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Publikation Discovering fundamental principles of antibody repertoires by large-scale systems and network analysis(ETH, 2017) Miho, Enkelejda05 - Forschungs- oder ArbeitsberichtPublikation Backtrainer. Computer-aided therapy system with augmented feedback for the lower back(SciTePress, 2009) Brodbeck, Dominique; Degen, Markus; Stanimirov, Michael; Kool, Jan; Scheermesser, Mandy; Oesch, Peter; Neuhaus, Cornelia; Azevedo, Luis; Londral, AnaLow back pain is an important problem in industrialized countries. Two key factors limit the effectiveness of physiotherapy: low compliance of patients with repetitive movement exercises, and inadequate awareness of patients of their own posture. The Backtrainer system addresses these problems by real-time monitoring of the spine position, by providing a framework for most common physiotherapy exercises for the low back, and by providing feedback to patients in a motivating way. A minimal sensor configuration was identified as two inertial sensors that measure the orientation of the lower back at two points with three degrees of freedom. The software was designed as a flexible platform to experiment with different hardware, and with various feedback modalities. Basic exercises for two types of movements are provided: mobilizing and stabilizing. We developed visual feedback - abstract as well as in the form of a virtual reality game - and complemented the on-screen graphics with an ambient feedback device. The system was evaluated during five weeks in a rehabilitation clinic with 26 patients and 15 physiotherapists. Subjective satisfaction of subjects was good, and we interpret the results as encouraging indication for the adoption of such a therapy support system by both patients and therapists.04B - Beitrag KonferenzschriftPublikation Augmented feedback system to support physical therapy of non-specific low back pain(Springer, 2010) Brodbeck, Dominique; Degen, Markus; Stanimirov, Michael; Kool, Jan; Scheermesser, Mandy; Oesch, Peter; Neuhaus, Cornelia; Fred, Ana; Filipe, Joaquim; Gamboa, HugoLow back pain is an important problem in industrialized countries. Two key factors limit the effectiveness of physiotherapy: low compliance of patients with repetitive movement exercises, and inadequate awareness of patients of their own posture. The Backtrainer system addresses these problems by real-time monitoring of the spine position, by providing a framework for most common physiotherapy exercises for the low back, and by providing feedback to patients in a motivating way. A minimal sensor configuration was identified as two inertial sensors that measure the orientation of the lower back at two points with three degrees of freedom. The software was designed as a flexible platform to experiment with different hardware, and with various feedback modalities. Basic exercises for two types of movements are provided: mobilizing and stabilizing. We developed visual feedback - abstract as well as in the form of a virtual reality game - and complemented the on-screen graphics with an ambient feedback device. The system was evaluated during five weeks in a rehabilitation clinic with 26 patients and 15 physiotherapists. Subjective satisfaction of subjects was good, and we interpret the results as encouraging indication for the adoption of such a therapy support system by both patients and therapists.04B - Beitrag KonferenzschriftPublikation Computational strategies for dissecting the high-dimensional complexity of adaptive immune repertoires(Frontiers Research Foundation, 2018) Miho, Enkelejda; Yermanos, Alexander; Weber, Cédric R.; Berger, Christoph T.; Reddy, Sai T.; Greiff, VictorThe adaptive immune system recognizes antigens via an immense array of antigen binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity and to understand the dynamics of adaptive immunity. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic, and (iv) machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Synthetic standards combined with error and bias correction improve the accuracy and quantitative resolution of antibody repertoire sequencing in human naïve and memory B cells(Frontiers Research Foundation, 20.06.2018) Friedensohn, Simon; Lindner, John M.; Cornacchione, Vanessa; Iazeolla, Mariavittoria; Miho, Enkelejda; Zingg, Andreas; Meng, Simon; Traggiai, Elisabetta; Reddy, Sai T.High-throughput sequencing of immunoglobulin (Ig) repertoires (Ig-seq) is a powerful method for quantitatively interrogating B cell receptor sequence diversity. When applied to human repertoires, Ig-seq provides insight into fundamental immunological questions, and can be implemented in diagnostic and drug discovery projects. However, a major challenge in Ig-seq is ensuring accuracy, as library preparation protocols and sequencing platforms can introduce substantial errors and bias that compromise immunological interpretation. Here, we have established an approach for performing highly accurate human Ig-seq by combining synthetic standards with a comprehensive error and bias correction pipeline. First, we designed a set of 85 synthetic antibody heavy-chain standards (in vitro transcribed RNA) to assess correction workflow fidelity. Next, we adapted a library preparation protocol that incorporates unique molecular identifiers (UIDs) for error and bias correction which, when applied to the synthetic standards, resulted in highly accurate data. Finally, we performed Ig-seq on purified human circulating B cell subsets (naïve and memory), combined with a cellular replicate sampling strategy. This strategy enabled robust and reliable estimation of key repertoire features such as clonotype diversity, germline segment, and isotype subclass usage, and somatic hypermutation. We anticipate that our standards and error and bias correction pipeline will become a valuable tool for researchers to validate and improve accuracy in human Ig-seq studies, thus leading to potentially new insights and applications in human antibody repertoire profiling.