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Computational Physiology and Biostatistics

This group is a subunit of the pediatric pulmonology research unit led by Prof. Urs Frey at the University Children's Hospital and the Department of Biomedical Engineering at University of Basel

Our research activities are devoted to the analysis of pathyophysiological measurements, particularly those related to respiratory and cardiac function, using mathematical, computational, and statistical techniques. Of central interest to our group is the study of physiological and pathological reactions to environmental stimuli such as air pollution and exposure to tobacco smoke.

Our unit works in close collaboration with clinical researchers and epidemiologists. We use well established computational techniques to analyze clinical data. We also work on the efficient implementation of such techniques, and on the improvement and de novo development of computational methods.

Main current projects

Please note that not every project listed here was necessarily initiated by our group.

Patient phenotyping based on lung function fluctuation

Research questions/goals: Approaches to identifying phenotypes or endotypes in asthma have become increasingly relevant. However, in the majority of published approaches, the characterising parameters are only assessed at a single point in time, yielding phenotypes that might not remain stable as time progresses. We hypothesised that we could identify asthma and functional healthy phenotypes by investigating the patterns of fluctuation in airway function measured over a predetermined, sufficiently long time window of observation.

Current main results and/or publications: We have developed and applied a computational data-driven method that allows us to classify healthy individuals and different types of asthmatic patients according to the fluctuation patterns in their lung function. By applying this methodology to three different patient cohorts, we were able to explore the potential clinical usefulness of our approach. Indeed, we found evidence for the existence of subtypes of asthma patients, who, if properly identified, would benefit from therapeutic strategies that differ from the commonly used anti-inflammatory treatment schemes. More details regarding our main findings can be found in the following publications: Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants (in this paper our methodology is presented in full detail); Fluctuation-based clustering reveals phenotypes of patients with different asthma severity; and Lung function fluctuation patternsunveil asthma and COPD phenotypes unrelated to type 2 inflammation.

Collaborators: Prof. Sven-Erik Dahlén, Dr. Anna James, and Dr. Maciej Kupczyk from the Experimental Asthma and Allergy Research Unit, The National Institute of Environmental Medicine, at Karolinska Institutet, Stockholm, Sweden. Prof. Andrew Bush and Dr. Louise Fleming from Imperial College London and the Royal Brompton and Harefield hospitals, London, UK. Prof. Erika von Mutzius, from the Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.

Assessing the effects of tobacco smoke and air pollution exposure on heart rate variability

Research questions/goals: In this project we aim to establish associations between air pollution and tobacco smoke exposure and changes in hear rate dynamics. To this end, we are using non-linear time series analysis methods to study interbeat interval time series from participants of the SAPALDIA cohort.

Current main results and/or publications:We have demonstrated a statistically significant association between tobacco smoke exposure and changes in heart rate variability, heart rate dynamics, and in the properties of the cardiovascular regulation. Moreover, we have explored the potential long term cardiovascular benefits of smoking cessation in former light and heavy smokers. We were honored with the “Best Paper of 2015” award by the scientific journal “Environmental research” for this work: Long-term smoking cessation and heart rate dynamics in an aging healthy cohort: Is it possible to fully recover? More recently, we also found out that long-term exposure to traffic-related particulate matter triggers adverse changes in the regulation of the cardiovascular system. For more details, check out our publication Association of long-term exposure to traffic-related PM10 with heart rate variability and heart rate dynamics in healthy subjects.

Funding: Tabakpräventionsfonds, Bundesamt für Gesundheit and Research Fund Junior Researchers at University of Basel.

Collaborators: Prof. Nicole Probst-Hensch, Prof. Nino Künzli, Dr. Emmanuel Schaffner, and Dr. Martin Adam from the Swiss Tropical and Public Health Institute and the SAPALDIA team.

Understanding the molecular mechanisms of angiogenesis

Research questions/goals: In collaboration with scientists at University of Leeds (UK), we have developed an experimental platform that will help improve our understanding of the molecular mechanisms that govern angiogenesis, i.e. vessel growth in the human body, in both physiological and pathological (e.g. tumor induced) conditions. To this end, we have developed and validated an experimental approach that combines microfluidics technologies with fluorescence imaging, and spectral analysis.

Current main results and/or publications: Our measurements suggest that the macroscopic outcomes (e.g., cell proliferation, cell migration, and eventually angiogenesis) of exposing vascular endothelial cells to extracellular growth factors appear to be frequency modulated, i.e., the rate at which pulses of biochemical responses emerge within the cell, rather than the amplitude of these pulses, regulates and controls further cellular processes. This counterintuitive finding, if found to be also valid in a more physiological in vivo context, might challenge the conventional view of dose-response relationship that underlies traditional, and unfortunately poorly performing anti-angiogenic treatment approaches to cancer. A first publication is currently in preparation.

Collaborators: Dr. Sreenivasan Ponnambalam, Dr. Adam Odell, and Prof. Carmen Molina-Paris from University of Leeds, UK.

Image of a human umbilical vein endothelial cell (HUVEC) obtained using fluorescence confocal microscopy. Within our project, we record and analyze the emission spectrum in such images in order to obtain real-time information about pathway activity upon stimulation with extracellular growth factors.

Mathematical modeling and computer simulation of host-pathogen interactions

Research questions/goals: Currently, our focus is to elucidate the mechanisms that allow for persistent Epstein-Barr virus (EBV) infection in humans using mathematical modeling and computer simulation.

