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  • Springer (CrossRef)  (9)
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  • 1
    In: PLoS ONE, 2014, Vol.9(9)
    Description: Recent advances in big data and analytics research have provided a wealth of large data sets that are too big to be analyzed in their entirety, due to restrictions on computer memory or storage size. New Bayesian methods have been developed for data sets that are large only due to large sample sizes. These methods partition big data sets into subsets and perform independent Bayesian Markov chain Monte Carlo analyses on the subsets. The methods then combine the independent subset posterior samples to estimate a posterior density given the full data set. These approaches were shown to be effective for Bayesian models including logistic regression models, Gaussian mixture models and hierarchical models. Here, we introduce the R package parallelMCMCcombine which carries out four of these techniques for combining independent subset posterior samples. We illustrate each of the methods using a Bayesian logistic regression model for simulation data and a Bayesian Gamma model for real data; we also demonstrate features and capabilities of the R package. The package assumes the user has carried out the Bayesian analysis and has produced the independent subposterior samples outside of the package. The methods are primarily suited to models with unknown parameters of fixed dimension that exist in continuous parameter spaces. We envision this tool will allow researchers to explore the various methods for their specific applications and will assist future progress in this rapidly developing field.
    Keywords: Research Article ; Computer And Information Sciences ; Physical Sciences ; Research And Analysis Methods
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: Immunogenetics, 2014, Vol.66(5), pp.287-297
    Description: Recently, evidence was provided for common familial occurrence of systemic mast cell activation disease (MCAD), i.e., mast cell disorders characterized by aberrant release of mast cell mediators and/or accumulation of pathological mast cells in potentially any tissue. Since there is accumulating evidence that epigenetic processes may have transgenerational consequences, the aim of the present study was to investigate by two different experimental approaches whether epigenetic effects may contribute to the familial occurrence of MCAD. (1) High throughput profiling of the methylation status of the genomic DNA in leukocytes from MCAD patients in comparison to healthy subjects revealed for the first time an association of MCAD with alterations in DNA methylation comprising genes encoding proteins crucially involved in DNA/RNA repair and processing, apoptosis, cell activity, and exocytosis/cell communication. A set of 195 differentially methylated CpG sites could be regarded as candidates for a MCAD signature at the methylation level of the DNA. (2) In a cohort of MCAD patients, a correlation between age at symptom onset and year of birth (reflecting different generations) was observed suggesting the presence of the phenomenon of anticipation. In conclusion, the present findings suggest that epigenetic processes could substantially contribute to the transgenerational transmission of MCAD.
    Keywords: Systemic mast cell activation disease ; Systemic mastocytosis ; Systemic mast cell activation syndrome ; Methylation ; Anticipation ; Epigenetics
    ISSN: 0093-7711
    E-ISSN: 1432-1211
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  • 3
    Language: English
    In: Bulletin of Mathematical Biology, 2015, Vol.77(12), pp.2180-2211
    Description: Model reduction of biochemical networks relies on the knowledge of slow and fast variables. We provide a geometric method, based on the Newton polytope, to identify slow variables of a biochemical network with polynomial rate functions. The gist of the method is the notion of tropical equilibration that provides approximate descriptions of slow invariant manifolds. Compared to extant numerical algorithms such as the intrinsic low-dimensional manifold method, our approach is symbolic and utilizes orders of magnitude instead of precise values of the model parameters. Application of this method to a large collection of biochemical network models supports the idea that the number of dynamical variables in minimal models of cell physiology can be small, in spite of the large number of molecular regulatory actors.
