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1.
  • Arndt, D. S., et al. (author)
  • STATE OF THE CLIMATE IN 2017
  • 2018
  • In: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
  • Research review (peer-reviewed)
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2.
  • Arndt, D. S., et al. (author)
  • State of the Climate in 2016
  • 2017
  • In: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 98:8, s. S1-S280
  • Journal article (peer-reviewed)abstract
    • In 2016, the dominant greenhouse gases released into Earth's atmosphere-carbon dioxide, methane, and nitrous oxide-continued to increase and reach new record highs. The 3.5 +/- 0.1 ppm rise in global annual mean carbon dioxide from 2015 to 2016 was the largest annual increase observed in the 58-year measurement record. The annual global average carbon dioxide concentration at Earth's surface surpassed 400 ppm (402.9 +/- 0.1 ppm) for the first time in the modern atmospheric measurement record and in ice core records dating back as far as 800000 years. One of the strongest El Nino events since at least 1950 dissipated in spring, and a weak La Nina evolved later in the year. Owing at least in part to the combination of El Nino conditions early in the year and a long-term upward trend, Earth's surface observed record warmth for a third consecutive year, albeit by a much slimmer margin than by which that record was set in 2015. Above Earth's surface, the annual lower troposphere temperature was record high according to all datasets analyzed, while the lower stratospheric temperature was record low according to most of the in situ and satellite datasets. Several countries, including Mexico and India, reported record high annual temperatures while many others observed near-record highs. A week-long heat wave at the end of April over the northern and eastern Indian peninsula, with temperatures surpassing 44 degrees C, contributed to a water crisis for 330 million people and to 300 fatalities. In the Arctic the 2016 land surface temperature was 2.0 degrees C above the 1981-2010 average, breaking the previous record of 2007, 2011, and 2015 by 0.8 degrees C, representing a 3.5 degrees C increase since the record began in 1900. The increasing temperatures have led to decreasing Arctic sea ice extent and thickness. On 24 March, the sea ice extent at the end of the growth season saw its lowest maximum in the 37-year satellite record, tying with 2015 at 7.2% below the 1981-2010 average. The September 2016 Arctic sea ice minimum extent tied with 2007 for the second lowest value on record, 33% lower than the 1981-2010 average. Arctic sea ice cover remains relatively young and thin, making it vulnerable to continued extensive melt. The mass of the Greenland Ice Sheet, which has the capacity to contribute similar to 7 m to sea level rise, reached a record low value. The onset of its surface melt was the second earliest, after 2012, in the 37-year satellite record. Sea surface temperature was record high at the global scale, surpassing the previous record of 2015 by about 0.01 degrees C. The global sea surface temperature trend for the 21st century-to-date of +0.162 degrees C decade(-1) is much higher than the longer term 1950-2016 trend of +0.100 degrees C decade(-1). Global annual mean sea level also reached a new record high, marking the sixth consecutive year of increase. Global annual ocean heat content saw a slight drop compared to the record high in 2015. Alpine glacier retreat continued around the globe, and preliminary data indicate that 2016 is the 37th consecutive year of negative annual mass balance. Across the Northern Hemisphere, snow cover for each month from February to June was among its four least extensive in the 47-year satellite record. Continuing a pattern below the surface, record high temperatures at 20-m depth were measured at all permafrost observatories on the North Slope of Alaska and at the Canadian observatory on northernmost Ellesmere Island. In the Antarctic, record low monthly surface pressures were broken at many stations, with the southern annular mode setting record high index values in March and June. Monthly high surface pressure records for August and November were set at several stations. During this period, record low daily and monthly sea ice extents were observed, with the November mean sea ice extent more than 5 standard deviations below the 1981-2010 average. These record low sea ice values contrast sharply with the record high values observed during 2012-14. Over the region, springtime Antarctic stratospheric ozone depletion was less severe relative to the 1991-2006 average, but ozone levels were still low compared to pre-1990 levels. Closer to the equator, 93 named tropical storms were observed during 2016, above the 1981-2010 average of 82, but fewer than the 101 storms recorded in 2015. Three basins-the North Atlantic, and eastern and western North Pacific-experienced above-normal activity in 2016. The Australian basin recorded its least active season since the beginning of the satellite era in 1970. Overall, four tropical cyclones reached the Saffir-Simpson category 5 intensity level. The strong El Nino at the beginning of the year that transitioned to a weak La Nina contributed to enhanced precipitation variability around the world. Wet conditions were observed throughout the year across southern South America, causing repeated heavy flooding in Argentina, Paraguay, and Uruguay. Wetter-than-usual conditions were also observed for eastern Europe and central Asia, alleviating the drought conditions of 2014 and 2015 in southern Russia. In the