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  1. Article ; Online: Mixture density networks for the indirect estimation of reference intervals

    Tobias Hepp / Jakob Zierk / Manfred Rauh / Markus Metzler / Sarem Seitz

    BMC Bioinformatics, Vol 23, Iss 1, Pp 1-

    2022  Volume 17

    Abstract: Abstract Background Reference intervals represent the expected range of physiological test results in a healthy population and are essential to support medical decision making. Particularly in the context of pediatric reference intervals, where ... ...

    Abstract Abstract Background Reference intervals represent the expected range of physiological test results in a healthy population and are essential to support medical decision making. Particularly in the context of pediatric reference intervals, where recruitment regulations make prospective studies challenging to conduct, indirect estimation strategies are becoming increasingly important. Established indirect methods enable robust identification of the distribution of “healthy” samples from laboratory databases, which include unlabeled pathologic cases, but are currently severely limited when adjusting for essential patient characteristics such as age. Here, we propose the use of mixture density networks (MDN) to overcome this problem and model all parameters of the mixture distribution in a single step. Results Estimated reference intervals from varying settings with simulated data demonstrate the ability to accurately estimate latent distributions from unlabeled data using different implementations of MDNs. Comparing the performance with alternative estimation approaches further highlights the importance of modeling the mixture component weights as a function of the input in order to avoid biased estimates for all other parameters and the resulting reference intervals. We also provide a strategy to generate partially customized starting weights to improve proper identification of the latent components. Finally, the application on real-world hemoglobin samples provides results in line with current gold standard approaches, but also suggests further investigations with respect to adequate regularization strategies in order to prevent overfitting the data. Conclusions Mixture density networks provide a promising approach capable of extracting the distribution of healthy samples from unlabeled laboratory databases while simultaneously and explicitly estimating all parameters and component weights as non-linear functions of the covariate(s), thereby allowing the estimation of age-dependent reference intervals in a single ...
    Keywords Mixture density networks ; Reference intervals ; Latent class regression ; Distributional regression ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
    Subject code 310
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Routine Surveillance of SARS-CoV-2 Serostatus in Pediatrics Allows Monitoring of Humoral Response

    Felix Wachter / Ferdinand Knieling / Roman Raming / David Simon / Joachim Woelfle / André Hoerning / Antje Neubert / Manfred Rauh / Adrian P. Regensburger

    Microorganisms, Vol 11, Iss 12, p

    2023  Volume 2919

    Abstract: The occurrence of SARS-CoV-2 infections during the pandemic was mainly based on PCR testing of symptomatic patients. However, with new variants, vaccinations, and the changing of the clinical disease severity, knowledge about general immunity is elusive. ...

    Abstract The occurrence of SARS-CoV-2 infections during the pandemic was mainly based on PCR testing of symptomatic patients. However, with new variants, vaccinations, and the changing of the clinical disease severity, knowledge about general immunity is elusive. For public health systems, timely knowledge of these conditions is essential, but it is particularly scarce for the pediatric population. Therefore, in this study, we wanted to investigate the spike and nucleocapsid seroprevalence in pediatric patients using routine residual blood tests collected during the pandemic. This prospective observational study was conducted over seven one-month periods. Herein, the latest four time periods (November 2021, January 2022, March 2022, and May 2022) are depicted. Each patient of a tertiary-care center in Germany was anonymized after collection of clinical diagnosis (ICD-10) and then routinely tested for the respective spike and nucleocapsid SARS-CoV-2 antibody titer. A total of 3235 blood samples from four time periods were included. Spike seroprevalence rose from 37.6% to 51.9% to 70.5% to 85.1% and nucleocapsid seroprevalence from 11.6% to 17.0% to 36.7% to 58.1% in May 2022. In detail, significant changes in seroprevalence between age groups but not between sex or diagnosis groups were found. Quantitative measures revealed rising spike and constant nucleocapsid antibody levels over the pandemic with a half-life of 102 days for spike and 45 days for nucleocapsid antibodies. Routine laboratory assessment of SARS-CoV-2 in residual blood specimens of pediatric hospitals enables monitoring of the seroprevalence and may allow inferences about general immunity in this cohort.
    Keywords COVID-19 ; pediatrics ; seroprevalence ; SARS-CoV-2 ; Omicron ; surveillance ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Latent class distributional regression for the estimation of non-linear reference limits from contaminated data sources

    Tobias Hepp / Jakob Zierk / Manfred Rauh / Markus Metzler / Andreas Mayr

    BMC Bioinformatics, Vol 21, Iss 1, Pp 1-

    2020  Volume 15

    Abstract: Abstract Background Medical decision making based on quantitative test results depends on reliable reference intervals, which represent the range of physiological test results in a healthy population. Current methods for the estimation of reference ... ...

