Risk assessment of recurrence in sporadic retinoblastoma using a molecular-based algorithm

Le rétinoblastome (Rb) est une tumeur provenant des cellules rétiniennes progénitrices des photorécepteurs. C'est la tumeur pédiatrique maligne la plus fréquente avec une incidence par naissance évaluée entre 1/15Ό00 et 1/20Ό00. Les enfants atteints de Rb sont diagnostiqué dans leur grande majorité avant l'âge de 4 ans, soit le temps nécessaire à la différentiation et à la maturation des photorécepteurs et donc à la disparition de la cellule d'origine du Rb. La survie du patient, la sauvegarde oculaire et le pronostic visuel restent excellents pour autant que le traitement ne soit pas différé. Dans sa variante non héréditaire (60%) le Rb est toujours unilatéral et sporadique. Le Rb héréditaire de transmission dominante autosomique (40%), se décline sous toutes les formes, familiale (10%) ou sporadique (30%), que l'atteinte soit unilatérale ou bilatérale. La majorité des mutations causales sont uniques et distribuées de façon aléatoire sur la totalité du gène RB1 sans région prédisposante. La détection de ces mutations est couteuse et chronophage, tout en présentant un taux de détection relativement bas; surtout dans les cas de Rb sporadiques unilatéraux. Dans le but d'identifier les patients présentant un risque réel de développer un Rb, et de réduire le nombre d'examens sous narcose requis pour le dépistage de la maladie chez les sujets à risque, nous avons développé une stratégie sensible, rapide, efficace et peu couteuse basée sur une analyse de l'haplotype intragénique. Cet algorithme prend en compte a) la perte d'hétérozygotie intratumorale du gène RB1, b) l'origine paternelle préférentielle des nouvelles mutations germinales et c) un risque a priori dérivé des données empiriques de Vogel. Pendant la période allant de janvier 1994 à décembre 2006, nous avons comparé l'apparition de nouveau Rb parmi la fratrie et la descendance de patient atteints au nombre de nouveaux cas attendus calculé par notre algorithme. 134 familles ont été étudiées. L'analyse moléculaire a été effectuée chez 570 personnes dont 99 patients âgés de moins de 4 ans et donc à risque de développer un Rb. Parmi cette cohorte, nous avons observé l'apparition d'un cas de Rb, alors que les risques cumulés a posteriori calculé par notre algorithme prédisait l'apparition de 1.77 nouveau cas. Dans cette étude, nous avons pu valider notre algorithme prédisant la récurrence de Rb chez les parents de 1er degré de patients atteints. Cet outil devrait grandement faciliter le conseil génétique ainsi que le suivi des patients à risque de développer un Rb, surtout dans les cas ou le séquençage direct du gène RB1 n'est pas disponible ou est resté non informatif. - Purpose: Most RBI mutations are unique and distributed throughout the RBI gene. Their detection can be time-consuming and the yield especially low in cases of conservatively-treated sporadic unilateral retinoblas-toma (Rb) patients. In order to identify patients with true risk of developing Rb, and to reduce the number of unnecessary examinations under anesthesia in all other cases, we developed a universal sensitive, efficient and cost-effective strategy based on intragenic haplotype analysis. Methods: This algorithm allows the calculation of the a posteriori risk of developing Rb and takes into account (a) RBI loss of heterozygosity in tumors, (b) preferential paternal origin of new germline mutations, (c) a priori risk derived from empirical data by Vogel, and (d) disease penetrance of 90% in most cases. We report the occurrence of Rb in first degree relatives of patients with sporadic Rb who visited the Jules Gonin Eye Hospital, Lausanne, Switzerland, from January 1994 to December 2006 compared to expected new cases of Rb using our algorithm. Results: A total of 134 families with sporadic Rb were enrolled; testing was performed in 570 individuals and 99 patients younger than 4 years old were identified. We observed one new case of Rb. Using our algorithm, the cumulated total a posteriori risk of recurrence was 1.77. Conclusions: This is the first time that linkage analysis has been validated to monitor the risk of recurrence in sporadic Rb. This should be a useful tool in genetic counseling, especially when direct RBI screening for mutations leaves a negative result or is unavailable.

