Locations of peculiar supernovae as a diagnostic of their origins

We put constraints on the properties of the progenitors of peculiar calcium-rich transients using the distribution of locations within their host galaxies. We confirm that this class of transients do not follow the galaxy stellar mass profile and are more likely to be found in remote locations of their apparent hosts. We test the hypothesis that these transients are from low-metallicity progenitors by comparing their spatial distributions with the predictions of self-consistent cosmological simulations that include star formation and chemical enrichment. We find that while metal-poor stars and our transient sample show a consistent preference for large offsets, metallicity alone cannot explain the extreme cases. Invoking a lower age limit on the progenitor helps to improve the match, indicating these events may result from a very old metal-poor population. We also investigate the radial distribution of globular cluster systems, and show that they too are consistent with the class of calcium-rich transients. Because photometric upper limits exist for globular clusters for some members of the class, a production mechanism related to the dense environment of globular clusters is not favoured for the calcium-rich events. However, the methods developed in this paper may be used in the future to constrain the effects of low metallicity on radially distant core-collapse events or help establish a correlation with globular clusters for other classes of peculiar explosions.

Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Diagnostic value of increased sensitivity by massively parallel sequencing

Routine molecular diagnostics modalities are unable to confidently detect low frequency mutations (<5-15%) that may indicate response to targeted therapies. We confirm the presence of a low frequency NRAS mutation in a rectal cancer patient using massively parallel sequencing when previous Sanger sequencing results proved negative and Q-PCR testing inconclusive. There is increasing evidence that these low frequency mutations may confer resistance to anti-EGFR therapy. In view of negative/inconclusive Sanger sequencing and Q-PCR results for NRAS mutations in a KRAS wt rectal case, the diagnostic biopsy and 4 distinct subpopulations of cells in the resection specimen after conventional chemo/radiotherapy were massively parallel sequenced using the Ion Torrent PGM. DNA was derived from FFPE rectal cancer tissue and amplicons produced using the Cancer Hotspot Panel V2 and sequenced using semiconductor technology. NRAS mutations were observed at varying frequencies in the patient biopsy (12.2%) and all four subpopulations of cells in the resection with an average frequency of 7.3% (lowest 2.6%). The results of the NGS also provided the mutational status of 49 other genes that may have prognostic or predictive value, including KRAS and PIK3CA. NGS technology has been postulated in diagnostics because of its capability to generate results in large panels of clinically meaningful genes in a cost-effective manner. This case illustrates another potential advantage of this technology: its use for detecting low frequency mutations that may influence therapeutic decisions in cancer treatment.

Immunohistochemistry should undergo robust validation equivalent to that of molecular diagnostics

Immunohistochemistry (IHC) is a widely available and highly utilised tool in diagnostic histopathology and is used to guide treatment options as well as provide prognostic information. IHC is subjected to qualitative and subjective assessment, which has been criticised for a lack of stringency, while PCR-based molecular diagnostic validations by comparison are regarded as very rigorous. It is essential that IHC tests are validated through evidence-based procedures. With the move to ISO15189 (2012), not just of the accuracy, specificity and reproducibility of each test need to be determined and managed, but also the degree of uncertainty and the delivery of such tests. The recent update to ISO 15189 (2012) states that it is appropriate to consider the potential uncertainty of measurement of the value obtained in the laboratory and how that may impact on prognostic or predictive thresholds. In order to highlight the problems surrounding IHC validity, we reviewed the measurement of Ki67and p53 in the literature. Both of these biomarkers have been incorporated into clinical care by pathology laboratories worldwide. The variation seen appears excessive even when measuring centrally stained slides from the same cases. We therefore propose in this paper to establish the basis on which IHC laboratories can bring the same level of robust validation seen in the molecular pathology laboratories and the principles applied to all routine IHC tests.

An interview with Manuel Salto-Tellez on diagnostic pathology: the future is morphomolecular

Professor Manuel Salto-Tellez of Queen’s University, Belfast, Northern Ireland is an expert histopathologist and molecular diagnostician. Professor Salto-Tellez is a lead investigator at the Northern Ireland Molecular Pathology Laboratory and also serves as a member of the Editorial Advisory Board for Expert Review of Molecular Diagnostics. In this interview, he proposes directions for the future of molecular pathology and molecular diagnostics, integrating all aspects of pathology toward a common goal.

