Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets.
We used exome sequence data and electronic health records from 46,544 participants in the ...DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples.
A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10
) and AST (P=6.2×10
). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% 95% confidence interval {CI}, 20 to 58 among heterozygotes and by 53% 95% CI, 3 to 77 among homozygotes), nonalcoholic liver disease (by 17% 95% CI, 8 to 25 among heterozygotes and by 30% 95% CI, 13 to 43 among homozygotes), alcoholic cirrhosis (by 42% 95% CI, 14 to 61 among heterozygotes and by 73% 95% CI, 15 to 91 among homozygotes), and nonalcoholic cirrhosis (by 26% 95% CI, 7 to 40 among heterozygotes and by 49% 95% CI, 15 to 69 among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity.
A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).
We presented an algorithm for inferring aerosol layer height (ALH) and optical depth (AOD) over ocean surface from radiances in oxygen A and B bands measured by the Earth Polychromatic Imaging Camera ...(EPIC) on the Deep Space Climate Observatory (DSCOVR) orbiting at Lagrangian‐1 point. The algorithm was applied to EPIC imagery of a 2 day dust outbreak over the North Atlantic Ocean. Retrieved ALHs and AODs were evaluated against counterparts observed by Cloud‐Aerosol Lidar with Orthogonal Polarization (CALIOP), Moderate Resolution Imaging Spectroradiometer, and Aerosol Robotic Network. The comparisons showed 71.5% of EPIC‐retrieved ALHs were within ±0.5 km of those determined from CALIOP and 74.4% of EPIC AOD retrievals fell within a ± (0.1 + 10%) envelope of MODIS retrievals. This study demonstrates the potential of EPIC measurements for retrieving global aerosol height multiple times daily, which are essential for evaluating aerosol profile simulated in climate models and for better estimating aerosol radiative effects.
Key Points
Algorithm to retrieve dust optical depth and centroid height using the O2 A and B bands is developed
First retrieval results of dust optical depth and altitude from EPIC/DSCOVR are shown in good agreement with the counterparts from MODIS and CALIPSO
Passive remote sensing of aerosol height multiple times within a day is demonstrated with EPIC and discussed for future studies
Plain Language Summary
DSCOVR is a satellite parked at Lagrange‐1 point, ~1.5 million kilometers from Earth. It was launched in February 2015 and started the data collection in June 2015. It carries a sensor called EPIC that looks at the sunlit surface every 1 to 2 h. This paper presents a new technique to retrieve dust optical depth and dust altitude from EPIC's measurements within and outside of oxygen A and B absorption bands. The results are validated with MODIS and CALIOP data. The technique represents, for the first time, that we can reliably retrieve dust plume height from passive remote sensing multiple times a day.
Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders.
We developed technical, bioinformatic, interpretive, and ...validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients.
We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders.
Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.).
Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder ...Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits' PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.
The Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC4RS) field mission based at Ellington Field, Texas, during August and September 2013 ...employed the most comprehensive airborne payload to date to investigate atmospheric composition over North America. The NASA ER‐2, DC‐8, and SPEC Inc. Learjet flew 57 science flights from the surface to 20 km. The ER‐2 employed seven remote sensing instruments as a satellite surrogate and eight in situ instruments. The DC‐8 employed 23 in situ and five remote sensing instruments for radiation, chemistry, and microphysics. The Learjet used 11 instruments to explore cloud microphysics. SEAC4RS launched numerous balloons, augmented AErosol RObotic NETwork, and collaborated with many existing ground measurement sites. Flights investigating convection included close coordination of all three aircraft. Coordinated DC‐8 and ER‐2 flights investigated the optical properties of aerosols, the influence of aerosols on clouds, and the performance of new instruments for satellite measurements of clouds and aerosols. ER‐2 sorties sampled stratospheric injections of water vapor and other chemicals by local and distant convection. DC‐8 flights studied seasonally evolving chemistry in the Southeastern U.S., atmospheric chemistry with lower emissions of NOx and SO2 than in previous decades, isoprene chemistry under high and low NOx conditions at different locations, organic aerosols, air pollution near Houston and in petroleum fields, smoke from wildfires in western forests and from agricultural fires in the Mississippi Valley, and the ways in which the chemistry in the boundary layer and the upper troposphere were influenced by vertical transport in convective clouds.
