Dr. Mark Read

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

Spartan released!

This week the “Spartan” paper was finally published in PLoS Computational Biology. Its always exciting to see the paper formatted in the journals own style. Its a shame about the layout of the two figures with captions falling on the following page – but never mind. The paper is first authored by one of Jon Timmis‘ past PhD students, Kieran Alden.

Spartan is an R package that encapsulates 4 key statistical analyses that have been of tremendous use in the computational immunology lab for understanding simulation results, revealing when these results are indicative of the biology rather than uncertainty regarding parameter assignments or the exact nature of the biological system itself. There’s a technique for determining how many samples of a stochastic simulation are required in an experiment to bring the effect of random variation down to a certain level of statistical significance (you want variation to be because of the experiment, not because you didn’t take enough samples). There is a robustness analysis that reveals how far simulation parameters can be perturbed before the simulation experiences a significant change in behaviour, and there are two global sensitivity analyses: eFast and a latin hypercube design with correlation measures.

If there’s a key message that has emerged from my own research, and echoed in other works coming from the lab, its that people probably trust simulation results a lot more than they should. The techniques gathered within spartan are a first step to understanding exactly how much you should believe the results coming from a simulation. I have a feeling I might make a career looking at this field, its important and very tricky.

PDF of paper, and the PLoS website.

CoSMoS book draws closer

The CoSMoS project may have concluded, but its research output certainly has not. Members and affiliates of the project met this week to discuss the current state of the CoSMoS book. CoSMoS is the “complex systems modelling and simulation infrastructure” (the “i” is AWOL), and the years of experience in how (and how not) to create representative simulations of complex systems that CoSMoS supported is now culminating in a book. It’s a patterns book – a familiar computer science concept – where each pattern tries to encapsulate and advise on some key concept or technique relating to the messy endeavour that in silico complex systems research can be. Its in good shape, despite the numerous “text to go here” placeholders: the structure and content seems strong to me. Of course the “stuff here” placeholders persist because the many authors, myself included, have yet to venture that far down the proverbial todo lists. Susan Stepney has done a tremendous job getting the book to where it is now, but we are each responsible for providing text for patterns that we either suggested or hold experience in. We’re all willing participants, yet I don’t envy Susan’s job. Studying the organisation and dynamics of complex systems through simulation is highly challenging, and so too is the job of organising the dynamics of academics tasked with writing about it. The current drive is to have the completed draft by end of summer, and the tweaked and polished final book by Christmas.

NB. CoSMoS does have a webpage, but it currently displays a charming “fatal error” communiqué.

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.

Mark & Jon in San Diego

I’m writing this at LAX airport as I await my flight out of California, at the end of another successful visit to my collaborator, Vipin Kumar. Jon has been with me this week, and we’ve had a fantastic time – its always a bit dull, even in a place as nice as La Jolla, to be visiting on your own.

As always, its been a hugely positive meeting. The CD200 modelling work that was largely conducted by Bjorn and James recently was well received, and we have submitted an abstract describing the preliminary findings. We’ve also made excellent progress on the Nature Biotech, now Methods, paper. And I have a stack of material to look at and distill into some interesting grant proposals; Jon pointed out that, incredibly, all the progress made within his lab on modelling EAE, Payers Patch development and Leishmaniasis has received not one cent of direct funding from any funding council. This is not for want of trying, and with a promising Nature Methods paper in the works, a Science Signalling paper already accepted, and two other high quality publications in review, it’s astonishing that the lab has accomplished so much on money scraped together from disparate sources. Just think what we could achieve with some hard backing!

Trips like this always highlight to me the value of face-to-face collaboration in interdisciplinary endeavours. Technologies like Skype are impressive in facilitating collaborations, and my own carbon footprint is nothing to boast about, but what we seem to accomplish in a few hours of meeting in person can dwarf months of work over conference calls. I think it comes down to the huge separation between computer science/engineering and immunology disciplines. A passing comment from Vipin concerning some aspect of immunology has decades of highly specialised experience backing it, and other immunologists can follow the thought process, However to a computer scientist dabbling in immunology I often find at least 5 interpretations for what Vipin has said, and this needs extensive clarification. There are aspects of communication across these subjects that is very difficult to cram into packets and send half-way across the globe and have arrive intact. We have been writing the (now) Nature Methods paper for nearly 2 years now, and I can quite happily believe that without this visit it could be another 2. Thankfully the paper is now in a state where we think submission within the next few months is possible. A big part of it is also building the relationship, which is hard to do across boarders. Like many walks of life, I see success in science as being largely due to the people undertaking it. Building good collaborations with good people who you can trust is essential (I’ll keep my observations concerning the other side of this line to myself…).

I will be sad to see the back of the beautiful blue cloudless skies, ocean, sand and sun. The 25-30 degree climate is about to be replaced with the half meter of snow that I hear has fallen on my holiday destination of Calgary. I’ll be out of the loop for a week, back just in time for the CoCoRo general assembly in Stuttgart in 9 days. In the meantime, I will be visiting one of my childhood friends who emigrated to Canada a few years ago, and raves about how good it is. I hear that horse riding (in half a meter of snow?) is on the cards.

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!).