United States, California had its first wetter-than-average year since 2012, after being plagued by drought for several years. Even so, the area covered by drought in 2016 at the global scale was among the largest in the post-1950 record. For each month, at least 12% of land surfaces experienced severe drought conditions or worse, the longest such stretch in the record. In northeastern Brazil, drought conditions were observed for the fifth consecutive year, making this the longest drought on record in the region. Dry conditions were also observed in western Bolivia and Peru; it was Bolivia's worst drought in the past 25 years. In May, with abnormally warm and dry conditions already prevailing over western Canada for about a year, the human-induced Fort McMurray wildfire burned nearly 590000 hectares and became the costliest disaster in Canadian history, with $3 billion (U.S. dollars) in insured losses.
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3.
  • Locke, Adam E, et al. (author)
  • Genetic studies of body mass index yield new insights for obesity biology.
  • 2015
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
  • Journal article (peer-reviewed)abstract
    • Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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4.
  • Blanton, Michael R., et al. (author)
  • Sloan Digital Sky Survey IV : Mapping the Milky Way, Nearby Galaxies, and the Distant Universe
  • 2017
  • In: Astronomical Journal. - : IOP Publishing Ltd. - 0004-6256 .- 1538-3881. ; 154:1
  • Journal article (peer-reviewed)abstract
    • We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and. high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median z similar to 0.03). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between z similar to 0.6 and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs. and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the. Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July.
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5.
  • Joshi, Peter K, et al. (author)
  • Directional dominance on stature and cognition in diverse human populations
  • 2015
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
  • Journal article (peer-reviewed)abstract
    • Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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6.
  • Abolfathi, Bela, et al. (author)
  • The Fourteenth Data Release of the Sloan Digital Sky Survey : First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment
  • 2018
  • In: Astrophysical Journal Supplement Series. - : IOP Publishing Ltd. - 0067-0049 .- 1538-4365. ; 235:2
  • Journal article (peer-reviewed)abstract
    • The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
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7.
  • Frazier-Wood, Alexis C., et al. (author)
  • Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
  • 2016
  • In: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
  • Journal article (peer-reviewed)abstract
    • Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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8.
  • Sawcer, Stephen, et al. (author)
  • Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
  • 2011
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
  • Journal article (peer-reviewed)abstract
    • Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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9.
  • van Rheenen, Wouter, et al. (author)
  • Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
  • 2016
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
  • Journal article (peer-reviewed)abstract
    • To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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10.
  • Estrada, Karol, et al. (author)
  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
  • 2012
  • In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
  • Journal article (peer-reviewed)abstract
    • Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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11.
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12.
  • Speakman, John R., et al. (author)
  • Total daily energy expenditure has declined over the past three decades due to declining basal expenditure, not reduced activity expenditure
  • 2023
  • In: Nature Metabolism. - : NATURE PORTFOLIO. - 2522-5812. ; 5:4, s. 579-588
  • Journal article (other academic/artistic)abstract
    • Obesity is caused by a prolonged positive energy balance(1,2). Whether reduced energy expenditure stemming from reduced activity levels contributes is debated(3,4). Here we show that in both sexes, total energy expenditure (TEE) adjusted for body composition and age declined since the late 1980s, while adjusted activity energy expenditure increased over time. We use the International Atomic Energy Agency Doubly Labelled Water database on energy expenditure of adults in the United States and Europe (n = 4,799) to explore patterns in total (TEE: n = 4,799), basal (BEE: n = 1,432) and physical activity energy expenditure (n = 1,432) over time. In males, adjusted BEE decreased significantly, but in females this did not reach significance. A larger dataset of basal metabolic rate (equivalent to BEE) measurements of 9,912 adults across 163 studies spanning 100 years replicates the decline in BEE in both sexes. We conclude that increasing obesity in the United States/Europe has probably not been fuelled by reduced physical activity leading to lowered TEE. We identify here a decline in adjusted BEE as a previously unrecognized factor.
