TrAp: a Tree Approach for Fingerprinting Subclonal Tumor Composition

Revealing the clonal composition of a single tumor is essential for identifying cell subpopulations with metastatic potential in primary tumors or with resistance to therapies in metastatic tumors. Sequencing technologies provide an overview of an aggregate of numerous cells, rather than subclonal-specific quantification of aberrations such as single nucleotide variants (SNVs). Computational approaches to de-mix a single collective signal from the mixed cell population of a tumor sample into its individual components are currently not available. Herein we propose a framework for deconvolving data from a single genome-wide experiment to infer the composition, abundance and evolutionary paths of the underlying cell subpopulations of a tumor. The method is based on the plausible biological assumption that tumor progression is an evolutionary process where each individual aberration event stems from a unique subclone and is present in all its descendants subclones. We have developed an efficient algorithm (TrAp) for solving this mixture problem. In silico analyses show that TrAp correctly deconvolves mixed subpopulations when the number of subpopulations and the measurement errors are moderate. We demonstrate the applicability of the method using tumor karyotypes and somatic hypermutation datasets. We applied TrAp to SNV frequency profile from Exome-Seq experiment of a renal cell carcinoma tumor sample and compared the mutational profile of the inferred subpopulations to the mutational profiles of twenty single cells of the same tumor. Despite the large experimental noise, specific co-occurring mutations found in clones inferred by TrAp are also present in some of these single cells. Finally, we deconvolve Exome-Seq data from three distinct metastases from different body compartments of one melanoma patient and exhibit the evolutionary relationships of their subpopulations

Ranking and combining multiple predictors without labeled data

In a broad range of classification and decision making problems, one is given the advice or predictions of several classifiers, of unknown reliability, over multiple questions or queries. This scenario is different from the standard supervised setting, where each classifier accuracy can be assessed using available labeled data, and raises two questions: given only the predictions of several classifiers over a large set of unlabeled test data, is it possible to a) reliably rank them; and b) construct a meta-classifier more accurate than most classifiers in the ensemble? Here we present a novel spectral approach to address these questions. First, assuming conditional independence between classifiers, we show that the off-diagonal entries of their covariance matrix correspond to a rank-one matrix. Moreover, the classifiers can be ranked using the leading eigenvector of this covariance matrix, as its entries are proportional to their balanced accuracies. Second, via a linear approximation to the maximum likelihood estimator, we derive the Spectral Meta-Learner (SML), a novel ensemble classifier whose weights are equal to this eigenvector entries. On both simulated and real data, SML typically achieves a higher accuracy than most classifiers in the ensemble and can provide a better starting point than majority voting, for estimating the maximum likelihood solution. Furthermore, SML is robust to the presence of small malicious groups of classifiers designed to veer the ensemble prediction away from the (unknown) ground truth.Comment: Supplementary Information is included at the end of the manuscript. This is a revision of our original submission of the manuscript entitled "The student's dilemma: ranking and improving prediction at test time without access to training data", which is now entitled "Ranking and combining multiple predictors without labeled data

Éric Rohmer: la transformació de la intimitat a la segona meitat del segle XX. Una mirada sociològica

