Mutation prediction models in Lynch syndrome: evaluation in a clinical genetic setting

Background/aims: The identification of Lynch syndrome is hampered by the absence of specific diagnostic features and underutilization of genetic testing. Prediction models have therefore been developed, but they have not been validated for a clinical genetic setting. The aim of the present study was to evaluate the usefulness of currently available prediction models. METHODS: We collected data of 321 index probands who were referred to the department of Clinical Genetics of the Erasmus Medical Center because of a family history of colorectal cancer. These data were used as input for five previously published models. External validity was assessed by discriminative ability (AUC: area under the receiver operating characteristic curve) and calibration. For further insight, predicted probabilities were categorized with cut-offs of 5%, 10%, 20% and 40%. Furthermore, costs of different testing strategies were related to the number of extra detected mutation carriers. RESULTS: Of the 321 index probands, 66 harboured a germline mutation. All models discriminated well between high risk and low risk index probands (AUC: 0.82-0.84). Calibration was well for the Premm1,2 and Edinburgh model, but poor for the other models. Cut-offs could be found for the prediction models where costs could be saved while missing only few mutations. CONCLUSIONS: The Edinburgh and Premm1,2 model were the models with the best performance for an intermediate to high-risk setting. These models may well be of use in clinical practice to select patients for further testing of mismatch repair gene mutations

Shell Structure Studies in the Pb-Region

This research was sponsored by the National Science Foundation Grant NSF PHY-931478

Search for 3S(1/2) Hole-Strength Fragments via the 208-Pb(d,3-He)207-Tl Reaction

This research was sponsored by the National Science Foundation Grant NSF PHY-931478

Shell Structure Studies in the Pb-Region

This research was sponsored by the National Science Foundation Grant NSF PHY-931478

Genetic testing for Lynch syndrome: family communication and motivation

Current genetic counselling practice for Lynch syndrome (LS) relies on diagnosed index patients to inform their biological family about LS, referred to as the family-mediated approach. The objective of this study was to evaluate this approach and to identify factors influencing the uptake of genetic testing for LS. In 59 mutation carriers, 70 non carriers and 16 non-tested relatives socio-demographic characteristics, family communication regarding LS, experiences and attitudes towards the family-mediated approach and motivations for genetic testing, were assessed. The majority of all respondents (73 %) were satisfied with the family-mediated approach. Nevertheless, 59 % of the respondents experienced informing a family member and 57 % being informed by a family member as burdensome. Non-tested differed from tested respondents, in that they were younger, less closely related to the index patient and a lower proportion had children. The most important reasons for declining genetic testing were (1) anticipating problems with life insurance and mortgage, (

Force-based Cooperative Search Directions in Evolutionary Multi-objective Optimization

International audienceIn order to approximate the set of Pareto optimal solutions, several evolutionary multi-objective optimization (EMO) algorithms transfer the multi-objective problem into several independent single-objective ones by means of scalarizing functions. The choice of the scalarizing functions' underlying search directions, however, is typically problem-dependent and therefore difficult if no information about the problem characteristics are known before the search process. The goal of this paper is to present new ideas of how these search directions can be computed \emph{adaptively} during the search process in a \emph{cooperative} manner. Based on the idea of Newton's law of universal gravitation, solutions attract and repel each other \emph{in the objective space}. Several force-based EMO algorithms are proposed and compared experimentally on general bi-objective $\rho$MNK landscapes with different objective correlations. It turns out that the new approach is easy to implement, fast, and competitive with respect to a $(\mu+\lambda)$-SMS-EMOA variant, in particular if the objectives show strong positive or negative correlations

