Jesper Tegnér

Karolinska University Hospital, Tukholma, Stockholm, Sweden

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Publications (108)407.25 Total impact

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    ABSTRACT: This article describes a Digital Health Framework (DHF), benefitting from the lessons learnt during the three-year life span of the FP7 Synergy-COPD project. The DHF aims to embrace the emerging requirements - data and tools - of applying systems medicine into healthcare with a three-tier strategy articulating formal healthcare, informal care and biomedical research. Accordingly, it has been constructed based on three key building blocks, namely, novel integrated care services with the support of information and communication technologies, a personal health folder (PHF) and a biomedical research environment (DHF-research). Details on the functional requirements and necessary components of the DHF-research are extensively presented. Finally, the specifics of the building blocks strategy for deployment of the DHF, as well as the steps toward adoption are analyzed. The proposed architectural solutions and implementation steps constitute a pivotal strategy to foster and enable 4P medicine (Predictive, Preventive, Personalized and Participatory) in practice and should provide a head start to any community and institution currently considering to implement a biomedical research platform.
    Journal of Translational Medicine 11/2014; 12(Suppl 2:S10). · 3.46 Impact Factor
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    ABSTRACT: Background and hypothesis: Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics. Objective and method: To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena. Results: (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering. Conclusions: The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.
    Journal of Translational Medicine 11/2014; 12(Suppl 2:S3). · 3.46 Impact Factor
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    ABSTRACT: IntroductionGenetic susceptibility to complex diseases has been intensively studied during the last decade, yet only signals with small effect have been found leaving open the possibility that subgroups within complex traits show stronger association signals. In rheumatoid arthritis (RA), autoantibody production serves as a helpful discriminator in genetic studies and today anti-citrullinated cyclic peptide (anti-CCP) antibody positivity is employed for diagnosis of disease. The HLA-DRB1 locus is known as the most important genetic contributor for the risk of RA, but is not sufficient to drive autoimmunity and additional genetic and environmental factors are involved. Hence, we addressed the association of previously discovered RA loci with disease-specific autoantibody responses in RA patients stratified by HLA-DRB1*04.Methods We investigated 2178 patients from three RA cohorts from Sweden and Spain for 41 genetic variants and four autoantibodies, including the generic anti-CCP as well as specific responses towards citrullinated peptides from vimentin, alpha-enolase and type II collagen.ResultsOur data demonstrated different genetic associations of autoantibody-positive disease subgroups in relation to the presence of DRB1*04. Two specific subgroups of autoantibody-positive RA were identified. The SNP in PTPN22 was associated with presence of anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Cochran-Mantel-Haenszel test P¿=¿0.0001, P corrected <0.05), whereas SNPs in CDK6 and PADI4 were associated with anti-CCP status in DRB1*04 negative patients (Cochran-Mantel-Haenszel test P¿=¿0.0004, P corrected <0.05 for both markers). Additionally we see allelic correlation with autoantibody titers for PTPN22 SNP rs2476601 and anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Mann Whitney test P¿=¿0.02) and between CDK6 SNP rs42041 and anti-CCP in non-carriers of HLA-DRB1*04 (Mann Whitney test P¿=¿0.02).Conclusion These data point to alternative pathways for disease development in clinically similar RA subgroups and suggest an approach for study of genetic complexity of disease with strong contribution of HLA.
    Arthritis research & therapy. 08/2014; 16(5):414.
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    ABSTRACT: The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies. Systems biology approaches that study pathway dysregulation should offer benefits by integrating molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NF-Kb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis/cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress, although which pathways contribute to the cascade of damage and can be modulated remains an open question. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. These data serve as a scaffold on which computational modeling can be performed to identify disease subgroups based on the contribution of different processes. Such an analysis, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies.
