popSTR2 enables clinical and population-scale genotyping of microsatellites

Summary: popSTR2 is an update and augmentation of our previous work ‘popSTR: a population-based microsatellite genotyper’. To make genotyping sensitive to inter-sample differences, we supply a kernel to estimate sample-specific slippage rates. For clinical sequencing purposes, a panel of known pathogenic repeat expansions is provided along with a script that scans and flags for manual inspection markers indicative of a pathogenic expansion. Like its predecessor, popSTR2 allows for joint genotyping of samples at a population scale. We now provide a binning method that makes the microsatellite genotypes more amenable to analysis within standard association pipelines and can increase association power. Availability and implementation: https://github.com/DecodeGenetics/popSTR. Contact: [email protected] or [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.Peer Reviewed (ritrýnd grein

The thick disk rotation-metallicity correlation as a fossil of an "inverse chemical gradient" in the early Galaxy

The thick disk rotation--metallicity correlation, \partial V_\phi/\partial[Fe/H] =40\div 50 km s^{-1}dex^{-1} represents an important signature of the formation processes of the galactic disk. We use nondissipative numerical simulations to follow the evolution of a Milky Way (MW)-like disk to verify if secular dynamical processes can account for this correlation in the old thick disk stellar population. We followed the evolution of an ancient disk population represented by 10 million particles whose chemical abundances were assigned by assuming a cosmologically plausible radial metallicity gradient with lower metallicity in the inner regions, as expected for the 10-Gyr-old MW. Essentially, inner disk stars move towards the outer regions and populate layers located at higher |z|. A rotation--metallicity correlation appears, which well resembles the behaviour observed in our Galaxy at a galactocentric distance between 8 kpc and 10 kpc. In particular,we measure a correlation of \partial V_\phi/\partial[Fe/H]\simeq 60 km s^{-1}dex^{-1} for particles at 1.5 kpc < |z| < 2.0 kpc that persists up to 6 Gyr. Our pure N-body models can account for the V_\phi vs. [Fe/H] correlation observed in the thick disk of our Galaxy, suggesting that processes internal to the disk such as heating and radial migration play a role in the formation of this old stellar component. In this scenario, the positive rotation-metallicity correlation of the old thick disk population would represent the relic signature of an ancient "inverse" chemical (radial) gradient in the inner Galaxy, which resulted from accretion of primordial gas.Comment: Accepted for publication on Astronomy and Astrophysic

Feasibility of ActivABLES to promote home-based exercise and physical activity of community-dwelling stroke survivors with support from caregivers : A mixed methods study

BackgroundTechnical applications can promote home-based exercise and physical activity of community-dwelling stroke survivors. Caregivers are often able and willing to assist with home-based exercise and physical activity but lack the knowledge and resources to do so. ActivABLES was established to promote home-based exercise and physical activity among community-dwelling stroke survivors, with support from their caregivers. The aim of our study is to investigate the feasibility of ActivABLES in terms of acceptability, demand, implementation and practicality.MethodsA convergent design of mixed methods research in which quantitative results were combined with personal experiences of a four-week use of ActivABLES by community-dwelling stroke survivors with support from their caregivers. Data collection before, during and after the four-week period included the Berg Balance Scale (BBS), Activities-Specific Balance Confidence Scale (ABC), Timed-Up-and-Go (TUG) and Five Times Sit to Stand Test (5xSST) and data from motion detectors. Semi-structured interviews were conducted with stroke survivors and caregivers after the four-week period. Descriptive statistics were used for quantitative data. Qualitative data was analysed with direct content analysis. Themes were identified related to the domains of feasibility: acceptability, demand, implementation and practicality. Data was integrated by examining any (dis)congruence in the quantitative and qualitative findings.ResultsTen stroke survivors aged 55-79years participated with their informal caregivers. Functional improvements were shown in BBS (+2.5), ABC (+0.9), TUG (-4.2) and 5xSST (-2.7). More physical activity was detected with motion detectors (stand up/sit down +2, number of steps +227, standing +0.3h, hours sitting/lying -0.3h). The qualitative interviews identified themes for each feasibility domain: (i) acceptability: appreciation, functional improvements, self-initiated activities and expressed potential for future stroke survivors; (2) demand: reported use, interest in further use and need for follow-up; (3) implementation: importance of feedback, variety of exercises and progression of exercises and (4) practicality: need for support and technical problems. The quantitative and qualitative findings converged well with each other and supported the feasibility of ActivABLES.ConclusionsActivABLES is feasible and can be a good asset for stroke survivors with slight or moderate disability to use in their homes. Further studies are needed with larger samples.Peer reviewe

Translation and cross-cultural adaptation of the European Health Literacy Survey Questionnaire, HLS-EU-Q16: The Icelandic version

