Ethical values supporting the disclosure of incidental and secondary findings in clinical genomic testing : a qualitative study

Background: Incidental findings (IFs) and secondary findings (SFs), being results that are unrelated to the diagnostic question, are the subject of an important debate in the practice of clinical genomic medicine. Arguments for reporting these results or not doing so typically relate to the principles of autonomy, nonmaleficence and beneficence. However, these principles frequently conflict and are insufficient by themselves to come to a conclusion. This study investigates empirically how ethical principles are considered when actually reporting IFs or SFs and how value conflicts are weighed. Methods: A qualitative focus group study has been undertaken, including a multidisciplinary group of professionals from Belgian centres for medical genetics. The data were analysed thematically. Results: All eight Belgian centres participated in this study. Ethical values were frequently referred to for disclosure policies on IFs and SFs. Participants invoked respect for patient autonomy to support the disclosure of IFs and optout options for IFs and SFs, non-maleficence for the professional delineation of reportable IFs and opt-out options for IFs and SFs and (the particular scope of) beneficence for the mandatory reporting of actionable IFs, the delineation of reportable IFs and a current decline of actively pursued SFs. Professional assumptions about patients’ genetic literacy were an important factor in the weighing of values. Conclusions: In line with the traditional bioethical discourse, the mandatory reporting of actionable IFs might be interpreted as a “technological, soft paternalism”. Restricting patients’ choices might be acceptable, but then its motives should be valid and its beneficent outcomes highly plausible. Hence, the presuppositions of technological, soft paternalism - patients’ inability to make informed decisions, normative rationality, the efficacy of beneficent outcomes and the delineated spectrum of beneficence - should be approached critically. Moreover, distributive justice should be considered an important value in the delineation of the current scope of the ethical debate on IFs and SFs. This study of guiding values may stimulate the debate on the ethical grounds for a solid policy on IFs and SFs internationally

The expected neutral frequency spectrum of linked sites

We present an exact, closed expression for the expected neutral Site Frequency Spectrum for two neutral sites, 2-SFS, without recombination. This spectrum is the immediate extension of the well known single site $\theta/f$ neutral SFS. Similar formulae are also provided for the case of the expected SFS of sites that are linked to a focal neutral mutation of known frequency. Formulae for finite samples are obtained by coalescent methods and remarkably simple expressions are derived for the SFS of a large population, which are also solutions of the multi-allelic Kolmogorov equations. Besides the general interest of these new spectra, they relate to interesting biological cases such as structural variants and introgressions. As an example, we present the expected neutral frequency spectrum of regions with a chromosomal inversion.Comment: 26 pages, 5 figure

Splicing factors Sf3A2 and Prp31 have direct roles in mitotic chromosome segregation

Several studies have shown that RNAi-mediated depletion of splicing factors (SFs) results in mitotic abnormalities. However, it is currently unclear whether these abnormalities reflect defective splicing of specific pre-mRNAs or a direct role of the SFs in mitosis. Here, we show that two highly conserved SFs, Sf3A2 and Prp31, are required for chromosome segregation in both Drosophila and human cells. Injections of anti-Sf3A2 and anti-Prp31 antibodies into Drosophila embryos disrupt mitotic division within 1 min, arguing strongly against a splicing-related mitotic function of these factors. We demonstrate that both SFs bind spindle microtubules (MTs) and the Ndc80 complex, which in Sf3A2- and Prp31-depleted cells is not tightly associated with the kinetochores; in HeLa cells the Ndc80/HEC1-SF interaction is restricted to the M phase. These results indicate that Sf3A2 and Prp31 directly regulate interactions among kinetochores, spindle microtubules and the Ndc80 complex in both Drosophila and human cells

