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- Gorski, Mathias, et al.
(author)
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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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In: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Journal article (peer-reviewed)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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| 2. |
- Herold, Janina M., et al.
(author)
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Genetic Risk Score Analysis Supports a Joint View of Two Classification Systems for Age-Related Macular Degeneration
- 2023
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In: Investigative Ophthalmology and Visual Science. - 0146-0404 .- 1552-5783. ; 64:12
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Journal article (peer-reviewed)abstract
- Purpose: The purpose of this study was to evaluate the utility of combining the Clinical Classification (CC) and the Three Continent age-related macular degeneration (AMD) Consortium Severity Scale (3CACSS) for classification of AMD.Methods: In two independent cross-sectional datasets of our population-based AugUR study (Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg), we graded AMD via color fundus images applying two established classification systems (CC and 3CACSS). We calculated the genetic risk score (GRS) across 50 previously identified variants for late AMD, its association via logistic regression, and area under the curve (AUC) for each AMD stage.Results: We analyzed 2188 persons aged 70 to 95 years. When comparing the two classification systems, we found a distinct pattern: CC “age-related changes” and CC “early AMD” distinguished individuals with 3CACSS “no AMD”; 3CACSS “mild/moderate/severe early AMD” stages, and distinguished CC “intermediate AMD”. This suggested a 7-step scale combining the 2 systems: (i) “no AMD”, (ii) “age-related changes”, (iii) “very early AMD”, (i.e. CC “early”), (iv) “mild early AMD”, (v) “moderate early AMD”, (vi) “severe early AMD”, and (vii) “late AMD”. GRS association and diagnostic accuracy increased stepwise by increased AMD severity in the 7-step scale and by increased restriction of controls (e.g. for CC “no AMD without age-related changes”: AUC = 55.1%, 95% confidence interval [CI] = 51.6, 58.6, AUC = 62.3%, 95% CI = 59.1, 65.6, AUC = 63.8%, 95% CI = 59.3, 68.3, AUC = 78.1%, 95% CI = 73.6, 82.5, AUC = 82.2%, 95% CI = 78.4, 86.0, and AUC = 79.2%, 95% CI = 75.4, 83.0). A stepwise increase was also observed by increased drusen size and area.Conclusions: The utility of a 7-step scale is supported by our clinical and GRS data. This harmonization and full data integration provides an immediate simplification over using either CC or 3CACSS and helps to sharpen the control group.
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| 4. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 5. |
- Mandrioli, Claudio, et al.
(author)
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Testing self-adaptive software with probabilistic guarantees on performance metrics
- 2020
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In: ESEC/FSE 2020 - Proceedings of the 28th ACM Joint Meeting European Software Engineering Conference and Symposium on the Foundations of Software Engineering. - New York, NY, USA : ACM. - 9781450370431 ; , s. 1002-1014
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Conference paper (peer-reviewed)abstract
- This paper discusses the problem of testing the performance of the adaptation layer in a self-adaptive system. The problem is notoriously hard, due to the high degree of uncertainty and variability inherent in an adaptive software application. In particular, providing any type of formal guarantee for this problem is extremely difficult. In this paper we propose the use of a rigorous probabilistic approach to overcome the mentioned difficulties and provide probabilistic guarantees on the software performance. We describe the set up needed for the application of a probabilistic approach. We then discuss the traditional tools from statistics that could be applied to analyse the results, highlighting their limitations and motivating why they are unsuitable for the given problem. We propose the use of a novel tool - the scenario theory - to overcome said limitations. We conclude the paper with a thorough empirical evaluation of the proposed approach, using two adaptive software applications: the Tele-Assistance Service and the Self-Adaptive Video Encoder. With the first, we empirically expose the trade-off between data collection and confidence in the testing campaign. With the second, we demonstrate how to compare different adaptation strategies.
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| 6. |
- Wärner, Hugo, 1988-
(author)
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High Temperature Fatigue Behaviour of Austenitic Stainless Steel : Microstructural Evolution during Dwell-Fatigue and Thermomechanical Fatigue
- 2021
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Doctoral thesis (other academic/artistic)abstract
- The global energy consumption is increasing and together with global warming from greenhouse gas emission, a need for more environmentally friendly energy production processes is created. Higher efficiency of biomass power plants can be achieved by increasing temperature and pressure in the boiler section, this would increase the generation of electricity along with the reduction in emission of greenhouse gases e.g. CO2. The generation of power must also be flexible to be able to follow the demands of the energy market and this results in a need for cyclic operating conditions with alternating output and multiple start-ups and shut-downs.Because of the need for flexibility, higher temperature and higher pressure of future biomass power plants, the demands of improved mechanical properties of the materials used for the components are also increased. Properties like creep strength, maintained structural integrity, thermomechanical fatigue resistance and high temperature corrosion resistance are critical for materials used in the next generation biomass power plants. Highly alloyed austenitic stainless steels are known to possess such good high temperature properties and are relatively cheap compared to the nickel-base alloys, which are already used in high temperature cyclic conditions for other applications. The behaviour of austenitic stainless steels subjected to future biomass power plants operating conditions are not yet fully investigated.This thesis presents research that includes investigations of the mechanical and microstructural behaviour during high temperature cyclic conditions of austenitic stainless steels. This is done using thermomechanical fatigue testing, dwell-fatigue testing and impact toughness testing at elevated temperatures. Material service degradation as an effect of microstructural evolution is investigated by ageing of some test specimens before testing. Microscopy is used to investigate the connection between the mechanical behaviour and the microstructural deformation- and damage mechanisms of the austenitic stainless steels after testing.The results show that creep-fatigue interaction damage, creep damage and oxidation assisted cracking are present during high temperature cyclic conditions. In addition, ageing results in a less favourable microstructural configuration which negatively affects the resistance to high temperature damage mechanisms. An example of this is the lowering of impact toughness due to precipitation and coarsening of detrimental phases of some aged austenitic stainless steels. Moreover, TMF testing of aged austenitic stainless steels induce oxidation assisted cracking and an embrittling effect that cause significant cyclic life decrease. The creep-fatigue interaction behaviour during dwell-fatigue testing of two austenitic stainless steels generates various crack propagation characteristics. The higher alloyed material shows interchanging intra- and intergranular propagation with dynamic recrystallization, while the lower alloyed material shows propagation exclusively along the grain boundaries by the assistance of fatigue induced slip bands interaction with grain boundary precipitates.The research of this thesis provides a deeper understanding of the structural integrity, deformation mechanisms, damage mechanisms and fracture mechanisms during high temperature cyclic conditions of austenitic stainless steels. Long term, this is believed to contribute to development of suitable materials used as components of future biomass-fired power plants to achieve sustainable power generation.
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