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188 Publications visible to you, out of a total of 188
On the impact of relatedness on SNP association analysis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND When testing for SNP (single nucleotide polymorphism) associations in related individuals, observations are not independent. Simple linear regression assuming independent normally distributed …d residuals results in an increased type I error and the power of the test is also affected in a more complicate manner. Inflation of type I error is often successfully corrected by genomic control. However, this reduces the power of the test when relatedness is of concern. In the present paper, we derive explicit formulae to investigate how heritability and strength of relatedness contribute to variance inflation of the effect estimate of the linear model. Further, we study the consequences of variance inflation on hypothesis testing and compare the results with those of genomic control correction. We apply the developed theory to the publicly available HapMap trio data (N=129), the Sorbs (a self-contained population with N=977 characterised by a cryptic relatedness structure) and synthetic family studies with different sample sizes (ranging from N=129 to N=999) and different degrees of relatedness. RESULTS We derive explicit and easily to apply approximation formulae to estimate the impact of relatedness on the variance of the effect estimate of the linear regression model. Variance inflation increases with increasing heritability. Relatedness structure also impacts the degree of variance inflation as shown for example family structures. Variance inflation is smallest for HapMap trios, followed by a synthetic family study corresponding to the trio data but with larger sample size than HapMap. Next strongest inflation is observed for the Sorbs, and finally, for a synthetic family study with a more extreme relatedness structure but with similar sample size as the Sorbs. Type I error increases rapidly with increasing inflation. However, for smaller significance levels, power increases with increasing inflation while the opposite holds for larger significance levels. When genomic control is applied, type I error is preserved while power decreases rapidly with increasing variance inflation. CONCLUSIONS Stronger relatedness as well as higher heritability result in increased variance of the effect estimate of simple linear regression analysis. While type I error rates are generally inflated, the behaviour of power is more complex since power can be increased or reduced in dependence on relatedness and the heritability of the phenotype. Genomic control cannot be recommended to deal with inflation due to relatedness. Although it preserves type I error, the loss in power can be considerable. We provide a simple formula for estimating variance inflation given the relatedness structure and the heritability of a trait of interest. As a rule of thumb, variance inflation below 1.05 does not require correction and simple linear regression analysis is still appropriate.

Authors: Arnd Gross, Anke Tönjes, Markus Scholz

Date Published: 1st Dec 2017

Publication Type: Journal article

Sevoflurane and Isoflurane-Pharmacokinetics, Hemodynamic Stability and Cardio-protective Effects During Cardiopulmonary Bypass
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: David Freiermuth, Berend Mets, Daniel Bolliger, Oliver Reuthebuch, Thomas Doebele, Markus Scholz, Michael Gregor, Marcel Haschke, Manfred Seeberger, Jens Fassl

Date Published: 1st Dec 2017

Publication Type: Journal article

Cholesterol esterification in plasma as a biomarker for liver function and prediction of mortality
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Advanced stages of liver cirrhosis lead to a dramatically increased mortality. For valid identification of these patients suitable biomarkers are essential. The most important biomarkers for …r liver function are bilirubin and prothrombin time expressed as International Normalized Ratio (INR). However, the influence of several anticoagulants on the prothrombin time limits its diagnostic value. Aim of this study was the evaluation of cholesterol esterification (CE) fraction (esterified cholesterol vs. total cholesterol) as an alternative biomarker for liver synthesis and mortality prediction. Under physiological conditions the CE fraction in blood is closely regulated by lecithin-cholesterol acyltransferase (LCAT) which is produced in the liver. METHODS One hundred forty-two patients with liver disease clinically considered for orthotopic liver transplant for different indications were enrolled in the study. One patient was excluded because of the intake of a direct oral factor Xa inhibitor which has a strong impact on prothrombin time. RESULTS Results of CE fraction were in good agreement with INR (R(2) = 0.73; p \textless 0.001). In patients who died or survived within three months mean CE fraction was 56% vs. 74% (p \textless 0.001) and mean INR was 2.0 vs. 1.3 (p \textless 0.001), respectively. The predictive value of CE fraction for three-month mortality risk was higher compared to INR (p = 0.04). Results for one-year mortality were comparable. CONCLUSIONS The cholesterol esterification fraction is a valid biomarker for liver synthesis and allows reliable prediction of mortality. In contrast to INR, it is independent of anticoagulation and other analytical limitations of coagulation tests.

