| 51. |
- Repsilber, Dirk, 1971-, et al.
(författare)
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Data rotation improves genomotyping efficiency
- 2005
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Ingår i: Biometrical Journal. - Berlin, Germany : Wiley. - 0323-3847 .- 1521-4036. ; 47:4, s. 585-598
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Tidskriftsartikel (refereegranskat)abstract
- Unsequenced bacterial strains can be characterized by comparing their genomic DNA to a sequenced reference genome of the same species. This comparative genomic approach, also called genomotyping, is leading to an increased understanding of bacterial evolution and pathogenesis. It is efficiently accomplished by comparative genomic hybridization on custom-designed cDNA microarrays. The microarray experiment results in fluorescence intensities for reference and sample genome for each gene. The logratio of these intensities is usually compared to a cut-off, classifying each gene of the sample genome as a candidate for an absent or present gene with respect to the reference genome. Reducing the usually high rate of false positives in the list of candidates for absent genes is decisive for both time and costs of the experiment. We propose a novel method to improve efficiency of genomotyping experiments in this sense, by rotating the normalized intensity data before setting up the list of candidate genes. We analyze simulated genomotyping data and also re-analyze an experimental data set for comparison and illustration. We approximately halve the proportion of false positives in the list of candidate absent genes for the example comparative genomic hybridization experiment as well as for the simulation experiments.
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| 52. |
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| 53. |
- Repsilber, Dirk, 1971-, et al.
(författare)
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Sample selection for microarray gene expression studies
- 2005
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Ingår i: Methods of Information in Medicine. - Stuttgart, Germany : Schattauer Gmbh. - 0026-1270 .- 2511-705X. ; 44:3, s. 461-7
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The choice of biomedical samples for microarray gene expression studies is decisive for both validity and interpretability of results. We present a consistent, comprehensive framework to deal with the typical selection problems in microarray studies.Methods: Microarray studies are designed either as case-control studies or as comparisons of parallel groups from cohort studies, since high levels of random variation in the experimental approach thwart absolute measurements of gene expression levels. Validity and results of gene expression studies heavily rely on the appropriate choice of these study groups. Therefore, the so-called principles of comparability, which are well known from both clinical and epidemiological studies, need to be applied to microarray experiments.Results: The principles of comparability are the study-base principle, the principle of deconfounding and the principle of comparable accuracy in measurements. We explain each of these principles, show how they apply to microarray experiments, and illustrate them with examples. The examples are chosen as to represent typical stumbling blocks of microarray experimental design, and to exemplify the benefits of implementing the principles of comparability in the setting of microarray experiments.Conclusions: Microarray studies are closely related to classical study designs and therefore have to obey the same principles of comparability as these. Their validity should not be compromised by selection, confounding or information bias. The so-called study-base principle, calling for comparability and thorough definition of the compared cell populations, is the key principle for the choice of biomedical samples and controls in microarray studies.
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| 54. |
- Repsilber, Dirk, 1971-, et al.
(författare)
-
Tutorial on microarray gene expression experiments : An introduction
- 2005
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Ingår i: Methods of Information in Medicine. - Stuttgart, Germany : Schattauer Gmbh. - 0026-1270 .- 2511-705X. ; 44:3, s. 392-9
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: With the collection of articles presented in this special issue, we aim at educating interested statisticians and biometricians on the one hand as well as biologists and medical researchers on the other with respect to basic necessities in planning, conducting and analyzing microarray gene expression experiments. The reader should get comprehensive directions to understand both the overall structure of this approach as well as the decisive details, which enable--or thwart--a meaningful data analysis.Methods: For a one-day workshop with tutorial character we brought together experts in design, conduct and analysis of microarray gene expression experiments who prepared a series of comprehensive lessons. These contributions were then reworked into a series of introductory articles and bundled in form and content as a Special Topic.Results: It was possible to present a tutorial overview of the field. The interested reader was able to learn the basic necessities and was referred to further references for details on the possible alternatives. A recipe style all-embracing plan, covering all eventualities and possibilities was not only beyond the scope of an introductory tutorial-like presentation, but was also not yet agreed upon by the scientific society.Conclusions: It proved feasible to find a framework for integrating the interdisciplinary approaches to the challenging field of gene expression analysis with microarrays, hopefully contributing to a rapid and comprehensive introduction for novices.
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| 55. |
- Repsilber, Dirk, 1971-, et al.