Risk assessment of recurrence in sporadic retinoblastoma using a molecular-based algorithm.

PURPOSE: Most RB1 mutations are unique and distributed throughout the RB1 gene. Their detection can be time-consuming and the yield especially low in cases of conservatively-treated sporadic unilateral retinoblastoma (Rb) patients. In order to identify patients with true risk of developing Rb, and to reduce the number of unnecessary examinations under anesthesia in all other cases, we developed a universal sensitive, efficient and cost-effective strategy based on intragenic haplotype analysis. METHODS: This algorithm allows the calculation of the a posteriori risk of developing Rb and takes into account (a) RB1 loss of heterozygosity in tumors, (b) preferential paternal origin of new germline mutations, (c) a priori risk derived from empirical data by Vogel, and (d) disease penetrance of 90% in most cases. We report the occurrence of Rb in first degree relatives of patients with sporadic Rb who visited the Jules Gonin Eye Hospital, Lausanne, Switzerland, from January 1994 to December 2006 compared to expected new cases of Rb using our algorithm. RESULTS: A total of 134 families with sporadic Rb were enrolled; testing was performed in 570 individuals and 99 patients younger than 4 years old were identified. We observed one new case of Rb. Using our algorithm, the cumulated total a posteriori risk of recurrence was 1.77. CONCLUSIONS: This is the first time that linkage analysis has been validated to monitor the risk of recurrence in sporadic Rb. This should be a useful tool in genetic counseling, especially when direct RB1 screening for mutations leaves a negative result or is unavailable.

Typing less common ovarian tumors: A training tool based on a pattern-based algorithm applied to a set of 20 virtual slides.

Context: Ovarian tumors (OT) typing is a competency expected from pathologists, with significant clinical implications. OT however come in numerous different types, some rather rare, with the consequence of few opportunities for practice in some departments. Aim: Our aim was to design a tool for pathologists to train in less common OT typing. Method and Results: Representative slides of 20 less common OT were scanned (Nano Zoomer Digital Hamamatsu®) and the diagnostic algorithm proposed by Young and Scully applied to each case (Young RH and Scully RE, Seminars in Diagnostic Pathology 2001, 18: 161-235) to include: recognition of morphological pattern(s); shortlisting of differential diagnosis; proposition of relevant immunohistochemical markers. The next steps of this project will be: evaluation of the tool in several post-graduate training centers in Europe and Québec; improvement of its design based on evaluation results; diffusion to a larger public. Discussion: In clinical medicine, solving many cases is recognized as of utmost importance for a novice to become an expert. This project relies on the virtual slides technology to provide pathologists with a learning tool aimed at increasing their skills in OT typing. After due evaluation, this model might be extended to other uncommon tumors.

Does introduction of thresholds in decision aids benefit the patient?: Comparison between findings-based and threshold-based diagnostic decision aids.

PURPOSE: To assess how different diagnostic decision aids perform in terms of sensitivity, specificity, and harm. METHODS: Four diagnostic decision aids were compared, as applied to a simulated patient population: a findings-based algorithm following a linear or branched pathway, a serial threshold-based strategy, and a parallel threshold-based strategy. Headache in immune-compromised HIV patients in a developing country was used as an example. Diagnoses included cryptococcal meningitis, cerebral toxoplasmosis, tuberculous meningitis, bacterial meningitis, and malaria. Data were derived from literature and expert opinion. Diagnostic strategies' validity was assessed in terms of sensitivity, specificity, and harm related to mortality and morbidity. Sensitivity analyses and Monte Carlo simulation were performed. RESULTS: The parallel threshold-based approach led to a sensitivity of 92% and a specificity of 65%. Sensitivities of the serial threshold-based approach and the branched and linear algorithms were 47%, 47%, and 74%, respectively, and the specificities were 85%, 95%, and 96%. The parallel threshold-based approach resulted in the least harm, with the serial threshold-based approach, the branched algorithm, and the linear algorithm being associated with 1.56-, 1.44-, and 1.17-times higher harm, respectively. Findings were corroborated by sensitivity and Monte Carlo analyses. CONCLUSION: A threshold-based diagnostic approach is designed to find the optimal trade-off that minimizes expected harm, enhancing sensitivity and lowering specificity when appropriate, as in the given example of a symptom pointing to several life-threatening diseases. Findings-based algorithms, in contrast, solely consider clinical observations. A parallel workup, as opposed to a serial workup, additionally allows for all potential diseases to be reviewed, further reducing false negatives. The parallel threshold-based approach might, however, not be as good in other disease settings.