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

Date Published: 1st Dec 2017

Publication Type: Journal article

Model-based optimization of G-CSF treatment during cytotoxic chemotherapy.
Genetical Statistics and Systems Biology

Abstract (Expand)

PURPOSE: Although G-CSF is widely used to prevent or ameliorate leukopenia during cytotoxic chemotherapies, its optimal use is still under debate and depends on many therapy parameters such as dosing … and timing of cytotoxic drugs and G-CSF, G-CSF pharmaceuticals used and individual risk factors of patients. METHODS: We integrate available biological knowledge and clinical data regarding cell kinetics of bone marrow granulopoiesis, the cytotoxic effects of chemotherapy and pharmacokinetics and pharmacodynamics of G-CSF applications (filgrastim or pegfilgrastim) into a comprehensive model. The model explains leukocyte time courses of more than 70 therapy scenarios comprising 10 different cytotoxic drugs. It is applied to develop optimized G-CSF schedules for a variety of clinical scenarios. RESULTS: Clinical trial results showed validity of model predictions regarding alternative G-CSF schedules. We propose modifications of G-CSF treatment for the chemotherapies 'BEACOPP escalated' (Hodgkin's disease), 'ETC' (breast cancer), and risk-adapted schedules for 'CHOP-14' (aggressive non-Hodgkin's lymphoma in elderly patients). CONCLUSIONS: We conclude that we established a model of human granulopoiesis under chemotherapy which allows predictions of yet untested G-CSF schedules, comparisons between them, and optimization of filgrastim and pegfilgrastim treatment. As a general rule of thumb, G-CSF treatment should not be started too early and patients could profit from filgrastim treatment continued until the end of the chemotherapy cycle.

Authors: S. Schirm, C. Engel, S. Loibl, M. Loeffler, M. Scholz

Date Published: 6th Nov 2017

Publication Type: Journal article

Growth and Final Height Among Children With Phenylketonuria
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND OBJECTIVES Growth is an important criterion to evaluate health in childhood and adolescence, especially in patients depending on special dietary treatment. Phenylketonuria (PKU) is the …e most common inherited disease of amino acid metabolism. Patients with PKU depend on a special phenylalanine-restricted diet, low in natural protein. The study aimed to evaluate growth, growth rate, and target height in 224 patients with PKU. METHODS Retrospective, longitudinal analysis of standardized, yearly measurements of height, weight, and calculated growth rate (SD score [SDS]) of patients with PKU aged 0 to 18 years were conducted by using the national computerized CrescNet database. Inclusion was restricted to patients carried to term with a confirmed diagnosis of PKU or mild hyperphenylalaninemia determined by newborn screening and early treatment initiation. RESULTS From birth to adulthood, patients with PKU were significantly shorter than healthy German children (height SDS at 18 years: -0.882 \pm 0.108, P \textless .001). They missed their target height by 3 cm by adulthood (women: P = .02) and 5 cm (men: P = .01). In patients receiving casein hydrolysate during childhood, this was more pronounced compared with patients receiving amino acid mixtures (P \textless .001). Growth rate was significantly reduced during their first 2 years of life and in puberty (growth rate SDS: -1.1 to -0.5 m/year, P \textless .001 and -0.5; P \textless .02). CONCLUSIONS Early diagnosed, treated, and continuously monitored patients with PKU showed reduced height from birth onward. During the last 2 decades, this phenomenon attenuated, probably because of advances in PKU therapy related to protein supplements and special low-protein foods.