    Keywords: Model reduction ; Algebraic systems biology ; Complexity
    ISSN: 0092-8240
    E-ISSN: 1522-9602
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  • 4
    Language: English
    In: EPMA Journal, 2018, Vol.9(2), pp.175-186
    Description: Background The breast cancer (BC) epidemic is a multifactorial disease attributed to the early twenty-first century: about two million of new cases and half a million deaths are registered annually worldwide. New trends are emerging now: on the one hand, with respect to the geographical BC prevalence and, on the other hand, with respect to the age distribution. Recent statistics demonstrate that young populations are getting more and more affected by BC in both Eastern and Western countries. Therefore, the old rule "the older the age, the higher the BC risk" is getting relativised now. Accumulated evidence shows that young premenopausal women deal with particularly unpredictable subtypes of BC such as triple-negative BC, have lower survival rates and respond less to conventional chemotherapy compared to the majority of postmenopausal BC. Working hypothesis Here we hypothesised that a multi-level diagnostic approach may lead to the identification of a molecular signature highly specific for the premenopausal BC. A multi-omic approach using machine learning was considered as a potent tool for stratifying patients with benign breast alterations into well-defined risk groups, namely individuals at high versus low risk for breast cancer development. Results and conclusions The study resulted in identifying multi-omic signature specific for the premenopausal BC that can be used for stratifying patients with benign breast alterations. Our predictive model is capable of discriminating individually between high and low BC-risk with high confidence (〉90%) and considered of potential clinical utility. Novel risk assessment approaches and advanced screening programmes--as the long-term target of this project--are of particular importance for predictive, preventive and personalised medicine as the medicine of the future, due to the expected health benefits for young subpopulations and the healthcare system as a whole. Keywords: Predictive preventive personalised medicine, Breast cancer, Menopause, Patient stratification, Bioinformatics, Machine learning, Multi-level diagnostics, Biomarker panel, Laboratory medicine
    Keywords: Predictive preventive personalised medicine ; Breast cancer ; Menopause ; Patient stratification ; Bioinformatics ; Machine learning ; Multi-level diagnostics ; Biomarker panel ; Laboratory medicine
    ISSN: 1878-5077
    E-ISSN: 1878-5085
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  • 5
    Language: English
    In: Annals of Hematology, 2015, Vol.94(1), pp.129-137
    Description: The recovery of the host immune system after allogeneic hematopoietic stem cell transplantation is pivotal to prevent infections, relapse, and secondary malignancies. In particular, numerical CD4+ T cells reconstitution is delayed and CD4 helper cell function is considered impaired as a consequence of the transplant procedure and concomitant immunosuppressive medication. From HIV/AIDS patients, it is known that numerical and functional CD4 defects increase the risk of opportunistic infections. However, and in contrast to patients with HIV, anti-infective prophylaxis after allogeneic transplantation is usually given for 6 months depending on immunosuppressive medication and existing graft-versus-host disease but independently of absolute CD4+ T cells counts. We hypothesized that a qualitative T cell defect is existing after allogeneic transplantation, especially in patients with delayed immune-reconstitution. Applying transcriptional as well as functional approaches, we show that CD4+ T cells with delayed recovery have a distinct transcriptional profile and cluster differently from T cells originated from patients with completed immune recovery. Moreover, inhibitory signatures are substantially enriched within the transcriptional profile of these T cells translating to functional defects and impaired interleukin 2 production. In addition to time after transplant, CD4+ T cells numbers should be considered for the decision to stop or maintain antimicrobial prophylaxis in patients after allogeneic stem cell transplantation.
    Keywords: Allogeneic stem cell transplantation ; Immune reconstitution ; CD4+ T cells ; Infection ; Antimicrobial prophylaxis
    ISSN: 0939-5555
    E-ISSN: 1432-0584
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  • 6
    Language: English
    In: Journal of Molecular Neuroscience, 2015, Vol.55(2), pp.466-479
    Description: Epilepsy affects around 50 million people worldwide, and in about 65 % of patients, the etiology of disease is unknown. MicroRNAs are small non-coding RNAs that have been suggested to play a role in the pathophysiology of epilepsy. Here, we compared microRNA expression patterns in the hippocampus using two chronic models of epilepsy characterised by recurrent spontaneous seizures (pilocarpine and self-sustained status epilepticus (SSSE)) and an acute 6-Hz seizure model. The vast majority of microRNAs deregulated in the acute model exhibited increased expression with 146 microRNAs up-regulated within 6 h after a single seizure. In contrast, in the chronic models, the number of up-regulated microRNAs was similar to the number of down-regulated microRNAs. Three microRNAs—miR-142-5p, miR-331-3p and miR-30a-5p—were commonly deregulated in all three models. However, there is a clear overlap of differentially expressed microRNAs within the chronic models with 36 and 15 microRNAs co-regulated at 24 h and at 28 days following status epilepticus, respectively. Pathway analysis revealed that the altered microRNAs are associated with inflammation, innate immunity and cell cycle regulation. Taken together, the identified microRNAs and the pathways they modulate might represent candidates for novel molecular approaches for the treatment of patients with epilepsy.
