MB-MDR: Model-Based Multifactor Dimensionality Reduction for detecting interactions in high-dimensional genomic data

L’anàlisi de l’efecte dels gens i els factors ambientals en el desenvolupament de malalties complexes és un gran repte estadístic i computacional. Entre les diverses metodologies de mineria de dades que s’han proposat per a l’anàlisi d’interaccions una de les més populars és el mètode Multifactor Dimensionality Reduction, MDR, (Ritchie i al. 2001). L’estratègia d’aquest mètode és reduir la dimensió multifactorial a u mitjançant l’agrupació dels diferents genotips en dos grups de risc: alt i baix. Tot i la seva utilitat demostrada, el mètode MDR té alguns inconvenients entre els quals l’agrupació excessiva de genotips pot fer que algunes interaccions importants no siguin detectades i que no permet ajustar per efectes principals ni per variables confusores. En aquest article il•lustrem les limitacions de l’estratègia MDR i d’altres aproximacions no paramètriques i demostrem la conveniència d’utilitzar metodologies parametriques per analitzar interaccions en estudis cas-control on es requereix l’ajust per variables confusores i per efectes principals. Proposem una nova metodologia, una versió paramètrica del mètode MDR, que anomenem Model-Based Multifactor Dimensionality Reduction (MB-MDR). La metodologia proposada té com a objectiu la identificació de genotips específics que estiguin associats a la malaltia i permet ajustar per efectes marginals i variables confusores. La nova metodologia s’il•lustra amb dades de l’Estudi Espanyol de Cancer de Bufeta

Competing risks methods

Competing risks data usually arises in studies in which the failure of an individual may be classified into one of k (k > 1) mutually exclusive causes of failure. When competing risks are present, classical survival analysis techniques may not be appropriate to use. The main goal of this paper is to review the specific methods to deal with competing risks. To this aim, we first focus on how to specify a competing risks model, which is the structure of observed data in this framework, and how components of the model are estimated from a given random sample. In addition, we discuss how to correctly interpret probabilities in the presence of competing risks, and regression models are considered in detail. To conclude, we illustrate the problem with data from a bladder cancer study

Instal·lacions de baix risc de proliferació i dispersió de legionel·la: anàlisi de circuits i eines de control

