| 1. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 2. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 3. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 4. |
- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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| 5. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 6. |
- Williamson, Alice, et al.
(författare)
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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
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Tidskriftsartikel (refereegranskat)abstract
- Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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| 7. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 8. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 9. |
- Buschur, Kristina L., et al.
(författare)
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Distinct COPD subtypes in former smokers revealed by gene network perturbation analysis
- 2023
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChronic obstructive pulmonary disease (COPD) varies significantly in symptomatic and physiologic presentation. Identifying disease subtypes from molecular data, collected from easily accessible blood samples, can help stratify patients and guide disease management and treatment.MethodsBlood gene expression measured by RNA-sequencing in the COPDGene Study was analyzed using a network perturbation analysis method. Each COPD sample was compared against a learned reference gene network to determine the part that is deregulated. Gene deregulation values were used to cluster the disease samples.ResultsThe discovery set included 617 former smokers from COPDGene. Four distinct gene network subtypes are identified with significant differences in symptoms, exercise capacity and mortality. These clusters do not necessarily correspond with the levels of lung function impairment and are independently validated in two external cohorts: 769 former smokers from COPDGene and 431 former smokers in the Multi-Ethnic Study of Atherosclerosis (MESA). Additionally, we identify several genes that are significantly deregulated across these subtypes, including DSP and GSTM1, which have been previously associated with COPD through genome-wide association study (GWAS).ConclusionsThe identified subtypes differ in mortality and in their clinical and functional characteristics, underlining the need for multi-dimensional assessment potentially supplemented by selected markers of gene expression. The subtypes were consistent across cohorts and could be used for new patient stratification and disease prognosis.
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| 10. |
- Gorski, Mathias, et al.
(författare)
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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| 11. |
- Simpson, Phoebe, et al.
(författare)
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Training of Physical Therapists to Deliver Individualized Biopsychosocial Interventions to Treat Musculoskeletal Pain Conditions : A Scoping Review
- 2021
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Ingår i: Physical Therapy. - : Oxford University Press. - 0031-9023 .- 1538-6724. ; 101:10
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Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE: Current guidelines recommend management of musculoskeletal pain conditions from a biopsychosocial approach, however biopsychosocial interventions delivered by physical therapists vary considerably in effectiveness. It is unknown whether the differences are explained by the intervention itself, the training and/or competency of physical therapists delivering the intervention, or fidelity of the intervention. The aim was to investigate and map the training, competency assessments and fidelity checking of individualized biopsychosocial interventions delivered by physical therapists to treat musculoskeletal pain conditions.METHODS: A scoping review methodology was employed, using Arksey and O'Malley's framework. Seven electronic databases were searched between January to March 2019, with a bridge search completed in January 2020. Full text peer-reviewed papers, with an individualized biopsychosocial intervention were considered, and thirty-two studies were included.RESULTS: Reporting overall was sparse and highly variable. There was a broad spectrum of the training. More sophisticated training involved workshops combining didactic and experiential learning, over longer durations with supervision and feedback. Less sophisticated training was brief, involving lectures or seminars, with no supervision or feedback. Competency assessments and fidelity testing were underperformed.CONCLUSION: Training in some interventions may not have facilitated the implementation of skills or techniques to enable the paradigm shift and behavior change required for physical therapists to effectively deliver a biopsychosocial intervention. Lack of competency assessments and fidelity checking may have impacted on the methodological quality of biopsychosocial interventions.IMPACT: This study highlighted problematic reporting, training, assessment of competency and fidelity checking of physical therapist delivered individualized biopsychosocial interventions. Findings here highlight why previous interventions may have shown small effect sizes and areas for improvement in future interventions. These findings can help inform future research and facilitate more widespread implementation of physical therapist delivered biopsychosocial interventions for people with musculoskeletal pain and thereby improve their quality of life.
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| 12. |
- Young, William J., et al.
(författare)
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Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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| 13. |
- Albert, Christian, et al.