Statistics of surface gravity wave turbulence in the space and time domains

We present experimental results on simultaneous space–time measurements for the gravity wave turbulence in a large laboratory flume. We compare these results with predictions of the weak turbulence theory (WTT) based on random waves, as well as with predictions based on the coherent singular wave crests. We see that the both wavenumber and frequency spectra are not universal and dependent on the wave strength, with some evidence in favour of the WTT at larger wave intensities when the finite-flume effects are minimal. We present further theoretical analysis of the role of the random and coherent waves in the wave probability density function (p.d.f.) and the structure functions (SFs). Analysing our experimental data we found that the random waves and the coherent structures/breaks coexist: the former show themselves in a quasi-Gaussian p.d.f. core and the low-order SFs and the latter in the p.d.f. tails and the high-order SFs. It appears that the x-space signal is more intermittent than the t-space signal, and the x-space SFs capture more singular coherent structures than the t-space SFs do. We outline an approach treating the interactions of these random and coherent components as a turbulence cycle characterized by the turbulence fluxes in both the wavenumber and the amplitude spaces

Geometry of the sample frequency spectrum and the perils of demographic inference

The sample frequency spectrum (SFS), which describes the distribution of mutant alleles in a sample of DNA sequences, is a widely used summary statistic in population genetics. The expected SFS has a strong dependence on the historical population demography and this property is exploited by popular statistical methods to infer complex demographic histories from DNA sequence data. Most, if not all, of these inference methods exhibit pathological behavior, however. Specifically, they often display runaway behavior in optimization, where the inferred population sizes and epoch durations can degenerate to 0 or diverge to infinity, and show undesirable sensitivity of the inferred demography to perturbations in the data. The goal of this paper is to provide theoretical insights into why such problems arise. To this end, we characterize the geometry of the expected SFS for piecewise-constant demographic histories and use our results to show that the aforementioned pathological behavior of popular inference methods is intrinsic to the geometry of the expected SFS. We provide explicit descriptions and visualizations for a toy model with sample size 4, and generalize our intuition to arbitrary sample sizes n using tools from convex and algebraic geometry. We also develop a universal characterization result which shows that the expected SFS of a sample of size n under an arbitrary population history can be recapitulated by a piecewise-constant demography with only k(n) epochs, where k(n) is between n/2 and 2n-1. The set of expected SFS for piecewise-constant demographies with fewer than k(n) epochs is open and non-convex, which causes the above phenomena for inference from data.Comment: 21 pages, 5 figure

The impact of sound field systems on learning and attention in elementary school classrooms

Purpose: An evaluation of the installation and use of sound field systems (SFS) was carried out to investigate their impact on teaching and learning in elementary school classrooms. Methods: The evaluation included acoustic surveys of classrooms, questionnaire surveys of students and teachers and experimental testing of students with and without the use of SFS. Students ’ perceptions of classroom environments and objective data evaluating change in performance on cognitive and academic assessments with amplification over a six month period are reported. Results: Teachers were positive about the use of SFS in improving children’s listening and attention to verbal instructions. Over time students in amplified classrooms did not differ from those in nonamplified classrooms in their reports of listening conditions, nor did their performance differ in measures of numeracy, reading or spelling. Use of SFS in the classrooms resulted in significantly larger gains in performance in the number of correct items on the nonverbal measure of speed of processing and the measure of listening comprehension. Analysis controlling for classroom acoustics indicated that students ’ listening comprehension score

Ground state and bias current induced rearrangement of semifluxons in 0-pi long Josephson junctions

We investigate numerically a long Josephson junction with several phase pi-discontinuity points. Such junctions are usually fabricated as a ramp between an anisotropic cuprate superconductor like YBCO and an isotropic metal superconductor like Nb. From the top, they look like zigzags with pi-jumps of the Josephson phase at the corners. These pi-jumps, at certain conditions, lead to the formation of half-integer flux quanta, which we call semifluxons (SF), pinned at the corners. We show (a) that the spontaneous formation of SFs depends on the junction length, (b) that the ground state without SFs can be converted to a state with SFs by applying a bias current, (c) that the SF configuration can be rearranged by the bias current. All these effects can be observed using a SQUID microscope.Comment: ~8 pages, 6 figures, submitted to PR