    Abstract Abstract Background Medical decision making based on quantitative test results depends on reliable reference intervals, which represent the range of physiological test results in a healthy population. Current methods for the estimation of reference limits focus either on modelling the age-dependent dynamics of different analytes directly in a prospective setting or the extraction of independent distributions from contaminated data sources, e.g. data with latent heterogeneity due to unlabeled pathologic cases. In this article, we propose a new method to estimate indirect reference limits with non-linear dependencies on covariates from contaminated datasets by combining the framework of mixture models and distributional regression. Results Simulation results based on mixtures of Gaussian and gamma distributions suggest accurate approximation of the true quantiles that improves with increasing sample size and decreasing overlap between the mixture components. Due to the high flexibility of the framework, initialization of the algorithm requires careful considerations regarding appropriate starting weights. Estimated quantiles from the extracted distribution of healthy hemoglobin concentration in boys and girls provide clinically useful pediatric reference limits similar to solutions obtained using different approaches which require more samples and are computationally more expensive. Conclusions Latent class distributional regression models represent the first method to estimate indirect non-linear reference limits from a single model fit, but the general scope of applications can be extended to other scenarios with latent heterogeneity.
    Keywords Latent class regression ; Finite mixture models ; Distributional regression ; Reference limits ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
    Subject code 310
    Language English
    Publishing date 2020-11-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: refineR

    Tatjana Ammer / André Schützenmeister / Hans-Ulrich Prokosch / Manfred Rauh / Christopher M. Rank / Jakob Zierk

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    A Novel Algorithm for Reference Interval Estimation from Real-World Data

    2021  Volume 17

    Abstract: Abstract Reference intervals are essential for the interpretation of laboratory test results in medicine. We propose a novel indirect approach to estimate reference intervals from real-world data as an alternative to direct methods, which require samples ...

    Abstract Abstract Reference intervals are essential for the interpretation of laboratory test results in medicine. We propose a novel indirect approach to estimate reference intervals from real-world data as an alternative to direct methods, which require samples from healthy individuals. The presented refineR algorithm separates the non-pathological distribution from the pathological distribution of observed test results using an inverse approach and identifies the model that best explains the non-pathological distribution. To evaluate its performance, we simulated test results from six common laboratory analytes with a varying location and fraction of pathological test results. Estimated reference intervals were compared to the ground truth, an alternative indirect method (kosmic), and the direct method (N = 120 and N = 400 samples). Overall, refineR achieved the lowest mean percentage error of all methods (2.77%). Analyzing the amount of reference intervals within ± 1 total error deviation from the ground truth, refineR (82.5%) was inferior to the direct method with N = 400 samples (90.1%), but outperformed kosmic (70.8%) and the direct method with N = 120 (67.4%). Additionally, reference intervals estimated from pediatric data were comparable to published direct method studies. In conclusion, the refineR algorithm enables precise estimation of reference intervals from real-world data and represents a viable complement to the direct method.
    Keywords Medicine ; R ; Science ; Q
    Subject code 310
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Influence of Turkish origin on hematology reference intervals in the German population

    Franz X. Mayr / Alexander Bertram / Holger Cario / Michael C. Frühwald / Hans-Jürgen Groß / Arndt Groening / Stefanie Grützner / Thomas Gscheidmeier / Reinhard Hoffmann / Alexander Krebs / Hans-Georg Ruf / Antje Torge / Joachim Woelfle / Oliver Razum / Manfred Rauh / Markus Metzler / Jakob Zierk

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 8

    Abstract: Abstract Reference intervals for laboratory test results have to be appropriate for the population in which they are used to be clinically useful. While sex and age are established partitioning criteria, patients’ origin also influences laboratory test ... ...

    Abstract Abstract Reference intervals for laboratory test results have to be appropriate for the population in which they are used to be clinically useful. While sex and age are established partitioning criteria, patients’ origin also influences laboratory test results, but is not commonly considered when creating or applying reference intervals. In the German population, stratification for ethnicity is rarely performed, and no ethnicity-specific hematology reference intervals have been reported yet. In this retrospective study, we investigated whether specific reference intervals are warranted for the numerically largest group of non-German descent, individuals originating from Turkey. To this end, we analyzed 1,314,754 test results from 167,294 patients from six German centers. Using a name-based algorithm, 1.9% of patients were identified as originating from Turkey, in line with census data and the algorithm’s sensitivity. Reference intervals and their confidence intervals were calculated using an indirect data mining approach, and Turkish and non-Turkish reference limits overlapped completely or partially in nearly all analytes, regardless of age and sex, and only 5/144 (3.5%) subgroups’ reference limits showed no overlap. We therefore conclude that the current practice of using common reference intervals is appropriate and allows correct clinical decision-making in patients originating from Turkey.
    Keywords Medicine ; R ; Science ; Q
    Subject code 310
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Dexamethasone alleviates tumor-associated brain damage and angiogenesis.