(författare)
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Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy : A Systematic Review and Meta-analysis
- 2020
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Ingår i: American Journal of Kidney Diseases. - : Elsevier BV. - 0272-6386 .- 1523-6838. ; 76:6, s. 826-
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Forskningsöversikt (refereegranskat)abstract
- Rationale & Objective: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction.Study Design: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines.Setting & Study Populations: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms.Selection Criteria for Studies: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI.Data Extraction: Individual-study-data meta analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis.Analytical Approach: Individual-study-data meta analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses.Results: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.790.81) and 0.86 (95% CI, 0.84-0.8 6). Cutoff concentrations at 95% specificity for urinary NGAL were >580 ng/mL with 27% sensitivity for severe AKI and >589 ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were >364 ng/mL with 44% sensitivity and >546 ng/mL with 26% sensitivity, respectively.Limitations: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. Conclusions: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.
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| 14. |
- Andersson, Linus, et al.
(författare)
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Efficient nonlinear reduced order modeling for dynamic analysis of flat structures
- 2023
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Ingår i: Mechanical Systems and Signal Processing. - : Elsevier BV. - 0888-3270. ; 191
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Tidskriftsartikel (refereegranskat)abstract
- In the present paper, strategies for reduced order modeling of geometrically nonlinear finite element models are investigated. Simulation-free, non-intrusive approaches are considered, which do not require access to the source code of a finite element program (e.g., proprietary knowledge). Our study focus on but is not restricted to flat structures. Reduction bases are generated using bending modes and the associated modal derivatives, which span the additional subspace needed for an adequate approximation of the geometrically nonlinear response. Moreover, the reduced nonlinear restoring forces are expressed as third order polynomials in modal coordinates. Consequently, the reduced systems can be effectively solved using time-integration schemes involving only the reduced coordinates. A bottleneck in the non-intrusive methods is typically the computational effort for precomputing the polynomial coefficients and generating the reduction basis. In this regard, we demonstrate that modal derivatives have several useful properties. In particular, the modal derivatives essentially provide all the information needed for generating the polynomial coefficients for the in-plane coordinates. For condensed systems, which ignores the inertia of the in-plane modes, we show that the modal derivatives can be used effectively for recovering the in-plane displacements. Based on these findings, we propose a methodology for generating reduced order models of geometrically nonlinear flat structures in a computationally efficient manner. Moreover, we demonstrate that the concepts extend also to curved structures. The modeling techniques are validated by means of numerical examples of solid beam models and continuously supported shell models. The computational efficiency of the proposed methodology is evaluated based on the number of static evaluations needed for identifying the polynomial coefficients, as compared to the state-of-the-art methods. Furthermore, strategies for efficient time integration are discussed and evaluated.
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| 15. |
- Andersson, Linus, et al.
(författare)
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Model reduction for structures subjected to blast loading by use of dynamic substructuring
- 2020
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Ingår i: EURODYN 2020 - 11th International Conference on Structural Dynamics, Proceedings. - 2311-9020. - 9786188507210 ; 2, s. 2544-2564
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Konferensbidrag (refereegranskat)abstract
- In the present study, strategies are developed to enable time-efficient models for structures subjected to blast loading, appropriate for use in a structural design process. Dynamic sub structuring is employed to obtain reduced models with localized nonlinearities, such as predefined plastic hinges in a beam column structure. The parts of the substructures that remains linear elastic are modeled by Ritz-vectors whereas parts with a nonlinear response are retained as physical degrees-of-freedom. Furthermore, a time-stepping method is presented that is shown to be suitable for reduced models including local and predefined rigid-plastic behavior. The proposed methodology is applied and demonstrated in a numerical example of a concrete frame structure. Both the well-established Craig-Bampton method and reduction bases enriched by so-called correction modes are evaluated. For the load case studied, it is shown that the standard Craig-Bampton technique is suitable for reducing the substructures. Furthermore, it is shown that only a few Ritz-vectors are needed to sufficiently describe the deformation of the structure. However, additional modes are needed to ensure an accurate representation of the interface forces between the substructures.
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| 16. |
- Andersson, Linus, et al.