Constraints on the pMSSM from LAT Observations of Dwarf Spheroidal Galaxies

We examine the ability for the Large Area Telescope (LAT) to constrain Minimal Supersymmetric Standard Model (MSSM) dark matter through a combined analysis of Milky Way dwarf spheroidal galaxies. We examine the Lightest Supersymmetric Particles (LSPs) for a set of ~71k experimentally valid supersymmetric models derived from the phenomenological-MSSM (pMSSM). We find that none of these models can be excluded at 95% confidence by the current analysis; nevertheless, many lie within the predicted reach of future LAT analyses. With two years of data, we find that the LAT is currently most sensitive to light LSPs (m_LSP < 50 GeV) annihilating into tau-pairs and heavier LSPs annihilating into b-bbar. Additionally, we find that future LAT analyses will be able to probe some LSPs that form a sub-dominant component of dark matter. We directly compare the LAT results to direct detection experiments and show the complementarity of these search methods.Comment: 24 pages, 9 figures, submitted to JCA

Prognostic significance of precordial ST segment depression during inferior myocardial infarction in the thrombolytic era: Results in 16,521 patients

Objectives. We examined the prognostic significance of precordial ST segment depression among patients with an acute inferior myocardial infarction. Background. Although precordial ST segment depression has been associated with a poor prognosis, this correlation has not been adequately quantified, partly because of small sample sizes and methodologic limitations in previous studies. Methods. We examined the clinical and angiographic outcomes of 16,521 patients with an acute inferior myocardial infarction who underwent thrombolysis in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) study. Patients were classified into those without precordial ST segment depression (n = 6,422 [38.9%]), those with ST segment depression in leads V1 to V3 only (n = 5,850 [35.4%]), those with ST segment depression in leads V4 to V6 only (n = 876 [5.3%]) and those with ST segment depression in both leads V1 to V3 and leads V4 to V6 (n = 3,373 [20.4%]) on initial electrocardiography. Outcome measures included postinfarction complications (second- or third-degree heart block, congestive heart failure or shock) and 30-day and 1-year mortality. Results. Patients with precordial ST segment depression had larger infarctions, more postinfarction complications and a higher mortality rate than those without precordial ST segment depression (4.7% vs. 3.2% at 30 days; 5.0% vs. 3.4% at 1 year; both p < 0.001), regardless of whether ST segment depression was noted in leads V1 to V6 or in leads V4 to V6. The magnitude of precordial ST segment depression (sum of leads V1 to V6) added significant independent prognostic information after adjustment for clinical risk factors; the risk of 30-day mortality increased by 36% for every 0.5 mV of precordial ST segment depression. Conclusions. Assessment of the magnitude of precordial ST segment depression is useful for acute risk stratification in patients with an inferior myocardial infarction

Baryon Charge Radii and Quadrupole Moments in the 1/N_c Expansion: The 3-Flavor Case

We develop a straightforward method to compute charge radii and quadrupole moments for baryons both with and without strangeness, when the number of QCD color charges is N_c. The minimal assumption of the single-photon exchange ansatz implies that only two operators are required to describe these baryon observables. Our results are presented so that SU(3) flavor and isospin symmetry breaking can be introduced according to any desired specification, although we also present results obtained from two patterns suggested by the quark model with gluon exchange interactions. The method also permits to extract a number of model-independent relations; a sample is r^2_Lambda / r_n^2 = 3/(N_c+3), independent of SU(3) symmetry breaking.Comment: 30 pages, no figures, REVTeX

Modelling the nucleation, growth and coarsening kinetics of γ^″ (D0<inf>22</inf>) precipitates in the Ni-base Alloy 625

Alloy 625 is susceptible to significant precipitation hardening through the formation of γ″ (D022-NbNi3) particles. These precipitates can form both during manufacture and in high temperature service and, consequently, the accurate prediction of their behaviour is crucial. To this end, a model is presented here which describes γ″ precipitation in Alloy 625, encompassing the concurrent nucleation, growth and coarsening of different particles and allowing for the particles to be shape changing. This model is calibrated with respect to the experimentally measured aspect ratio evolution observed at 650 °C. The resultant outputs for interfacial energy, particle size distribution and number density are in agreement with experimental data for a simulation of 1000 h at 650 °C