Hackathons and a brief history of mathematical oncology

It was Friday — two in the morning. And I was busy fine-tuning a model in Mathematica and editing slides for our presentation. My team and I had been running on coffee and snacks all week. Most of us had met each other for the first time on Monday, got an inkling of the problem space we’d be working on, brainstormed, and hacked together a number of equations and a few chunks of code to prototype a solution. In seven hours, we would have to submit our presentation to the judges. Fifty thousand dollars in start-up funding was on the line.

A classic hackathon, except for one key difference: my team wasn’t just the usual mathematicians, programmers, computer & physical scientists. Some of the key members were biologists and clinicians specializing in blood cancers. And we weren’t prototyping a new app. We were trying to predict the risk of relapse for patients with chronic myeloid leukemia, who had stopped receiving imatinib. This was 2013 and I was at the 3rd annual integrated mathematical oncology workshop. It was one of my first exposures to using mathematical and computational tools to study cancer; the field of mathematical oncology.

As you can tell from other posts on TheEGG, I’ve continued thinking about and working on mathematical oncology. The workshops have also continued. The 7th annual IMO workshop — focused on stroma this year — is starting right now. If you’re not in Tampa then you can follow #MoffittIMO on twitter.

Since I’m not attending in person this year, I thought I’d provide a broad overview based on an article I wrote for Oxford Computer Science’s InSPIRED Research (see pg. 20-1 of this pdf for the original) and a paper by Helen Byrne (2010).

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Poor reasons for preprints & post-publication peer-review

Last week, I revived the blog with some reflections on open science. In particular, I went into the case for pre-prints and the problem with the academic publishing system. This week, I want to continue this thread by examining three common arguments for preprints: speed, feedback, and public access. I think that these arguments are often motivated in the wrong way. In their standard presentation, they are bad arguments for a good idea. By pointing out these perceived shortcoming, I hope that we can develop more convincing arguments for preprints. Or maybe methods of publication that are even better than the current approach to preprints.

These thoughts are not completely formed, and I am eager to refine them in follow up posts. As it stand, this is more of a hastily written rant.

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Preprints and a problem with academic publishing

This is the 250th post on the Theory, Evolutionary, and Games Group Blog. And although my posting pace has slowed in recent months, I see this as a milestone along the continuing road of open science. And I want to take this post as an opportunity to make some comments on open science.

To get this far, I’ve relied on a lot of help and encouragement. Both directly from all the wonderful guest posts and comments, and indirectly from general recognition. Most recently, this has taken the form of the Canadian blogging and science outreach network Science Borealis recognized us as one of the top 12 science blogs in Canada.

Given this connection, it is natural to also view me as an ally of other movements associated with open science; like, (1) preprints and (2) post-publication peer-review (PPPR). To some extent, I do support both of these activities. First, I regularly post my papers to ArXiv & BioRxiv. Just in the two preceeding months, I’ve put out a paper on the complexity of evolutionary equilibria and joint work on how fibroblasts and alectinib switch the games that cancers play. Another will follow later this month based on our project during the 2016 IMO Workshop. And I’ve been doing this for a while: the first draft of my evolutionary equilibria paper, for example, is older than BioRxiv — which only launched in November 2013. More than 20 years after physicists, mathematicians, and computer scientists started using ArXiv.

Second, some might think of my blog posts as PPPRs. For example. occasionally I try to write detailed comments on preprints and published papers. For example, my post on fusion and sex in proto-cells commenting on a preprint by Sam Sinai, Jason Olejarz and their colleagues. Finally, I am impressed and made happy by the now iconic graphic on the growth of preprints in biology.

But that doesn’t mean I find these ideas to be beyond criticism, and — more importantly — it doesn’t mean that there aren’t poor reasons for supporting preprints and PPPR.

Recently, I’ve seen a number of articles and tweets written on this topic both for and against (or neutral toward) pre-prints and for PPPR. Even Nature is telling us to embrace preprints. In the coming series of posts, I want to share some of my reflections on the case for preprints, and also argue that there isn’t anything all that revolutionary or transformative in them. If we want progress then we should instead think in terms of working papers. And as for post-publications peer review — instead, we should promote a culture of commentaries, glosses, and literature review/synthesis.

Currently, we do not publish papers to share ideas. We have ideas just to publish papers. And we need to change this aspect academic culture.

In this post, I will sketch some of the problems with academic publishing. Problems that I think any model of sharing results will have to address.