(författare)
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Reduced order modeling of soft-body impact on glass panels
- 2022
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Ingår i: Engineering Structures. - : Elsevier BV. - 0141-0296. ; 256
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Tidskriftsartikel (refereegranskat)abstract
- In the paper, strategies for reduced order modeling of glass panels subjected to soft-body impact are developed by means of dynamic substructuring. The aim is to obtain accurate and computationally efficient models for prediction of the pre-failure elastic response. More specifically, a reduction basis for the subsystem representing the glass panel is established using correction modes, being fixed-interface component modes that considers loading on the substructure boundary. The soft-body impactor is effectively modeled by a nonlinear single-degree-of-freedom system, calibrated by experimental data. Furthermore, a simplified and computationally efficient modeling approach is proposed for the contact interaction between the glass panel and the impact body. An experimental campaign was carried out to validate the developed models. In particular, the glass strain was measured on simply supported monolithic glass panels subjected to soft-body impact. Additional impact tests were performed to determine the dynamic characteristics of the impactor. Moreover, a detailed numerical reference model was developed to evaluate the discrepancy between the experimental tests and the results provided by the reduced order models. The developed models show good agreement with the experimental results. For the studied load cases, it is shown that an accurate prediction of the pre-failure glass strain can be obtained by systems including only a few generalized degrees-of-freedom.
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| 17. |
- Brown, Brielin C., et al.
(författare)
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Multiset correlation and factor analysis enables exploration of multi-omics data
- 2023
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Ingår i: Cell Genomics. - : Elsevier BV. - 2666-979X. ; 3:8, s. 100359-
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Tidskriftsartikel (refereegranskat)abstract
- Multi-omics datasets are becoming more common, necessitating better integration methods to realize their revolutionary potential. Here, we introduce multi-set correlation and factor analysis (MCFA), an unsupervised integration method tailored to the unique challenges of high-dimensional genomics data that enables fast inference of shared and private factors. We used MCFA to integrate methylation markers, protein expression, RNA expression, and metabolite levels in 614 diverse samples from the Trans-Omics for Precision Medicine/Multi-Ethnic Study of Atherosclerosis multi-omics pilot. Samples cluster strongly by ancestry in the shared space, even in the absence of genetic information, while private spaces frequently capture dataset-specific technical variation. Finally, we integrated genetic data by conducting a genome-wide association study (GWAS) of our inferred factors, observing that several factors are enriched for GWAS hits and trans-expression quantitative trait loci. Two of these factors appear to be related to metabolic disease. Our study provides a foundation and framework for further integrative analysis of ever larger multi-modal genomic datasets.
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| 18. |
- Buli, Benti Geleta
(författare)
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Mental health problems among adolescents in Sweden : Analysis of trends, developmental trajectories, and associated factors
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to investigate trends and trajectories of mental health problems and associated factors among adolescents in Sweden. The project consisted of four studies, with the first presenting trends and the subsequent ones exploring influencing factors. The first two studies used data from SALVe, repeated cross-sectional surveys from 2004 – 2020, while the third used national HBSC data from 2002 – 2018. Study IV was based on data from SALVe cohorts conducted among young people born in 1997 and 1999 where data were collected in four waves every three years from 2012 – 2021. Study I investigated trends in mental health problems among adolescents in Västmanland County, revealing an overall decrease but disparities based on socioeconomic status (SES) and sex. Higher SES was associated with reduced mental health problems, while lower SES showed an increase. Girls exhibited a more pronounced decrease in depressive symptoms and suicidal ideations than boys. Study II, using the same dataset, confirmed these trends and identified school-related factors influencing mental health problems, with improvements correlating with reduced problems in the high SES group. Study III found a significant increase in PSS over time, higher in girls, and linked to lifestyle factors, particularly alcohol drunkenness among high SES adolescents. Study IV focused on cohorts born in 1997 and 1999, exploring the impact of family and peer relationships on depressive and anxiety symptoms among young people.The results indicate that intermediary factors, including school-related factors, lifestyle choices, and social relationships, which vary across SES gradients, are linked to adolescent mental health problems. The associations between these intermediary factors and the mental health problems were, in most cases, influenced by a group of factors, including SES, sex, country of origin, and birth cohort, collectively named structural determinants. These determinants discriminated results between boys and girls, high SES and low SES, Nordic and non-Nordic origin, and the 1997 and 1999 cohorts. This underscores the need for at least two-tiered policy intervention. The first involves an immediate to mid-term response, targeting these intermediary factors with a special focus on the low SES group, girls, and young people with foreign backgrounds. The second entails a long-term policy intervention to narrow the divide.
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| 19. |
- Buli, Benti Geleta, et al.
(författare)
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Trends in adolescent mental health problems 2004–2020 : do sex and socioeconomic status play any role?