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13.
  • Berndt, Sonja I., et al. (author)
  • Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
  • 2013
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
  • Journal article (peer-reviewed)abstract
    • Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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14.
  • Manning, Alisa, et al. (author)
  • A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
  • 2017
  • In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
  • Journal article (peer-reviewed)abstract
    • To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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15.
  • Ebersole, Charles R., et al. (author)
  • Many Labs 5: Testing Pre-Data-Collection Peer Review as an Intervention to Increase Replicability
  • 2020
  • In: Advances in Methods and Practices in Psychological Science. - : Sage. - 2515-2467 .- 2515-2459. ; 3:3, s. 309-331
  • Journal article (peer-reviewed)abstract
    • Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3-9; median total sample = 1,279.5, range = 276-3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (Delta r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00-.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19-.50).
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16.
  • Flannick, Jason, et al. (author)
  • Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
  • 2017
  • In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
  • Journal article (peer-reviewed)abstract
    • To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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17.
  • Fuchsberger, Christian, et al. (author)
  • The genetic architecture of type 2 diabetes
  • 2016
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
  • Journal article (peer-reviewed)abstract
    • The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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18.
  • Mahajan, Anubha, et al. (author)
  • Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
  • 2018
  • In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
  • Journal article (peer-reviewed)abstract
    • We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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19.
  • Ng, Bobby G, et al. (author)
  • ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.
  • 2016
  • In: Human Mutation. - : Hindawi Limited. - 1059-7794.
  • Journal article (peer-reviewed)abstract
    • Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder. This article is protected by copyright. All rights reserved.
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20.
  • Keogan, Katharine, et al. (author)
  • Global phenological insensitivity to shifting ocean temperatures among seabirds
  • 2018
  • In: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 8:4, s. 313-318
  • Journal article (peer-reviewed)abstract
    • Reproductive timing in many taxa plays a key role in determining breeding productivity(1), and is often sensitive to climatic conditions(2). Current climate change may alter the timing of breeding at different rates across trophic levels, potentially resulting in temporal mismatch between the resource requirements of predators and their prey(3). This is of particular concern for higher-trophic-level organisms, whose longer generation times confer a lower rate of evolutionary rescue than primary producers or consumers(4). However, the disconnection between studies of ecological change in marine systems makes it difficult to detect general changes in the timing of reproduction(5). Here, we use a comprehensive meta-analysis of 209 phenological time series from 145 breeding populations to show that, on average, seabird populations worldwide have not adjusted their breeding seasons over time (-0.020 days yr(-1)) or in response to sea surface temperature (SST) (-0.272 days degrees C-1) between 1952 and 2015. However, marked between-year variation in timing observed in resident species and some Pelecaniformes and Suliformes (cormorants, gannets and boobies) may imply that timing, in some cases, is affected by unmeasured environmental conditions. This limited temperature-mediated plasticity of reproductive timing in seabirds potentially makes these top predators highly vulnerable to future mismatch with lower-trophic-level resources(2).
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21.
