A robust DF-REML framework for variance components estimation in genetic studies.

MOTIVATION: In genetic association studies, linear mixed models (LMMs) are used to test for associations between phenotypes and candidate single nucleotide polymorphisms (SNPs). These same models are also used to estimate heritability, which is central not only to evolutionary biology but also to the prediction of the response to selection in plant and animal breeding, as well as the prediction of disease risk in humans. However, when one or more of the underlying assumptions are violated, the estimation of variance components may be compromised and therefore so may the estimates of heritability and any other functions of these. Considering that datasets obtained from real life experiments are prone to several sources of contamination, which usually induce the violation of the assumption of the normality of the errors, a robust derivative-free restricted-maximum likelihood framework (DF-REML) together with a robust coefficient of determination are proposed for the LMM in the context of genetic studies of continuous traits. RESULTS: The proposed approach, in addition to the robust estimation of variance components and robust computation of the coefficient of determination, allows in particular for the robust estimation of SNP-based heritability by reducing the bias and increasing the precision of its estimates. The performance of both classical and robust DF-REML approaches is compared via a Monte Carlo simulation study. Additionally, three examples of application of the methodologies to real datasets are given in order to validate the usefulness of the proposed robust approach. Although the main focus of this article is on plant breeding applications, the proposed methodology is applicable to both human and animal genetic studies. AVAILABILITY AND IMPLEMENTATION: Source code implemented in R is available in the Supplementary Material. CONTACT: vmml@fct.unl.pt. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Novel production method for traceable surface sources by aluminium functionalisation.

Accurate detection of low-level radioactivity is critical in decommissioning. However, commercial sources used for calibration lack representativeness due to their flat surface. The objective of this work is to produce flexible and large area surface sources for alpha and beta emitters by functionalising aluminium foil. Functionalisation strategies were developed to provide these sources. The manganese oxide coated sample shows the highest fixation yield for 241Am: (70.0 ± 2.6)% and conforms to ISO 8769 for uniformity (92%).

Robust linear regression methods in association studies.

MOTIVATION: It is well known that data deficiencies, such as coding/rounding errors, outliers or missing values, may lead to misleading results for many statistical methods. Robust statistical methods are designed to accommodate certain types of those deficiencies, allowing for reliable results under various conditions. We analyze the case of statistical tests to detect associations between genomic individual variations (SNP) and quantitative traits when deviations from the normality assumption are observed. We consider the classical analysis of variance tests for the parameters of the appropriate linear model and a robust version of those tests based on M-regression. We then compare their empirical power and level using simulated data with several degrees of contamination. RESULTS: Data normality is nothing but a mathematical convenience. In practice, experiments usually yield data with non-conforming observations. In the presence of this type of data, classical least squares statistical methods perform poorly, giving biased estimates, raising the number of spurious associations and often failing to detect true ones. We show through a simulation study and a real data example, that the robust methodology can be more powerful and thus more adequate for association studies than the classical approach. AVAILABILITY: The code of the robustified version of function lmekin() from the R package kinship is provided as Supplementary Material.

Measurement of the absolute gamma-ray emission intensities from the decay of 103Pd.

Palladium-103 decays through electron capture to excited levels of 103Rh, and especially to the 39.748-keV metastable state. A high activity palladium chloride solution was standardized by liquid scintillation, using the Triple-to-Double Coincidence Ratio method. The absolute photon emission intensities were determined by gamma-ray spectrometry using point sources prepared with the standard solution. Different detectors and measuring conditions were used to cross-reference the results. The most intense photon emission intensities are derived with about 1% relative combined standard uncertainty.

Measurement of the absolute gamma-ray emission intensities from the decay of 147Nd.

The 2011 Decay Data Evaluation Project (DDEP) evaluation for 147Nd includes recommended absolute emission intensities for the two main gamma-rays at 91.105 (2) keV and 531.016 (22) keV of 0.284 (18) and 0.127 (9) respectively, i.e. with uncertainties of 6.3% and 7.1%. These large uncertainties stem from inconsistencies in the published data and are unfit for modern purposes, since the production of 147Nd is used as an important neutron flux dosimeter. The LNE-LNHB has undertaken new absolute gamma-ray emission intensity measurements. The results of these measurements will be presented, along with a full uncertainty budget, and their effect on the recommended data uncertainties will be discussed.