    Zheng Fan / Tina Sehm / Manfred Rauh / Michael Buchfelder / Ilker Y Eyupoglu / Nicolai E Savaskan

    PLoS ONE, Vol 9, Iss 4, p e

    2014  Volume 93264

    Abstract: Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA), a steroidal anti- ... ...

    Abstract Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA), a steroidal anti-inflammatory drug with pleiotropic action profile. Here we show that dexamethasone reduces murine and rodent glioma tumor growth in a concentration-dependent manner. Low concentrations of DEXA are already capable of inhibiting glioma cell proliferation and at higher levels induce cell death. Further, the expression of the glutamate antiporter xCT (system Xc-; SLC7a11) and VEGFA is up-regulated after DEXA treatment indicating early cellular stress responses. However, in human gliomas DEXA exerts differential cytotoxic effects, with some human glioma cells (U251, T98G) resistant to DEXA, a finding corroborated by clinical data of dexamethasone non-responders. Moreover, DEXA-resistant gliomas did not show any xCT alterations, indicating that these gene expressions are associated with DEXA-induced cellular stress. Hence, siRNA-mediated xCT knockdown in glioma cells increased the susceptibility to DEXA. Interestingly, cell viability of primary human astrocytes and primary rodent neurons is not affected by DEXA. We further tested the pharmacological effects of DEXA on brain tissue and showed that DEXA reduces tumor-induced disturbances of the microenvironment such as neuronal cell death and tumor-induced angiogenesis. In conclusion, we demonstrate that DEXA inhibits glioma cell growth in a concentration and species-dependent manner. Further, DEXA executes neuroprotective effects in brains and reduces tumor-induced angiogenesis. Thus, our investigations reveal that DEXA acts pleiotropically and impacts tumor growth, tumor vasculature and tumor-associated brain damage.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) drives the resolution of allergic asthma

    Nina Li / Hoomann Mirzakhani / Alexander Kiefer / Julia Koelle / Tytti Vuorinen / Manfred Rauh / Zuqin Yang / Susanne Krammer / Paraskevi Xepapadaki / Anna Lewandowska-Polak / Heikki Lukkarinen / Nan Zhang / Barbara Stanic / Theodor Zimmermann / Marek L. Kowalski / Tuomas Jartti / Claus Bachert / Mübeccel Akdis / Nikolaos G. Papadopoulos /
    Benjamin A. Raby / Scott T. Weiss / Susetta Finotto

    iScience, Vol 24, Iss 10, Pp 103163- (2021)

    2021  

    Abstract: Summary: RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with ... ...

    Abstract Summary: RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses like Rhinovirus cause induction of RANTES production by epithelial cells. Here, we studied the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma and validated and extended this study to the airways of adults with and without asthma. We further translated these studies to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Here we show an unpredicted therapeutic role of RANTES in the resolution of allergen-induced asthma by orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung.
    Keywords Biological sciences ; Immunology ; Respiratory medicine ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Determination of steroid hormones in human hair as a retrospective biomarker with HPLC-MS/MS

    Wei Gao / Tobias Stalder / Susann Steudte / Clemens Kirschbaum / Paul Foley / Manfred Rauh / Huihua Deng

    European Journal of Psychotraumatology, Vol 3, Iss 0, Pp 1-

    2012  Volume 1

    Abstract: Statement of the problem : The analysis of steroid hormones in hair is increasingly used in psychoneuroendocrinological research as a valid and easily implementable method for the retrospective assessment of cumulative long-term hormone secretion. To ... ...