  • Tapia-Ruiz, Nuria, et al. (author)
  • 2021 roadmap for sodium-ion batteries
  • 2021
  • In: Journal of Physics. - : Institute of Physics Publishing (IOPP). - 2515-7655. ; 3:3
  • Journal article (peer-reviewed)abstract
    • Increasing concerns regarding the sustainability of lithium sources, due to their limited availability and consequent expected price increase, have raised awareness of the importance of developing alternative energy-storage candidates that can sustain the ever-growing energy demand. Furthermore, limitations on the availability of the transition metals used in the manufacturing of cathode materials, together with questionable mining practices, are driving development towards more sustainable elements. Given the uniformly high abundance and cost-effectiveness of sodium, as well as its very suitable redox potential (close to that of lithium), sodium-ion battery technology offers tremendous potential to be a counterpart to lithium-ion batteries (LIBs) in different application scenarios, such as stationary energy storage and low-cost vehicles. This potential is reflected by the major investments that are being made by industry in a wide variety of markets and in diverse material combinations. Despite the associated advantages of being a drop-in replacement for LIBs, there are remarkable differences in the physicochemical properties between sodium and lithium that give rise to different behaviours, for example, different coordination preferences in compounds, desolvation energies, or solubility of the solid-electrolyte interphase inorganic salt components. This demands a more detailed study of the underlying physical and chemical processes occurring in sodium-ion batteries and allows great scope for groundbreaking advances in the field, from lab-scale to scale-up. This roadmap provides an extensive review by experts in academia and industry of the current state of the art in 2021 and the different research directions and strategies currently underway to improve the performance of sodium-ion batteries. The aim is to provide an opinion with respect to the current challenges and opportunities, from the fundamental properties to the practical applications of this technology.
  •  
22.
  • Anney, Richard, et al. (author)
  • A genome-wide scan for common alleles affecting risk for autism.
  • 2010
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
  • Journal article (peer-reviewed)abstract
    • Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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23.
  • Beaumont, Robin N, et al. (author)
  • Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
  • 2018
  • In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 1460-2083 .- 0964-6906. ; 27:4, s. 742-756
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
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24.
  • Pasquini, Marcelo C., et al. (author)
  • Hematopoietic Cell Transplantation Outcomes in Monosomal Karyotype Myeloid Malignancies
  • 2016
  • In: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 22:2, s. 248-257
  • Journal article (peer-reviewed)abstract
    • The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed.
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25.
  • Pinto, Dalila, et al. (author)
  • Functional impact of global rare copy number variation in autism spectrum disorders.
  • 2010
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
  • Journal article (peer-reviewed)abstract
    • The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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26.
  • Radivoyevitch, Tomas, et al. (author)
  • Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma
  • 2018
  • In: Leukemia Research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 74, s. 130-136
  • Journal article (peer-reviewed)abstract
    • Background: Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).Methods: 9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; n=916), non-Hodgkin lymphoma (NHL; n=3546) and plasma cell myeloma (PCM; n=4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS.Results: 335 MDS/ AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR=4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR=2.5 [1.1, 2.5]); (2) >= 3 versus 1 line of chemotherapy for NHL (HR=1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HR=2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/ MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort.Conclusions: There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.
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27.
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28.
  • Tyrrell, Jessica, et al. (author)
  • Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.
  • 2016
  • In: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 315:11, s. 1129-40
  • Journal article (peer-reviewed)abstract
    • Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Offspring birth weight from 18 studies.Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P=.008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P=7×10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P=1×10(-5)), respectively. A 1-SD (≈4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD (≈7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD (≈10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
  •  
29.
  • Anney, Richard, et al. (author)
  • Individual common variants exert weak effects on the risk for autism spectrum disorders.
  • 2012
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:21, s. 4781-92
  • Journal article (peer-reviewed)abstract
    • While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating association of individual SNPs, we also sought evidence that common variants, en masse, might affect risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest p-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. By contrast, allele-scores derived from the transmission of common alleles to Stage 1 cases significantly predict case-status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele-score results, it is reasonable to conclude that common variants affect ASD risk but their individual effects are modest.
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30.
  • Gaulton, Kyle J, et al. (author)
  • Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
  • 2015
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
  • Journal article (peer-reviewed)abstract
    • We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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31.
  • Meyer, Esther, et al. (author)
  • Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
  • 2017
  • In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 49, s. 223-237
  • Journal article (peer-reviewed)abstract
    • Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
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32.
  • Phillip, Moshe, et al. (author)
  • Consensus Guidance for Monitoring Individuals With Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes
  • In: Diabetes Care. - 1935-5548.
  • Journal article (peer-reviewed)abstract
    • Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in nonspecialized settings. To inform this monitoring, JDRF, in conjunction with international experts and societies, developed consensus guidance. Broad advice from this guidance includes the following: 1) partnerships should be fostered between endocrinologists and primary care providers to care for people who are IAb+; 2) when people who are IAb+ are initially identified, there is a need for confirmation using a second sample; 3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; 4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; 5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and 6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasizes significant unmet needs for further research on early-stage type 1 diabetes to increase the rigor of future recommendations and inform clinical care.