Spectral unmixing applied to fast identification of γ-emitting radionuclides using NaI(Tl) detectors.

Spectral unmixing was investigated for fast spectroscopic identification in γ-emitter mixtures at low-statistics in the case of measurements performed to prevent illegal nuclear material trafficking or for in situ environmental analysis following a radiological or nuclear accident. For that purpose, a multiplicative update algorithm based on full-spectrum analysis was tested in the case of a 3″x3″ NaI(Tl) detector. Automatic decision-making was addressed using Monte Carlo calculations of decision thresholds and detection limits. The first results obtained with a portable instrument equipped with a 3″x3″ NaI(Tl) detector designed for the control of food samples by non-expert users following a radiological or nuclear accident, are also presented.

Activity measurements and determination of nuclear decay data of 166Ho in the MRTDosimetry project.

Holmium-166 is a high-energy ß--emitter radionuclide (~ 1.8 MeV) with a short half-life (~26.8h) that offers great potential as an alternative to 90Y for the treatment of liver cancer based on radioembolization. The possibility of quantitative Single Photon Emission Computed Tomography (SPECT) imaging of the main γ-ray emission at 80.6 keV, in addition to strong paramagnetic properties suitable for Magnetic Resonance Imaging (MRI), complement this therapeutic potential. The present paper describes the measurements carried out in three European radionuclide metrology laboratories for primary standardization of 166Ho and new determinations of X- and γ-ray photon-emission intensities in the framework of the European EMPIR project MRTDosimetry. New half-life measurements were also performed.

Measurement of absolute K X-ray emission intensities in the decay of 103mRh.

A new experiment was designed to measure the photon emission intensities in the decay of 103mRh. The rhodium samples were activated in the ISIS experimental nuclear reactor at CEA Saclay. The procedure includes an absolute activity measurement by liquid scintillation counting using the Triple-to-Double Coincidence Ratio method, followed by X-ray spectrometry using a high-purity germanium detector to determine the photon emission intensities. The new result (IX = 0.0825 (17)) is derived with a significant reduction of the uncertainty.

Current and future radionuclide speciation studies in biological media.

Radionuclides may be released into the environment accidentally or incidentally, which could raise health risks when ingested or inhaled by humans. In order to study the behaviour of radionuclides in the human organism (metabolism, retention, excretion), knowledge of radionuclide speciation is indispensable: speciation governs the transfer, bioavailability and toxicity of elements and is also of considerable interest for decorporation. In this context, the Commissariat à l'Energie Atomique has created a working group on speciation to share data both on thermodynamic constants and on speciation analysis methods of interest to chemists, environmentalists and biologists. The initial focus was on the 31 radionuclides described in different International Commission on Radiological Protection models (HRTM, HAT) and the National Council on Radiation Protection model (wound). Particular attention was devoted to selecting the inorganic and organic ligands, most representative of biological media. The base applied to speciation in solution and at interfaces and solubility (BASSIST) thermodynamic database was developed for this purpose. The aim of this paper is to present the state of the art on radionuclide speciation tools within biological media and to emphasise some missing data in order to orient future research.

Real-time radionuclide identification in γ-emitter mixtures based on spiking neural network.

Portal radiation monitors dedicated to the prevention of illegal traffic of nuclear materials at international borders need to deliver as fast as possible a radionuclide identification of a potential radiological threat. Spectrometry techniques applied to identify the radionuclides contributing to γ-emitter mixtures are usually performed using off-line spectrum analysis. As an alternative to these usual methods, a real-time processing based on an artificial neural network and Bayes' rule is proposed for fast radionuclide identification. The validation of this real-time approach was carried out using γ-emitter spectra ((241)Am, (133)Ba, (207)Bi, (60)Co, (137)Cs) obtained with a high-efficiency well-type NaI(Tl). The first tests showed that the proposed algorithm enables a fast identification of each γ-emitting radionuclide using the information given by the whole spectrum. Based on an iterative process, the on-line analysis only needs low-statistics spectra without energy calibration to identify the nature of a radiological threat.