Legionel·la; Control oficial; Seguretat ambientalLegionela; Control oficial; Seguridad ambientalLegionella; Official control; Environmental securityAquesta Comunitat de Pràctica (CoP) es va crear amb l’objectiu de disposar d’uns documents, consensuats per tècnics de les diferents administracions implicades en el control i la prevenció de la legionel·losi (ASPCAT, DIBA, municipis, i, fins i tot, el Govern andorrà), perquè siguin una eina pràctica de treball. En un mateix model s’inclou la normativa, la informació ja disponible i les recomanacions tècniques per a aquells paràmetres que no conté ni la normativa ni la informació complementària ja disponible. D’una banda, aquests documents han de permetre la inspecció, tant als tècnics de l’ASPCAT com als tècnics municipals i/o a altres institucions encarregades de fer aquestes tasques. D’una altra banda, han de servir per donar suport a tots els agents implicats en la gestió i el control d’aquestes instal·lacions de baix risc. Presentem la documentació generada fins ara. Som conscients que no està del tot acabada i esperem que aquesta CoP tingui la continuïtat necessària per tal de concloure aquests documents i, si és possible, d’ampliar-los a altres instal·lacions de baix risc. Esperem que això ajudi a millorar l’estat higienicosanitari de les instal·lacions considerades de baix risc i a disminuir els brots i els casos de legionel·losi que, en els darrers anys, s’ha detectat que podrien ser les principals causants d’aquesta malaltia al nostre territori.Esta Comunidad de Práctica (CoP) se creó con el objetivo de disponer de unos documentos, consensuados por técnicos de las diferentes administraciones implicadas en el control y la prevención de la legionelosis (ASPCAT, DIBA, municipios, y, hasta y todo, el Gobierno andorrano), para que sean una herramienta práctica de trabajo. En un mismo modelo se incluye la normativa, información ya disponible y recomendaciones técnicas para aquellos parámetros que no contiene ni la normativa ni la información complementaria ya disponible. Por un lado, estos documentos deben permitir la inspección, tanto a los técnicos de la ASPCAT como a los técnicos municipales y/oa otras instituciones encargadas de realizar estas tareas. Por otro lado, deben servir para apoyar a todos los agentes implicados en la gestión y control de estas instalaciones de bajo riesgo. Presentamos la documentación generada hasta ahora. Somos conscientes de que no está del todo terminada y esperamos que esta CoP tenga la continuidad necesaria para concluir estos documentos y, si es posible, ampliarlos a otras instalaciones de bajo riesgo. Esperamos que esto ayude a mejorar el estado higiénico-sanitario de las instalaciones consideradas de bajo riesgo ya disminuir los brotes y los casos de legionelosis que, en los últimos años, se ha detectado que podrían ser las principales causantes de ésta enfermedad en nuestro territorio.This Community of Practice (CoP) was created with the aim of having some documents agreed upon by technicians from the different administrations involved in the control and prevention of legionellosis (ASPCAT, DIBA, municipalities, and, even and all, the Government Andorran), so that they are a practical work tool. The same model includes the regulations, information already available and technical recommendations for those parameters that neither the regulations nor the complementary information already available contain. On the one hand, these documents must allow inspection, both by ASPCAT technicians and by municipal technicians and/or other institutions in charge of carrying out these tasks. On the other hand, they must serve to support all the agents involved in the management and control of these low-risk facilities. We present the documentation generated so far. We are aware that it is not completely finished and we hope that this CoP will have the necessary continuity to finalize these documents and, if possible, extend them to other low-risk facilities. We hope this will help improve the hygienic-sanitary status of facilities considered low risk and reduce outbreaks and cases of legionellosis which, in recent years, have been found to be the main causes of this disease in our territory

Determinación de las constantes ópticas de películas delgadas de óxido de estaño y de plata para su utilización en recubrimientos multicapa de baja emisividad

The determination of the values of the optical constants (n, refractive index and k, extinction coefficient) in the visible range of both silver (Ag) and tin oxide (SnO2) films is a necessary condition to predict the behaviour of a SnO2/Ag/SnO2 multilayer for low emissivity coatings, improving the visual comfort. For this purpose, thin films of Ag and SnO2 with a thickness similar to that of multilayer coatings (90 Å and 380 Å respectively) were used in order to avoid the thickness dependence of the optical constants. A simulation computational program based on the matrix method was employed to estimate the values of the optical constants of these films in the visible range. It has been also determined the dependence on the wavelength of the absorption coefficient (α), as well as the value of the energy gap, and the nature of the optical transitions.<br><br>La determinación de los valores de las constantes ópticas (n, índice de refracción y k, coeficiente de extinción) en el espectro visible de películas tanto de plata (Ag) como de óxido de estaño (SnO2), es una condición necesaria para predecir el comportamiento de un recubrimiento multicapa de baja emisividad con la estructura SnO2/Ag/SnO2 en relación al confort visual. Para este propósito, se han caracterizado láminas delgadas de Ag y de SnO2 con un espesor similar al que tienen en los recubrimientos multicapa (90 Å y 380 Å respectivamente), evitando así la dependencia con el espesor de las constantes ópticas. Se ha utilizado un programa informático de simulación basado en el método matricial para determinar los valores de las constantes ópticas de dichas películas en el espectro visible. Ha sido determinada asimismo la dependencia del coeficiente de absorción (α) con la longitud de onda, así como el valor del ancho de banda prohibida del óxido de estaño, y la naturaleza de la transición óptica

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.The initial experiments were supported by the DFG (Wi 2036/1-1). This work was supported by the Sonnenfeld-Stiftung, Berlin, Germany (to H.W.), the US National Institutes of Health (NIH) (grant DK058088 to M.S.-T.), INSERM (Institut National de la Santé et de la Recherche Médicale) and the Programme Hospitalier de Recherche Clinique (grant PHRC R 08-04 to C.F.

