Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Process-conditioned bias correction for seasonal forecasting: a case-study with ENSO in Peru

This work assesses the suitability of a first simple attempt for process-conditioned bias correction in the context of seasonal forecasting. To do this, we focus on the northwestern part of Peru and bias correct 1- and 4-month lead seasonal predictions of boreal winter (DJF) precipitation from the ECMWF System4 forecasting system for the period 1981–2010. In order to include information about the underlying large-scale circulation which may help to discriminate between precipitation affected by different processes, we introduce here an empirical quantile–quantile mapping method which runs conditioned on the state of the Southern Oscillation Index (SOI), which is accurately predicted by System4 and is known to affect the local climate. Beyond the reduction of model biases, our results show that the SOI-conditioned method yields better ROC skill scores and reliability than the raw model output over the entire region of study, whereas the standard unconditioned implementation provides no added value for any of these metrics. This suggests that conditioning the bias correction on simple but well-simulated large-scale processes relevant to the local climate may be a suitable approach for seasonal forecasting. Yet, further research on the suitability of the application of similar approaches to the one considered here for other regions, seasons and/or variables is needed.This work has received funding from the MULTI-SDM project (MINECO/FEDER, CGL2015-66583-R). The authors are grateful to SENAMHI for the observational data, which are publicly available from http://www.senamhi.gob.pe/?p=data-historica, and to the European Center for Medium-Range Weather Forecast (ECMWF), for the access to the System4 seasonal forecasting hindcast

HelexKids:a word frequency database for Greek and Cypriot primary school children

In this article, we introduce HelexKids, an online written-word database for Greek-speaking children in primary education (Grades 1 to 6). The database is organized on a grade-by-grade basis, and on a cumulative basis by combining Grade 1 with Grades 2 to 6. It provides values for Zipf, frequency per million, dispersion, estimated word frequency per million, standard word frequency, contextual diversity, orthographic Levenshtein distance, and lemma frequency. These values are derived from 116 textbooks used in primary education in Greece and Cyprus, producing a total of 68,692 different word types. HelexKids was developed to assist researchers in studying language development, educators in selecting age-appropriate items for teaching, as well as writers and authors of educational books for Greek/Cypriot children. The database is open access and can be searched online at www.helexkids.org

Costs and benefits of orthographic inconsistency in reading:evidence from a cross-linguistic comparison

We compared reading acquisition in English and Italian children up to late primary school analyzing RTs and errors as a function of various psycholinguistic variables and changes due to experience. Our results show that reading becomes progressively more reliant on larger processing units with age, but that this is modulated by consistency of the language. In English, an inconsistent orthography, reliance on larger units occurs earlier on and it is demonstrated by faster RTs, a stronger effect of lexical variables and lack of length effect (by fifth grade). However, not all English children are able to master this mode of processing yielding larger inter-individual variability. In Italian, a consistent orthography, reliance on larger units occurs later and it is less pronounced. This is demonstrated by larger length effects which remain significant even in older children and by larger effects of a global factor (related to speed of orthographic decoding) explaining changes of performance across ages. Our results show the importance of considering not only overall performance, but inter-individual variability and variability between conditions when interpreting cross-linguistic differences

Dark Energy Survey Year 1 Results: Cross-correlation between Dark Energy Survey Y1 galaxy weak lensing and South Pole Telescope +Planck CMB weak lensing

We cross-correlate galaxy weak lensing measurements from the Dark Energy Survey (DES) year-one data with a cosmic microwave background (CMB) weak lensing map derived from South Pole Telescope (SPT) and Planck data, with an effective overlapping area of 1289 deg2. With the combined measurements from four source galaxy redshift bins, we obtain a detection significance of 5.8σ. We fit the amplitude of the correlation functions while fixing the cosmological parameters to a fiducial ΛCDM model, finding A=0.99±0.17. We additionally use the correlation function measurements to constrain shear calibration bias, obtaining constraints that are consistent with previous DES analyses. Finally, when performing a cosmological analysis under the ΛCDM model, we obtain the marginalized constraints of ωm=0.261-0.051+0.070 and S8σ8ωm/0.3=0.660-0.100+0.085. These measurements are used in a companion work that presents cosmological constraints from the joint analysis of two-point functions among galaxies, galaxy shears, and CMB lensing using DES, SPT, and Planck data