Aquest estudi aplica una mirada sociològica a l’obra cinematogràfica d’Éric Rohmer, en tant que el seu caràcter realista i documentalista, reflecteix amb precisió les dinàmiques de la transformació de l’amor a la segona meitat del segle XX. Un cop feta l’anàlisi de contingut i la narratològica de diferents pel·lícules, es demostra que Rohmer va capturar diferents maneres i postures d’adaptar-se al nou context social postindustrial marcat per la revolució sexual i la transformació de les relacions de gènere. La sociologia de l’amor i de la sexualitat (a partir d’Illouz, Giddens, Bozon, Beck & Beck-Gernsheim i Bauman, entre d’altres) proporciona les claus interpretatives noves per a l’anàlisi dels cinema de Rohmer ja que senyalen l’impacte que van exercir els canvis econòmics i culturals postmoderns a les mirades individuals sobre l’amor. Partint d’aquestes claus s’observa com les narratives contradictòries i les normes socials canviants van pressionar els individus a replantejar-se la seva identitat i la seva visió de la intimitat varis cops durant el llarg de la seva vida. Tenint en compte això, es pot observar a través de les pel·lícules de Rohmer les dinàmiques de canvi en matèria de sexualitat, la modificació de les expectatives matrimonials i de l’elecció de la parella. Finalment es subratllen les diferents visions de l’amor romàntic, amor lliure i matrimoni monògam, les visions femenines i masculines coexisteixen i com es negocien a la vida quotidiana de les últimes quatre dècades del segle passat reflectides en aquestes pel·lícules.Este estudio aplica una mirada sociológica a la obra cinematográfica de Éric Rohmer que, dado su carácter realista y documentalista, refleja con precisión las dinámicas de transformación del amor en la segunda mitad del siglo XX. Tras el análisis de contenido y el narratológico de varias películas, se demuestra que Rohmer capturó diferentes posturas y maneras de adaptarse al nuevo contexto social postindustrial marcado por la revolución sexual y la transformación de las relaciones de género. La sociología del amor y de la sexualidad (a partir de Illouz, Giddens, Bozon, Beck & Beck-Gernsheim y Bauman, entre otros) proporciona claves interpretativas nuevas para el análisis del cine de Rohmer, ya que señala el impacto que ejercieron los cambios económicos y culturales postmodernos en las miradas individuales sobre el amor. Partiendo de estas claves se observa como las narrativas contradictorias y normas sociales cambiantes presionan a los sujetos a replantear su identidad y su visión de la intimidad, varias veces a lo largo de su vida. Teniendo en cuenta esto, también se observan, a través de las películas de Rohmer, las dinámicas de cambio en materia de sexualidad, la modificación de las expectativas matrimoniales y de la elección de la pareja. Finalmente se iluminan diferentes visiones del amor romántico, amor libre y matrimonio monógamo, visiones femeninas y masculinas que coexisten y se negocian en la vida cotidiana de las últimas cuatro décadas del siglo pasado reflejadas en estas películas.This present study gives a sociological regard towards the cinematographic work of Éric Rohmer. Due to his realistic and documentary sort of films, he reflected precisely the dynamics of the love transformation on the last decades of the 20th century. Once the content and the narratology of different films are analyzed, it is shown that Rohmer captured different ways and postures of adaptation to the new postindustrial social context, influenced by the sexual revolution and the transformation of gender roles. Sociology of love and sexuality (from Illouz, Giddens, Bozon, Beck & Beck-Gernsheim and Bauman, among others) give us new ways of analyzing the cinema of Éric Rohmer, since they focus on the impact of the economic and cultural changes in postmodernity in the individual visions of love. From those new ways we observe the contradictory narrations and changing social rules that pressured people to rearrange their identities and their vision of intimacy even several times among their lives. On account of this and throughout Rohmer’s films, the dynamics of change towards sexual relationships, marriage expectations and the choice of partner can be observed. Finally, different visions of romantic love, free love and monogamous marriage are noted, along with masculine and feminine coexisting visions, and the negotiations in everyday life in the last four decades of the last century shown in these films

General practitioners' beliefs about people with schizophrenia and whether they should be subject to discriminatory treatment when in medical hospital: the mediating role of dangerousness perception

This study explored the relationships between General Practitioners’ (GPs) beliefs about People With Schizophrenia (PWS) and GPs’ recommendations regarding restrictions for such people when in medical (nonpsychiatric) hospital, and whether these relationships were mediated by dangerousness perception. There were 322 randomly selected Italian GPs who completed a questionnaire measuring beliefs about PWS. Structural Equation Model (SEM) was used to explore the effects of these beliefs on the GPs’ views about the need for restrictive rules in hospital. Thirty-1 percent of GPs firmly believed that, in medical wards, PWS should be supervised and 18% that they should be separated from other patients. SEM revealed that belief in such differential treatment was positively related to a belief that PWS need medication for the rest of their lives, and to perceptions of others’ need for social distance, and of dangerousness. Dangerousness was, in turn, positively related to the belief that PWS need medication for their lives, and to a perception of the need for social distance, but negatively related to perceived capacity to report health problems. Analyses of indirect effects showed that the relationships of belief in discriminatory treatment with belief in medication for life and with perceived social distance were mediated by perceived dangerousness. GPs’ attitudes about PWS appear closely with their beliefs on discriminatory behaviors in hospital, and the mediating role of dangerousness perceptions. Providing GPs with education about schizophrenia treatments and prognosis, and countering stereotypes about dangerousness, could be helpful to reduce GPs’ beliefs in the need for discriminatory treatment of PWS

Effects of the diagnostic label “schizophrenia”, actively used or passively accepted, on general practitioners’ views of this disorder.

Background. General Practitioners (GPs) play a key-role in the care of somatic and psychiatric problems in People With Schizophrenia (PWS). It is probable that, like other health professionals, GPs are not all free of prejudices towards PWS. In clinical practice, GPs sometimes interact with clients diagnosed with schizophrenia by specialists, passively accepting this diagnosis. Other times, GPs interact with clients having symptoms of schizophrenia but who have not been diagnosed. In this case, GPs are expected to actively make a diagnosis. Giving the key-role of GPs in the process of care, it is worthwhile examining whether passive acceptance and active usage of the diagnosis schizophrenia have differential effects on GPs’ attitudes toward people with this disorder. Aims. To investigate GPs’ views of schizophrenia and whether they were influenced by a “schizophrenia” label, passively accepted or actively used. Methods. Four-hundred and thirty randomly selected GPs were invited to complete a questionnaire about their views of schizophrenia, either after reading a description of this disorder and making a diagnosis, or without being provided with a description but passively accepting the label “schizophrenia” given in the questionnaire. Results. The GPs who passively accepted the label schizophrenia (N=195) and those who actively identified schizophrenia from the description (N=127) had similar views. Compared to the GPs who did not identify schizophrenia in the description (N=65), those who used the diagnosis, actively or passively: more frequently reported heredity and less frequently psychosocial factors as causes of the disorder; were more sceptical about recovery; were more convinced of the need for long-term pharmacotherapies, believed more strongly that PWS should be discriminated against when in medical hospital; and perceived PWS as more dangerous and as kept at greater social distance. Conclusions. The diagnosis “schizophrenia”, however used, is associated with pessimistic views. Stigma education should be provided to GPs

