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227 Publications visible to you, out of a total of 227
A Biomathematical Model of Pneumococcal Lung Infection and Antibiotic Treatment in Mice
Genetical Statistics and Systems Biology

Abstract (Expand)

Pneumonia is considered to be one of the leading causes of death worldwide. The outcome depends on both, proper antibiotic treatment and the effectivity of the immune response of the host. However, due … to the complexity of the immunologic cascade initiated during infection, the latter cannot be predicted easily. We construct a biomathematical model of the murine immune response during infection with pneumococcus aiming at predicting the outcome of antibiotic treatment. The model consists of a number of non-linear ordinary differential equations describing dynamics of pneumococcal population, the inflammatory cytokine IL-6, neutrophils and macrophages fighting the infection and destruction of alveolar tissue due to pneumococcus. Equations were derived by translating known biological mechanisms and assuming certain response kinetics. Antibiotic therapy is modelled by a transient depletion of bacteria. Unknown model parameters were determined by fitting the predictions of the model to data sets derived from mice experiments of pneumococcal lung infection with and without antibiotic treatment. Time series of pneumococcal population, debris, neutrophils, activated epithelial cells, macrophages, monocytes and IL-6 serum concentrations were available for this purpose. The antibiotics Ampicillin and Moxifloxacin were considered. Parameter fittings resulted in a good agreement of model and data for all experimental scenarios. Identifiability of parameters is also estimated. The model can be used to predict the performance of alternative schedules of antibiotic treatment. We conclude that we established a biomathematical model of pneumococcal lung infection in mice allowing predictions regarding the outcome of different schedules of antibiotic treatment. We aim at translating the model to the human situation in the near future.

Authors: Sibylle Schirm, Peter Ahnert, Sandra Wienhold, Holger Mueller-Redetzky, Geraldine Nouailles-Kursar, Markus Loeffler, Martin Witzenrath, Markus Scholz

Date Published: 19th May 2016

Publication Type: Journal article

Reliability of 3D laser-based anthropometry and comparison with classical anthropometry
Genetical Statistics and Systems Biology

Abstract (Expand)

Anthropometric quantities are widely used in epidemiologic research as possible confounders, risk factors, or outcomes. 3D laser-based body scans (BS) allow evaluation of dozens of quantities in short … time with minimal physical contact between observers and probands. The aim of this study was to compare BS with classical manual anthropometric (CA) assessments with respect to feasibility, reliability, and validity. We performed a study on 108 individuals with multiple measurements of BS and CA to estimate intra- and inter-rater reliabilities for both. We suggested BS equivalents of CA measurements and determined validity of BS considering CA the gold standard. Throughout the study, the overall concordance correlation coefficient (OCCC) was chosen as indicator of agreement. BS was slightly more time consuming but better accepted than CA. For CA, OCCCs for intra- and inter-rater reliability were greater than 0.8 for all nine quantities studied. For BS, 9 of 154 quantities showed reliabilities below 0.7. BS proxies for CA measurements showed good agreement (minimum OCCC \textgreater 0.77) after offset correction. Thigh length showed higher reliability in BS while upper arm length showed higher reliability in CA. Except for these issues, reliabilities of CA measurements and their BS equivalents were comparable.

Authors: Andreas Kuehnapfel, Peter Ahnert, Markus Loeffler, Anja Broda, Markus Scholz

Date Published: 1st May 2016

Publication Type: Journal article

Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study.
Genetical Statistics and Systems Biology, LIFE Adult

Abstract (Expand)

The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep-related phenotypes, known genetic variants explain only a small proportion of the phenotypical … variance. However, most previous studies were based solely upon self-report measures. The present study aimed to conduct the first genome-wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle- to older-aged subjects (40-79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night- and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms (SNPs) were analysed after imputation and quality control. We identified several variants below the significance threshold of P </= 5x 10(-8) (not corrected for analysis of multiple traits). The most significant was a hit near UFL1 associated with sleep efficiency on weekdays (P = 1.39 x 10(-8) ). Further SNPs were close to significance, including an association between sleep latency and a variant in CSNK2A1 (P = 8.20 x 10(-8) ), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow-up studies.

Authors: J. Spada, M. Scholz, H. Kirsten, T. Hensch, K. Horn, P. Jawinski, C. Ulke, R. Burkhardt, K. Wirkner, M. Loeffler, U. Hegerl, C. Sander

Date Published: 30th Apr 2016

Publication Type: Journal article

Improved prediction of complex diseases by common genetic markers: state of the art and further perspectives
Genetical Statistics and Systems Biology

Abstract (Expand)

Reliable risk assessment of frequent, but treatable diseases and disorders has considerable clinical and socio-economic relevance. However, as these conditions usually originate from a complex interplay … between genetic and environmental factors, precise prediction remains a considerable challenge. The current progress in genotyping technology has resulted in a substantial increase of knowledge regarding the genetic basis of such diseases and disorders. Consequently, common genetic risk variants are increasingly being included in epidemiological models to improve risk prediction. This work reviews recent high-quality publications targeting the prediction of common complex diseases. To be included in this review, articles had to report both, numerical measures of prediction performance based on traditional (non-genetic) risk factors, as well as measures of prediction performance when adding common genetic variants to the model. Systematic PubMed-based search finally identified 55 eligible studies. These studies were compared with respect to the chosen approach and methodology as well as results and clinical impact. Phenotypes analysed included tumours, diabetes mellitus, and cardiovascular diseases. All studies applied one or more statistical measures reporting on calibration, discrimination, or reclassification to quantify the benefit of including SNPs, but differed substantially regarding the methodological details that were reported. Several examples for improved risk assessments by considering disease-related SNPs were identified. Although the add-on benefit of including SNP genotyping data was mostly moderate, the strategy can be of clinical relevance and may, when being paralleled by an even deeper understanding of disease-related genetics, further explain the development of enhanced predictive and diagnostic strategies for complex diseases.

