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188 Publications visible to you, out of a total of 188
Validity and reliability of three-dimensional scanning compared with conventional anthropometry for children and adolescents-response to the rebuttal by Sabour
Genetical Statistics and Systems Biology

Abstract

Pediatric Research accepted article preview online, 29 March 2017. doi:10.1038/pr.2017.76.

Authors: Fabian Glock, Markus Scholz, Andreas Kuehnapfel, Wieland Kiess

Date Published: 1st Aug 2017

Publication Type: Journal article

Model-based individual managing of thrombocytopenia during multi-cyclic chemotherapy
HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

Background: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual’s risk. Methodology/Principle … Findings: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and –dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N=135 high-grade non-Hodgkin’s lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. Conclusions: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.

Authors: Y. Kheifetz, Markus Scholz, Markus Löffler

Date Published: 9th Jun 2017

Publication Type: Not specified

Human Diseases: thrombocytopenia

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term … mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung fur Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Authors: S. Zewinger, M. E. Kleber, V. Tragante, R. O. McCubrey, A. F. Schmidt, K. Direk, U. Laufs, C. Werner, W. Koenig, D. Rothenbacher, U. Mons, L. P. Breitling, H. Brenner, R. T. Jennings, I. Petrakis, S. Triem, M. Klug, A. Filips, S. Blankenberg, C. Waldeyer, C. Sinning, R. B. Schnabel, K. J. Lackner, E. Vlachopoulou, O. Nygard, G. F. T. Svingen, E. R. Pedersen, G. S. Tell, J. Sinisalo, M. S. Nieminen, R. Laaksonen, S. Trompet, R. A. J. Smit, N. Sattar, J. W. Jukema, H. V. Groesdonk, G. Delgado, T. Stojakovic, A. P. Pilbrow, V. A. Cameron, A. M. Richards, R. N. Doughty, Y. Gong, R. Cooper-DeHoff, J. Johnson, M. Scholz, F. Beutner, J. Thiery, J. G. Smith, R. O. Vilmundarson, R. McPherson, A. F. R. Stewart, S. Cresci, P. A. Lenzini, J. A. Spertus, O. Olivieri, D. Girelli, N. I. Martinelli, A. Leiherer, C. H. Saely, H. Drexel, A. Mundlein, P. S. Braund, C. P. Nelson, N. J. Samani, D. Kofink, I. E. Hoefer, G. Pasterkamp, A. A. Quyyumi, Y. A. Ko, J. A. Hartiala, H. Allayee, W. H. W. Tang, S. L. Hazen, N. Eriksson, C. Held, E. Hagstrom, L. Wallentin, A. Akerblom, A. Siegbahn, I. Karp, C. Labos, L. Pilote, J. C. Engert, J. M. Brophy, G. Thanassoulis, P. Bogaty, W. Szczeklik, M. Kaczor, M. Sanak, S. S. Virani, C. M. Ballantyne, V. V. Lee, E. Boerwinkle, M. V. Holmes, B. D. Horne, A. Hingorani, F. W. Asselbergs, R. S. Patel, B. K. Kramer, H. Scharnagl, D. Fliser, W. Marz, T. Speer

Date Published: 2nd Jun 2017

Publication Type: Journal article

Validity and intraobserver reliability of three-dimensional scanning compared with conventional anthropometry for children and adolescents from a population-based cohort study
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Conventional anthropometric measurements are time consuming and require well trained medical staff. To use three-dimensional whole body laser scanning in daily clinical work, validity, and …d reliability have to be confirmed. METHODS We compared a whole body laser scanner with conventional anthropometry in a group of 473 children and adolescents from the Leipzig Research Centre for Civilization Diseases (LIFE-Child). Concordance correlation coefficients (CCC) were calculated separately for sex, weight, and age to assess validity. Overall CCC (OCCC) was used to analyze intraobserver reliability. RESULTS Body height and the circumferences of waist, hip, upper arm, and calf had an \textquotedblexcellent\textquotedbl (CCC ≥0.9); neck and thigh circumference, a \textquotedblgood\textquotedbl (CCC ≥0.7); and head circumference, a \textquotedbllow\textquotedbl (CCC \textless 0.5) degree of concordance over the complete study population. We observed dependencies of validity on sex, weight, and age. Intraobserver reliability of both techniques is \textquotedblexcellent\textquotedbl (OCCC ≥0.9). CONCLUSION Scanning is faster, requires less intensive staff training and provides more information. It can be used in an epidemiologic setting with children and adolescents but some measurements should be considered with caution due to reduced agreement with conventional anthropometry.