BACKGROUND: Health literacy (HL) is defined as the knowledge and competences of people to meet the complex demands of health in modern society. It is an important factor in ensuring positive health outcomes, yet Iceland is one of many countries with limited knowledge of HL and no valid HL measurement. The aim of this study was to translate the European Health Literacy Survey Questionnaire- short version (HLS-EU-Q16) into Icelandic, adapt the version, explore its psychometric properties and establish preliminary norms. METHODS: The HLS-EU-Q16 translation model included three steps: 1) translation-back-translation of HLS-EU-Q16 including specialists' review (n = 6); 2) cognitive interviewing of lay people (n = 17); and 3) psychometric analysis with survey participants. The HLS-EU-Q16 includes 16 items, with scores ranges from zero (low/no HL) to 16 (high HL). Statistics included were descriptive, internal consistency measured by Cronbach's α, exploratory factor analysis, and multivariate linear regression. RESULTS: After the translation and cognitive interviewing, 11 of the HLS-EU-Q16 items were reworded to adapt the instrument to Icelandic culture while maintaining their conceptual objectives. Survey participants were 251. Internal consistency of the translated and adapted instrument was α = .88. Four factors with eigenvalues > 1.0 explained 62.6% of variance. Principal component analysis with Oblimin rotation presented four latent constructs, "Processing and Using Information from the Doctor" (4 items, α = .77), "Processing and Using Information from the Family and Media" (4 items, α = .85), "Processing Information in Connection to Healthy Lifestyle" (5 items, α = .76), and "Finding Information about Health Problems/Illnesses" (3 items, α = .73). Lower self-rated health was an independent predictor of lower HL (β = -.484, p = .008). Preliminary norms for HL ranged from five to 16 (M 13.7, SD ± 2.6) with 72.5% with sufficient HL (score 13-16), 22% with problematic HL (score 9-12) and 5.5% with inadequate HL (score 0-8). CONCLUSIONS: The Icelandic version of HLS-EU-Q16 is psychometrically sound, with reasonably clear factor structure, and comparable to the original model. This opens possibilities to study HL in Iceland and compare the results internationally. The translation model introduced might be helpful for other countries where information on HL is missing based on lack of validated tools.Háskólinn á Akureyri (IS) research fundPeer Reviewe

Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesAIMS: Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland. METHODS AND RESULTS: Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10-7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10-6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10-4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67-1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10-18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD. CONCLUSION: Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk.deCODE genetics/Amge

Kinematical and chemical vertical structure of the Galactic thick disk II. A lack of dark matter in the solar neighborhood

We estimated the dynamical surface mass density Sigma at the solar position between Z=1.5 and 4 kpc from the Galactic plane, as inferred from the kinematics of thick disk stars. The formulation is exact within the limit of validity of a few basic assumptions. The resulting trend of Sigma(Z) matches the expectations of visible mass alone, and no dark component is required to account for the observations. We extrapolate a dark matter (DM) density in the solar neighborhood of 0+-1 mM_sun pc^-3, and all the current models of a spherical DM halo are excluded at a confidence level higher than 4sigma. A detailed analysis reveals that a small amount of DM is allowed in the volume under study by the change of some input parameter or hypothesis, but not enough to match the expectations of the models, except under an exotic combination of non-standard assumptions. Identical results are obtained when repeating the calculation with kinematical measurements available in the literature. We demonstrate that a DM halo would be detected by our method, and therefore the results have no straightforward interpretation. Only the presence of a highly prolate (flattening q>2) DM halo can be reconciled with the observations, but this is highly unlikely in LambdaCDM models. The results challenge the current understanding of the spatial distribution and nature of the Galactic DM. In particular, our results may indicate that any direct DM detection experiment is doomed to fail, if the local density of the target particles is negligible.Comment: Accepted for publication in the Astrophysical Journa

Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesEpileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease.We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease.We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease

Self-rated health and socio-economic status among older adults in Northern Iceland

Publisher's version (útgefin grein)Little is known about self-rated health (SRH) of older people living in more remote and Arctic areas. Iceland is a high-income country with one of the lowest rates of income inequality in the world, which may influence SRH. The research aim was to study factors affecting SRH, in such a population living in Northern Iceland. Stratified random sample according to the place of residency, age and gender was used and data collected via face-to-face interviews. Inclusion criteria included community-dwelling adults ≥65 years of age. Response rate was 57.9% (N = 175), average age 74.2 (sd 6.3) years, range 65–92 years and 57% were men. The average number of diagnosed diseases was 1.5 (sd 1.3) and prescribed medications 3.0 (sd 1.7). SRH ranged from 5 (excellent) to 1 (bad), with an average of 3.26 (sd 1.0) and no difference between the place of residency. Lower SRH was independently explained by depressed mood (OR = 0.88, 95% CI = 0.80–0.96), higher body mass index (OR = 0.93, 95% CI = 0.87–0.99), number of prescribed medications (OR = 0.88, 95% CI = 0.78–1.00) and perception of inadequate income (OR = 0.45, 95% CI = 0.21–0.98). The results highlight the importance of physical and mental health promotion for general health and for ageing in place and significance of economic factors as predictors of SRH.This work was supported by the Háskólinn á Akureyri [R-1803]; Icelandic Regional Development Institute (Byggðastofnun) [102022].Peer Reviewe

The Metallicity Distribution Functions of SEGUE G and K dwarfs: Constraints for Disk Chemical Evolution and Formation

We present the metallicity distribution function (MDF) for 24,270 G and 16,847 K dwarfs at distances from 0.2 to 2.3 kpc from the Galactic plane, based on spectroscopy from the Sloan Extension for Galactic Understanding and Exploration (SEGUE) survey. This stellar sample is significantly larger in both number and volume than previous spectroscopic analyses, which were limited to the solar vicinity, making it ideal for comparison with local volume-limited samples and Galactic models. For the first time, we have corrected the MDF for the various observational biases introduced by the SEGUE target selection strategy. The SEGUE sample is particularly notable for K dwarfs, which are too faint to examine spectroscopically far from the solar neighborhood. The MDF of both spectral types becomes more metal-poor with increasing |Z|, which reflects the transition from a sample with small [alpha/Fe] values at small heights to one with enhanced [alpha/Fe] above 1 kpc. Comparison of our SEGUE distributions to those of two different Milky Way models reveals that both are more metal-rich than our observed distributions at all heights above the plane. Our unbiased observations of G and K dwarfs provide valuable constraints over the |Z|-height range of the Milky Way disk for chemical and dynamical Galaxy evolution models, previously only calibrated to the solar neighborhood, with particular utility for thin- and thick-disk formation models.Comment: 70 pages, 25 figures, 7 tables. Accepted by The Astrophysical Journa