Key Points
The SEAC4RS field mission was based near Houston, Texas during August and September of 2013
The paper overviews the mission to aid those interested in this data set to understand its context
The data can be accessed at http://www‐air.larc.nasa.gov/cgi‐bin/ArcView/seac4rs
Data assimilation of Aerosol Robotic Network (AERONET) and Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol optical thickness (AOT) for aerosol forecasting was tested within the Navy ...Aerosol Analysis Prediction System (NAAPS) framework, using variational and ensemble data assimilation methods. Navy aerosol forecasting currently makes use of a deterministic NAAPS simulation coupled to Navy Variational Data Assimilation System for aerosol optical depth, a two-dimensional variational data assimilation system, for MODIS AOT assimilation. An ensemble version of NAAPS (ENAAPS) coupled to an ensemble adjustment Kalman filter (EAKF) from the Data Assimilation Research Testbed was recently developed, allowing for a range of data assimilation and forecasting experiments to be run with deterministic NAAPS and ENAAPS. The main findings are that the EAKF, with its flow-dependent error covariances, makes better use of sparse observations such as AERONET AOT. Assimilating individual AERONET observations in the two-dimensional variational system can increase the analysis errors when observations are located in high AOT gradient regions. By including AERONET with MODIS AOT assimilation, the magnitudes of peak aerosol events (AOT> 1) were better captured with improved temporal variability, especially in India and Asia where aerosol prediction is a challenge. Assimilating AERONET AOT with MODIS had little impact on the 24 h forecast skill compared to MODIS assimilation only, but differences were found downwind of AERONET sites. The 24 h forecast skill was approximately the same for forecasts initialized with analyses from AERONET AOT assimilation alone compared to MODIS assimilation, particularly in regions where the AERONET network is dense; including the United States and Europe, indicating that AERONET could serve as a backup observation network for over-land synoptic-scale aerosol events.
Population screening for medically relevant genomic variants that cause diseases such as hereditary cancer and cardiovascular disorders is increasing to facilitate early disease detection or ...prevention. Neuropsychiatric disorders (NPDs) are common, complex disorders with clear genetic causes; yet, access to genetic diagnosis is limited. We explored whether inclusion of NPD in population-based genomic screening programs is warranted by assessing 3 key factors: prevalence, penetrance, and personal utility.
To evaluate the suitability of including pathogenic copy number variants (CNVs) associated with NPD in population screening by determining their prevalence and penetrance and exploring the personal utility of disclosing results.
In this cohort study, the frequency of 31 NPD CNVs was determined in patient-participants via exome data. Associated clinical phenotypes were assessed using linked electronic health records. Nine CNVs were selected for disclosure by licensed genetic counselors, and participants' psychosocial reactions were evaluated using a mixed-methods approach. A primarily adult population receiving medical care at Geisinger, a large integrated health care system in the United States with the only population-based genomic screening program approved for medically relevant results disclosure, was included. The cohort was identified from the Geisinger MyCode Community Health Initiative. Exome and linked electronic health record data were available for this cohort, which was recruited from February 2007 to April 2017. Data were collected for the qualitative analysis April 2017 through February 2018. Analysis began February 2018 and ended December 2019.
The planned outcomes of this study include (1) prevalence estimate of NPD-associated CNVs in an unselected health care system population; (2) penetrance estimate of NPD diagnoses in CNV-positive individuals; and (3) qualitative themes that describe participants' responses to receiving NPD-associated genomic results.
Of 90 595 participants with CNV data, a pathogenic CNV was identified in 708 (0.8%; 436 women 61.6%; mean SD age, 50.04 18.74 years). Seventy percent (n = 494) had at least 1 associated clinical symptom. Of these, 28.8% (204) of CNV-positive individuals had an NPD code in their electronic health record, compared with 13.3% (11 835 of 89 887) of CNV-negative individuals (odds ratio, 2.21; 95% CI, 1.86-2.61; P < .001); 66.4% (470) of CNV-positive individuals had a history of depression and anxiety compared with 54.6% (49 118 of 89 887) of CNV-negative individuals (odds ratio, 1.53; 95% CI, 1.31-1.80; P < .001). 16p13.11 (71 0.078%) and 22q11.2 (108 0.119%) were the most prevalent deletions and duplications, respectively. Only 5.8% of individuals (41 of 708) had a previously known genetic diagnosis. Results disclosure was completed for 141 individuals. Positive participant responses included poignant reactions to learning a medical reason for lifelong cognitive and psychiatric disabilities.