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33.
  • Phillip, Moshe, et al. (author)
  • Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes
  • In: Diabetologia. - 1432-0428.
  • Journal article (peer-reviewed)abstract
    • Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.
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34.
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35.
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36.
  • Wood, Angela M., et al. (author)
  • Risk thresholds for alcohol consumption : combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies
  • 2018
  • In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 391:10129, s. 1513-1523
  • Journal article (peer-reviewed)abstract
    • Background: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.Methods: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12.5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5.6 years [5th-95th percentile 1.04-13.5]) from 71 011 participants from 37 studies.Findings: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5.4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1.14, 95% CI, 1.10-1.17), coronary disease excluding myocardial infarction (1.06, 1.00-1.11), heart failure (1.09, 1.03-1.15), fatal hypertensive disease (1.24, 1.15-1.33); and fatal aortic aneurysm (1.15, 1.03-1.28). By contrast, increased alcohol consumption was loglinearly associated with a lower risk of myocardial infarction (HR 0.94, 0.91-0.97). In comparison to those who reported drinking >0-<= 100 g per week, those who reported drinking >100-<= 200 g per week, >200-<= 350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.Interpretation: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.
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37.
  • Wood, William A., et al. (author)
  • Country-Level Macroeconomic Indicators Predict Early Post-Allogeneic Hematopoietic Cell Transplantation Survival in Acute Lymphoblastic Leukemia : A CIBMTR Analysis
  • 2018
  • In: Biology of blood and marrow transplantation. - : ELSEVIER SCIENCE INC. - 1083-8791 .- 1523-6536. ; 24:9, s. 1928-1935
  • Journal article (peer-reviewed)abstract
    • For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross national income per capita, health expenditure per capita, and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (n = 697) were associated with increased hazard for mortality (hazard ratio, 2.42; 95% confidence interval, 1.64 to 3.57; P < .001) in comparison with transplants performed in the countries with the highest HDI quartile. This translated into an 11% survival difference at 100 days (77% for lowest HDI quartile versus 88% for all other quartiles). Country-level macroeconomic indices were associated with lower survival at 100 days after alloHCT for ALL. The reasons for this disparity require further investigation.
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38.
  • D'Souza, Anita, et al. (author)
  • Improved Outcomes After Autologous Hematopoietic Cell Transplantation for Light Chain Amyloidosis : A Center for International Blood and Marrow Transplant Research Study
  • 2015
  • In: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 33:32, s. 3741-
  • Journal article (peer-reviewed)abstract
    • Purpose Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chain amyloidosis (AL), but it is associated with a high risk of early mortality (EM). In a multicenter randomized comparison against oral chemotherapy, autotransplantation was associated with 24% EM. We analyzed trends in outcomes after autologous hematopoietic cell transplantation for AL in North America. Patients and Methods Between 1995 and 2012, 1,536 patients with AL who underwent autotransplantation at 134 centers were identified in the Center for International Blood and Marrow Transplant Research database. EM and overall survival (OS) were analyzed in three time cohorts: 1995 to 2000 (n = 140), 2001 to 2006 (n = 596), and 2007 to 2012 (n = 800). Hematologic and renal responses and factors associated with EM, relapse and/or progression, progression-free survival and OS were analyzed in more recent subgroups from 2001 to 2006 (n = 197) and from 2007 to 2012 (n = 157). Results Mortality at 30 and 100 days progressively declined over successive time periods from 11% and 20%, respectively, in 1995 to 2000 to 5% and 11%, respectively, in 2001 to 2006, and to 3% and 5%, respectively, in 2007 to 2012. Correspondingly, 5-year OS improved from 55% in 1995 to 2000 to 61% in 2001 to 2006 and to 77% in 2007 to 2012. Hematologic response to transplantation improved in the latest cohort. Renal response rate was 32%. Centers performing more than four AL transplantations per year had superior survival outcomes. In the multivariable analysis, cardiac AL was associated with high EM and inferior progression-free survival and OS. Autotransplantation in 2007 to 2012 and use of higher dosages of melphalan were associated with a lowered relapse risk. A Karnofsky score less than 80 and creatinine levels 2 mg/m(2) or greater were associated with worsened OS. Conclusion Post-transplantation survival in AL has improved, with a dramatic reduction in early post-transplantation mortality and excellent 5-year survival. The risk-benefit ratio for autotransplantation has changed, and randomized comparison with nontransplantation approaches is again warranted.
