamin D levels (11.9 +/- 1.2 and 11.7 +/- 1.2 micrograms/l; normal range 6.4-40.2 micrograms/l) and normal mean serum parathyroid hormone (PTH) levels (43.1 +/- 3.2 and 44.6 +/- 3.5 ng/l; normal range 10-70 ng/l, normal mean 31.8 +/- 2.3 ng/l). The treatment led to a correction of the metabolic disturbances, with an increase in 25-hydroxyvitamin D by 123% (p < 0.01) and a decrease in PTH by 18% (p < 0.05) and of alkaline phosphatase by 15% (p < 0.01). In the controls there was a worsening of the hypovitaminosis D, with a decrease of 25-hydroxyvitamin D by 51% (p < 0.01) and an increase in PTH by 51% (p < 0.01), while the serum calcium level decreased by only 2% (p < 0.01). After 2 years of treatment BUA increased significantly by 1.6% in the treated group (p < 0.05), and decreased by 2.3% in the controls (p < 0.01). Therefore, the difference in BUA between the treated subjects and the controls (3.9%) was significant after 2 years (p < 0.01). However, SOS decreased by the same amount in both groups (approximately 0.5%). In conclusion, BUA, but not SOS, reflected the positive effect on bone of supplementation with calcium and vitamin D3 in a population of elderly institutionalized women.

Valganciclovir in adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma concentration measurements.

Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on patients' morbidity and mortality. Oral valganciclovir, the ester prodrug of ganciclovir, has been developed to enhance the oral bioavailability of ganciclovir. It crosses the gastrointestinal barrier through peptide transporters and is then hydrolysed into ganciclovir. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of therapeutic drug monitoring. Based on currently available literature, ganciclovir pharmacokinetics in adult solid organ transplant recipients receiving oral valganciclovir are characterized by bioavailability of 66 +/- 10% (mean +/- SD), a maximum plasma concentration of 3.1 +/- 0.8 mg/L after a dose of 450 mg and of 6.6 +/- 1.9 mg/L after a dose of 900 mg, a time to reach the maximum plasma concentration of 3.0 +/- 1.0 hours, area under the plasma concentration-time curve values of 29.1 +/- 5.3 mg.h/L and 51.9 +/- 18.3 mg.h/L (after 450 mg and 900 mg, respectively), apparent clearance of 12.4 +/- 3.8 L/h, an elimination half-life of 5.3 +/- 1.5 hours and an apparent terminal volume of distribution of 101 +/- 36 L. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Unexplained interpatient variability is limited (18% in apparent clearance and 28% in the apparent central volume of distribution). There is no indication of erratic or limited absorption in given subgroups of patients; however, this may be of concern in patients with severe malabsorption. The in vitro pharmacodynamics of ganciclovir reveal a mean concentration producing 50% inhibition (IC(50)) among CMV clinical strains of 0.7 mg/L (range 0.2-1.9 mg/L). Systemic exposure of ganciclovir appears to be moderately correlated with clinical antiviral activity and haematotoxicity during CMV prophylaxis in high-risk transplant recipients. Low ganciclovir plasma concentrations have been associated with treatment failure and high concentrations with haematotoxicity and neurotoxicity, but no formal therapeutic or toxic ranges have been validated. The pharmacokinetic parameters of ganciclovir after valganciclovir administration (bioavailability, apparent clearance and volume of distribution) are fairly predictable in adult transplant patients, with little interpatient variability beyond the effect of renal function and bodyweight. Thus ganciclovir exposure can probably be controlled with sufficient accuracy by thorough valganciclovir dosage adjustment according to patient characteristics. In addition, the therapeutic margin of ganciclovir is loosely defined. The usefulness of systematic therapeutic drug monitoring in adult transplant patients therefore appears questionable; however, studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.

FastEpistasis: a high performance computing solution for quantitative trait epistasis.

Motivation: Genome-wide association studies have become widely used tools to study effects of genetic variants on complex diseases. While it is of great interest to extend existing analysis methods by considering interaction effects between pairs of loci, the large number of possible tests presents a significant computational challenge. The number of computations is further multiplied in the study of gene expression quantitative trait mapping, in which tests are performed for thousands of gene phenotypes simultaneously. Results: We present FastEpistasis, an efficient parallel solution extending the PLINK epistasis module, designed to test for epistasis effects when analyzing continuous phenotypes. Our results show that the algorithm scales with the number of processors and offers a reduction in computation time when several phenotypes are analyzed simultaneously. FastEpistasis is capable of testing the association of a continuous trait with all single nucleotide polymorphism ( SNP) pairs from 500 000 SNPs, totaling 125 billion tests, in a population of 5000 individuals in 29, 4 or 0.5 days using 8, 64 or 512 processors.

Prediction of cross-recognition of peptide-HLA A2 by Melan-A-specific cytotoxic T lymphocytes using three-dimensional quantitative structure-activity relationships.

The cross-recognition of peptides by cytotoxic T lymphocytes is a key element in immunology and in particular in peptide based immunotherapy. Here we develop three-dimensional (3D) quantitative structure-activity relationships (QSARs) to predict cross-recognition by Melan-A-specific cytotoxic T lymphocytes of peptides bound to HLA A*0201 (hereafter referred to as HLA A2). First, we predict the structure of a set of self- and pathogen-derived peptides bound to HLA A2 using a previously developed ab initio structure prediction approach [Fagerberg et al., J. Mol. Biol., 521-46 (2006)]. Second, shape and electrostatic energy calculations are performed on a 3D grid to produce similarity matrices which are combined with a genetic neural network method [So et al., J. Med. Chem., 4347-59 (1997)] to generate 3D-QSAR models. The models are extensively validated using several different approaches. During the model generation, the leave-one-out cross-validated correlation coefficient (q (2)) is used as the fitness criterion and all obtained models are evaluated based on their q (2) values. Moreover, the best model obtained for a partitioned data set is evaluated by its correlation coefficient (r = 0.92 for the external test set). The physical relevance of all models is tested using a functional dependence analysis and the robustness of the models obtained for the entire data set is confirmed using y-randomization. Finally, the validated models are tested for their utility in the setting of rational peptide design: their ability to discriminate between peptides that only contain side chain substitutions in a single secondary anchor position is evaluated. In addition, the predicted cross-recognition of the mono-substituted peptides is confirmed experimentally in chromium-release assays. These results underline the utility of 3D-QSARs in peptide mimetic design and suggest that the properties of the unbound epitope are sufficient to capture most of the information to determine the cross-recognition.