Picking ChIP-seq peak detectors for analyzing chromatin modification experiments

Numerous algorithms have been developed to analyze ChIP-Seq data. However, the complexity of analyzing diverse patterns of ChIP-Seq signals, especially for epigenetic marks, still calls for the development of new algorithms and objective comparisons of existing methods. We developed Qeseq, an algorithm to detect regions of increased ChIP read density relative to background. Qeseq employs critical novel elements, such as iterative recalibration and neighbor joining of reads to identify enriched regions of any length. To objectively assess its performance relative to other 14 ChIP-Seq peak finders, we designed a novel protocol based on Validation Discriminant Analysis (VDA) to optimally select validation sites and generated two validation datasets, which are the most comprehensive to date for algorithmic benchmarking of key epigenetic marks. In addition, we systematically explored a total of 315 diverse parameter configurations from these algorithms and found that typically optimal parameters in one dataset do not generalize to other datasets. Nevertheless, default parameters show the most stable performance, suggesting that they should be used. This study also provides a reproducible and generalizable methodology for unbiased comparative analysis of high-throughput sequencing tools that can facilitate future algorithmic development

Symmetric dithiodigalactoside: strategic combination of binding studies and detection of selectivity between a plant toxin and human lectins

Thioglycosides offer the advantage over O-glycosides to be resistant to hydrolysis. Based on initial evidence of this recognition ability for glycosyldisulfides by screening dynamic combinatorial libraries, we have now systematically studied dithiodigalactoside on a plant toxin (Viscum album agglutinin) and five human lectins (adhesion/growth-regulatory galectins with medical relevance e.g. in tumor progression and spread). Inhibition assays with surface-presented neoglycoprotein and in solution monitored by saturation transfer difference NMR spectroscopy, flanked by epitope mapping, as well as isothermal titration calorimetry revealed binding properties to VAA (Ka: 1560 ± 20 M-1). They were reflected by the structural model and the affinity on the level of toxin-exposed cells. In comparison, galectins were considerably less reactive, with intrafamily grading down to very minor reactivity for tandem-repeat-type galectins, as quantitated by radioassays for both domains of galectin-4. Model building indicated contact formation to be restricted to only one galactose moiety, in contrast to thiodigalactoside. The tested lycosyldisulfide exhibits selectivity between the plant toxin and the tested human lectins, and also between these proteins. Therefore, glycosyldisulfides have potential as chemical platform for inhibitor design

Computational Cancer Biology: An Evolutionary Perspective

ISSN:1553-734XISSN:1553-735

Shape: automatic conformation prediction of carbohydrates using a genetic algorithm

<p>Abstract</p> <p>Background</p> <p>Detailed experimental three dimensional structures of carbohydrates are often difficult to acquire. Molecular modelling and computational conformation prediction are therefore commonly used tools for three dimensional structure studies. Modelling procedures generally require significant training and computing resources, which is often impractical for most experimental chemists and biologists. <monospace>Shape</monospace> has been developed to improve the availability of modelling in this field.</p> <p>Results</p> <p>The <monospace>Shape</monospace> software package has been developed for simplicity of use and conformation prediction performance. A trivial user interface coupled to an efficient genetic algorithm conformation search makes it a powerful tool for automated modelling. Carbohydrates up to a few hundred atoms in size can be investigated on common computer hardware. It has been shown to perform well for the prediction of over four hundred bioactive oligosaccharides, as well as compare favourably with previously published studies on carbohydrate conformation prediction.</p> <p>Conclusion</p> <p>The <monospace>Shape</monospace> fully automated conformation prediction can be used by scientists who lack significant modelling training, and performs well on computing hardware such as laptops and desktops. It can also be deployed on computer clusters for increased capacity. The prediction accuracy under the default settings is good, as it agrees well with experimental data and previously published conformation prediction studies. This software is available both as open source and under commercial licenses.</p

VDA, a Method of Choosing a Better Algorithm with Fewer Validations

The multitude of bioinformatics algorithms designed for performing a particular computational task presents end-users with the problem of selecting the most appropriate computational tool for analyzing their biological data. The choice of the best available method is often based on expensive experimental validation of the results. We propose an approach to design validation sets for method comparison and performance assessment that are effective in terms of cost and discrimination power