This study informs critical factors central to the development of population-based genomic screening programs and supports the inclusion of NPD in future designs to promote equitable access to clinically useful genomic information.
This study characterizes impacts of peat-forest (PF) smoke on an urban environment through carbonaceous profiles of >260 daily PM2.5 samples collected during 2012, 2013 and 2015. Organic carbon (OC) ...and elemental carbon (EC) comprising eight carbonaceous fractions are examined for four sample groups – non-smoke-dominant (NSD), smoke-dominant (SD), episodic PM2.5 samples at the urban receptor, and near-source samples collected close to PF burning sites. PF smoke introduced much larger amounts of OC than EC, with OC accounting for up to 94% of total carbon (TC), or increasing by up to 20 times in receptor PM2.5. SD PM2.5 at the receptor site and near-source samples have OC3 and EC1 as the dominant fractions. Both sample classes also exhibit char-EC >1.4 times of soot-EC, characterizing smoldering-dominant PF smoke, unlike episodic PM2.5 at the receptor site featuring large amounts of pyrolyzed organic carbon (POC) and soot-EC. Relative to the mean NSD PM2.5 at the receptor, increasing strength of transboundary PF smoke enriches OC3 and OC4 fractions, on average, by factors of >3 for SD samples, and >14 for episodic samples. A peat-forest smoke (PFS) indicator, representing the concentration ratio of (OC2+OC3+POC) to soot-EC, shows a temporal trend satisfactorily correlating with an organic marker (levoglucosan) of biomass burning. The PFS indicator systematically differentiates influences of PF smoke from source to urban receptor sites, with a progressive mean of 3.6, 13.4 and 20.1 for NSD, SD and episodic samples respectively at the receptor site, and 54.7 for the near-source PM2.5. A PFS indicator of ≥5.0 is proposed to determine dominant influence of transboundary PF smoke on receptor urban PM2.5 in the equatorial Asia with ∼90% confidence. Assessing >2900 hourly OCEC data in 2017–2018 supports the applicability of the PFS indicator to evaluate hourly impacts of PF smoke on receptor urban PM2.5 in the Maritime Continent.
Display omitted
•Peat-forest (PF) smoke enriches OC, up to 94% of total carbon in receptor PM2.5.•Higher OC3 & OC4 by factors of >3–10 features dominant PF smoke impact on urban PM2.5.•Char-EC >1.4 times soot-EC shows dominant influence of smoldering emissions.•PFS ratio ≥5 suggests dominant PF smoke impacts on receptor urban PM2.5.•PFS ratios indicate severity of PF smoke impact on urban environment on hourly basis.
Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.
To perform clinical whole-exome sequencing and report (1) the rate of ...molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.
Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 88%; mean age, 6 years; 888 females 44%, 1101 males 55%, and 11 fetuses 1% gender unknown), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.
Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.
A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.
Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
Massively parallel DNA sequencing generates staggering amounts of data. Decreasing cost, increasing throughput, and improved annotation have expanded the diversity of genomics applications in ...research and clinical practice. This expanding scale creates analytical challenges: accommodating peak compute demand, coordinating secure access for multiple analysts, and sharing validated tools and results.
To address these challenges, we have developed the Mercury analysis pipeline and deployed it in local hardware and the Amazon Web Services cloud via the DNAnexus platform. Mercury is an automated, flexible, and extensible analysis workflow that provides accurate and reproducible genomic results at scales ranging from individuals to large cohorts.
By taking advantage of cloud computing and with Mercury implemented on the DNAnexus platform, we have demonstrated a powerful combination of a robust and fully validated software pipeline and a scalable computational resource that, to date, we have applied to more than 10,000 whole genome and whole exome samples.
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