Investigation of the response variability of ionization chambers for the standard transfer of SIR-Spheres(®).

The present paper addresses the calibration of well-type ionization chambers (ICs) used at LNE-LNHB as standard transfer instruments to calibrate hospitals in the case of SIR-Spheres(®)(90)Y resin microspheres (Sirtex, Australia). Developed for interventional oncology, this radiopharmaceutical is directly injected in the liver for cancer treatment via a selective internal radiation therapy. The present work was carried out in the framework of the European project "Metrology for molecular radiotherapy" (MetroMRT). As commonly performed in radionuclide metrology for radiopharmaceuticals, the objective is to ensure the metrological traceability of SIR-Spheres(®) to hospitals. Preceding studies were focused on primary measurements of SIR-Spheres(®) based on the TDCR (Triple to Double Coincidence Ratio) method, applied after the dissolution of the (90)Y-labeled resin microspheres. As (90)Y is a high-energy ß(-)-emitter, the IC response strongly depends on the transport of electrons in the radioactive solution and surroundings (vial, chamber liners and materials). The variability of the IC-response due to the geometry dependence is investigated by means of measurements and Monte Carlo simulations in the case of a Vinten IC. The aim of the present study was also to propose a reliable uncertainty for ICs calibrations for the standard transfer of SIR-Spheres(®) to hospitals.

Primary standardization of SIR-Spheres based on the dissolution of the (90)Y-labeled resin microspheres.

The project "Metrology for molecular radiotherapy" is a collaborative European project initiated to bring together expertize in ionizing radiation metrology and nuclear medicine research. This project deals with the development of personalized dosimetry to individual patients who are undergoing molecular radiotherapy (also known as targeted radionuclide therapy). The general aim is to provide a metrological traceability to primary standards for individual dosimetry in the case of molecular radiotherapy. In particular, one objective is the standardization of (90)Y-labeled resin microspheres SIR-Spheres (Sirtex, Sydney, Australia) used for the treatment of liver cancer by radioembolization. The present paper describes the primary measurements carried out using the Triple to Double Coincidence Ratio (TDCR) method applied after the complete dissolution of the SIR-Spheres in the Sirtex vial. A method for the dissolution was developed to optimize the homogeneity of the solution to enable the primary measurements based on Cherenkov and liquid scintillation counting. A comprehensive description of the protocol implemented for the microsphere dissolution is reported. First calibration factors obtained with the reference ionization chambers at LNE-LNHB are also given.

Concomitant use of glycoprotein IIb/IIIa inhibitor and streptokinase after unsuccessful rescue angioplasty.

A 38-year-old man with acute myocardial infarction in the lower wall affecting the right ventricle underwent thrombolytic treatment with streptokinase. Approximately 2 hours after the thrombolytic treatment started, he presented with signs of coronary reocclusion. He underwent emergency cineangiocoronariography that revealed that his right coronary artery was completely occluded by a clot. He unsuccessfully underwent angioplasty and stent implantation. After the concomitant use of glycoprotein IIb/IIIa inhibitor, coronary TIMI III flow was achieved without additional dilations, and he was discharged from the hospital 5 days later with no further complications.

Preparation of spiked grass for use as an environmental radioactivity reference material.

Measurement of radionuclides from environmental samples includes a wide variety of matrix compositions and densities. To improve the traceability of environmental monitoring, LNE-LNHB intends to produce mixed γ-ray reference materials with a known mass activity and a composition as representative as possible of real environmental samples. This paper describes the preparation and characterization of a low density treated grass matrix spiked with mixed γ-emitters. This material was used in a proficiency test exercise whose results are presented.

Using LiF:Mg,Cu,P TLDs to estimate the absorbed dose to water in liquid water around an 192Ir brachytherapy source.