Lichen response to ammonia deposition defines the footprint of a penguin rookery

Ammonia volatilized from penguin rookeries is a major nitrogen source in Antarctic coastal terrestrial ecosystems. However, the spatial extent of ammonia dispersion from rookeries and its impacts have not been quantified previously. We measured ammonia concentration in air and lichen ecophysiological response variables proximate to an Adèlie penguin rookery at Cape Hallett, northern Victoria Land. Ammonia emitted from the rookery was 15N-enriched (δ15N value +6.9) and concentrations in air ranged from 36–75 µg m−3 at the rookery centre to 0.05 µg m−3 at a distance of 15.3 km. δ15N values and rates of phosphomonoesterase (PME) activity in the lichens Usnea sphacelata and Umbilicaria decussata were strongly negatively related to distance from the rookery and PME activity was positively related to thallus N:P mass ratio. In contrast, the lichen Xanthomendoza borealis, which is largely restricted to within an area 0.5 km from the rookery perimeter, had high N, P and 15N concentrations but low PME activity suggesting that nutrient scavenging capacity is suppressed in highly eutrophicated sites. An ammonia dispersion model indicates that ammonia concentrations sufficient to significantly elevate PME activity and δ15N values (≥0.1 µg NH3 m−3) occurred over c. 40–300 km2 surrounding the rookery suggesting that penguin rookeries potentially can generate large spatial impact zones. In a general linear model NH3 concentration and lichen species identity were found to account for 72 % of variation in the putative proportion of lichen thallus N originating from penguin derived NH3. The results provide evidence of large scale impact of N transfer from a marine to an N-limited terrestrial ecosystem

Dark energy survey year 1 results: Redshift distributions of the weak-lensing source galaxies

We describe the derivation and validation of redshift distribution estimates and their uncertainties for the populations of galaxies used as weak-lensing sources in the Dark Energy Survey (DES) Year 1 cosmological analyses. The Bayesian Photometric Redshift (BPZ) code is used to assign galaxies to four redshift bins between z ≈ 0.2 and ≈1.3, and to produce initial estimates of the lensing-weighted redshift distributions nPZi(z) ∝ dni/dz for members of bin i. Accurate determination of cosmological parameters depends critically on knowledge of ni, but is insensitive to bin assignments or redshift errors for individual galaxies. The cosmological analyses allow for shifts ni (z) = nPZi(z - Δzi) to correct themean redshift of ni(z) for biases in nPZi. The Δzi are constrained by comparison of independently estimated 30-band photometric redshifts of galaxies in the Cosmic Evolution Survey (COSMOS) field to BPZ estimates made from the DES griz fluxes, for a sample matched in fluxes, pre-seeing size, and lensing weight to the DES weak-lensing sources. In companion papers, the Δzi of the three lowest redshift bins are further constrained by the angular clustering of the source galaxies around red galaxies with secure photometric redshifts at 0.15 < z < 0.9. This paper details the BPZ and COSMOS procedures, and demonstrates that the cosmological inference is insensitive to details of the ni(z) beyond the choice of Δzi. The clustering and COSMOS validation methods produce consistent estimates of Δzi in the bins where both can be applied, with combined uncertainties of σΔzi = 0.015, 0.013, 0.011, and 0.022 in the four bins. Repeating the photo-z procedure instead using the Directional Neighbourhood Fitting algorithm, or using the ni(z) estimated from the matched sample in COSMOS, yields no discernible difference in cosmological inferences

