Decision curve analysis revisited: overall net benefit, relationships to ROC curve analysis, and application to case-control studies.

ABSTRACT: BACKGROUND: Decision curve analysis has been introduced as a method to evaluate prediction models in terms of their clinical consequences if used for a binary classification of subjects into a group who should and into a group who should not be treated. The key concept for this type of evaluation is the "net benefit", a concept borrowed from utility theory. METHODS: We recall the foundations of decision curve analysis and discuss some new aspects. First, we stress the formal distinction between the net benefit for the treated and for the untreated and define the concept of the "overall net benefit". Next, we revisit the important distinction between the concept of accuracy, as typically assessed using the Youden index and a receiver operating characteristic (ROC) analysis, and the concept of utility of a prediction model, as assessed using decision curve analysis. Finally, we provide an explicit implementation of decision curve analysis to be applied in the context of case-control studies. RESULTS: We show that the overall net benefit, which combines the net benefit for the treated and the untreated, is a natural alternative to the benefit achieved by a model, being invariant with respect to the coding of the outcome, and conveying a more comprehensive picture of the situation. Further, within the framework of decision curve analysis, we illustrate the important difference between the accuracy and the utility of a model, demonstrating how poor an accurate model may be in terms of its net benefit. Eventually, we expose that the application of decision curve analysis to case-control studies, where an accurate estimate of the true prevalence of a disease cannot be obtained from the data, is achieved with a few modifications to the original calculation procedure. CONCLUSIONS: We present several interrelated extensions to decision curve analysis that will both facilitate its interpretation and broaden its potential area of application.

The mouse Lyt-2/3 antigen complex--II. Structural analysis of the subunits.

Surface- or biosynthetically labeled Lyt-2/3 antigens were isolated from cell lysates by immunoprecipitation and affinity chromatography with a monoclonal antibody. Tryptic digests of the individual subunits of 37,000, 32,000 and 28,000 apparent mol. wts were analysed by reverse-phase high-performance liquid chromatography and by two-dimensional peptide mapping. The results indicate that the 37,000 and 32,000 mol. wt components are structurally very similar whereas the 28,000 mol. wt component appears as a different molecule.

Molecular analysis and mating behaviour of the Trichophyton mentagrophytes species complex.

Isolates of the Trichophyton mentagrophytes complex vary phenotypically. Whether the closely related zoophilic and anthropophilic anamorphs currently associated with Arthroderma vanbreuseghemii have to be considered as members of the same biological species remains an open question. In order to better delineate species in the T. mentagrophytes complex, we performed a mating analysis of freshly collected isolates from humans and animals with A. benhamiae and A. vanbreuseghemii reference strains, in comparison to internal transcribed spacer (ITS) and 28S rDNA sequencing. Mating experiments as well as ITS and 28S sequencing unambiguously allowed the distinction of A. benhamiae and A. vanbreuseghemii. We have also shown that all the isolates from tinea pedis and tinea unguium identified as T. interdigitale based on ITS sequences mated with A. vanbreuseghemii tester strains, but had lost their ability to give fertile cleistothecia. Therefore, T. interdigitale has to be considered as a humanized species derived from the sexual relative A. vanbreuseghemii.

Reversible major histocompatibility complex I-peptide multimers containing Ni(2+)-nitrilotriacetic acid peptides and histidine tags improve analysis and sorting of CD8(+) T cells.

MHC-peptide multimers containing biotinylated MHC-peptide complexes bound to phycoerythrin (PE) streptavidin (SA) are widely used for analyzing and sorting antigen-specific T cells. Here we describe alternative T cell-staining reagents that are superior to conventional reagents. They are built on reversible chelate complexes of Ni(2+)-nitrilotriacetic acid (NTA) with oligohistidines. We synthesized biotinylated linear mono-, di-, and tetra-NTA compounds using conventional solid phase peptide chemistry and studied their interaction with HLA-A*0201-peptide complexes containing a His(6), His(12), or 2×His(6) tag by surface plasmon resonance on SA-coated sensor chips and equilibrium dialysis. The binding avidity increased in the order His(6) < His(12) < 2×His(6) and NTA(1) < NTA(2) < NTA(4), respectively, depending on the configuration of the NTA moieties and increased to picomolar K(D) for the combination of a 2×His(6) tag and a 2×Ni(2+)-NTA(2). We demonstrate that HLA-A2-2×His(6)-peptide multimers containing either Ni(2+)-NTA(4)-biotin and PE-SA- or PE-NTA(4)-stained influenza and Melan A-specific CD8+ T cells equal or better than conventional multimers. Although these complexes were highly stable, they very rapidly dissociated in the presence of imidazole, which allowed sorting of bona fide antigen-specific CD8+ T cells without inducing T cell death as well as assessment of HLA-A2-peptide monomer dissociation kinetics on CD8+ T cells.