- 2023
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Ingår i: Scandinavian Journal of Public Health. - 1403-4948 .- 1651-1905.
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Tidskriftsartikel (refereegranskat)abstract
- Aims: This study aims to investigate trends in four types of adolescent mental health problems; that is, psychosomatic symptoms, depressive symptoms, suicidal ideations, and suicide attempts 2004–2020. A second aim is to investigate the moderating roles of socioeconomic status and sex in these trends.Methods: The analysis is based on repeated cross-sectional data 2004–2020 among grade 9 students in secondary schools in a Swedish county. In total, data from 19,873 students were included in the analysis. We fitted linear and logistic regression equations and used survey-years’ coefficients to estimate the trends. We also estimated the moderating effects of socioeconomic status and sex using interactions between survey year and socioeconomic status and sex, respectively.Results: The trends in all mental health problems declined over time. Through its interaction with survey year, socioeconomic status moderated the trends; psychosomatic symptoms (B = −0.115, P<0.001), depressive symptoms (B = −0.084, P<0.001) and suicidal ideations (odds ratio 0.953, confidence interval 0.924–0.983) significantly declined over time among those with high socioeconomic status. However, socioeconomic status did not have an association with the trend in suicide attempts. Interaction between sex and year of survey was associated with significant decreasing trends in depressive symptoms and suicidal ideations only among girls.Conclusions: Adolescent mental health problems have decreased over time, but only for adolescents with high socioeconomic status, or only in depressive symptoms and suicidal ideations for girls. The results shed light on the growing inequalities in health outcomes across levels of socioeconomic status.
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| 20. |
- Buli, Benti Geleta, et al.
(författare)
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Trends in adolescent mental health problems and the role of lifestyle factors
- 2023
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background:Adolescent mental health problems are on the rise globally, including in Sweden. One indicator is an increase in psychosomatic symptoms (PSS) over time. Lifestyle factors such as physical activity (PA), diet, smoking, and alcohol consumption may influence the trends in PSS. However, we found limited research on such associations.Methods:This study is based on data collected every four years from nationally representative samples of 15-year-old boys and girls in Sweden (N = 9,196, 50.5% girls), as part of the Health Behavior in School-aged Children (HBSC) study. PSS was measured using a scale developed from the HBSC symptom checklist. We analyzed the trends in PSS from 2002 to 2018 and fitted models to investigate the associations between the trends and lifestyle factors. We included interaction terms between time and each lifestyle factor and fitted separate models for the high and low socioeconomic status (SES) groups.ResultsIn general, the mean scores for PSS increased from 2.26 in 2002 to 2.49 in 2018 (p<.001). Compared to the average mean scores during preceding years, the changes in PSS mean scores at each survey year were also significant in all years except 2010. More frequent breakfast intake, daily consumption of fruits and vegetables, and higher PA were associated with lower PSS mean scores while smoking and alcohol consumption had the opposite association. The only significant interaction (B = .050; CI: .015, ¬ .085; p<.01) was observed in the high SES group, indicating that the increasing trend in PSS was stronger among those who had been drunk once or more in a lifetime, compared to those who had never been drunk.ConclusionsThe results indicate increasing trends in mental health problems among young people in Sweden. Furthermore, the study revealed that alcohol drunkenness was associated with a more substantial rise in PSS over time among those in the high SES group. Further research is needed to understand the reasons behind these findings.
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| 21. |
- Buli, Benti Geleta, et al.
(författare)
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Trends in mental health problems among Swedish adolescents : Do school-related factors play a role?
- 2024
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Ingår i: PLOS ONE. - 1932-6203. ; 19:3
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Tidskriftsartikel (refereegranskat)abstract
- AimThe aim of this study is to investigate the extent to which school-related factors, such as school liking, participation in decision-making, school-related parental support, teachers’ support, and school physical environment, explain trends in mental health problems. The problems considered are psychosomatic symptoms (PSS), depressive symptoms (DS), suicidal ideations (SI), and suicide attempts (SA) among Swedish adolescents of varying socioeconomic status (SES) from 2004 to 2020.MethodsWe analyzed data collected through repeated cross-sectional surveys from 19,873 15-year-old students at schools in a county in Sweden. Boys and girls each constituted 50% of the participants. We fitted linear and logistic regression models to investigate associations between the school-related factors and trends in mental health problems.ResultsIncreased school-related parental support and school liking were cross-sectionally associated with decreased PSS, DS and SI, with school liking also associated with decreased SA. Conducive school physical environment was also found to be cross-sectionally associated with lower PSS and DS scores. Over time, mental health problems have shown a general increase among adolescents in the low SES group and a decrease among those in the high SES group. While school-related factors explained the improvement in mental health in the high SES group, we found such association only between parental support trends in PSS and DS, along with participation and trends in SA over time among adolescents in the low SES group.ConclusionsThe results show that school-related factors play significant roles in influencing adolescent mental health. The influence, however, varied across SES gradients over time. This suggests that working against inequities in school-related factors would help address inequities in mental health.
