Dr. Mark Read

Research Fellow, Charles Perkins Centre, The University of Sydney
Research Gate
My Research Gate

Paper on Calibrating Complex Biological Simulations Released!

RSInterfaceIt’s publishing season. Like the buses, nothing comes along for a while, and then all the papers are published at once. Another grand effort that has been 3 years in the making (since I started at the University of Sydney), the Journal of the Royal Society Interface this week released our manuscript on automated calibration of complex biological simulations. The original idea was formed near the end of my PhD, and is part of a larger theme on how to engineer accurate and representative simulations of biological systems that are incompletely understood: how do you simulate something if you don’t know how it works?

The answer in part rests on “calibration“, a process whereby you adjust the simulation such that its output matches that of known reality. Typically this involves finding parameter values, where the biological correlate is unknown. There are any number of approaches for doing this; the trick for complex system simulations is how you measure that difference between simulation and reality. Being complex, these systems cannot be well characterised in single observations or metrics alone, and that immediately blows standard techniques out of the water. An example, in this paper we employ the “ARTIMMUS” simulation as a test case, it simulates mouse multiple sclerosis. There are four chief T cell populations involved in the disease and subsequent recovery stages of this disease, each growing in population size, peaking, and falling again in a unique manner. They are all critical, and you can’t calibrate on the basis of one alone. Now that’s quite lot level, why not just characterise “disease severity” instead? Well, for starters “disease” is a very emergent property that is hard to replicate in simulation, we tend to deal with more concrete measures that can be tied to specific phenomenon. Take multiple sclerosis, there’s any number of ways that different areas of the nervous system can be impacted to deliver a given degree of debilitation.

mocEnter our approach. We use multi-objective optimisation to simultaneously evaluate several metrics of simulation’s capture of important biological features simultaneously, and evaluate find appropriate parameter values accordingly. We name this technique Multi-Objective Calibration (MOC). MOC exposes where several parameters may trade off against one another to deliver a given simulation dynamic, or where certain aspects of the simulation dynamic are maximised at the expense of others. This raises another intriguing possibility: what does it mean if no parameter values can be found that simultaneously align all aspects of a simulation’s output with that of reality? We propose that this points to a simulation that fails to adequately capture the complexities of the biological components; the changes that need to be made are not parameter values, but rather what those parameters represent. Perhaps an important cell population or component in the biology is missing from the simulation, or has been incorrectly captured. In this manner, we propose that MOC can play a vital role in guiding simulation design and development, not only parameter tuning at the end.

SPARTAN paper accepted to PLoS Computational Biology

It’s been a while since I put anything on the blog. This doesn’t mean that I’ve not been doing anything – rather I’ve been doing so much that the blog gets neglected! There’ll likely be a flurry of activity in the run up to Christmas as I (and others) wind down.

Anyway, great news received last week. The SPARTAN paper has been accepted to PLoS Computational Biology. This is an excellent journal, so great cause for celebration. That can be added to the celebration that its first author, Kieran Alden, passed his PhD VIVA last week too.

SPARTAN is a collection of tools focused on sensitivity analysis, and understanding the link between simulations and biology. It provides (amongst other things) an implementation of the robustness analysis technique I published earlier this year. It also includes comprehensive tutorials for how to use the package, and it is already being used by others within Jon Timmis’s lab. PLoS Comp Bio is an open access journal, so I’ll provide links to the manuscript once its been typeset and placed online by the journal.

PS. We have also heard that the BMC Bioinformatics paper should be in print in February 2013.

Journal paper accepted to BioSystems

We have just had word that our paper, first authored by Richard Greaves, has been accepted for publications in BioSystems. It is an extension of the conference paper presented at IPCAT this year, firth authored by Richard Greaves, and includes work that Bjorn and James did on modelling CD200 regulation of dendritic cells in EAE. Bjorn and James were placement students from Leeds university who are both starting PhDs under Jon Timmis (and others). It is truly remarkable that the placement students’ work would end up in a journal, and a testament to their potential.

The paper examines several possible mechanistic models of how CD200 negative signalling of DCs suppresses their ability to promote autoimmune T cell responses, and clearly motivates further work in the computational immunology field on principled approaches to designing and building simulations. As luck would have it, this is work that is on our horizons.

Manuscript accepted by BMC Bioinformatics

During their respective Masters degrees, Richard Williams and Richard Greaves conducted some very elegant experiments using the ARTIMMUS simulation that elucidated the nature of regulation in EAE. Richard Williams’ work won the Best Immunological Modelling Paper award at ICARIS 2011, and it was his abstract that lead to the current journal submission. Richard W’s work was combined with work from Richard G, and yesterday the manuscript was accepted for publication in the BMC Bioinformatics journal. Winning a best paper prize and then being accepted for publication in this very respectable journal is a fantastic testament to the very high quality of work that these two have conducted (as Master’s students, no less)!

The paper reports three experiments, all excellent exemplars of how simulation facilitates work that could not be conducted in vivo. Manipulation of dendritic cell peptide presentation demonstrates that the regulation mediating recovery from autoimmunity in this model of EAE does not require regulatory T cells and their autoimmunity-inducing targets to be primed by the same dendritic cells. The paper reports that although CD4Th cells are invaluable in facilitating the cytotoxic T cell response, their physical presence and the temporal aspects of signals they deliver to dendritic cells modulate the magnitude of this response. Artificial means to deliver the signals that CD4Th cells are responsible for could yield more aggressive CTL responses that might overcome otherwise persisting disease.

Submission to IPCAT 2012 accepted

Starting the new year off with some fantastic news, a paper first-authored by Richard Greaves has been accepted to IPCAT 2012! Richard submitted his excellent MSc thesis in autumn, and this will be an added bonus for him. The paper examines the issues in extending an established and calibrated simulation when the influence of new pathways/cells are to be investigated – a common pattern in many strands of research. Extension of simulations with new components can have a profound effect on its behaviour, and the logical course of action is to re-calibrate. However, this in itself can have substantial implications on existing results and predictions. The paper calls for the investigation of more principled simulation design and calibration methodologies that, it is hoped, can indicate when influential pathways or components are absent from a simulation in the first place. Richard has been working with my ARTIMMUS simulation, and the paper is tied to a case study in extending this EAE simulation. (The paper presenting ARTIMMUS to the world has been a very long work in progress… I’m looking forward to its publication, hopefully this year!).