How to assign a likelihood ratio in a footwear mark case: an analysis and discussion in the light of R v T

This article analyses and discusses issues that pertain to the choice of relevant databases for assigning values to the components of evaluative likelihood ratio procedures at source level. Although several formal likelihood ratio developments currently exist, both case practitioners and recipients of expert information (such as judiciary) may be reluctant to consider them as a framework for evaluating scientific evidence in context. The recent ruling R v T and ensuing discussions in many forums provide illustrative examples for this. In particular, it is often felt that likelihood ratio-based reasoning amounts to an application that requires extensive quantitative information along with means for dealing with technicalities related to the algebraic formulation of these approaches. With regard to this objection, this article proposes two distinct discussions. In a first part, it is argued that, from a methodological point of view, there are additional levels of qualitative evaluation that are worth considering prior to focusing on particular numerical probability assignments. Analyses will be proposed that intend to show that, under certain assumptions, relative numerical values, as opposed to absolute values, may be sufficient to characterize a likelihood ratio for practical and pragmatic purposes. The feasibility of such qualitative considerations points out that the availability of hard numerical data is not a necessary requirement for implementing a likelihood ratio approach in practice. It is further argued that, even if numerical evaluations can be made, qualitative considerations may be valuable because they can further the understanding of the logical underpinnings of an assessment. In a second part, the article will draw a parallel to R v T by concentrating on a practical footwear mark case received at the authors' institute. This case will serve the purpose of exemplifying the possible usage of data from various sources in casework and help to discuss the difficulty associated with reconciling the depth of theoretical likelihood ratio developments and limitations in the degree to which these developments can actually be applied in practice.

Analysis and spatial modeling of the indoor radon Swiss data

The present research deals with an important public health threat, which is the pollution created by radon gas accumulation inside dwellings. The spatial modeling of indoor radon in Switzerland is particularly complex and challenging because of many influencing factors that should be taken into account. Indoor radon data analysis must be addressed from both a statistical and a spatial point of view. As a multivariate process, it was important at first to define the influence of each factor. In particular, it was important to define the influence of geology as being closely associated to indoor radon. This association was indeed observed for the Swiss data but not probed to be the sole determinant for the spatial modeling. The statistical analysis of data, both at univariate and multivariate level, was followed by an exploratory spatial analysis. Many tools proposed in the literature were tested and adapted, including fractality, declustering and moving windows methods. The use of Quan-tité Morisita Index (QMI) as a procedure to evaluate data clustering in function of the radon level was proposed. The existing methods of declustering were revised and applied in an attempt to approach the global histogram parameters. The exploratory phase comes along with the definition of multiple scales of interest for indoor radon mapping in Switzerland. The analysis was done with a top-to-down resolution approach, from regional to local lev¬els in order to find the appropriate scales for modeling. In this sense, data partition was optimized in order to cope with stationary conditions of geostatistical models. Common methods of spatial modeling such as Κ Nearest Neighbors (KNN), variography and General Regression Neural Networks (GRNN) were proposed as exploratory tools. In the following section, different spatial interpolation methods were applied for a par-ticular dataset. A bottom to top method complexity approach was adopted and the results were analyzed together in order to find common definitions of continuity and neighborhood parameters. Additionally, a data filter based on cross-validation was tested with the purpose of reducing noise at local scale (the CVMF). At the end of the chapter, a series of test for data consistency and methods robustness were performed. This lead to conclude about the importance of data splitting and the limitation of generalization methods for reproducing statistical distributions. The last section was dedicated to modeling methods with probabilistic interpretations. Data transformation and simulations thus allowed the use of multigaussian models and helped take the indoor radon pollution data uncertainty into consideration. The catego-rization transform was presented as a solution for extreme values modeling through clas-sification. Simulation scenarios were proposed, including an alternative proposal for the reproduction of the global histogram based on the sampling domain. The sequential Gaussian simulation (SGS) was presented as the method giving the most complete information, while classification performed in a more robust way. An error measure was defined in relation to the decision function for data classification hardening. Within the classification methods, probabilistic neural networks (PNN) show to be better adapted for modeling of high threshold categorization and for automation. Support vector machines (SVM) on the contrary performed well under balanced category conditions. In general, it was concluded that a particular prediction or estimation method is not better under all conditions of scale and neighborhood definitions. Simulations should be the basis, while other methods can provide complementary information to accomplish an efficient indoor radon decision making.