Memory-based scheduling of scientific computing clusters

This study looks at how increased memory utilisation affects throughput and energy consumption in scientific computing, especially in high-energy physics. Our aim is to minimise energy consumed by a set of jobs without increasing the processing time. The earlier tests indicated that, especially in data analysis, throughput can increase over 100% and energy consumption decrease 50% by processing multiple jobs in parallel per CPU core. Since jobs are heterogeneous, it is not possible to find an optimum value for the number of parallel jobs. A better solution is based on memory utilisation, but finding an optimum memory threshold is not straightforward. Therefore, a fuzzy logic-based algorithm was developed that can dynamically adapt the memory threshold based on the overall load. In this way, it is possible to keep memory consumption stable with different workloads while achieving significantly higher throughput and energy-efficiency than using a traditional fixed number of jobs or fixed memory threshold approaches.

Rockfall detection from LIDAR point clouds: A clustering approach using R

The analysis of rockfall characteristics and spatial distribution is fundamental to understand and model the main factors that predispose to failure. In our study we analysed LiDAR point clouds aiming to: (1) detect and characterise single rockfalls; (2) investigate their spatial distribution. To this end, different cluster algorithms were applied: 1a) Nearest Neighbour Clutter Removal (NNCR) in combination with the Expectation?Maximization (EM) in order to separate feature points from clutter; 1b) a density based algorithm (DBSCAN) was applied to isolate the single clusters (i.e. the rockfall events); 2) finally we computed the Ripley's K-function to investigate the global spatial pattern of the extracted rockfalls. The method allowed proper identification and characterization of more than 600 rockfalls occurred on a cliff located in Puigcercos (Catalonia, Spain) during a time span of six months. The spatial distribution of these events proved that rockfall were clustered distributed at a welldefined distance-range. Computations were carried out using R free software for statistical computing and graphics. The understanding of the spatial distribution of precursory rockfalls may shed light on the forecasting of future failures.

Behind the Scenes of an Ant Genome Project

Dramatic improvements in DNA sequencing technologies have led to amore than 1,000-fold reduction in sequencing costs over the past five years.Genome-wide research approaches can thus now be applied beyond medicallyrelevant questions to examine the molecular-genetic basis of behavior,development and unique life histories in almost any organism. A first step foran emerging model organism is usually establishing a reference genomesequence. I offer insight gained from the fire ant genome project. First, I detailhow the project came to be and how sequencing, assembly and annotationstrategies were chosen. Subsequently, I describe some of the issues linked toworking with data from recently sequenced genomes. Finally, I discuss anapproach undertaken in a follow-up project based on the fire ant genomesequence.

Epidemiology of multiple congenital anomalies in Europe: a EUROCAT population-based registry study.

BACKGROUND: This study describes the prevalence, associated anomalies, and demographic characteristics of cases of multiple congenital anomalies (MCA) in 19 population-based European registries (EUROCAT) covering 959,446 births in 2004 and 2010. METHODS: EUROCAT implemented a computer algorithm for classification of congenital anomaly cases followed by manual review of potential MCA cases by geneticists. MCA cases are defined as cases with two or more major anomalies of different organ systems, excluding sequences, chromosomal and monogenic syndromes. RESULTS: The combination of an epidemiological and clinical approach for classification of cases has improved the quality and accuracy of the MCA data. Total prevalence of MCA cases was 15.8 per 10,000 births. Fetal deaths and termination of pregnancy were significantly more frequent in MCA cases compared with isolated cases (p < 0.001) and MCA cases were more frequently prenatally diagnosed (p < 0.001). Live born infants with MCA were more often born preterm (p < 0.01) and with birth weight < 2500 grams (p < 0.01). Respiratory and ear, face, and neck anomalies were the most likely to occur with other anomalies (34% and 32%) and congenital heart defects and limb anomalies were the least likely to occur with other anomalies (13%) (p < 0.01). However, due to their high prevalence, congenital heart defects were present in half of all MCA cases. Among males with MCA, the frequency of genital anomalies was significantly greater than the frequency of genital anomalies among females with MCA (p < 0.001). CONCLUSION: Although rare, MCA cases are an important public health issue, because of their severity. The EUROCAT database of MCA cases will allow future investigation on the epidemiology of these conditions and related clinical and diagnostic problems.