(författare)
-
Two-color microarray experiments. Technology and sources of variance
- 2005
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Ingår i: Methods of Information in Medicine. - Stuttgart, Germany : Schattauer Gmbh. - 0026-1270 .- 2511-705X. ; 44:3, s. 400-4
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Microarray gene expression experiments have a complex technical background. Knowledge about certain technical details is inevitable to judge alternatives for both experimental design and analysis. Here, we introduce the necessary details for the so-called two-color microarray experiments and review major sources of technical variance.Methods: We follow the sequence of experimental steps during a typical two-color microarray gene expression experiment, stressing decisive points in the choice of technique, experimental handling and biophysical basics. We point out where technical variation is to be expected.Results: Tissue storage, RNA extraction techniques, as well as the microarray hybridization represent major components of technical variance to be considered. Depending on the possibilities for access to the biomedical material under investigation, choice of amplification and labeling techniques can also be decisive to avoid additional technical variance. The two-color microarray experimental approach seeks to avoid a group of probe-level technical biases making use of the advantages of an incomplete block-design.Conclusions: It is worth to know the major sources of technical variance during the typical experimental sequence, both for choice of experimental design and techniques of molecular biology, as well as for the understanding of quality control and normalization approaches. Here, early investments pay at the level of reduced technical variance, allowing for enhanced detection levels for the effects under investigation.
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| 56. |
- Rodriguez, D., et al.
(författare)
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MATS and LaSpec : High-precision experiments using ion traps and lasers at FAIR
- 2010
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Ingår i: The European physical journal. Special topics. - : Springer Science and Business Media LLC. - 1951-6355 .- 1951-6401. ; 183, s. 1-123
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Forskningsöversikt (refereegranskat)abstract
- Nuclear ground state properties including mass, charge radii, spins and moments can be determined by applying atomic physics techniques such as Penning-trap based mass spectrometry and laser spectroscopy. The MATS and LaSpec setups at the low-energy beamline at FAIR will allow us to extend the knowledge of these properties further into the region far from stability. The mass and its inherent connection with the nuclear binding energy is a fundamental property of a nuclide, a unique ""fingerprint"". Thus, precise mass values are important for a variety of applications, ranging from nuclear-structure studies like the investigation of shell closures and the onset of deformation, tests of nuclear mass models and mass formulas, to tests of the weak interaction and of the Standard Model. The required relative accuracy ranges from 10(-5) to below 10(-8) for radionuclides, which most often have half-lives well below 1 s. Substantial progress in Penning trap mass spectrometry has made this method a prime choice for precision measurements on rare isotopes. The technique has the potential to provide high accuracy and sensitivity even for very short-lived nuclides. Furthermore, ion traps can be used for precision decay studies and offer advantages over existing methods. With MATS (Precision Measurements of very short-lived nuclei using an Advanced Trapping System for highly-charged ions) at FAIR we aim to apply several techniques to very short-lived radionuclides: High-accuracy mass measurements, in-trap conversion electron and alpha spectroscopy, and trap-assisted spectroscopy. The experimental setup of MATS is a unique combination of an electron beam ion trap for charge breeding, ion traps for beam preparation, and a high-precision Penning trap system for mass measurements and decay studies. For the mass measurements, MATS offers both a high accuracy and a high sensitivity. A relative mass uncertainty of 10(-9) can be reached by employing highly-charged ions and a non-destructive Fourier-Transform Ion-Cyclotron-Resonance (FT-ICR) detection technique on single stored ions. This accuracy limit is important for fundamental interaction tests, but also allows for the study of the fine structure of the nuclear mass surface with unprecedented accuracy, whenever required. The use of the FT-ICR technique provides true single ion sensitivity. This is essential to access isotopes that are produced with minimum rates which are very often the most interesting ones. Instead of pushing for highest accuracy, the high charge state of the ions can also be used to reduce the storage time of the ions, hence making measurements on even shorter-lived isotopes possible. Decay studies in ion traps will become possible with MATS. Novel spectroscopic tools for in-trap high-resolution conversion-electron and charged-particle spectroscopy from carrier-free sources will be developed, aiming e. g. at the measurements of quadrupole moments and E0 strengths. With the possibility of both high-accuracy mass measurements of the shortest-lived isotopes and decay studies, the high sensitivity and accuracy potential of MATS is ideally suited for the study of very exotic nuclides that will only be produced at the FAIR facility. Laser spectroscopy of radioactive isotopes and isomers is an efficient and model-independent approach for the determination of nuclear ground and isomeric state properties. Hyperfine structures and isotope shifts in electronic transitions exhibit readily accessible information on the nuclear spin, magnetic dipole and electric quadrupole moments as well as root-mean-square charge radii. The dependencies of the hyperfine splitting and isotope shift on the nuclear moments and mean square nuclear charge radii are well known and the theoretical framework for the extraction of nuclear parameters is well established. These extracted parameters provide fundamental information on the structure of nuclei at the limits of stability. Vital information on both bulk and valence nuclear properties are derived and an exceptional sensitivity to changes in nuclear deformation is achieved. Laser spectroscopy provides the only mechanism for such studies in exotic systems and uniquely facilitates these studies in a model-independent manner. The accuracy of laser-spectroscopic-determined nuclear properties is very high. Requirements concerning production rates are moderate; collinear spectroscopy has been performed with production rates as few as 100 ions per second and laser-desorption resonance ionization mass spectroscopy (combined with beta-delayed neutron detection) has been achieved with rates of only a few atoms per second. This Technical Design Report describes a new Penning trap mass spectrometry setup as well as a number of complementary experimental devices for laser spectroscopy, which will provide a complete system with respect to the physics and isotopes that can be studied. Since MATS and LaSpec require high-quality low-energy beams, the two collaborations have a common beamline to stop the radioactive beam of in-flight produced isotopes and prepare them in a suitable way for transfer to the MATS and LaSpec setups, respectively.