PURPOSE: The absorbed dose to water is the fundamental reference quantity for brachytherapy treatment planning systems and thermoluminescence dosimeters (TLDs) have been recognized as the most validated detectors for measurement of such a dosimetric descriptor. The detector response in a wide energy spectrum as that of an (192)Ir brachytherapy source as well as the specific measurement medium which surrounds the TLD need to be accounted for when estimating the absorbed dose. This paper develops a methodology based on highly sensitive LiF:Mg,Cu,P TLDs to directly estimate the absorbed dose to water in liquid water around a high dose rate (192)Ir brachytherapy source. METHODS: Different experimental designs in liquid water and air were constructed to study the response of LiF:Mg,Cu,P TLDs when irradiated in several standard photon beams of the LNE-LNHB (French national metrology laboratory for ionizing radiation). Measurement strategies and Monte Carlo techniques were developed to calibrate the LiF:Mg,Cu,P detectors in the energy interval characteristic of that found when TLDs are immersed in water around an (192)Ir source. Finally, an experimental system was designed to irradiate TLDs at different angles between 1 and 11 cm away from an (192)Ir source in liquid water. Monte Carlo simulations were performed to correct measured results to provide estimates of the absorbed dose to water in water around the (192)Ir source. RESULTS: The dose response dependence of LiF:Mg,Cu,P TLDs with the linear energy transfer of secondary electrons followed the same variations as those of published results. The calibration strategy which used TLDs in air exposed to a standard N-250 ISO x-ray beam and TLDs in water irradiated with a standard (137)Cs beam provided an estimated mean uncertainty of 2.8% (k = 1) in the TLD calibration coefficient for irradiations by the (192)Ir source in water. The 3D TLD measurements performed in liquid water were obtained with a maximum uncertainty of 11% (k = 1) found at 1 cm from the source. Radial dose values in water were compared against published results of the American Association of Physicists in Medicine and the European Society for Radiotherapy and Oncology and no significant differences (maximum value of 3.1%) were found within uncertainties except for one position at 9 cm (5.8%). At this location the background contribution relative to the TLD signal is relatively small and an unexpected experimental fluctuation in the background estimate may have caused such a large discrepancy. CONCLUSIONS: This paper shows that reliable measurements with TLDs in complex energy spectra require a study of the detector dose response with the radiation quality and specific calibration methodologies which model accurately the experimental conditions where the detectors will be used. The authors have developed and studied a method with highly sensitive TLDs and contributed to its validation by comparison with results from the literature. This methodology can be used to provide direct estimates of the absorbed dose rate in water for irradiations with HDR (192)Ir brachytherapy sources.

Photon emission intensities in the decay of 108mAg and 110mAg.

This study focuses on two radioisotopes of silver, (108m)Ag and (110m)Ag, characterized by a complex decay scheme. Each isotope has two disintegration modes, the isomeric transition leading to the daughter isotope ((108)Ag and (110)Ag, respectively) with a short half-life. The radioactive solution was obtained by neutron activation on silver powder enriched in (109)Ag. Gamma-spectrometry was carried out using a calibrated high purity germanium detector. The main relative photon emission intensities for both radionuclides were obtained and compared with previously published values.

Uso concomitante de inibidor da glicoproteína IIb/IIa com estreptoquinase após angioplastia de salvamento sem sucesso / Concomitant use of glycoprotein IIb/IIIa inhibitor and streptokinase after unsuccessful rescue angioplasty

A 38-year-old man with acute myocardial infarction in the lower wall affecting the right ventricle underwent thrombolytic treatment with streptokinase. Approximately 2 hours after the thrombolytic treatment started, he presented with signs of coronary reocclusion. He underwent emergency cineangiocoronariography that revealed that his right coronary artery was completely occluded by a clot. He unsuccessfully underwent angioplasty and stent implantation. After the concomitant use of glycoprotein IIb/IIIa inhibitor, coronary TIMI III flow was achieved without additional dilations, and he was discharged from the hospital 5 days later with no further complications