Dark Energy Survey Year 1 results: galaxy-galaxy lensing

We present galaxy-galaxy lensing measurements from 1321 sq. deg. of the Dark Energy Survey (DES) Year 1 (Y1) data. The lens sample consists of a selection of 660,000 red galaxies with high-precision photometric redshifts, known as redMaGiC, split into five tomographic bins in the redshift range 0.15<z<0.9 . We use two different source samples, obtained from the Metacalibration (26 million galaxies) and Im3shape (18 million galaxies) shear estimation codes, which are split into four photometric redshift bins in the range 0.2<z<1.3 . We perform extensive testing of potential systematic effects that can bias the galaxy-galaxy lensing signal, including those from shear estimation, photometric redshifts, and observational properties. Covariances are obtained from jackknife subsamples of the data and validated with a suite of log-normal simulations. We use the shear-ratio geometric test to obtain independent constraints on the mean of the source redshift distributions, providing validation of those obtained from other photo-z studies with the same data. We find consistency between the galaxy bias estimates obtained from our galaxy-galaxy lensing measurements and from galaxy clustering, therefore showing the galaxy-matter cross-correlation coefficient r to be consistent with one, measured over the scales used for the cosmological analysis. The results in this work present one of the three two-point correlation functions, along with galaxy clustering and cosmic shear, used in the DES cosmological analysis of Y1 data, and hence the methodology and the systematics tests presented here provide a critical input for that study as well as for future cosmological analyses in DES and other photometric galaxy surveys

Tracking seasonal changes in North Sea zooplankton trophic dynamics using stable isotopes

Trophodynamics of meso-zooplankton in the North Sea (NS) were assessed at a site in the southern NS, and at a shallow and a deep site in the central NS. Offshore and neritic species from different ecological niches, including Calanus spp., Temora spp. and Sagitta spp., were collected during seven cruises over 14 months from 2007 to 2008. Bulk stable isotope (SI) analysis, phospholipid-derived fatty acid (PLFA) compositions, and δ 13CPLFA data of meso-zooplankton and particulate organic matter (POM) were used to describe changes in zooplankton relative trophic positions (RTPs) and trophodynamics. The aim of the study was to test the hypothesis that the RTPs of zooplankton in the North Sea vary spatially and seasonally, in response to hydrographic variability, with the microbial food web playing an important role at times. Zooplankton RTPs tended to be higher during winter and lower during the phytoplankton bloom in spring. RTPs were highest for predators such as Sagitta sp. and Calanus helgolandicus and lowest for small copepods such as Pseudocalanus elongatus and zoea larvae (Brachyura). δ 15NPOM-based RTPs were only moderate surrogates for animals’ ecological niches, because of the plasticity in source materials from the herbivorous and the microbial loop food web. Common (16:0) and essential (eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA) structural lipids showed relatively constant abundances. This could be explained by incorporation of PLFAs with δ 13C signatures which followed seasonal changes in bulk δ 13CPOM and PLFA δ 13CPOM signatures. This study highlighted the complementarity of three biogeochemical approaches for trophodynamic studies and substantiated conceptual views of size-based food web analysis, in which small individuals of large species may be functionally equivalent to large individuals of small species. Seasonal and spatial variability was also important in altering the relative importance of the herbivorous and microbial food webs

Dark Energy Survey year 1 results: cosmological constraints from cluster abundances and weak lensing

We perform a joint analysis of the counts and weak lensing signal of redMaPPer clusters selected from the Dark Energy Survey (DES) Year 1 dataset. Our analysis uses the same shear and source photometric redshifts estimates as were used in the DES combined probes analysis. Our analysis results in surprisingly low values for S8=σ8(Ωm/0.3)0.5=0.65±0.04, driven by a low matter density parameter, Ωm=0.179+0.031−0.038, with σ8−Ωm posteriors in 2.4σ tension with the DES Y1 3x2pt results, and in 5.6σ with the Planck CMB analysis. These results include the impact of post-unblinding changes to the analysis, which did not improve the level of consistency with other data sets compared to the results obtained at the unblinding. The fact that multiple cosmological probes (supernovae, baryon acoustic oscillations, cosmic shear, galaxy clustering and CMB anisotropies), and other galaxy cluster analyses all favor significantly higher matter densities suggests the presence of systematic errors in the data or an incomplete modeling of the relevant physics. Cross checks with x-ray and microwave data, as well as independent constraints on the observable-mass relation from Sunyaev-Zeldovich selected clusters, suggest that the discrepancy resides in our modeling of the weak lensing signal rather than the cluster abundance. Repeating our analysis using a higher richness threshold (λ≥30) significantly reduces the tension with other probes, and points to one or more richness-dependent effects not captured by our model