Accuracy of rural refractionists in western China

Purpose. We assessed the prevalence and predictors of inaccurate refractive error among rural refractionists in western China. Methods. A subset of primary school children with visual acuity (VA) ≤6/12 in ≥1 eye, undergoing subjective refinement by local refractionists after cycloplegic autorefraction in an ongoing population-based study, received repeat refraction by university optometrists for quality control. Results. Among 502 children (mean age 10.5 years, 53.2% girls), independent predictors of poor (inaccurate by ≥1.0 diopter [D]) refraction by 21 rural practitioners (66.7% with high school or lower education) included hyperopia (odds ratio [OR], 4.2; 95% confidence interval [CI], 2.4-7.3, P < 0.001), astigmatism (OR = 3.8; 95% CI, 2.5-5.6; P < 0.001) and VA uncorrectable to >6/12 by the rural refractionist (OR = 4.7; 95% CI, 3.1-7.3; P = < 0.001). Among 201 children whose vision was uncorrectable in ≥1 eye by the rural refractionists, vision could be improved to >6/12 by the university optometrist in 110 (54.7%). We estimate vision could be so improved in 9.1% of all children refracted by these rural refractionists. A reason for inaccuracy in this setting is the erroneous tendency of rural refractionists to adjust instrument values for accommodation, even under cycloplegia. Conclusions. Rural refractionists in western China have little formal training and frequently fail to optimize VA among children, even when autorefractors are used. Training is needed emphasizing better use of automated refraction, particularly in children with astigmatism and hyperopia. © 2014 The Association for Research in Vision and Ophthalmology, Inc.

Biometric measurements in highly myopic eyes

Purpose: To assess the repeatability and accuracy of optical biometry (Lenstar LS900 optical low-coherence reflectometry [OLCR] and IOLMaster partial coherence interferometry [PCI]) and applanation ultrasound biometry in highly myopic eyes. Setting: Division of Preventive Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China. Design: Comparative evaluation of diagnostic technology. Methods: Biometric measurements were taken in highly myopic subjects with a spherical equivalent (SE) of -6.00 diopters (D) or higher and an axial length (AL) longer than 25.0 mm. Measurements of AL and anterior chamber depth (ACD) obtained by OLCR were compared with those obtained by PCI and applanation A-scan ultrasound. Right eyes were analyzed. Repeatability was evaluated using the coefficient of variation (CoV) and agreement, using Bland-Altman analyses. Results: The mean SE was -11.20 D ± 4.65 (SD). The CoVs for repeated AL measurements using OLCR, PCI, and applanation ultrasound were 0.06%, 0.07%, and 0.20%, respectively. The limits of agreement (LoA) for AL were 0.11 mm between OLCR and PCI, 1.01 mm between OLCR and applanation ultrasound, and 1.03 mm between PCI and ultrasound. The ACD values were 0.29 mm, 0.53 mm, and 0.51 mm, respectively. These repeatability and agreement results were comparable in eyes with extreme myopia (AL ≥27.0 mm) or posterior staphyloma. The mean radius of corneal curvature was similar between OLCR and PCI (7.66 ± 0.24 mm versus 7.64 ± 0.25 mm), with an LoA of 0.12 mm. Conclusion: Optical biometry provided more repeatable and precise measurements of biometric parameters, including AL and ACD, than applanation ultrasound biometry in highly myopic eyes. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2012 ASCRS and ESCRS.

Strategies to improve the accuracy of vision measurement by teachers in rural Chinese secondary schoolchildren: Xichang Pediatric Refractive Error Study (X-PRES) report no. 6.

OBJECTIVE: To assess and improve the accuracy of lay screeners compared with vision professionals in detecting visual impairment in secondary schoolchildren in rural China. METHODS: After brief training, 32 teachers and a team of vision professionals independently measured vision in 1892 children in Xichang. The children also underwent vision measurement by health technicians in a concurrent government screening program. RESULTS: Of 32 teachers, 28 (87.5%) believed that teacher screening was worthwhile. Sensitivity (93.5%) and specificity (91.2%) of teachers detecting uncorrected presenting visual acuity of 20/40 or less were better than for presenting visual acuity (sensitivity, 85.2%; specificity, 84.8%). Failure of teachers to identify children owning but not wearing glasses and teacher bias toward better vision in children wearing glasses explain the worse results for initial vision. Wearing glasses was the student factor most strongly predictive of inaccurate teacher screening (P < .001). The sensitivity and specificity of the government screening program detecting low presenting visual acuity were 86.7% and 28.7%, respectively. CONCLUSIONS: Teacher vision screening after brief training can achieve accurate results in this setting, and there is support among teachers for screening. Screening of uncorrected rather than presenting visual acuity is recommended in settings with a high prevalence of corrected and uncorrected refractive error. Low specificity in the government program renders it ineffective.

Pupil constriction can alter the accuracy of dark room provocative test.