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39.
  • Hong, Sanghee, et al. (author)
  • Community health status and outcomes after allogeneic hematopoietic cell transplantation in the United States
  • 2021
  • In: Cancer. - : John Wiley & Sons. - 0008-543X .- 1097-0142. ; 127:4, s. 609-618
  • Journal article (peer-reviewed)abstract
    • Background: The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.Methods: This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.Results: The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08;P= .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08;P= .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15;P= .0004). CCS was not significantly associated with survival, relapse, or NRM.Conclusions: Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.
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40.
  • Klyuchnikov, Evgeny, et al. (author)
  • Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors
  • 2015
  • In: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 21:12, s. 2091-2099
  • Journal article (peer-reviewed)abstract
    • This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P <.0001); relapse/progression: 54% versus 20% (P <.0001); progression-free survival (PFS): 41% versus 58% (P <.001), and overall survival (OS): 74% versus 66% (P =.05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P <.0001) and worse PFS (RR, 2.9; P <.0001) beyond 11 months after HCT. In the first 24 months after HO', auto-HCT was associated with improved OS (RR,.41; P <.0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P =.006). A landmark analysis of patients alive and progression-free at 2 years after HO' confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P <.0001) and inferior PFS (RR, 3.2; P <.0001) and OS (RR, 2.1; P =.04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors.
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41.
  • Marklund, Matti, et al. (author)
  • Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
  • 2019
  • In: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
  • Journal article (peer-reviewed)abstract
    • Background:Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.Methods:We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).Results:In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.Conclusions:In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
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42.
  • Murphy, Rachel A, et al. (author)
  • Omega-3 and omega-6 polyunsaturated fatty acid biomarkers and sleep : a pooled analysis of cohort studies On behalf of the Fatty Acids and Outcomes Research Consortium (FORCE).
  • 2022
  • In: American Journal of Clinical Nutrition. - : Oxford University Press (OUP). - 0002-9165 .- 1938-3207. ; 115:3, s. 864-876
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: n-3 and n-6 polyunsaturated fatty acids (PUFAs) have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.OBJECTIVES: To assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were between 35 to 96 years old and from 5 nations. Circulating measures included alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), EPA + DPA + DHA, linoleic acid and arachidonic acid. Sleep duration (10 cohorts, N = 18,791) was categorized as short (≤6 hours), 7-8 hours (reference) or long (9 + hours). Difficulty falling sleeping (8 cohorts, N = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted odds ratios (ORs) per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.RESULTS: In pooled analysis adjusted for sociodemographics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. Comparing top vs. bottom quintiles, the multivariable-adjusted OR (95% confidence interval, CI) for long-sleep was 0.78 (0.65, 0.95) for DHA and for EPA + DPA + DHA, 0.76 (0.63, 0.93). Significant associations were not identified for ALA and n-6 PUFA with short sleep duration, or difficulty falling sleeping.CONCLUSIONS: Participants with higher levels of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relationship. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.
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43.