    Multiple Sclerosis 08/2014; · 4.47 Impact Factor
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    ABSTRACT: High-throughput sequencing assays are now routinely used to study different aspects of genome organization. As decreasing costs and widespread availability of sequencing enable more laboratories to use sequencing assays in their research projects, the number of samples and replicates in these experiments can quickly grow to several dozens of samples and thus require standardized annotation, storage and management of preprocessing steps. As a part of the STATegra project, we have developed an Experiment Management System (EMS) for high throughput omics data that supports different types of sequencing-based assays such as RNA-seq, ChIP-seq, Methyl-seq, etc, as well as proteomics and metabolomics data. The STATegra EMS provides metadata annotation of experimental design, samples and processing pipelines, as well as storage of different types of data files, from raw data to ready-to-use measurements. The system has been developed to provide research laboratories with a freely-available, integrated system that offers a simple and effective way for experiment annotation and tracking of analysis procedures.
    BMC Systems Biology 03/2014; 8(Suppl 2):S9. · 2.98 Impact Factor
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    Hector Zenil, Jesper Tegnér
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    ABSTRACT: Network theory is today a central topic in computational systems biology as a framework to understand and reconstruct relations among biological components. For example, constructing networks from a gene expression dataset provides a set of possible hypotheses explaining connections among genes, vital knowledge to advancing our understanding of living organisms as systems. Here we briefly survey aspects at the intersection of information theory and network biology. We show that Shannon's information entropy, Kolmogorov complexity and algorithmic probability quantify different aspects of biological networks at the interplay of local and global pattern detection. We provide approximations to the algorithmic probability and Kolmogorov complexity of motifs connected to the asymptotic topological properties of networks.
    01/2014;
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    ABSTRACT: To integrate heterogeneous and large omics data constitutes not only a conceptual challenge but a practical hurdle in the daily analysis of omics data. With the rise of novel omics technologies and through large-scale consortia projects, biological systems are being further investigated at an unprecedented scale generating heterogeneous and often large data sets. These data-sets encourage researchers to develop novel data integration methodologies. In this introduction we review the definition and characterize current efforts on data integration in the life sciences. We have used a web-survey to assess current research projects on data-integration to tap into the views, needs and challenges as currently perceived by parts of the research community.
    BMC Systems Biology 01/2014; 8. · 2.98 Impact Factor
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    Journal of Translational Medicine 01/2014; 12. · 3.46 Impact Factor
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    ABSTRACT: The production of reactive oxygen species (ROS) from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po2 ([Formula: see text]). Because [Formula: see text] depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the "death zone" in mountaineering.
    PLoS ONE 01/2014; 9(11):e111068. · 3.53 Impact Factor
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    ABSTRACT: Translational medicine is becoming increasingly dependent upon data generated from health care, clinical research, and molecular investigations. This increasing rate of production and diversity in data has brought about several challenges, including the need to integrate fragmented databases, enable secondary use of patient clinical data from health care in clinical research, and to create information systems that clinicians and biomedical researchers can readily use. Our case study effectively integrates requirements from the clinical and biomedical researcher perspectives in a translational medicine setting. Our three principal achievements are (a) a design of a user-friendly web-based system for management and integration of clinical and molecular databases, while adhering to proper de-identification and security measures; (b) providing a real-world test of the system functionalities using clinical cohorts; and (c) system integration with a clinical decision support system to demonstrate system interoperability. We engaged two active clinical cohorts, 747 psoriasis patients and 2001 rheumatoid arthritis patients, to demonstrate efficient query possibilities across the data sources, enable cohort stratification, extract variation in antibody patterns, study biomarker predictors of treatment response in RA patients, and to explore metabolic profiles of psoriasis patients. Finally, we demonstrated system interoperability by enabling integration with an established clinical decision support system in health care. To assure the usefulness and usability of the system, we followed two approaches. First, we created a graphical user interface supporting all user interactions. Secondly we carried out a system performance evaluation study where we measured the average response time in seconds for active users, http errors, and kilobits per second received and sent. The maximum response time was found to be 0.12 seconds; no server or client errors of any kind were detected. In conclusion, the system can readily be used by clinicians and biomedical researchers in a translational medicine setting.
