Computational Physiology and Biostatistics

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.

Prof. Dr. Peter Sterk, an expert in the field, has written a very appealing commentary on this topic on the website of the European Respiratory Society.

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 validate our approach. Moreover, 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. Check out our very recent paper: http://thorax.bmj.com/cgi/content/full/thoraxjnl-2016-209919Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants.
Currently we are investigating in a cohort of adult asthma and COPD patients the mid-term temporal stability of the phenotype determined with our methodology.

Funding: Forschungsfond für Nachwuchsforschende der Universität Basel.

Collaborators: Prof. Sven-Erik Dahlén and Dr. Maciej Kupczyk from the Experimental Asthma and Allergy Research Unit, The National Institute of Environmental Medicine, at Karolinska Institutet, Stockholm, Sweden. Prof. Erika von Mutzius, from the Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany.

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?

Funding: Tabakpräventionsfonds, Bundesamt für Gesundheit and Forschungsfond für Nachwuchsforschende der Universität 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.

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.

Funding: Marie Curie Intra-European Fellowship for Career Development (IEF) from the European Union.

Collaborators: Dr. Sreenivasan Ponnambalam and Prof. Carmen Molina-Paris,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.

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 regulation. PLoS 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, Prof. David Thorley-Lawson at Tufts Medical School, Tufts University, Boston, and Dr. Jared Hawkins at the Laboratory for Personalized Medicine at Harvard Medical School, Boston

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.

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.

Currently, we are analyzing this data set from a control theoretical point of view.

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

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 are currently analyzing the lung function data, exhaled nitric oxide (FeNO) data, eosinophils and neutrophils cell counts, as well as cytokine concentrations in nasal lavage fluid. We are using standard statistical techniques, pattern recognition algorithms, and non-linear time series analysis methods.

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 Sinha, Prof. 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.

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, University of Bath, England, UK.