Computational Feature of Selection and Classification of RET Phenotypic Severity

pre-printAlthough many reported mutations in the RET oncogene have been directly associated with hereditary thyroid carcinoma, other mutations are labelled as uncertain gene variants because they have not been clearly associated with a clinical phenotype. The process of determining the severity of a mutation is costly and time consuming. Informatics tools and methods may aid to bridge this genotype-phenotype gap. Towards this goal, machine-learning classification algorithms were evaluated for their ability to distinguish benign and pathogenic RET gene variants as characterized by differences in values of physicochemical properties of the residue present in the wild type and the one in the mutated sequence. Representative algorithms were chosen from different categories of machine learning classification techniques, including rules, bayes, and regression, nearest neighbour, support vector machines and trees. Machine-learning models were then compared to well-established techniques used for mutation severity prediction. Machine-learning classification can be used to accurately predict RET mutation status using primary sequence information only. Existing algorithms that are based on sequence homology (ortholog conservation) or protein structural data are not necessarily superior

Predicting phenotypic severity of uncertain gene variants in the RET Proto-Oncogene

pre-printAlthough reported gene variants in the RET oncogene have been directly associated with multiple endocrine neoplasia type 2 and hereditary medullary thyroid carcinoma, other mutations are classified as variants of uncertain significance (VUS) until the associated clinical phenotype is made clear. Currently, some 46 non-synonymous VUS entries exist in curated archives. In the absence of a gold standard method for predicting phenotype outcomes, this follow up study applies feature selected amino acid physical and chemical properties feeding a Bayes classifier to predict disease association of uncertain gene variants into categories of benign and pathogenic. Algorithm performance and VUS predictions were compared to established phylogenetic based mutation prediction algorithms. Curated outcomes and unpublished RET gene variants with known disease association were used to benchmark predictor performance. Reliable classification of RET uncertain gene variants will augment current clinical information of RET mutations and assist in improving prediction algorithms as knowledge increases

The Practice of Transformative Consumer Research - Some Issues and Suggestions

Transformative consumer research (TCR) is a new academic initiative among researchers committed to studying the role consumption plays in the major social problems of our day. These problems may involve the over consumption of products among the obese, the addicted, and the materialistic, or the under consumption of products among the hungry, the homeless, and the poor. The goal of transformative research is to do practical research that can be used by consumers, activists, policy makers, and businesses to improve consumer well-being. In this article, we propose rethinking the way that research is traditionally conducted in consumer research to make it more conducive to achieving TCR objectives. We start with the conventional approaches to consumer research and then offer alternative approaches to increase the likelihood that research will deliver useful and useable results

Inference of trustworthiness from intuitive moral judgments

Moral judgments play a critical role in motivating and enforcing human cooperation, and research on the proximate mechanisms of moral judgments highlights the importance of intuitive, automatic processes in forming such judgments. Intuitive moral judgments often share characteristics with deontological theories in normative ethics, which argue that certain acts (such as killing) are absolutely wrong, regardless of their consequences. Why do moral intuitions typically follow deontological prescriptions, as opposed to those of other ethical theories? Here, we test a functional explanation for this phenomenon by investigating whether agents who express deontological moral judgments are more valued as social partners. Across 5 studies, we show that people who make characteristically deontological judgments are preferred as social partners, perceived as more moral and trustworthy, and are trusted more in economic games. These findings provide empirical support for a partner choice account of moral intuitions whereby typically deontological judgments confer an adaptive function by increasing a person’s likelihood of being chosen as a cooperation partner. Therefore, deontological moral intuitions may represent an evolutionarily prescribed prior that was selected for through partner choice mechanisms

Follow-Up Observations of PTFO 8-8695: A 3 MYr Old T-Tauri Star Hosting a Jupiter-mass Planetary Candidate

We present Spitzer 4.5\micron\ light curve observations, Keck NIRSPEC radial velocity observations, and LCOGT optical light curve observations of PTFO~8-8695, which may host a Jupiter-sized planet in a very short orbital period (0.45 days). Previous work by \citet{vaneyken12} and \citet{barnes13} predicts that the stellar rotation axis and the planetary orbital plane should precess with a period of $300 - 600$ days. As a consequence, the observed transits should change shape and depth, disappear, and reappear with the precession. Our observations indicate the long-term presence of the transit events ($>3$ years), and that the transits indeed do change depth, disappear and reappear. The Spitzer observations and the NIRSPEC radial velocity observations (with contemporaneous LCOGT optical light curve data) are consistent with the predicted transit times and depths for the $M_\star = 0.34\ M_\odot$ precession model and demonstrate the disappearance of the transits. An LCOGT optical light curve shows that the transits do reappear approximately 1 year later. The observed transits occur at the times predicted by a straight-forward propagation of the transit ephemeris. The precession model correctly predicts the depth and time of the Spitzer transit and the lack of a transit at the time of the NIRSPEC radial velocity observations. However, the precession model predicts the return of the transits approximately 1 month later than observed by LCOGT. Overall, the data are suggestive that the planetary interpretation of the observed transit events may indeed be correct, but the precession model and data are currently insufficient to confirm firmly the planetary status of PTFO~8-8695b.Comment: Accepted for publication in The Astrophysical Journa

Consensus: a framework for evaluation of uncertain gene variants in laboratory test reporting

Accurate interpretation of gene testing is a key component in customizing patient therapy. Where confirming evidence for a gene variant is lacking, computational prediction may be employed. A standardized framework, however, does not yet exist for quantitative evaluation of disease association for uncertain or novel gene variants in an objective manner. Here, complementary predictors for missense gene variants were incorporated into a weighted Consensus framework that includes calculated reference intervals from known disease outcomes. Data visualization for clinical reporting is also discussed

Trial Protocol: Using genotype to tailor prescribing of nicotine replacement therapy: a randomised controlled trial assessing impact of communication upon adherence.