    PLoS ONE 01/2014; 9(9):e104382. · 3.53 Impact Factor
  • Hector Zenil, Jesper Tegnér
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    ABSTRACT: Network theory is today a central topic in computational systems biology as a framework to understand and reconstruct relations among biological components. For example, constructing networks from a gene expression dataset provides a set of possible hypotheses explaining connections among genes, vital knowledge to advancing our understanding of living organisms as systems. Here we briefly survey aspects at the intersection of information theory and network biology. We show that Shannon's information entropy, Kolmogorov complexity and algorithmic probability quantify different aspects of biological networks at the interplay of local and global pattern detection. We provide approximations to the algorithmic probability and Kolmogorov complexity of motifs connected to the asymptotic topological properties of networks.
    12/2013;
  • Hector Zenil, Narsis A. Kiani, Jesper Tegner
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    ABSTRACT: Representing biological systems as networks has proved to be very powerful. For example, local graph analysis of substructures such as subgraph over representation (or motifs) has elucidated different sub-types of networks. Here we report that using numerical approximations of Kolmogorov complexity, by means of algorithmic probability, clusters different classes of networks. For this, we numerically estimate the algorithmic probability of the sub-matrices from the adjacency matrix of the original network (hence including motifs). We conclude that algorithmic information theory is a powerful tool supplementing other network analysis techniques.
    2013 IEEE International Conference on Bioinformatics and Biomedicine (BIBM); 12/2013
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    ABSTRACT: In previous calculations of how the O2 transport system limits [Formula: see text] , it was reasonably assumed that mitochondrial [Formula: see text] ( [Formula: see text] ) could be neglected (set to zero). However, in reality, [Formula: see text] must exceed zero and the red cell to mitochondrion diffusion gradient may therefore be reduced, impairing diffusive transport of O2 and [Formula: see text] . Accordingly, we investigated the influence of [Formula: see text] on these calculations by coupling previously used equations for O2 transport to one for mitochondrial respiration relating mitochondrial [Formula: see text] to [Formula: see text] . This hyperbolic function, characterized by its P50 and V˙MAX, allowed [Formula: see text] to become a model output (rather than set to zero as previously). Simulations using data from exercising normal subjects showed that at [Formula: see text] , [Formula: see text] was usually<1mm Hg, and that the effects on [Formula: see text] were minimal. However, when O2 transport capacity exceeded mitochondrial V˙MAX, or if P50 were elevated, [Formula: see text] often reached double digit values, thereby reducing the diffusion gradient and significantly decreasing [Formula: see text] .
    Respiratory Physiology & Neurobiology 09/2013; · 2.05 Impact Factor
  • Hector Zenil, Gordon Ball, Jesper Tegnér
    European Conference on Artificial Life 2013; 09/2013
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    ABSTRACT: The new discipline of computational biomedicine is concerned with the application of computer-based techniques and particularl modelling and simulation to human health. Since 2007, this discipline has been synonymous, in Europe, with the name give to the European Union's ambitious investment in integrating these techniques with the eventual aim of modelling the huma body as a whole: the virtual physiological human. This programme and its successors are expected, over the next decades, t transform the study and practice of healthcare, moving it towards the priorities known as ‘4P's’: predictive, preventative personalized and participatory medicine.