Molecular variation at a candidate gene implicated in the regulation of fire ant social behavior

The fire ant Solenopsis invicta and its close relatives display an important social polymorphism involving differences in colony queen number. Colonies are headed by either a single reproductive queen (monogyne form) or multiple queens (polygyne form). This variation in social organization is associated with variation at the gene Gp-9, with monogyne colonies harboring only B-like allelic variants and polygyne colonies always containing b-like variants as well. We describe naturally occurring variation at Gp-9 in fire ants based on 185 full-length sequences, 136 of which were obtained from S. invicta collected over much of its native range. While there is little overall differentiation between most of the numerous alleles observed, a surprising amount is found in the coding regions of the gene, with such substitutions usually causing amino acid replacements. This elevated coding-region variation may result from a lack of negative selection acting to constrain amino acid replacements over much of the protein, different mutation rates or biases in coding and non-coding sequences, negative selection acting with greater strength on non-coding than coding regions, and/or positive selection acting on the protein. Formal selection analyses provide evidence that the latter force played an important role in the basal b-like lineages coincident with the emergence of polygyny. While our data set reveals considerable paraphyly and polyphyly of S. invicta sequences with respect to those of other fire ant species, the b-like alleles of the socially polymorphic species are monophyletic. An expanded analysis of colonies containing alleles of this clade confirmed the invariant link between their presence and expression of polygyny. Finally, our discovery of several unique alleles bearing various combinations of b-like and B-like codons allows us to conclude that no single b-like residue is completely predictive of polygyne behavior and, thus, potentially causally involved in its expression. Rather, all three typical b-like residues appear to be necessary.

A musculoskeletal shoulder model based on pseudo-inverse and null-space optimization.

The goal of the present work was assess the feasibility of using a pseudo-inverse and null-space optimization approach in the modeling of the shoulder biomechanics. The method was applied to a simplified musculoskeletal shoulder model. The mechanical system consisted in the arm, and the external forces were the arm weight, 6 scapulo-humeral muscles and the reaction at the glenohumeral joint, which was considered as a spherical joint. The muscle wrapping was considered around the humeral head assumed spherical. The dynamical equations were solved in a Lagrangian approach. The mathematical redundancy of the mechanical system was solved in two steps: a pseudo-inverse optimization to minimize the square of the muscle stress and a null-space optimization to restrict the muscle force to physiological limits. Several movements were simulated. The mathematical and numerical aspects of the constrained redundancy problem were efficiently solved by the proposed method. The prediction of muscle moment arms was consistent with cadaveric measurements and the joint reaction force was consistent with in vivo measurements. This preliminary work demonstrated that the developed algorithm has a great potential for more complex musculoskeletal modeling of the shoulder joint. In particular it could be further applied to a non-spherical joint model, allowing for the natural translation of the humeral head in the glenoid fossa.

An objective anisotropic elastic plastic model and Algorithm applicable to bone mechanics

The implicit projection algorithm of isotropic plasticity is extended to an objective anisotropic elastic perfectly plastic model. The recursion formula developed to project the trial stress on the yield surface, is applicable to any non linear elastic law and any plastic yield function.A curvilinear transverse isotropic model based on a quadratic elastic potential and on Hill's quadratic yield criterion is then developed and implemented in a computer program for bone mechanics perspectives. The paper concludes with a numerical study of a schematic bone-prosthesis system to illustrate the potential of the model.