Authors: Bent Müller, Arndt Wilcke, Anne-Laure Boulesteix, Jens Brauer, Eberhard Passarge, Johannes Boltze, Holger Kirsten

Date Published: 1st Mar 2016

Publication Type: Journal article

Evaluation eines Mikromanipulators für die Mittelohrchirurgie: Eine präklinische Studie
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Microsurgical preparation is limited by geometric and mechanical constraints. In preparation for clinical use, this study investigates performance, ease of handling and precision of a novel …l manipulator concept for microsurgery. MATERIAL AND METHODS A group of 15 ENT experienced doctors, as well as a group of 17 medical students with low/non surgical experience participated in the study. Each of the subjects carried out 4 trials of simulated surgeries on a phantom with built-in force sensors. The task was to apply a defined force between 1.5 and 2 N using a Fisch micro perforator, 16 cm length, 0.4 mm (Storz) targeting holes with a diameter of 0.5 mm. For comparison, the Fisch micro perforator was moved manually or with the manipulator. RESULTS Assessing the total number of errors proved a significantly lower error number (p\textless0.0001) and an improvement of the accuracy of 76% with the manipulator. The time requirement for the procedure with the micro manipulator is on average 2-3 times higher than with manual control (p\textless0.0001). But it is notable that this time requirement significantly decreases with training (p\textless0.0001). CONCLUSION The study shows a significant reduction in the number of errors by using a new manipulator concept compared to the non-augmented human hand in an experimental setup. We observed a significant learning effect when subjects applied the micro manipulator, resulting in reduction of the time requirement while maintaining a constant number of errors.

Authors: A. Peschka, Th Berger, Th Maier, M. Scholz, T. C. Lüth, G. Strauß

Date Published: 9th Feb 2016

Publication Type: Journal article

High acceptance of an early dyslexia screening test involving genetic analyses in Germany
Genetical Statistics and Systems Biology

Abstract (Expand)

Dyslexia is a developmental disorder characterized by severe problems in the acquisition of reading and writing skills. It has a strong neurobiological basis. Genetic influence is estimated at 50-70%. … One of the central problems with dyslexia is its late diagnosis, normally not before the end of the 2nd grade, resulting in the loss of several years for early therapy. Currently, research is focusing on the development of early tests for dyslexia, which may be based on EEG and genetics. Our aim was to determine the acceptance of such a future test among parents. We conducted a representative survey in Germany with 1000 parents of children aged 3-7 years, with and without experience of dyslexia. 88.7% of the parents supported the introduction of an early test for dyslexia based on EEG and genetics; 82.8% would have their own children tested, and 57.9% were willing to pay for the test if health insurance did not cover the costs. Test acceptance was significantly higher if parents had prior experience with dyslexia. The perceived benefits of such a test were early recognition and remediation and, preventing deficits. Concerns regarded the precision of the test, its potentially stigmatizing effect and its costs. The high overall support for the test leads to the conclusion that parents would accept a test for dyslexia based on EEG and genetics.

Authors: Arndt Wilcke, Bent Müller, Gesa Schaadt, Holger Kirsten, Johannes Boltze

Date Published: 1st Feb 2016

Publication Type: Journal article

Association of metabolic parameters and rs726344 in FNDC5 with serum irisin concentrations
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND/OBJECTIVES Irisin has been suggested as a novel myokine with beneficial effects in rodents. However, previous data in humans showed conflicting results regarding its association with metabolic …c phenotypes and regulation of secretion. Furthermore, although an association of rs726344 in FNDC5 (fibronectin type III domain containing 5) coding for irisin with insulin sensitivity was reported, the effects of genetic variation at this locus on irisin serum levels have not been investigated, so far. Therefore, we investigated circulating irisin and the associations with rs726344 in a cohort of \textgreater1000 subjects. SUBJECTS/METHODS Irisin serum concentrations were measured with enzyme-linked immunosorbent assay. Associations with metabolic parameters including renal function, glucose and lipid metabolism, inflammation, as well as adipokine profiles, were assessed in regression models. Dynamic changes of serum irisin were investigated during oral glucose tolerance test (OGTT) in a subset of the cohort (n=136). rs726344 was genotyped in all subjects and analyzed for associations with serum irisin and traits of the metabolic syndrome. RESULTS Irisin was negatively associated with fat mass, fasting glucose and dyslipidemia but not with other adipokines. Moreover, irisin decreased during an OGTT in a subcohort comprising subjects with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus. rs726344 was not associated with serum irisin levels or with other anthropometric and biochemical parameters. CONCLUSIONS Circulating irisin levels are associated with a beneficial metabolic profile but not with other adipokines and not with rs726344 in our cohort. Our data suggest a potential favorable role of irisin in the regulation of metabolism.

Authors: T. Ebert, S. Kralisch, U. Wurst, M. Scholz, M. Stumvoll, P. Kovacs, M. Fasshauer, A. Tönjes

Date Published: 1st Feb 2016

Publication Type: Journal article

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