Predictive analysis and mapping of indoor radon concentrations in a complex environment using kernel estimation: an application to Switzerland.

PURPOSE: The aim of this study was to develop models based on kernel regression and probability estimation in order to predict and map IRC in Switzerland by taking into account all of the following: architectural factors, spatial relationships between the measurements, as well as geological information. METHODS: We looked at about 240,000 IRC measurements carried out in about 150,000 houses. As predictor variables we included: building type, foundation type, year of construction, detector type, geographical coordinates, altitude, temperature and lithology into the kernel estimation models. We developed predictive maps as well as a map of the local probability to exceed 300 Bq/m(3). Additionally, we developed a map of a confidence index in order to estimate the reliability of the probability map. RESULTS: Our models were able to explain 28% of the variations of IRC data. All variables added information to the model. The model estimation revealed a bandwidth for each variable, making it possible to characterize the influence of each variable on the IRC estimation. Furthermore, we assessed the mapping characteristics of kernel estimation overall as well as by municipality. Overall, our model reproduces spatial IRC patterns which were already obtained earlier. On the municipal level, we could show that our model accounts well for IRC trends within municipal boundaries. Finally, we found that different building characteristics result in different IRC maps. Maps corresponding to detached houses with concrete foundations indicate systematically smaller IRC than maps corresponding to farms with earth foundation. CONCLUSIONS: IRC mapping based on kernel estimation is a powerful tool to predict and analyze IRC on a large-scale as well as on a local level. This approach enables to develop tailor-made maps for different architectural elements and measurement conditions and to account at the same time for geological information and spatial relations between IRC measurements.

Analysis and clinical relevance of microparticles from red blood cells.

PURPOSE OF REVIEW: The mechanisms involved in the formation of red blood cell (RBC) microparticles in vivo as well as during erythrocyte storage are reviewed, and the potential role of microparticles in transfusion medicine is described. RECENT FINDINGS: Microparticles release is an integral part of the erythrocyte ageing process, preventing early removal of RBCs. Proteomics analyses have outlined the key role of band 3-ankyrin anchoring complex and the occurrence of selective RBC membrane remodelling mechanisms in microparticles formation. The presence of several RBC antigens, expressed on microparticles, has been demonstrated. The potential deleterious effects of RBC microparticles in transfused recipients, including hypercoagulability, microcirculation impairment and immunosuppression, are discussed. SUMMARY: Formation and role of RBC microparticles are far from being completely understood. Combining various approaches to elucidate these mechanisms could improve blood product quality and transfusion safety. Implementation of RBC microparticles as biomarkers in the laboratory routine needs to overcome technical barriers involved in their analysis.

Functional analysis and structural modeling of human APOBEC3G reveal the role of evolutionarily conserved elements in the inhibition of human immunodeficiency virus type 1 infection and Alu transposition.