  • Myers, Regina M., et al. (author)
  • Long-Term Outcomes Among 2-Year Survivors of Autologous Hematopoietic Cell Transplantation for Hodgkin and Diffuse Large B-Cell Lymphoma
  • 2018
  • In: Cancer. - : WILEY. - 0008-543X .- 1097-0142. ; 124:4, s. 816-825
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Autologous hematopoietic cell transplantation (auto-HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL); however, long-term outcomes are not well described.METHODS: This study analyzed survival, nonrelapse mortality, late effects, and subsequent malignant neoplasms (SMNs) in 1617 patients who survived progression-free for >= 2 years after auto-HCT for cHL or DLBCL between 1990 and 2008. The median age at auto-HCT was 40 years; the median follow-up was 10.6 years.RESULTS: The 5-year overall survival rate was 90% (95% confidence interval [CI], 87%-92%) for patients with cHL and 89% (95% CI, 87%-91%) for patients with DLBCL. The risk of late mortality in comparison with the general population was 9.6-fold higher for patients with cHL (standardized mortality ratio [SMR], 9.6) and 3.4-fold higher for patients with DLBCL (SMR, 3.4). Relapse accounted for 44% of late deaths. At least 1 late effect was reported for 9% of the patients. A total of 105 SMNs were confirmed: 44 in the cHL group and 61 in the DLBCL group. According to a multivariate analysis, older age, male sex, a Karnofsky score < 90, total body irradiation (TBI) exposure, and a higher number of lines of chemotherapy before auto-HCT were risk factors for overall mortality in cHL. Risk factors in DLBCL were older age and TBI exposure. A subanalysis of 798 adolescent and young adult patients mirrored the outcomes of the overall study population.CONCLUSIONS: Despite generally favorable outcomes, 2-year survivors of auto-HCT for cHL or DLBCL have an excess late-mortality risk in comparison with the general population and experience an assortment of late complications.
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44.
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45.
  • Wood, Sylvia L. R., et al. (author)
  • Distilling the role of ecosystem services in the Sustainable Development Goals
  • 2018
  • In: Ecosystem Services. - : Elsevier BV. - 2212-0416 .- 2212-0416. ; 29, s. 70-82
  • Journal article (peer-reviewed)abstract
    • Achieving well-being for all, while protecting the environment, is one of the most pressing global challenges of our time, and a central idea in the UN Sustainable Development Goals (SDGs). We believe that integrating ecosystem services, the benefits nature provides to people, into strategies for meeting the SDGs can help achieve this. Many development goals are likely underpinned by the delivery of one or more ecosystem services. Understanding how these services could support multiple development targets will be essential for planning synergistic and cost-effective interventions. Here we present the results of an expert survey on the contributions of 16 ecosystem services to achieving SDG targets linked to environment and human well-being, and review the capacity of modelling tools to evaluate SDG-relevant ecosystem services interactions. Survey respondents judged that individual ecosystem services could make important contributions to achieving 41 targets across 12 SDGs. The provision of food and water, habitat & biodiversity maintenance, and carbon storage & sequestration were perceived to each make contributions to > 14 SDG targets, suggesting cross-target interactions are likely, and may present opportunities for synergistic outcomes across multiple SDGs. Existing modelling tools are well-aligned to support SDG-relevant ecosystem service planning. Together, this work identifies entry points and tools to further analyze the role of ecosystem services to support the SDGs.
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46.
  • Arnold, Staci D., et al. (author)
  • The Impact of Donor Type on Outcomes and Cost of Allogeneic Hematopoietic Cell Transplantation for Pediatric Leukemia : A Merged Center for International Blood and Marrow Transplant Research and Pediatric Health Information System Analysis
  • 2020
  • In: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 26:9, s. 1747-1756
  • Journal article (peer-reviewed)abstract
    • Allogeneic hematopoietic stem cell transplantation (alloHCT) may be associated with significant morbidity and mortality, resulting in increased healthcare utilization (HCU). To date, no multicenter comparative cost analyses have specifically evaluated alloHCT in children with acute leukemia. In this retrospective cohort study, we examined the relationship between survival and HCU while investigating the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower inpatient HCU with unrelated donor (URD) alloHCT, and that among URDs, umbilical cord blood (UCB) alloHCT will have higher initial utilization but lower long-term utilization. Clinical and transplantation outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were merged with inpatient cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. The merged dataset comprised US patients age 1 to 21 years who underwent alloHCT