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| 22. |
- Buli, Benti Geleta, et al.
(författare)
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Trends in psychosomatic symptoms among adolescents and the role of lifestyle factors
- 2024
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Ingår i: BMC Public Health. - 1471-2458. ; 24
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Tidskriftsartikel (refereegranskat)abstract
- Background Adolescent mental health problems are on the rise globally, including in Sweden. One indicator of this trend is increased psychosomatic symptoms (PSS) over time. Lifestyle factors such as physical activity (PA), diet, smoking, and alcohol consumption may influence the time trends in PSS; however, the evidence base is scarce. The aim of this study was to investigate associations between time trends in PSS and lifestyle factors.Methods The study was based on data collected from a nationally representative sample of 9,196 fifteen-year-old boys and girls in Sweden using the Health Behavior in School-aged Children (HBSC) symptom checklist. The sample comprised nearly equal proportions of girls (50.5%) and boys. The lifestyle factors examined in this study included PA, regular breakfast intake, consumption of fruits, vegetables, sweets, or soft drinks, smoking, and alcohol drunkenness. We used data from 2002 to 2018 and stratified by family affluence scale (FAS) to demonstrate how the associations varied among the FAS groups. We fitted separate regression models for the high- and low-FAS groups, where interaction terms between the year of survey and each lifestyle factor were used to estimate the level and direction of associations between the factors and trends in PSS.Results There was a generally increasing trend in PSS mean scores from 2.26 in 2002 to 2.49 in 2018 (p <.001). The changes in each survey year compared to the average mean scores during the preceding years were significant in all years except 2010. Regular breakfast intake, daily fruit and vegetable consumption, and higher PA were associated with lower PSS mean scores, while smoking and drunkenness had opposite associations with PSS. The only significant interaction between survey year and the lifestyle factors was observed regarding drunkenness in the high FAS group, suggesting that the association between trends in PSS and the experience of getting drunk at least twice got stronger over time (B = 0.057; CI:0.016, 0.097; p <.01).Conclusions The results indicate increasing trends in PSS among young people in Sweden from 2002 to 2018, with a significant increase observed among adolescents in the high FAS group who reported getting drunk on at least two occasions.
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| 23. |
- Castillo, Daniel, 1977-, et al.
(författare)
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Brott i nära relation : Polisiär utredningsverksamhet på lokal eller central nivå?
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Utgångspunkten för den här rapporten är frågan om det spelar någon roll var i polisorganisationen utredningar av brott i nära relation genomförs. Genom intervjuer med polisanställda på polisområdes- och lokalpolisområdesnivå, åklagare och andra verksamhetsexperter har frågor om utredningsorganisation, arbetsmiljö, samverkan och utredningsresultat avseende brott i nära relation undersökts inom ramen för en försöksverksamhet vid tre lokalpolisområden. Studien visar att det finns såväl för- som nackdelar med att decentralisera utredningar av brott i nära relation. Fördelarna är bland annat ökade möjligheter till samverkan såväl internt som med det omkringliggande samhället medan nackdelarna kan vara att den specialiserade utredningsverksamheten riskerar att integreras med andra arbetsuppgifter vid lokalpolisområdet.
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| 24. |
- Draper-Joyce, Christopher J., et al.
(författare)
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Positive allosteric mechanisms of adenosine A(1) receptor-mediated analgesia
- 2021
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 597:7877, s. 571-576
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Tidskriftsartikel (refereegranskat)abstract
- The adenosine A(1) receptor (A,R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain(1,2). However, development of analgesic orthosteric A(1)R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects(3). Here we show that [2-amino-4-(3,5-bis(trifluoromethyl) phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A(1)R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the co-bound to adenosine, MIPS521 and a G(12) heterotrimer, revealing an extrahelicallipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.
