VFISV: Very Fast Inversion of the Stokes Vector for the Helioseismic and Magnetic Imager

In this paper we describe in detail the implementation and main properties of a new inversion code for the polarized radiative transfer equation (VFISV: Very Fast inversion of the Stokes vector). VFISV will routinely analyze pipeline data from the Helioseismic and Magnetic Imager (HMI) on-board of the Solar Dynamics Observatory (SDO). It will provide full-disk maps (4096$\times$4096 pixels) of the magnetic field vector on the Solar Photosphere every 10 minutes. For this reason VFISV is optimized to achieve an inversion speed that will allow it to invert 16 million pixels every 10 minutes with a modest number (approx. 50) of CPUs. Here we focus on describing a number of important details, simplifications and tweaks that have allowed us to significantly speed up the inversion process. We also give details on tests performed with data from the spectropolarimeter on-board of the Hinode spacecraft.Comment: 23 pages, 9 figures (2 color). Submitted for publication to Solar Physic

A hybrid semantic approach to building dynamic maps of research communities

In the last ten years, ontology-based recommender systems have been shown to be effective tools for predicting user preferences and suggesting items. There are however some issues associated with the ontologies adopted by these approaches, such as: 1) their crafting is not a cheap process, being time consuming and calling for specialist expertise; 2) they may not represent accurately the viewpoint of the targeted user community; 3) they tend to provide rather static models, which fail to keep track of evolving user perspectives. To address these issues, we propose Klink UM, an approach for extracting emergent semantics from user feedbacks, with the aim of tailoring the ontology to the users and improving the recommendations accuracy. Klink UM uses statistical and machine learning techniques for finding hierarchical and similarity relationships between keywords associated with rated items and can be used for: 1) building a conceptual taxonomy from scratch, 2) enriching and correcting an existing ontology, 3) providing a numerical estimate of the intensity of semantic relationships according to the users. The evaluation shows that Klink UM performs well with respect to handcrafted ontologies and can significantly increase the accuracy of suggestions in content-based recommender systems

The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases

Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes

Marijuana Use and Estimated Glomerular Filtration Rate in Young Adults.

Marijuana use has become more widely accepted in the United States and has been legalized in many areas. Although it is biologically plausible that marijuana could affect kidney function, epidemiologic data are lacking. We conducted a cohort study among young adults with preserved eGFR ( <i>i.e.</i> , eGFR≥60 ml/min per 1.73 m <sup>2</sup> ) using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. At scheduled examinations occurring every 5 years and starting at study year 10 (calendar years, 1995-1996), cystatin C was collected over a 10-year period, and urine albumin-to-creatinine ratio was collected over a 15-year period. We investigated the cross-sectional association between current and cumulative marijuana use (in marijuana-years; one marijuana-year equals 365 days of marijuana use) and eGFR by cystatin C (eGFR <sub>cys</sub> ) at year 10. In longitudinal analyses, we investigated the association between cumulative marijuana use and eGFR <sub>cys</sub> change and rapid (≥3%/year) eGFR <sub>cys</sub> decline over two 5-year intervals and prevalent albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) over a 15-year period. Past or current marijuana use was reported by 83% (3131 of 3765) of the cohort, and the mean eGFR <sub>cys</sub> was 111 ml/min per 1.73 m <sup>2</sup> at year 10. Over the following 10 years, 504 had rapid eGFR <sub>cys</sub> decline, and over the following 15 years, 426 had prevalent albuminuria. Compared with no use, daily current use and ≥5 marijuana-years of cumulative use were associated with lower eGFR <sub>cys</sub> at year 10: -4.5% (95% confidence interval, -8.1 to -0.7%; <i>P</i> =0.02) and -3.0% (95% confidence interval, -5.6 to -0.4%; <i>P</i> =0.03), respectively. Marijuana use was not significantly associated with eGFR <sub>cys</sub> change, rapid eGFR <sub>cys</sub> decline, or prevalent albuminuria. Although we identified a modest cross-sectional association between higher marijuana exposure and lower eGFR <sub>cys</sub> among young adults with preserved eGFR, our findings were largely null and did not demonstrate a longitudinal association between marijuana use and eGFR <sub>cys</sub> change, rapid eGFR <sub>cys</sub> decline, or prevalent albuminuria. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_24_CJASNPodcast_17_10.mp3