    Keywords: Epilepsy ; miRNA ; Status epilepticus ; Microarray ; Hippocampus
    ISSN: 0895-8696
    E-ISSN: 1559-1166
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  • 7
    Language: English
    In: neurogenetics, 2017, Vol.18(1), pp.7-22
    Description: Numerous studies have elucidated the genetics of Parkinson’s disease; however, the aetiology of the majority of sporadic cases has not yet been resolved. We hypothesized that epigenetic variations could be associated with PD and evaluated the DNA methylation pattern in PD patients compared to brothers or twins without PD. The methylation of DNA from peripheral blood mononuclear cells of 62 discordant siblings including 24 monozygotic twins was characterized with Illumina DNA Methylation 450K bead arrays and subsequently validated in two independent cohorts: 221 PD vs. 227 healthy individuals (cohort 1) applying Illumina’s VeraCode and 472 PD patients vs. 487 controls (cohort 2) using pyrosequencing. We choose a delta beta of 〉15 % and selected 62 differentially methylated CpGs in 51 genes from the discordant siblings. Among them, three displayed multiple CpGs per gene: microRNA 886 ( MIR886 , 10 CpGs), phosphodiesterase 4D ( PDE4D , 2 CpGs) and tripartite motif-containing 34 ( TRIM34 , 2 CpGs). PDE4D was confirmed in both cohorts ( p value 2.44e−05). In addition, for biomarker construction, we used the penalized logistic regression model, resulting in a signature of eight CpGs with an AUC of 0.77. Our findings suggest that a distinct level of PD susceptibility stems from individual, epigenetic modifications of specific genes. We identified a signature of CpGs in blood cells that could separate control from disease with a reasonable discriminatory power, holding promise for future epigenetically based biomarker development.
    Keywords: Neurodegeneration ; Microarray ; Biomarker ; Movement disorder
    ISSN: 1364-6745
    E-ISSN: 1364-6753
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  • 8
    Language: English
    In: Journal of Molecular Medicine, 2019, Vol.97(6), pp.871-877
    Description: Byline: Thorsten Buch (1), Katharina Moos (2,3), Filipa M. Ferreira (1), Holger Frohlich (4), Catherine Gebhard (5), Achim Tresch (2,3) Keywords: Sex; Animal experimentation; Factorial design; Power Abstract: Abstract Disease occurrence, clinical manifestations, and outcomes differ between men and women. Yet, women and men are most of the time treated similarly, which is often based on experimental data over-representing one sex. Accounting for persisting sex bias in biomedical research is the misconception that the analysis of sex-specific effects would double sample size and costs. We designed an analysis to test the potential benefits of a factorial study design in the context of a study including male and female animals. We chose a 2x2 factorial design approach to study the effect of treatment, sex, and an interaction term of treatment and sex in a hypothetical situation. We calculated the sample sizes required to detect an effect of a given magnitude with sufficient power and under different experimental setups. We demonstrated that the inclusion of both sexes in experimental setups, without testing for sex effects, requires no or few additional animals in our scenarios. These experimental designs still allow for the exploration of sex effects at low cost. In a confirmatory instead of an exploratory design, we observed an increase in total sample sizes by 33%, at most. Since the complexities associated with this mathematical model require statistical expertise, we generated and provide a sample size calculator for planning factorial design experiments. For the inclusion of sex, a factorial design is advisable, and a sex-specific analysis can be performed without excessive additional effort. Our easy-to-use calculation tool provides help in designing studies with both sexes and addresses the current sex bias in preclinical studies. Key messages acents Both sexes should be included into animal studies. acents Exploratory study of sex effects can be conducted with no or small increase in