BACKGROUND: The behavioural impact of pharmacogenomics is untested; informing smokers of genetic test results for responsiveness to smoking cessation medication may increase adherence to this medication. The objective of this trial is to estimate the impact upon adherence to nicotine replacement therapy (NRT) of informing smokers that their oral dose of NRT has been tailored to a DNA analysis. Hypotheses to be tested are as follows: I Adherence to NRT is greater among smokers informed that their oral dose of NRT is tailored to an analysis of DNA (genotype), compared to one tailored to nicotine dependence questionnaire score (phenotype). II Amongst smokers who fail to quit at six months, motivation to make another quit attempt is lower when informed that their oral dose of NRT was tailored to genotype rather than phenotype. METHODS/DESIGN: An open label, parallel groups randomised trial in which 630 adult smokers (smoking 10 or more cigarettes daily) using National Health Service (NHS) stop smoking services in primary care are randomly allocated to one of two groups:i. NRT oral dose tailored by DNA analysis (OPRM1 gene) (genotype), orii. NRT oral dose tailored by nicotine dependence questionnaire score (phenotype)The primary outcome is proportion of prescribed NRT consumed in the first 28 days following an initial quit attempt, with the secondary outcome being motivation to make another quit attempt, amongst smokers not abstinent at six months. Other outcomes include adherence to NRT in the first seven days and biochemically validated smoking abstinence at six months. The primary outcome will be collected on 630 smokers allowing sufficient power to detect a 7.5% difference in mean proportion of NRT consumed using a two-tailed test at the 5% level of significance between groups. The proportion of all NRT consumed in the first four weeks of quitting will be compared between arms using an independent samples t-test and by estimating the 95% confidence interval for observed between-arm difference in mean NRT consumption (Hypothesis I). Motivation to make another quit attempt will be compared between arms in those failing to quit by six months (Hypothesis II). DISCUSSION: This is the first clinical trial evaluating the behavioural impact on adherence of prescribing medication using genetic rather than phenotypic information. Specific issues regarding the choice of design for trials of interventions of this kind are discussed. TRIAL DETAILS: Funder: Medical Research Council (MRC)Grant number: G0500274. ISRCTN: 14352545. Date trial stated: June 2007. Expected end date: December 2009. Expected reporting date: December 2010.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Suppression of electron emission from metal electrodes : LDRD 28771 final report.

This research consisted of testing surface treatment processes for stainless steel and aluminum for the purpose of suppressing electron emission over large surface areas to improve the pulsed high voltage hold-off capabilities of these metals. Improvements to hold-off would be beneficial to the operation of the vacuum-insulator grading rings and final self-magnetically insulated transmission line on the ZR-upgrade machine and other pulsed power applications such as flash radiograph and pulsed-microwave machines. The treatments tested for stainless steel include the Z-protocol (chemical polish, HVFF, and gold coating), pulsed E-beam surface treatments by IHCE, Russia, and chromium oxide coatings. Treatments for aluminum were anodized and polymer coatings. Breakdown thresholds also were measured for a range of surface finishes and gap distances. The study found that: (1.) Electrical conditioning and solvent cleaning in a filtered air environment each improve HV hold-off 30%. (2.) Anodized coatings on aluminum give a factor of two improvement in high voltage hold-off. However, anodized aluminum loses this improvement when the damage is severe. Chromium oxide coatings on stainless steel give a 40% and 20% improvement in hold-off before and after damage from many arcs. (3.) Bare aluminum gives similar hold-off for surface roughness, R{sub a}, ranging from 0.08 to 3.2 {micro}m. (4.) The various EBEST surfaces tested give high voltage hold-off a factor of two better than typical machined and similar to R{sub a} = 0.05 {micro}m polished stainless steel surfaces. (5.) For gaps > 2 mm the hold-off voltage increases as the square root of the gap for bare metal surfaces. This is inconsistent with the accepted model for metals that involves E-field induced electron emission from dielectric inclusions. Micro-particles accelerated across the gap during the voltage pulse give the observed voltage dependence. However the similarity in observed breakdown times for large and small gaps places a requirement that the particles be of molecular size. This makes accelerated micro-particle induced breakdown seem improbable also

Formation and Evolution of Planetary Systems: Placing Our Solar System in Context with Spitzer

We summarize the progress to date of our Legacy Science Program entitled "The Formation and Evolution of Planetary Systems" (FEPS) based on observations obtained with the Spitzer Space Telescope during its first year of operation. In addition to results obtained from our ground-based preparatory program and our early validation program, we describe new results from a survey for near-infrared excess emission from the youngest stars in our sample as well as a search for cold debris disks around sun-like stars. We discuss the implications of our findings with respect to current understanding of the formation and evolution of our own solar system.Comment: 8 postscript pages including 3 figures. To appear in "Spitzer New Views of the Cosmos" ASP Conference Series, eds. L. Armus et al. FEPS website at http://feps.as.arizona.ed