Current main results and/or publications: Hawkins JB, Delgado-Eckert E, Thorley-Lawson DA, Shapiro M. The cycle of EBV infection explains persistence, the sizes of the infected cell populations and which come under CTL regulationPLoS Pathogens. 2013 Oct;9(10):e1003685. doi:10.1371/journal.ppat.1003685

If you are interested in this topic, please watch the following video of a talk I gave at the 3rd Workshop and Conference on "Modeling Infectious Diseases" organized by The Indian Institute of Mathematical Sciences (IMSc), Chennai, India, November 2015. 

Funding: New collaborations and facets of this research line were funded by a Marie Curie International Research Staff Exchange Scheme grant from the European Union, which started on May 2013.

Collaborators: Dr. Michael Shapiro at the Francis Crick Institute, London, UK, Prof. David Thorley-Lawson at Tufts Medical School, Tufts University, Boston, USA, and Dr. Jared Hawkins at the Laboratory for Personalized Medicine at Harvard Medical School, Boston.

Biological model of EBV infection in humans

Many years of scientific research have led our collaborators to propose a cycle of replication for the Epstein-Barr virus (EBV) in the human body. Indeed, experimental evidence suggests that the virus takes advantage of the physiological cycle of B cells. We have tested some of the logical consequences of this model using mathematical modelling and computer simulation. We were able to derive consequences concerning the differences in the pathology of EBV infection between individuals in a population of EBV positive persons. It turns out that the differences predicted by the model are actually observed in the human population! This is a strong argument in favor of the validity of the “cyclic pathogen model” of EBV infection. Find out more.

Assessment of body temperature control in preterm infants

Research questions/goals: In this project we are looking at time series of body temperature measurements in infants to learn more about the relationship between physiological development and temperature regulation mechanisms.

Current main results and/or publications: We finished recruiting participants, and a large amount of measurements have been successfully completed. The collected time series of body temperature measurements have been analyzed. Furthermore, we have found associations between some of the time-series analysis parameters and clinical, particularly developmental, magnitudes. The results of this analysis have been recently published.

Collaborators: Prof. Sven Schulzke, Dr. med. Isabelle Pramana, and Dr. Kerstin Jost, from UKBB.

Characterization and comparison of healthy and asthmatic cohort participants before and after deliberate rhinovirus infection

Research questions/goals: The aim of this study is to use longitudinal respiratory, inflammatory, and immunological biomarker data in order to characterize and compare healthy and asthmatic cohort participants before and after a deliberate infection with a rhinovirus. In this project the participant recruitment and data collection was carried out at the Academic Medical Centre at University of Amsterdam, Netherlands. Longitudinal data of lung function, exhaled air, inflammatory and immunological biomarkers in nasal lavage, and many other parameters were collected during two months prior to deliberate rhinovirus infection and during the first month after the viral challenge.

Current main results and/or publications: We have found evidence for a loss of adaptive capacity in asthmatics. Learn more in our recently published paper Loss of adaptive capacity in asthmatics revealed by biomarker fluctuation dynamics upon experimental rhinovirus challenge.

Funding: This project is being funded by an ERS-RESPIRE2 – Marie Curie postdoctoral fellowship awarded to Dr. Anirban Sinha by the European Respiratory Society and the European Commission, and by a research grant from the Swiss Lung Association (Lungenliga).

Collaborators: Dr. Anirban SinhaProf. Dr. Peter Sterk, and Prof. Dr. Rene Lutter from the Academic Medical Centre at University of Amsterdam, Netherlands, who initiated this exciting and pioneering project.

Epistasis on networks

Research questions/goals:The biochemical and molecular mechanisms underlying epistatic phenomena observed in various living organisms are poorly understood. Epistasis, or genetic interactions, refers to functional relationships between genes. It describes the phenotypic effect of perturbing (e.g., knocking down or knocking out) two genes separately versus jointly relative to the unperturbed system. Thus, epistasis is a property of the underlying network of biochemical interactions in the cell.
In this project, we use a mathematical framework linking epistatic gene interactions to the redundancy of biological networks. This approach is based on network reliability, an engineering concept that allows for computing the probability of functional network operation under different network perturbations, such as the failure of specific components, which, in a genetic system, correspond to the knock-out or knock-down of specific genes. Using this framework, we want to study how to infer functional constraints in biological networks from observed genetic interactions.

Current main results and/or publications: Preliminary work in collaboration with Prof. Dr. Niko Beerenwinkel (D-BSSE, ETH Zürich) led to a formal definition of epistasis in terms of network reliability. These initial steps are presented in a book chapter contained in the book Systems Genetics, Linking Genotypes andPhenotypes, edited by Dr. Florian Markowetz and Prof. Dr. Michael Boutros.

Collaborators: Dr. Michael Shapiro at the Francis Crick Institute, London, UK

Current openings

Currently no open positions available. Please keep coming back, as this may change soon again.

 

Group members

Former group members

  • Ivo Strebel, PhD (PhD completed)
  • Thilagavathy Jagan, MSc (former data analyst and developer)
  • Anirban Sinha, PhD (former postdoc)
  • Binbin Xu, PhD (former postdoc)
  • Hoda Sharifian, PhD (former postdoc)
  • Nitin Kumar, PhD (former postdoc)
  • Pharm. D. Delphine Meier-Girard, PhD (PhD completed)

 
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0900 712 712

(3.23 CHF/min. CH-landline, possibly additionally 8 Rp. / min. by network operator)

0900 712 713

(3.12 CHF/min. prepaid cell phones, possibly additionally 8 Rp. / min. by network operator)

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4056 Basel / Switzerland

T +41 61 704 12 12
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