    Abstract Statement of the problem : The analysis of steroid hormones in hair is increasingly used in psychoneuroendocrinological research as a valid and easily implementable method for the retrospective assessment of cumulative long-term hormone secretion. To determine steroid hormone concentrations in hair, most laboratories have so far relied on immunochemical assays which are fast and easy to perform, but have a reduced reliability and analytical specificity due to cross-reactivity with other substances. Furthermore, immunoassay can only measure a single steroid at one time. By contrast, liquid chromatography tandem mass spectrometry (LC-MS/MS) has better specificity, sensitivity and reproducibility, and can measure a wide spectrum of steroid hormones simultaneously. Here, we report data on the development of a new LC-MS/MS-based method for the identification of endogenous concentrations of seven steroid hormones (cortisol, cortisone, testosterone, progesterone, corticosterone, DHEA, androstendione) in human hair. Methods : Hair samples were first washed with isopropanol. Steroid hormones were extracted from 10 mg whole hair by 1.8 ml methanol incubation at room temperature. One milliliter methanol was transferred to a new tube and evaporated to dryness. Then the extraction was resuspended with 0.25 ml water, 0.20 ml of which was injected into the machine for analysis. Results : The limits of detection were 0.1 pg/mg (cortisol), 0.1 pg/mg (cortisone), 0.4 pg/mg (testosterone), 0.9 pg/mg (progesterone), 0.4 pg/mg (corticosterone), 9.0 pg/mg (DHEA), 0.1 pg/mg (androstendione). Linear ranges were 0.5–100 pg/mg (cortisol), 0.5–100 pg/mg (cortisone), 2–100 pg/mg (testosterone), 4–100 pg/mg (progesterone), 2–100 pg/mg (corticosterone), 40–1000 pg/mg (DHEA) and 0.5–100 pg/mg (androstendione). Conclusions : This LC-MS/MS method provides a highly specific analytical strategy for the detection of seven endogenous hormones in human hair and is thus likely to further enhance the accuracy of future research in this field.
    Keywords human hair ; steroid hormones ; high performance liquid chromatography ; mass spectrometry ; Medicine (General) ; R5-920 ; Medicine ; R ; DOAJ:Medicine (General) ; DOAJ:Health Sciences ; Psychiatry ; RC435-571
    Language English
    Publishing date 2012-09-01T00:00:00Z
    Publisher Co-Action Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8

    Ines Marek / Maurizio Canu / Nada Cordasic / Manfred Rauh / Gudrun Volkert / Fabian B. Fahlbusch / Wolfgang Rascher / Karl F. Hilgers / Andrea Hartner / Carlos Menendez-Castro

    Biology of Sex Differences, Vol 8, Iss 1, Pp 1-

    2017  Volume 13

    Abstract: Abstract Background Apoe-deficient (Apoe −/−) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal ... ...

    Abstract Abstract Background Apoe-deficient (Apoe −/−) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe −/− mice deficient in the mesenchymal integrin chain Itga8 (Itga8 −/−). Here, we used this Apoe −/−, Itga8 −/− mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model. Methods Apoe −/− mice were backcrossed with Itga8 −/− mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe −/− Itga8 +/+ mice or Apoe −/− Itga8 −/− mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed. Results When compared to male mice, Apoe −/− Itga8 +/+ female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe −/− mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different. Conclusions In this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice ...
    Keywords α8 integrin ; Itga8 ; Atherosclerotic lesions ; Renal lesions ; Knockout mice ; Sex differences ; Medicine ; R ; Physiology ; QP1-981
    Subject code 616
    Language English
    Publishing date 2017-05-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ciliary integrity and causes renal disease and hydrocephalus

    Claudia Dafinger / Markus M. Rinschen / Lori Borgal / Carolin Ehrenberg / Sander G. Basten / Mareike Franke / Martin Höhne / Manfred Rauh / Heike Göbel / Wilhelm Bloch / F. Thomas Wunderlich / Dorien J. M. Peters / Dirk Tasche / Tripti Mishra / Sandra Habbig / Jörg Dötsch / Roman-Ulrich Müller / Jens C. Brüning / Thorsten Persigehl /
    Rachel H. Giles / Thomas Benzing / Bernhard Schermer / Max C. Liebau

    Experimental and Molecular Medicine, Vol 50, Iss 6, Pp 1-

    2018  Volume 17

    Abstract: Cell cilia: Protein crucial for function identified A protein involved in building and maintaining thin protrusions from cell surfaces called cilia is implicated in “ciliopathies”, diseases in which ciliary function is disrupted. These include polycystic ...

    Abstract Cell cilia: Protein crucial for function identified A protein involved in building and maintaining thin protrusions from cell surfaces called cilia is implicated in “ciliopathies”, diseases in which ciliary function is disrupted. These include polycystic kidney disease and disorders collectively known as ciliary dyskinesias. “Primary cilia” perform sensory functions, detecting external chemical and physical signals and initiating responses within cells. In addition, “motile cilia” beat rhythmically to move fluids surrounding cells. Researchers in Germany and the Netherlands, led by Bernhard Schermer and Max C. Liebau at the University of Cologne, studied a protein called Ruvbl1, known to interact with DNA and other proteins. The researchers found it is crucial for the functioning of both types of cilia. Deleting the gene for Ruvbl1 in mice caused kidney failure and a build-up of fluid in the brain known as hydrocephalus. The research could help understand and ultimately treat ciliopathies.
    Keywords Medicine ; R ; Biochemistry ; QD415-436
    Subject code 612
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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