for acute leukemia between 2004 and 2011 with comprehensive CIBMTR data at a PHIS hospital. AlloHCT was analyzed by donor type, with specific analysis of utilization and costs using PHIS claims data. The primary outcomes of overall survival (OS), leukemia-free survival (LFS), and inpatient costs were evaluated using Kaplan-Meier curves and Cox and Poisson models. A total of 632 patients were identified in both the CIBMTR and PHIS data. The 5-year LFS was 60% for MSD alloHCT, 47% for well-matched matched unrelated donor bone marrow (MUD) alloHCT, 48% for mismatched unrelated donor alloHCT, and 45% for UCB alloHCT (P = .09). Total adjusted costs were significantly lower for MSD alloHCT versus MUD alloHCT by day 100 (adjusted cost ratio [ACR], .73; 95% confidence interval [CI], .62 to .86; P < .001), and higher for UCB alloHCT versus MUD alloHCT (ACR, 1.27; 95% CI, 1.11 to 1.45; P < .001). By 2 years, total adjusted costs remained significantly lower for MSD alloHCT compared with MUD alloHCT (ACR, .67; 95% CI, .56 to .81; P < .001) and higher for UCB alloHCT compared with MUD alloHCT (ACR, 1.25; 95% CI, 1.02 to 1.52; P = .0280). Our data show that UCB and MUD alloHCT provide similar survival outcomes; however, MUD alloHCT has a significant advantage in cost by day 100 and 2 years. More research is needed to determine whether the cost difference among URD alloHCT approaches remains significant with a larger sample size and/or beyond 2 years post-alloHCT.
  •  
47.
  • Lai, Heidi T. M., et al. (author)
  • Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes : Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE)
  • 2022
  • In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 45:4, s. 854-863
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.RESEARCH DESIGN AND METHODS: We included data from an international consortium of 12 prospective cohorts and nested case-control studies from six nations. TFA biomarkers were measured in blood collected between 1990 and 2008 from 25,126 participants aged >= 18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.RESULTS: During a mean follow-up of 13.5 years, 2,843 cases of incident T2D were identified. In multivariable-adjusted pooled analyses, no significant associations with T2D were identified for trans/trans-18:2, relative risk (RR) 1.09 (95% CI 0.94-1.25); cis/trans-18:2, 0.89 (0.73-1.07); and trans/cis-18:2, 0.87 (0.73-1.03). Trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated with T2D (RR 0.81 [95% CI 0.67-0.99], 0.86 [0.75-0.99], and 0.84 [0.74-0.96], respectively). Findings were not significantly different according to prespecified sources of potential heterogeneity (each P >= 0.1).CONCLUSIONS: Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.
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48.
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49.
  • McCarthy, Shane, et al. (author)
  • A reference panel of 64,976 haplotypes for genotype imputation
  • 2016
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1279-1283
  • Journal article (peer-reviewed)abstract
    • We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
  •  
50.
  • Rhodes, Olin E., et al. (author)
  • Integration of ecosystem science into radioecology : A consensus perspective
  • 2020
  • In: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 740
  • Journal article (peer-reviewed)abstract
    • In the Fall of 2016 a workshop was held which brought together over 50 scientists from the ecological and radiological fields to discuss feasibility and challenges of reintegrating ecosystem science into radioecology. There is a growing desire to incorporate attributes of ecosystem science into radiological risk assessment and radioecological research more generally, fueled by recent advances in quantification of emergent ecosystem attributes and the desire to accurately reflect impacts of radiological stressors upon ecosystem function. This paper is a synthesis of the discussions and consensus of the workshop participant's responses to three primary questions, which were: 1) How can ecosystem science support radiological risk assessment? 2) What ecosystem level endpoints potentially could be used for radiological risk assessment? and 3) What inference strategies and associated methods would be most appropriate to assess the effects of radionuclides on ecosystem structure and function? The consensus of the participants was that ecosystem science can and should support radiological risk assessment through the incorporation of quantitative metrics that reflect ecosystem functions which are sensitive to radiological contaminants. The participants also agreed that many such endpoints exit or are thought to exit and while many are used in ecological risk assessment currently, additional data need to be collected that link the causal mechanisms of radiological exposure to these endpoints. Finally, the participants agreed that radiological risk assessments must be designed and informed by rigorous statistical frameworks capable of revealing the causal inference tying radiological exposure to the endpoints selected for measurement.
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