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| 57. |
- Schnabel, Renate B, et al.
(författare)
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Early diagnosis and better rhythm management to improve outcomes in patients with atrial fibrillation : the 8th AFNET/EHRA consensus conference
- 2023
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Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 25:1, s. 6-27
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Tidskriftsartikel (refereegranskat)abstract
- Despite marked progress in the management of atrial fibrillation (AF), detecting AF remains difficult and AF-related complications cause unacceptable morbidity and mortality even on optimal current therapy. This document summarizes the key outcomes of the 8th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eighty-three international experts met in Hamburg for 2 days in October 2021. Results of the interdisciplinary, hybrid discussions in breakout groups and the plenary based on recently published and unpublished observations are summarized in this consensus paper to support improved care for patients with AF by guiding prevention, individualized management, and research strategies. The main outcomes are (i) new evidence supports a simple, scalable, and pragmatic population-based AF screening pathway; (ii) rhythm management is evolving from therapy aimed at improving symptoms to an integrated domain in the prevention of AF-related outcomes, especially in patients with recently diagnosed AF; (iii) improved characterization of atrial cardiomyopathy may help to identify patients in need for therapy; (iv) standardized assessment of cognitive function in patients with AF could lead to improvement in patient outcomes; and (v) artificial intelligence (AI) can support all of the above aims, but requires advanced interdisciplinary knowledge and collaboration as well as a better medico-legal framework. Implementation of new evidence-based approaches to AF screening and rhythm management can improve outcomes in patients with AF. Additional benefits are possible with further efforts to identify and target atrial cardiomyopathy and cognitive impairment, which can be facilitated by AI.
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| 58. |
- Schumacher, J, et al.
(författare)
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Linkage analyses of chromosomal region 18p11-q12 in dyslexia
- 2006
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Ingår i: Journal of neural transmission. - Vienna, Austria : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 113:3, s. 417-23
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Tidskriftsartikel (refereegranskat)abstract
- Dyslexia is characterized as a significant impairment in reading and spelling ability that cannot be explained by low intelligence, low school attendance or deficits in sensory acuity. It is known to be a hereditary disorder that affects about 5% of school aged children, making it the most common of childhood learning disorders. Several susceptibility loci have been reported on chromosomes 1, 2, 3, 6, 15, and 18. The locus on chromosome 18 has been described as having the strongest influence on single word reading, phoneme awareness, and orthographic coding in the largest genome wide linkage study published to date (Fisher et al., 2002). Here we present data from 82 German families in order to investigate linkage of various dyslexia-related traits to the previously described region on chromosome 18p11-q12. Using two- and multipoint analyses, we did not find support for linkage of spelling, single word reading, phoneme awareness, orthographic coding and rapid naming to any of the 14 genotyped STR markers. Possible explanations for our non-replication include differences in study design, limited power of our study and overestimation of the effect of the chromosome 18 locus in the original study.
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| 59. |
- Schunkert, Heribert, et al.
(författare)
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
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Tidskriftsartikel (refereegranskat)abstract
- We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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| 60. |
- Snipen, Lars, et al.
(författare)
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Detection of divergent genes in microbial aCGH experiments
- 2006
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Ingår i: BMC Bioinformatics. - London, UK : BioMed Central. - 1471-2105. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Array-based comparative genome hybridization (aCGH) is a tool for rapid comparison of genomes from different bacterial strains. The purpose of such analysis is to detect highly divergent or absent genes in a sample strain compared to an index strain. Development of methods for analyzing aCGH data has primarily focused on copy number abberations in cancer research. In microbial aCGH analyses, genes are typically ranked by log-ratios, and classification into divergent or present is done by choosing a cutoff log-ratio, either manually or by statistics calculated from the log-ratio distribution. As experimental settings vary considerably, it is not possible to develop a classical discriminant or statistical learning approach.Methods: We introduce a more efficient method for analyzing microbial aCGH data using a finite mixture model and a data rotation scheme. Using the average posterior probabilities from the model fitted to log-ratios before and after rotation, we get a score for each gene, and demonstrate its advantages for ranking and detecting divergent genes with enlarged specificity and sensitivity.Results: The procedure is tested and compared to other approaches on simulated data sets, as well as on four experimental validation data sets for aCGH analysis on fully sequenced strains of Staphylococcus aureus and Streptococcus pneumoniae.Conclusion: When tested on simulated data as well as on four different experimental validation data sets from experiments with only fully sequenced strains, our procedure out-competes the standard procedures of using a simple log-ratio cutoff for classification into present and divergent genes.
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