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation 01B - Beitrag in Magazin oder ZeitungPublikation Large-scale network analysis reveals the sequence space architecture of antibody repertoires(Nature, 01.12.2019) Miho, Enkelejda; Roškar, Rok; Greiff, Victor; Reddy, Sai T.The architecture of mouse and human antibody repertoires is defined by the sequence similarity networks of the clones that compose them. The major principles that define the architecture of antibody repertoires have remained largely unknown. Here, we establish a high-performance computing platform to construct large-scale networks from comprehensive human and murine antibody repertoire sequencing datasets (>100,000 unique sequences). Leveraging a network-based statistical framework, we identify three fundamental principles of antibody repertoire architecture: reproducibility, robustness and redundancy. Antibody repertoire networks are highly reproducible across individuals despite high antibody sequence dissimilarity. The architecture of antibody repertoires is robust to the removal of up to 50–90% of randomly selected clones, but fragile to the removal of public clones shared among individuals. Finally, repertoire architecture is intrinsically redundant. Our analysis provides guidelines for the large-scale network analysis of immune repertoires and may be used in the future to define disease-associated and synthetic repertoires.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Maturation of the human B-cell receptor repertoire with age(Cold Spring Harbor Laboratory, 20.12.2019) Ghraichy, Marie; Galson, Jacob D.; Kovaltsuk, Aleksandr; Niederhäusern, Valentin von; Schmid, Jana Pachlopnik; Recher, Mike; Jauch, Annaïse J; Miho, Enkelejda; Kelly, Dominic F.; Deane, Charlotte M.; Trück, JohannesB cells play a central role in adaptive immune processes, mainly through the production of antibodies. The maturation of the B-cell system with age is poorly studied. We extensively investigated age-related alterations of naïve and antigen-experienced B-cell receptor (BCR) repertoires. The most significant changes were observed in the first 10 years of life, and were characterized by altered immunoglobulin gene usage and an increased frequency of mutated antibodies structurally diverging from their germline precursors. Older age was associated with an increased usage of downstream constant region genes and fewer antibodies with self-reactive properties. As mutations accumulated with age, the frequency of germline-encoded self-reactive antibodies decreased, indicating a possible beneficial role of self-reactive B-cells in the developing immune system. Our results suggest a continuous process of change through childhood across a broad range of parameters characterizing BCR repertoires and stress the importance of using well-selected, age-appropriate controls in BCR studies01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Comparison of methods for phylogenetic B-cell lineage inference using time-resolved antibody repertoire simulations (AbSim)(Oxford University Press, 31.08.2017) Yermanos, Alexander; Greiff, Victor; Krautler, Nike Julia; Menzel, Ulrike; Dounas, Andreas; Miho, Enkelejda; Oxenius, Annette; Stadler, Tanja; Reddy, Sai T.; Kelso, JanetMotivation: The evolution of antibody repertoires represents a hallmark feature of adaptive B-cell immunity. Recent advancements in high-throughput sequencing have dramatically increased the resolution to which we can measure the molecular diversity of antibody repertoires, thereby offering for the first time the possibility to capture the antigen-driven evolution of B cells. However, there does not exist a repertoire simulation framework yet that enables the comparison of com monly utilized phylogenetic methods with regard to their accuracy in inferring antibody evolution.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Learning the high-dimensional immunogenomic features that predict public and private antibody repertoires(American Association of Immunologists, 15.10.2017) Greiff, Victor; Weber, Cédric R.; Palme, Johannes; Bodenhofer, Ulrich; Miho, Enkelejda; Menzel, Ulrike; Reddy, Sai T.Recent studies have revealed that immune repertoires contain a substantial fraction of public clones, which may be defined as Ab or TCR clonal sequences shared across individuals. It has remained unclear whether public clones possess predictable sequence features that differentiate them from private clones, which are believed to be generated largely stochastically. This knowledge gap represents a lack of insight into the shaping of immune repertoire diversity. Leveraging a machine learning approach capable of capturing the high-dimensional compositional information of each clonal sequence (defined by CDR3), we detected predictive public clone and private clone–specific immunogenomic differences concentrated in CDR3’s N1–D–N2 region, which allowed the prediction of public and private status with 80% accuracy in humans and mice. Our results unexpectedly demonstrate that public, as well as private, clones possess predictable high-dimensional immunogenomic features. Our support vector machine model could be trained effectively on large published datasets (3 million clonal sequences) and was sufficiently robust for public clone prediction across individuals and studies prepared with different library preparation and high-throughput sequencing protocols. In summary, we have uncovered the existence of high-dimensional immunogenomic rules that shape immune repertoire diversity in a predictable fashion. Our approach may pave the way for the construction of a comprehensive atlas of public mouse and human immune repertoires with potential applications in rational vaccine design and immunotherapeutics.01A - Beitrag in wissenschaftlicher Zeitschrift