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| 25. |
- Giannotta, Fabrizia, et al.
(författare)
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Among the swedish generation of adolescents who experience an increased trend of psychosomatic symptoms. Do they develop depression and/or anxiety disorders as they grow older?
- 2022
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Ingår i: BMC Psychiatry. - : NLM (Medline). - 1471-244X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Despite an increase in mental health problems, with psychosomatic symptoms having been observed in new generations of Swedish youth, the extent to which these problems correspond to an increase in adult mental problems is unknown. The present study investigates whether Swedish adolescents with high levels of psychosomatic symptoms are at risk of developing depression and anxiety problems in adulthood and whether sex moderates any association. Moreover, we aim to understand whether different clusters of youth psychosomatic symptoms - somatic, psychological and musculoskeletal - have different impacts on adult mental health. METHODS: One thousand five hundred forty-five Swedish adolescents - aged 13 (49%) and 15 (51%) - completed surveys at baseline (T1) and 3 years later (T2); of them, 1174 (61% females) also participated after 6 years (T3). Multivariate logistic models were run. RESULTS: Youth with high levels of psychosomatic symptoms had higher odds of high levels of depressive symptoms at T2 and T3. Moreover, psychosomatic symptoms at T1 predicted a high level of anxiety symptoms and diagnoses of anxiety disorders at T3. When analyzed separately, musculoskeletal symptoms predicted higher odds of having high levels of depressive symptoms at T2 and T3 while somatic symptoms predicted high levels of anxiety symptoms at T2. Moreover, somatic symptoms at T1 predicted diagnoses of depression and anxiety disorders at T3. Sex did not moderate any of the relationships. CONCLUSIONS: The study supports the idea that an increase in mental health problems, such as psychosomatic symptoms, can seriously impact the psychological health of new generations of young adults.
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| 26. |
- Giannotta, Fabrizia, 1978-, et al.
(författare)
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Frequency of vigorous physical activity and depressive symptoms across adolescence : Disentangling the reciprocal associations between different groups and subtypes of symptoms
- 2023
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Ingår i: Mental Health and Physical Activity. - : Elsevier BV. - 1755-2966 .- 1878-0199. ; 25
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity has a demonstrated positive effect on youth depressive symptoms. However, very few studies have explored the bi-directionality of the links between physical activity and depression. The present study aims at filling this gap and tests whether any associations are moderated by sex. Moreover, the role of subtype of depressive symptoms, vegetative (i.e., lack of energy, poor sleep) or non-vegetative (i.e., mood-related), is explored. Participants were 910 12-13 year-old Swedish adolescents (56% girls) who answered a three-wave survey at ages 12-13 (T1), 15-16 (T2), and 18-19 (T3). Using a cross-lagged structural model, depression predicted decreased frequency of vigorous physical activity (VPA) from T1 to T2 (& beta; = -0.09, p < .05) and from T2 to T3 (& beta; = -0.10, p < .01), while frequency of VPA at T2 decreased depression at T3 (& beta; = -0.12, p < .05). Associations did not differ between boys and girls. Non-vegetative symptoms predicted decreased frequency of VPA from T1 to T2 (& beta; = -0.10, p < .05), while frequency of VPA at T2 predicted decreased non-vegetative symptoms at T3 (& beta; = -0.15, p < .05). Vegetative symptoms predicted decreased frequency of VPA from T1 to T2 (& beta; = -0.09, p < .05), while have a reciprocal influence with VPA from T2 to T3. Overall, our results highlight an association across adolescence between VPA and depression. The association becomes stronger and reciprocal in middle adolescence, which suggests this period as an effective developmental time to plan physical-activity-based interventions to decrease youth depressive symptoms.
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| 27. |
- Hult, Gunnar, Professor, 1952-, et al.