    Interface focus: a theme supplement of Journal of the Royal Society interface 04/2013; 3(2). · 2.21 Impact Factor
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    ABSTRACT: BACKGROUND: Sequencing of the human genome and the subsequent analyses have produced immense volumes of data. The technological advances have opened new windows into genomics beyond the DNA sequence. In parallel, clinical practice generate large amounts of data. This represents an underused data source that has much greater potential in translational research than is currently realized. This research aims at implementing a translational medicine informatics platform to integrate clinical data (disease diagnosis, diseases activity and treatment) of Rheumatoid Arthritis (RA) patients from Karolinska University Hospital and their research database (biobanks, genotype variants and serology) at the Center for Molecular Medicine, Karolinska Institutet. METHODS: Requirements engineering methods were utilized to identify user requirements. Unified Modeling Language and data modeling methods were used to model the universe of discourse and data sources. Oracle11g were used as the database management system, and the clinical development center (CDC) was used as the application interface. Patient data were anonymized, and we employed authorization and security methods to protect the system. RESULTS: We developed a user requirement matrix, which provided a framework for evaluating three translation informatics systems. The implementation of the CDC successfully integrated biological research database (15172 DNA, serum and synovial samples, 1436 cell samples and 65 SNPs per patient) and clinical database (5652 clinical visit) for the cohort of 379 patients presents three profiles. Basic functionalities provided by the translational medicine platform are research data management, development of bioinformatics workflow and analysis, sub-cohort selection, and re-use of clinical data in research settings. Finally, the system allowed researchers to extract subsets of attributes from cohorts according to specific biological, clinical, or statistical features. CONCLUSIONS: Research and clinical database integration is a real challenge and a road-block in translational research. Through this research we addressed the challenges and demonstrated the usefulness of CDC. We adhered to ethical regulations pertaining to patient data, and we determined that the existing software solutions cannot meet the translational research needs at hand. We used RA as a test case since we have ample data on active and longitudinal cohort.
    Journal of Translational Medicine 04/2013; 11(1):85. · 3.46 Impact Factor
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    ABSTRACT: European funding under Framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for 5 years. The VPH Network of Excellence (NoE) has been set up to help develop common standards, open source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also working to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by the FP6 STEP project in 2006. In 2010, we wrote an assessment of the accomplishments of the first two years of the VPH in which we considered the biomedical science, healthcare and information and communications technology challenges facing the project (Hunter et al. 2010 Phil. Trans. R. Soc. A 368, 2595–2614 (doi:10.1098/rsta.2010.0048)). We proposed that a not-for-profit professional umbrella organization, the VPH Institute, should be established as a means of sustaining the VPH vision beyond the time-frame of the NoE. Here, we update and extend this assessment and in particular address the following issues raised in response to Hunter et al.: (i) a vision for the VPH updated in the light of progress made so far, (ii) biomedical science and healthcare challenges that the VPH initiative can address while also providing innovation opportunities for the European industry, and (iii) external changes needed in regulatory policy and business models to realize the full potential that the VPH has to offer to industry, clinics and society generally.
    Interface focus: a theme supplement of Journal of the Royal Society interface 02/2013; Interface Focus(3). · 2.21 Impact Factor
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    ABSTRACT: The proper identification of differentially methylated CpGs is central in most epigenetic studies. The Illumina HumanMethylation450 BeadChip is widely used to quantify DNA methylation; nevertheless, the design of an appropriate analysis pipeline faces severe challenges due to the convolution of biological and technical variability and the presence of a signal bias between Infinium I and II probe design types. Despite recent attempts to investigate how to analyze DNA methylation data with such an array design, it has not been possible to perform a comprehensive comparison between different bioinformatics pipelines due to the lack of appropriate data sets having both large sample size and sufficient number of technical replicates. Here we perform such a comparative analysis, targeting the problems of reducing the technical variability, eliminating the probe design bias and reducing the batch effect by exploiting two unpublished data sets, which included technical replicates and were profiled for DNA methylation either on peripheral blood, monocytes or muscle biopsies. We evaluated the performance of different analysis pipelines and demonstrated that: (1) it is critical to correct for the probe design type, since the amplitude of the measured methylation change depends on the underlying chemistry; (2) the effect of different normalization schemes is mixed, and the most effective method in our hands were quantile normalization and Beta Mixture Quantile dilation (BMIQ); (3) it is beneficial to correct for batch effects. In conclusion, our comparative analysis using a comprehensive data set suggests an efficient pipeline for proper identification of differentially methylated CpGs using the Illumina 450K arrays.