Authors: Fabian Glock, Mandy Vogel, Stephanie Naumann, Andreas Kuehnapfel, Markus Scholz, Andreas Hiemisch, Toralf Kirsten, Kristin Rieger, Antje Koerner, Markus Loeffler, Wieland Kiess

Date Published: 1st May 2017

Publication Type: Journal article

Low sphingosine-1-phosphate plasma levels are predictive for increased mortality in patients with liver cirrhosis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND & AIM: The association of circulating sphingosine-1-phosphate (S1P), a bioactive lipid involved in various cellular processes, and related metabolites such as sphinganine-1-phosphate … (SA1P) and sphingosine (SPH) with mortality in patients with end-stage liver disease is investigated in the presented study. S1P as a bioactive lipid mediator, is involved in several cellular processes, however, in end-stage liver disease its role is not understood. METHODS: The study cohort consisted of 95 patients with end-stage liver disease and available information on one-year outcome. The median MELD (Model for end-stage liver disease) score was 12.41 (Range 6.43-39.63). The quantification of sphingolipids in citrated plasma specimen was performed after methanolic protein precipitation followed by hydrophilic interaction liquid chromatography and tandem mass spectrometric detection. RESULTS: S1P and SA1P displayed significant correlations with the MELD score. Patients with circulating S1P levels below the lowest tertile (110.68 ng/ml) showed the poorest one-year survival rate of only 57.1%, whereas one-year survival rate in patients with S1P plasma levels above 165.67 ng/ml was 93.8%. In a multivariate cox regression analysis including platelet counts, concentrations of hemoglobin and MELD score, S1P remained a significant predictor for three-month and one-year mortality. CONCLUSIONS: Low plasma S1P concentrations are highly significantly associated with prognosis in end-stage liver disease. This association is independent of the stage of liver disease. Further studies should be performed to investigate S1P, its role in the pathophysiology of liver diseases and its potential for therapeutic interventions.

Authors: Susen Becker, Benedict Kinny-Koster, Michael Bartels, Markus Scholz, Daniel Seehofer, Thomas Berg, Cornelius Engelmann, Joachim Thiery, Uta Ceglarek, Thorsten Kaiser

Date Published: 23rd Mar 2017

Publication Type: Journal article

On the Conditional Power in Survival Time Analysis Considering Cure Fractions.
Genetical Statistics and Systems Biology

Abstract (Expand)

Conditional power of survival endpoints at interim analyses can support decisions on continuing a trial or stopping it for futility. When a cure fraction becomes apparent, conditional power cannot be … calculated accurately using simple survival models, e.g. the exponential model. Non-mixture models consider such cure fractions. In this paper, we derive conditional power functions for non-mixture models, namely the non-mixture exponential, the non-mixture Weibull, and the non-mixture Gamma models. Formulae were implemented in the R package CP. For an example data set of a clinical trial, we calculated conditional power under the non-mixture models and compared results with those under the simple exponential model.

Authors: A. Kuehnapfel, F. Schwarzenberger, M. Scholz

Date Published: 17th Mar 2017

Publication Type: Journal article

Genome-wide meta-analysis identifies novel loci of plaque burden in carotid artery.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND AIMS: Carotid artery plaque is an established marker of subclinical atherosclerosis and common patho-mechanisms with coronary artery disease (CAD) are hypothesized. We aimed to identify … genetic variants associated with carotid plaque and to examine the potential shared genetic basis with CAD. METHODS: After investigating the reliability of plaque detection, we performed a genome-wide meta-association study in two independent cohorts (LIFE-Adult, n = 4037 and LIFE-Heart, n = 3152) for carotid plaque score (PS), defined as the sum of the plaque load of common carotid artery and carotid bulb. Further, we analyzed whether previously reported CAD and stroke loci were also associated with PS. RESULTS: We identified two loci with genome-wide significance for PS. One locus is the known CAD-locus at chromosome 9p21 (lead SNP rs9644862, p = 8.73 x 10(-12)). We also describe a novel locus on chromosome 10q24 within the SFXN2 gene as the most probable candidate (lead SNP rs2902548, p = 1.97 x 10(-8)). In addition, 17 out of 58 known CAD loci and six of 17 known stroke loci were associated with PS at a nominal level of significance. CONCLUSIONS: We showed that PS is a reliable trait to analyze genetics of atherosclerosis. Two new loci of genome-wide significant association with PS were found. The observed non-random overlap of CAD and PS associations strengthens the hypothesis of a shared genetic basis for these atherosclerotic manifestations.

Authors: J. Pott, R. Burkhardt, F. Beutner, K. Horn, A. Teren, H. Kirsten, L. M. Holdt, G. Schuler, D. Teupser, M. Loeffler, J. Thiery, M. Scholz

Date Published: 11th Mar 2017

Publication Type: Journal article

Human Diseases: atherosclerosis

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