Vorname - Rufname - Übername

Objective: Genomic profiling, the use of genetic variants at multiple loci simultaneously for the prediction of disease risk, requires the selection of a set of genetic variants that best predicts disease status. The goal of this work was to provide a new selection algorithm for genomic profiling. Methods: We propose a new algorithm for genomic profiling based on optimizing the area under the receiver operating characteristic curve (AUC) of the random forest (RF). The proposed strategy implements a backward elimination process based on the initial ranking of variables. Results and Conclusions: We demonstrate the advantage of using the AUC instead of the classification error as a measure of predictive accuracy of RF. In particular, we show that the use of the classification error is especially inappropriate when dealing with unbalanced data sets. The new procedure for variable selection and prediction, namely AUC-RF, is illustrated with data from a bladder cancer study and also with simulated data. The algorithm is publicly available as an R package, named AUCRF, at http://cran.r-project.org/.This work was partially supported by grant MTM2008-06747-C02-02 from the Ministerio de Educacion y Ciencia (Spain), grant 050831 from the Marato de TV3 Foundation, grant 2009SGR-581 from the AGAUR-Generalitat de Catalunya and the LMU-innovativ Project BioMed-

mbmdr: an R package for exploring gene-gene interactions associated with binary or quantitative traits

Summary: We describe mbmdr, an R package for implementing the model-based multifactor dimensionality reduction (MB-MDR) method. MB-MDR has been proposed by Calle et al. as a dimension reduction method for exploring gene–gene interactions in casecontrol association studies. It is an extension of the popular multifactor dimensionality reduction (MDR) method of Ritchie et al. allowing a more flexible definition of risk cells. In MB-MDR, risk categories are defined using a regression model which allows adjustment for covariates and main effects and, in addition to the classical low risk and high risk categories, MB-MDR considers a third category of indeterminate or not informative cells. An important improvement added to the current mbmdr algorithm with respect to the original MB-MDR formulation in Calle et al. and also to the classical MDR approach, is the extension of the methodology to different outcome types. While MB-MDR was initially proposed for binary traits in the context of case-control studies, the mbmdr package provides options to analyze both binary or quantitative traits for unrelated individuals.The Ministerio de Educacion y Ciencia (Spain) (MTM2008-06747-C02-02); La Marato de TV3 Foundation (Grant 050831); Generalitat de Catalunya (2009SGR-581)

Improving strategies for detecting genetic patterns of disease susceptibility in association studies

The analysis of gene interactions and epistatic patterns of susceptibility is especially important for investigating complex diseases such as cancer characterized by the joint action of several genes. This work is motivated by a case-control study of bladder cancer, aimed at evaluating the role of both genetic and environmental factors in bladder carcinogenesis. In particular, the analysis of the inflammation pathway is of interest, for which information on a total of 282 SNPs in 108 genes involved in the inflammatory response is available. Detecting and interpreting interactions with such a large number of polymorphisms is a great challenge from both the statistical and the computational perspectives. In this paper we propose a two-stage strategy for identifying relevant interactions: (1) the use of a synergy measure among interacting genes and (2) the use of the model-based multifactor dimensionality reduction method (MB-MDR), a model-based version of the MDR method, which allows adjustment for confounders

Competing risks methods

Competing risks data usually arises in studies in which the failure of an individual may be classified into one of k (k > 1) mutually exclusive causes of failure. When competing risks are present, classical survival analysis techniques may not be appropriate to use. The main goal of this paper is to review the specific methods to deal with competing risks. To this aim, we first focus on how to specify a competing risks model, which is the structure of observed data in this framework, and how components of the model are estimated from a given random sample. In addition, we discuss how to correctly interpret probabilities in the presence of competing risks, and regression models are considered in detail. To conclude, we illustrate the problem with data from a bladder cancer study