animal number. acents Confirmatory analysis of sex effects requires maximum 33% more animals per study. acents Our calculation tool supports the design of studies with both sexes. Author Affiliation: (1) 0000 0004 1937 0650, grid.7400.3, Institute of Laboratory Animal Science, University of Zurich, Wagistrasse 12, 8952 Schlieren, Zurich, Switzerland (2) 0000 0000 8580 3777, grid.6190.e, Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Bachemer Str. 86, 50931, Cologne, Germany (3) 0000 0000 8580 3777, grid.6190.e, Center for Data and Simulation Science (CDS), University of Cologne, Cologne, Germany (4) 0000 0001 2240 3300, grid.10388.32, Bonn-Aachen International Center for IT (b-it), University of Bonn, Bonn, Germany (5) 0000 0004 1937 0650, grid.7400.3, Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland Article History: Registration Date: 11/03/2019 Received Date: 01/12/2018 Accepted Date: 10/03/2019 Online Date: 13/04/2019 Article note: Electronic supplementary material The online version of this article ( https://doi.org/10.1007/s00109-019-01774-0) contains supplementary material, which is available to authorized users.
    Keywords: Sex ; Animal experimentation ; Factorial design ; Power
    ISSN: 0946-2716
    E-ISSN: 1432-1440
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  • 9
    Language: English
    In: Archives of Orthopaedic and Trauma Surgery, 2014, Vol.134(7), pp.925-931
    Description: Byline: Paola Koenen (1), Holger Bathis (1), Marco M. Schneider (1), Matthias Frohlich (1), Bertil Bouillon (1), Sven Shafizadeh (1) Keywords: Patients' expectations; Total knee arthroplasty; Total hip arthroplasty; Joint replacement surgery Abstract: Introduction Patients' expectations have become increasingly important over the last decade, as the fulfilment of preoperative expectations has been shown to be associated with postoperative satisfaction. Understanding the pattern of patients' expectations is necessary to provide a better basis for recommendations to patients opting for arthroplasty. The aim of this study was to show patients' expectations of joint replacement surgery in Germany and to elucidate factors, which might have an influence. Materials and methods A retrospective analysis of anonymously collected data was performed on people participating in a patient information event for joint replacement surgery. They were asked to complete a survey, which consisted of five questions requesting demographic data and three questions regarding preoperative expectations. The latter were taken from the New Knee Society Score. An expectation score (0--12 points) was generated by adding the single point values of the three questions. Results 180 attendees were included in this study. The distribution of patients' expectations was remarkably skewed towards high expectations, the mean expectation score was 10.17. 87.2 % of participants had high and very high expectations and only 12.8 % had low and moderate expectations. Patients' expectations were independent of age and previous participation in a patient information event. Female gender and a history of arthroplasty led to a slightly higher expectation score. Patients with isolated knee pain had significantly lower expectations than patients suffering from isolated hip pain. Conclusions This study shows that the majority of patients have high expectations regarding joint replacement surgery. To improve postoperative patients' satisfaction a straightforward physician--patient communication is necessary to prevent patients from potentially unrealistic expectations and therefore dissatisfaction with surgery. Author Affiliation: (1) Department of Trauma and Orthopaedic Surgery, University of Witten/Herdecke, Cologne-Merheim Medical Center, Ostmerheimer Str. 200, 51109, Cologne, Germany Article History: Registration Date: 09/05/2014 Received Date: 26/12/2013 Online Date: 24/05/2014
    Keywords: Patients’ expectations ; Total knee arthroplasty ; Total hip arthroplasty ; Joint replacement surgery
    ISSN: 0936-8051
    E-ISSN: 1434-3916
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