BACKGROUND: Primary angle-closure glaucoma (PACG) is a major cause of visual morbidity in East Asia. Dark-room provocative test (DRPT) has been used to determine which narrow angles have the risk to develop angle closure. However, the accuracy of DRPT might be altered because that after emerging from the dark room, the configuration of the angle is affected by the light of the slit-lamp and the appositionally closed angle reopens. The aim of this study was to examine the pupillary diameter in different light conditions and use it as a parameter to assess the accuracy of dark-room provocative test. METHODS: Patients with suspected primary angle-closure glaucoma undergoing DRPT were recruited. The anterior chamber angle was examined by anterior segment optical coherence tomography under the following conditions: (1) in standard room illumination; (2) after short-term dark-adaptation and (3) after DRPT. Mean values of pupil size and numbers of appositionally closed angle under different conditions were compared. RESULTS: A total of 47 eyes of 47 patients were analyzed. The pupil size after DRPT was smaller than that after short-term dark-adaptation (P < 0.001) and smaller than that in standard room illumination (P = 0.026). The numbers of appositionally closed angles after short-term dark-adaptation were significantly larger than those after DRPT (P < 0.001). There was no significant difference between the numbers of appositionally closed angles in standard room illumination and after DRPT (P = 0.157). CONCLUSIONS: Constriction of pupil size immediately after prolonged dark room provocative test may lead to change in the angle configuration, which may lead to false negative results. We suggest a modified protocol of recording intraocular pressure immediately after DRPT and performing gonioscopy following short-term dark adaptation to improve the accuracy of angle closure assessment.

Validating the accuracy of a model to predict the onset of myopia in children.

PURPOSE: To assess the sensitivity and specificity of models predicting myopia onset among ethnically Chinese children. METHODS: Visual acuity, height, weight, biometry (A-scan, keratometry), and refractive error were assessed at baseline and 3 years later using the same equipment and protocol in primary schools in Xiamen (China) and Singapore. A regression model predicting the onset of myopia < -0.75 diopters (D) after 3 years in either eye among Xiamen children was validated with Singapore data. RESULTS: Baseline data were collected from 236 Xiamen children (mean age, 7.82 ± 0.63 years) and from 1979 predominantly Chinese children in Singapore (7.83 ± 0.84 years). Singapore children were significantly taller and heavier, and had more myopia (31.4% vs. 6.36% < -0.75 D in either eye, P < 0.001) and longer mean axial length. Three-year follow-up was available for 80.0% of Xiamen children and 83.1% in Singapore. For Xiamen, the area under the receiver-operator curve (AUC) in a model including ocular biometry, height, weight, and presenting visual acuity was 0.974 (95% confidence interval [CI], 0.945-0.997). In Singapore, the same model achieved sensitivity, specificity, and positive predictive value of 0.844, 0.650, and 0.669, with an AUC of 0.815 (95% CI, 0.791-0.839). CONCLUSIONS: Accuracy in predicting myopia onset based on simple measurements may be sufficient to make targeted early intervention practical in settings such as Singapore with high myopia prevalence. Models based on cohorts with a greater prevalence of high myopia than that in Xiamen could be used to assess accuracy of models predicting more severe forms of myopia.

The effects of radiative cascades on the x-ray diagnostic lines of Fe16+

We present complete collisional-radiative modelling results for the soft x-ray emission lines of Fe16+ in the 15 Å–17 Å range. These lines have been the subject of much controversy in the astrophysical and laboratory plasma community. Radiative transition rates are generated from fully relativistic atomic structure calculations. Electron-impact excitation cross sections are determined using a fully relativistic R-matrix method employing 139 coupled atomic levels through n = 5. We find that, in all cases, using a simple ratio of the collisional rate coefficient times a radiative branching factor is not sufficient to model the widely used diagnostic line ratios. One has to include the effects of collisional-radiative cascades in a population model to achieve accurate line ratios. Our line ratio results agree well with several previous calculations and reasonably well with tokamak experimental measurements, assuming a Maxwellian electron-energy distribution. Our modelling results for four EBIT line ratios, assuming a narrow Gaussian electron-energy distribution, are in generally poor agreement with all four NIST measurements but are in better agreement with the two LLNL measurements. These results suggest the need for an investigation of the theoretical polarization calculations that are required to interpret the EBIT line ratio measurements.

Hybrid time dependent/independent solution for the He i line ratio temperature and density diagnostic for a thermal helium beam with applications in the scrape-off layer-edge regions in tokamaks

Spectroscopic studies of line emission intensities and ratios offer an attractive option in the\r\ndevelopment of non-invasive plasma diagnostics. Evaluating ratios of selected He I line\r\nemission profiles from the singlet and triplet neutral helium spin systems allows for simultaneous\r\nmeasurement of electron density (ne) and temperature (Te) profiles. Typically, this powerful\r\ndiagnostic tool is limited by the relatively long relaxation times of the 3S metastable term of helium\r\nthat populates the triplet spin system, and on which electron temperature sensitive lines are based.\r\nBy developing a time dependent analytical solution, we model the time evolution of the two spin\r\nsystems. We present a hybrid time dependent/independent line ratio solution that improves the\r\nrange of application of this diagnostic technique in the scrape-off layer (SOL) and edge plasma\r\nregions when comparing it against the current equilibrium line ratio helium model used at\r\nTEXTOR.