Authors: Alena G. Thiele, Ruth Gausche, Cornelia Lindenberg, Christoph Beger, Maria Arelin, Carmen Rohde, Ulrike Mütze, Johannes F. Weigel, Klaus Mohnike, Christoph Baerwald, Markus Scholz, Wieland Kiess, Roland Pfäffle, Skadi Beblo

Date Published: 1st Nov 2017

Publication Type: Journal article

Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin
Genetical Statistics and Systems Biology

Abstract (Expand)

AIMS Inverse relationships have been described between the largely genetically determined levels of serum/plasma lipoprotein(a) [Lp(a)], type 2 diabetes (T2D) and fasting insulin. Here, we aimed to …o evaluate the nature of these relationships with respect to causality. METHODS We tested whether we could replicate the recent negative findings on causality between Lp(a) and T2D by employing the Mendelian randomization (MR) approach using cross-sectional data from three independent cohorts, Berlin Aging Study II (BASE-II; n = 2012), LIFE-Adult (n = 3281) and LIFE-Heart (n = 2816). Next, we explored another frequently discussed hypothesis in this context: Increasing insulin levels during the course of T2D disease development inhibits hepatic Lp(a) synthesis and thereby might explain the inverse Lp(a)-T2D association. We used two fasting insulin-associated variants, rs780094 and rs10195252, as instrumental variables in MR analysis of n = 4937 individuals from BASE-II and LIFE-Adult. We further investigated causality of the association between fasting insulin and Lp(a) by combined MR analysis of 12 additional SNPs in LIFE-Adult. RESULTS While an Lp(a)-T2D association was observed in the combined analysis (meta-effect of OR [95% CI] = 0.91 [0.87-0.96] per quintile, p = 1.3x10(-4)), we found no evidence of causality in the Lp(a)-T2D association (p = 0.29, fixed effect model) when using the variant rs10455872 as the instrumental variable in the MR analyses. Likewise, no evidence of a causal effect of insulin on Lp(a) levels was found. CONCLUSIONS While these results await confirmation in larger cohorts, the nature of the inverse Lp(a)-T2D association remains to be elucidated.

Authors: Nikolaus Buchmann, Markus Scholz, Christina M. Lill, Ralph Burkhardt, Rahel Eckardt, Kristina Norman, Markus Loeffler, Lars Bertram, Joachim Thiery, Elisabeth Steinhagen-Thiessen, Ilja Demuth

Date Published: 1st Nov 2017

Publication Type: Journal article

Genome-Wide Association Analysis for Severity of Coronary Artery Disease Using the Gensini Scoring System
Genetical Statistics and Systems Biology

Abstract (Expand)

Coronary artery disease (CAD) has a complex etiology involving numerous environmental and genetic factors of disease risk. To date, the genetic 9p21 locus represents the most robust genetic finding for … prevalent and incident CAD. However, limited information is available on the genetic background of the severity and distribution of CAD. CAD manifests itself as stable CAD or acute coronary syndrome. The Gensini score quantifies the extent CAD but requires coronary angiography. Here, we aimed to identify novel genetic variants associated with Gensini score severity and distribution of CAD. A two-stage approach including a discovery and a replication stage was used to assess genetic variants. In the discovery phase, a meta-analysis of genome-wide association data of 4,930 CAD-subjects assessed by the Gensini score was performed. Selected single nucleotide polymorphisms (SNPs) were replicated in 2,283 CAD-subjects by de novo genotyping. We identified genetic loci located on chromosome 2 and 9 to be associated with Gensini score severity and distribution of CAD in the discovery stage. Although the loci on chromosome 2 could not be replicated in the second stage, the known CAD-locus on chromosome 9p21, represented by rs133349, was identified and, thus, was confirmed as risk locus for CAD severity.

Authors: Tanja Zeller, Moritz Seiffert, Christian Müller, Markus Scholz, Anna Schäffer, Francisco Ojeda, Heinz Drexel, Axel Mündlein, Marcus E. Kleber, Winfried März, Christoph Sinning, Fabian J. Brunner, Christoph Waldeyer, Till Keller, Christoph H. Saely, Karsten Sydow, Joachim Thiery, Daniel Teupser, Stefan Blankenberg, Renate Schnabel

Date Published: 20th Sep 2017

Publication Type: Journal article

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