(författare)
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Technology Forecast 2021 – Military Utility of Future Technologies
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- For the purpose of Technology Forecast 2021 five reports from the German Fraunhofer Institute were chosen by FMV (and SwAF) and given to Systems Science for Defence and Security Division to analyse and assess within the timeframe up to 2040.The following research reports were reviewed by the working group at SEDU:· Adversarial Machine Learning · High Entropy Ceramics· Large Unmanned Underwater Vehicles· Living Sensors· Machine Learning in Materials DevelopmentThe aim of the Technology Forecast seminars and the finished product, this report, is to assess the potential military utility of the reviewed technologies and how they may contribute to the Swedish Armed Forces’ operational capabilities based on the presented concept(s) and scenario(s). The military utility is categorised by one of four assessments: Significant, Moderate, Negligible or Uncertain.The following technologies were assessed to potentially have significant military utility:· High Entropy Ceramics· Machine Learning in Materials Development· Adversarial Machine LearningThe following technology was assessed to potentially have moderate military utility:· Large Unmanned Underwater Vehicles The following technology was assessed to have uncertain military utility:· Living Sensors
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| 28. |
- In ’t Veld, Sjors G.J.G., et al.
(författare)
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Detection and localization of early- and late-stage cancers using platelet RNA
- 2022
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Ingår i: Cancer Cell. - : Elsevier. - 1535-6108 .- 1878-3686. ; 40:9, s. 999-1009.e6
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Tidskriftsartikel (refereegranskat)abstract
- Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.
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| 29. |
- Karell, Patrik, et al.
(författare)
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Mammalian nest predation induces small-scale nest site switching in territorial tawny owl (Strix aluco) females
- 2020
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Ingår i: Ornis Fennica. - 0030-5685. ; 97:2, s. 45-52
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Tidskriftsartikel (refereegranskat)abstract
- Nest predation is a major factor affecting fitness in birds. Individuals are expected to respond to nest predation by selecting safe nesting sites and by moving away from risky sites. Thereby, perceived risk or experience of predation should lead to shifts in nest site selection. Experimental studies on behavioural and life-history consequences of nest predation have traditionally manipulated the risk of predation and studied the immediate consequences thereof. Fewer studies have however analysed the behavioural consequences of perceived predation risk to future breeding events and we know little about how sedentary territorial species respond to nest predation. We experimentally manipulated tawny owl (Strix aluco) breeding nest site choice by providing an additional alternative nest box within the territory, nearby the original nesting sites. The new nest box was provided either after a successful reproductive event (control group), or following a failed reproductive event caused by a nest predator (i.e. pine marten Martes martes, predated group). We show that tawny owls generally switched to the alternative nest site in the current breeding season when the nest was predated in the previous year, whereas they used the same nest after a successful breeding. We found no effects of previous predation experience on the probability to breed nor on clutch size. We conclude that small scale movement within the territory are used by tawny owls to minimize predation risk and that the owls use information on past predation events and nest failure to optimize their breeding decision in the following season.
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| 30. |
- Kasela, Silva, et al.
(författare)
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Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects
- 2024
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 111:1, s. 133-149
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Tidskriftsartikel (refereegranskat)abstract
- Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.
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| 31. |
- Larm, Peter, et al.
(författare)
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Do non-drinking youth drink less alcohol in young adulthood or do they catch up? : Findings from a Swedish birth cohort
- 2023
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Ingår i: European Journal of Public Health. - : Oxford University Press. - 1101-1262 .- 1464-360X. ; 33:4, s. 640-644
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Tidskriftsartikel (refereegranskat)abstract
- Background Alcohol consumption among adolescents has declined considerably during the last two decades. However, it is unknown if these adolescents' alcohol consumption will remain low as they grow older. To our knowledge, this is one of the first studies that uses longitudinal data to examine if non-drinking adolescents have a lower alcohol consumption in young adulthood or if they catch up. Methods A self-report survey was distributed to a birth cohort (n = 794) born in 1997 in a Swedish region when cohort members attended ninth grade (age 14-15 years) in 2012. Responders were divided into non-drinkers and alcohol users and assessed again in their late teens (17-18 years) and young adulthood (20-21 years). Results In their late teens (17-18 years), non-drinkers at baseline consumed less alcohol and had a lower probability of harmful use compared with their alcohol-using peers. In young adulthood (20-21 years), these effects disappeared when adjustment was made for covariates. However, a stratified analysis showed that non-drinking adolescents low in conduct problems consumed less alcohol and had a lower probability of harmful use in young adulthood than alcohol-using peers. Conclusions This study suggests that the decline in alcohol use among adolescents in the past decades may be associated with a lower alcohol consumption in the late teens and young adulthood among those low in conduct problems. This may have promising implications for alcohol-related morbidity and mortality.