The worldwide expansion of the Argentine ant

Aim The aim of this study was to determine the number of successful establishments of the invasive Argentine ant outside native range and to see whether introduced supercolonies have resulted from single or multiple introductions. We also compared the genetic diversity of native versus introduced supercolonies to assess the size of the propagules (i.e. the number of founding individuals) at the origin of the introduced supercolonies. Location Global. Methods We used mitochondrial DNA (mtDNA) markers and microsatellite loci to study 39 supercolonies of the Argentine ant Linepithema humile covering both the native (n = 25) and introduced range (n = 14). Results Data from three mitochondrial genes and 13 nuclear microsatellites suggest that the introduced supercolonies studied originated from at least seven founding events out of the native area in Argentina (primary introductions). The distribution of mtDNA haplotypes also suggests that supercolonies in the introduced range each derive from a single source supercolony and that one of these source supercolonies has been particularly successful, being the basis of many introduced populations spread across the world. Comparison of the genetic diversity of supercolonies based on the five most diverse loci also revealed that native and introduced supercolonies have greatly overlapping ranges of diversity, although the genetic diversity is on average less in introduced than in native supercolonies. Main conclusions Both primary introductions (from the native range) and secondary introductions (from sites with established invasive supercolonies) were important in the global expansion of the Argentine ant. In combination with the similar social organization of colonies in the native and introduced range, this indicates that invasiveness did not evolve recently as a unique and historically contingent event (e.g. reduction of genetic diversity) in this species. Rather, native L. humile supercolonies have characteristics that make them pre-adapted to invade new - and in particular disturbed - habitats when given the opportunity. These results have important implications with regard to possible strategies to be used to control invasive ants.

Species delimitation: A case study in a problematic ant taxon

Species delimitation has been invigorated as a discipline in systematics by an influx of new character sets, analytical methods, and conceptual advances. We use genetic data from 68 markers, combined with distributional, bioclimatic, and coloration information, to hypothesize boundaries of evolutionarily independent lineages (species) within the widespread and highly variable nominal fire ant species Solenopsis saevissima, a member of a species group containing invasive pests as well as species that are models for ecological and evolutionary research. Our integrated approach uses diverse methods of analysis to sequentially test whether populations meet specific operational criteria (contingent properties) for candidacy as morphologically cryptic species, including genetic clustering, monophyly, reproductive isolation, and occupation of distinctive niche space. We hypothesize that nominal S. saevissima comprises at least 4-6 previously unrecognized species, including several pairs whose parapatric distributions implicate the development of intrinsic premating or postmating barriers to gene flow. Our genetic data further suggest that regional genetic differentiation in S. saevissima has been influenced by hybridization with other nominal species occurring in sympatry or parapatry, including the quite distantly related Solenopsis geminata. The results of this study illustrate the importance of employing different classes of genetic data (coding and noncoding regions and nuclear and mitochondrial DNA [mtDNA] markers), different methods of genetic data analysis (tree-based and non-tree based methods), and different sources of data (genetic, morphological, and ecological data) to explicitly test various operational criteria for species boundaries in clades of recently diverged lineages, while warning against over reliance on any single data type (e.g., mtDNA sequence variation) when drawing inferences.

Semi-supervised segmentation of ultrasound images based on patch representation and continuous min cut.

Ultrasound segmentation is a challenging problem due to the inherent speckle and some artifacts like shadows, attenuation and signal dropout. Existing methods need to include strong priors like shape priors or analytical intensity models to succeed in the segmentation. However, such priors tend to limit these methods to a specific target or imaging settings, and they are not always applicable to pathological cases. This work introduces a semi-supervised segmentation framework for ultrasound imaging that alleviates the limitation of fully automatic segmentation, that is, it is applicable to any kind of target and imaging settings. Our methodology uses a graph of image patches to represent the ultrasound image and user-assisted initialization with labels, which acts as soft priors. The segmentation problem is formulated as a continuous minimum cut problem and solved with an efficient optimization algorithm. We validate our segmentation framework on clinical ultrasound imaging (prostate, fetus, and tumors of the liver and eye). We obtain high similarity agreement with the ground truth provided by medical expert delineations in all applications (94% DICE values in average) and the proposed algorithm performs favorably with the literature.