    Epigenetics: official journal of the DNA Methylation Society 02/2013; 8(3). · 4.58 Impact Factor
  • Jesper Tegnér, Imad Abugessaisa
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    ABSTRACT: Medicine and pediatrics are changing and healthcare is moving from being reactive to becoming preventive. Despite rapid developments of new technologies for molecular profiling and systems analysis of diseases significant hurdles remain. Here we use the clinical setting of congenital heart block (CHB) to uncover and illustrate key informatics challenges impeding development of a systems medicine approach emphasizing prevention and prediction of disease. We find that there is paucity in useful bioinformatics tools enabling integrative analysis of different databases of molecular information and clinical sources in a disease context such as CHB, contrasting with the current emphasis on developing bioinformatics tools for the analysis of individual data-types. Moreover, informatics solutions for managing data, such as i2b2 or STRIDE, requires serious software engineering support for maintenance and import of data beyond the capabilities of clinicians working with CHB. Hence, there is an urgent unmet need for user-friendly tools facilitating integrative analysis and management of omics data and clinical information. Pediatrics represents an untapped potential to execute such a systems medicine program in close collaboration with clinicians and families who are keen to do what is needed for their children to prevent, predict disease and nurture wellness.Pediatric Research (2013); doi:10.1038/pr.2013.19.
    Pediatric Research 01/2013; · 2.67 Impact Factor
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    ABSTRACT: Autoimmune rheumatic diseases are complex disorders, whose etiopathology is attributed to a crosstalk between genetic predisposition and environmental factors. Both variants of autoimmune susceptibility genes and environment are involved in the generation of aberrant epigenetic profiles in a cell-specific manner, which ultimately result in dysregulation of expression. Furthermore, changes in miRNA expression profiles also cause gene dysregulation associated with aberrant phenotypes. In rheumatoid arthritis, several cell types are involved in the destruction of the joints, synovial fibroblasts being among the most important. In this study we performed DNA methylation and miRNA expression screening of a set of rheumatoid arthritis synovial fibroblasts and compared the results with those obtained from osteoarthritis patients with a normal phenotype. DNA methylation screening allowed us to identify changes in novel key target genes like IL6R, CAPN8 and DPP4, as well as several HOX genes. A significant proportion of genes undergoing DNA methylation changes were inversely correlated with expression. miRNA screening revealed the existence of subsets of miRNAs that underwent changes in expression. Integrated analysis highlighted sets of miRNAs that are controlled by DNA methylation, and genes that are regulated by DNA methylation and are targeted by miRNAs with a potential use as clinical markers. Our study enabled the identification of novel dysregulated targets in rheumatoid arthritis synovial fibroblasts and generated a new workflow for the integrated analysis of miRNA and epigenetic control.
    Journal of Autoimmunity 01/2013; · 8.15 Impact Factor

Publication Stats

4k Citations
407.25 Total Impact Points

Institutions

  • 2007–2014
    • Karolinska University Hospital
      • Center for Molecular Medicine (CMM)
      Tukholma, Stockholm, Sweden
  • 2009–2011
    • Stockholm University
      • Department of Mathematics
      Stockholm, Stockholm, Sweden
  • 2010
    • University of Auckland
      Окленд, Auckland, New Zealand
  • 2005–2009
    • Linköping University
      • Institute of Technology
      Linköping, Östergötland, Sweden
    • Stockholm Spine Center
      Tukholma, Stockholm, Sweden
  • 2008
    • University of California, San Diego
      • Department of Bioengineering
      San Diego, CA, United States
  • 2000–2007
    • KTH Royal Institute of Technology
      • • School of Computer Science and Communication (CSC)
      • • Division of Numerical Analysis
      Stockholm, Stockholm, Sweden
  • 1993–2006
    • Karolinska Institutet
      • Institutionen för neurovetenskap
      Solna, Stockholm, Sweden
  • 2003
    • Uppsala University
      • Department of Cell and Molecular Biology
      Uppsala, Uppsala, Sweden
    • Boston University
      Boston, Massachusetts, United States
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States