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| 32. |
- Lee, Catherine J., et al.
(författare)
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Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia
- 2020
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 4:6, s. 983-992
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Tidskriftsartikel (refereegranskat)abstract
- There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.
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| 33. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 34. |
- Schweinsberg, Martin, et al.
(författare)
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Same data, different conclusions : Radical dispersion in empirical results when independent analysts operationalize and test the same hypothesis
- 2021
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Ingår i: Organizational Behavior and Human Decision Processes. - : Elsevier BV. - 0749-5978 .- 1095-9920. ; 165, s. 228-249
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Tidskriftsartikel (refereegranskat)abstract
- In this crowdsourced initiative, independent analysts used the same dataset to test two hypotheses regarding the effects of scientists' gender and professional status on verbosity during group meetings. Not only the analytic approach but also the operationalizations of key variables were left unconstrained and up to individual analysts. For instance, analysts could choose to operationalize status as job title, institutional ranking, citation counts, or some combination. To maximize transparency regarding the process by which analytic choices are made, the analysts used a platform we developed called DataExplained to justify both preferred and rejected analytic paths in real time. Analyses lacking sufficient detail, reproducible code, or with statistical errors were excluded, resulting in 29 analyses in the final sample. Researchers reported radically different analyses and dispersed empirical outcomes, in a number of cases obtaining significant effects in opposite directions for the same research question. A Boba multiverse analysis demonstrates that decisions about how to operationalize variables explain variability in outcomes above and beyond statistical choices (e.g., covariates). Subjective researcher decisions play a critical role in driving the reported empirical results, underscoring the need for open data, systematic robustness checks, and transparency regarding both analytic paths taken and not taken. Implications for orga-nizations and leaders, whose decision making relies in part on scientific findings, consulting reports, and internal analyses by data scientists, are discussed.
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| 35. |
- Sun, Jing, 1987-
(författare)
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Integration of BIM and 3D GIS for sustainable cadastre
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Building Information Modelling (BIM) has prominently innovated and digitalized buildingenvironment through digital representation of buildings, lifecycle process and managementfor involved actors. Rapidly developed from Geographical Information System (GIS) domain,three-dimensionally (3D) GIS provides powerful and comprehensive functions of planning,modelling, visualizing and analyzing 3D geodata in large scale. BIM and 3D GIS, both asmodern 3D spatial technologies, overlap partly but focus on different purposes andapplications with own international standards, for example Industry Foundation Classes (IFC)for BIM and CityGML for 3D GIS respectively. Therefore, the sharing and integration of BIMdata and geodata is mutually beneficial for comprehensive 3D city modelling.The cadastre playing a pivotal role of land use is a land information system that records legaland spatial information of land parcels, traditionally in textual files and 2D cadastral maps. In order to satisfy the needs for better urban land use and avoid ambiguous problems due tomore complex spaces, cadastre is under transition from 2D to 3D for representing, modellingand visualizing property units, rights and boundaries practically.This thesis explores the integration of BIM and 3D GIS for sustainable 3D cadastre from legal,technical, registration and organizational perspectives. The outcomes include a method toevaluate geometric aspects of BIM data quality, a framework for representing and visualizing3D cadastre by integrating Land Administration Domain Model (LADM), BIM and 3D GIS, alifecycle process of 3D property formation developed by Information Delivery Manual (IDM),a business ecosystem-based 3D cadastral management, and cadastre ecosystem. The value ofmultidisciplinary integrating these topics is to fulfil the demands of sustainable urbandevelopment and lifecycle management of cadastre in the digitalization of cadastre and smartcity. Overall, the findings show that the integration of BIM and 3D GIS for 3D cadastre canprovide involved actors with necessary and accurate information, knowledge and insight thatenhances financial, environmental, and social outcomes sustainably for both cities andcitizens.
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| 36. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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| 37. |
- Yu, Zhi, et al.
(författare)
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Genetic modification of inflammation- and clonal hematopoiesis-associated cardiovascular risk
- 2023
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 133:18
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Tidskriftsartikel (refereegranskat)abstract
- Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVDprotective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.
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