Retroelements are important evolutionary forces but can be deleterious if left uncontrolled. Members of the human APOBEC3 family of cytidine deaminases can inhibit a wide range of endogenous, as well as exogenous, retroelements. These enzymes are structurally organized in one or two domains comprising a zinc-coordinating motif. APOBEC3G contains two such domains, only the C terminal of which is endowed with editing activity, while its N-terminal counterpart binds RNA, promotes homo-oligomerization, and is necessary for packaging into human immunodeficiency virus type 1 (HIV-1) virions. Here, we performed a large-scale mutagenesis-based analysis of the APOBEC3G N terminus, testing mutants for (i) inhibition of vif-defective HIV-1 infection and Alu retrotransposition, (ii) RNA binding, and (iii) oligomerization. Furthermore, in the absence of structural information on this domain, we used homology modeling to examine the positions of functionally important residues and of residues found to be under positive selection by phylogenetic analyses of primate APOBEC3G genes. Our results reveal the importance of a predicted RNA binding dimerization interface both for packaging into HIV-1 virions and inhibition of both HIV-1 infection and Alu transposition. We further found that the HIV-1-blocking activity of APOBEC3G N-terminal mutants defective for packaging can be almost entirely rescued if their virion incorporation is forced by fusion with Vpr, indicating that the corresponding region of APOBEC3G plays little role in other aspects of its action against this pathogen. Interestingly, residues forming the APOBEC3G dimer interface are highly conserved, contrasting with the rapid evolution of two neighboring surface-exposed amino acid patches, one targeted by the Vif protein of primate lentiviruses and the other of yet-undefined function.

Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut.

Secretory IgA (SIgA) serves as the first line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms. Through a process known as immune exclusion, SIgA promotes the clearance of antigens and pathogenic microorganisms from the intestinal lumen by blocking their access to epithelial receptors, entrapping them in mucus, and facilitating their removal by peristaltic and mucociliary activities. In addition, SIgA functions in mucosal immunity and intestinal homeostasis through mechanisms that have only recently been revealed. In just the past several years, SIgA has been identified as having the capacity to directly quench bacterial virulence factors, influence composition of the intestinal microbiota by Fab-dependent and Fab-independent mechanisms, promote retro-transport of antigens across the intestinal epithelium to dendritic cell subsets in gut-associated lymphoid tissue, and, finally, to downregulate proinflammatory responses normally associated with the uptake of highly pathogenic bacteria and potentially allergenic antigens. This review summarizes the intrinsic biological activities now associated with SIgA and their relationships with immunity and intestinal homeostasis.

Le conseil génétique: aspects théoriques et pratique en prénatal [Genetic counselling: theoretical aspects and prenatal practice]

Le conseil génétique doit fournir aux individus une information médicale précise et un soutien psychologique. L'importance des principes d'autonomie et de confidentialité, dogmes du conseil génétique, est renforcée par la nouvelle loi suisse (LAGH). Dans certains pays, une grande partie du conseil génétique est assurée par des conseillers en génétique non médecins ayant une formation postgraduée spécifique. Le conseil génétique joue un rôle grandissant dans différents domaines de la médecine. En particulier, il est indispensable dans le contexte du prénatal où les couples reçoivent des informations complexes et doivent bénéficier d’un soutien pour prendre une décision. Genetic counselling provides families with accurate medical information and psychological support. Respect and concern for the emotional well-being should be taken into account while discussing genetics aspects and recurrence risks. The importance of autonomy and confidentiality, central to genetic counselling, is reinforced by the new Swiss law (LAGH). In many countries, most of the genetic counselling is provided by genetic counsellors who have a specialised post-graduate training. Genetic counselling plays an increasing role in different medical specialities. In particular, it is essential in the context of prenatal and pre-conceptual care, where couples are confronted to complex information and should have access to appropriate support during the decision-making process

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Interdisciplinary research for the analysis and risk assesment : the case of the municipality of Uspantan Guatemala

Short description of the proposed presentation * lees than 100 words This paper describes the interdisciplinary work done in Uspantán, Guatemala, a city vulnerable to natural hazards. We investigated local responses to landslides that happened in 2007 and 2010 and had a strong impact on the local community. We show a complete example of a systemic approach that incorporates physical, social and environmental aspects in order to understand risks. The objective of this work is to present the combination of social and geological data (mapping), and describe the methodology used for identification and assessment of risk. The article discusses both the limitations and methodological challenges encountered when conducting interdisciplinary research. Describe why it is important to present this topic at the Global Platform in less than 50 words This work shows the benefits of addressing risk in an interdisciplinary perspective, in particular how integrating social sciences can help identify new phenomena and natural hazards and assess risk. It gives a practical example of how one can integrate data from different fields. What is innovative about this presentation? * The use of mapping to combine qualitative and quantitative data. By coupling approaches, we could associate a hazard map with qualitative data gathered by interviews with the population. This map is an important document for the authorities. Indeed, it allows them to be aware of the most dangerous zones, the affected families and the places where it is most urgent to intervene.