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Fusion and sex in protocells & the start of evolution

In 1864, five years after reading Darwin’s On the Origin of Species, Pyotr Kropotkin — the anarchist prince of mutual aid — was leading a geographic survey expedition aboard a dog-sleigh — a distinctly Siberian variant of the HMS Beagle. In the harsh Manchurian climate, Kropotkin did not see competition ‘red in tooth and claw’, but a flourishing of cooperation as animals banded together to survive their environment. From this, he built a theory of mutual aid as a driving factor of evolution. Among his countless observations, he noted that no matter how selfish an animal was, it still had to come together with others of its species, at least to reproduce. In this, he saw both sex and cooperation as primary evolutionary forces.

Now, Martin A. Nowak has taken up the challenge of putting cooperation as a central driver of evolution. With his colleagues, he has tracked the problem from myriad angles, and it is not surprising that recently he has turned to sex. In a paper released at the start of this month, Sam Sinai, Jason Olejarz, Iulia A. Neagu, & Nowak (2016) argue that sex is primary. We need sex just to kick start the evolution of a primordial cell.

In this post, I want to sketch Sinai et al.’s (2016) main argument, discuss prior work on the primacy of sex, a similar model by Wilf & Ewens, the puzzle over emergence of higher levels of organization, and the difference between the protocell fusion studied by Sinai et al. (2016) and sex as it is normally understood. My goal is to introduce this fascinating new field that Sinai et al. (2016) are opening to you, dear reader; to provide them with some feedback on their preprint; and, to sketch some preliminary ideas for future extensions of their work.

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Don’t take Pokemon Go for dead: a model of product growth

In the last month, some people wrote about the decay in active users for Pokemon Go after its first month, in a tone that presents the game as likely a mere fad – with article on 538, cinemablend and Bloomberg, for example. “Have you deleted Pokémon Go yet?” was even trending on Twitter. Although it is of course certainly possible that this ends up being an accurate description for the game, I posit that such conclusions are rushed. To do so, I examine some systemic reasons that would make the Pokemon Go numbers for August be inevitably lower than those for July, without necessarily implying that the game is doomed to dwindle into irrelevance.

Students in Waterloo playing Pokemon Go. Photo courtesy of Maylin Cui.

Students in Waterloo playing Pokemon Go. Photo courtesy of Maylin Cui.

Others have made similar points before – see this article and the end of this one for example. However, in the spirit of TheEGG, and unlike what most of the press articles can afford to do, we’ll bring some mathematical modeling into our arguments.
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Evolutionary dynamics of acid and VEGF production in tumours

Today was my presentation day at ECMTB/SMB 2016. I spoke in David Basanta’s mini-symposium on the games that cancer cells play and postered during the poster session. The mini-symposium started with a brief intro from David, and had 25 minute talks from Jacob Scott, myself, Alexander Anderson, and John Nagy. David, Jake, Sandy, and John are some of the top mathematical oncologists and really drew a crowd, so I felt privileged at the opportunity to address that crowd. It was also just fun to see lots of familiar faces in the same place.

A crowded room by the end of Sandy's presentation.

A crowded room by the end of Sandy’s presentation.

My talk was focused on two projects. The first part was the advertised “Evolutionary dynamics of acid and VEGF production in tumours” that I’ve been working on with Robert Vander Velde, Jake, and David. The second part — and my poster later in the day — was the additional “(+ measuring games in non-small cell lung cancer)” based on work with Jeffrey Peacock, Andriy Marusyk, and Jake. You can download my slides here (also the poster), but they are probably hard to make sense of without a presentation. I had intended to have a preprint out on this prior to today, but it will follow next week instead. Since there are already many blog posts about the double goods project on TheEGG, in this post I will organize them into a single annotated linkdex.

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Eukaryotes without Mitochondria and Aristotle’s Ladder of Life

In 348/7 BC, fearing anti-Macedonian sentiment or disappointed with the control of Plato’s Academy passing to Speusippus, Aristotle left Athens for Asian Minor across the Aegean sea. Based on his five years[1] studying of the natural history of Lesbos, he wrote the pioneering work of zoology: The History of Animals. In it, he set out to catalog the what of biology before searching for the answers of why. He initiated a tradition of naturalists that continues to this day.

Aristotle classified his observations of the natural world into a hierarchical ladder of life: humans on top, above the other blooded animals, bloodless animals, and plants. Although we’ve excised Aristotle’s insistence on static species, this ladder remains for many. They consider species as more complex than their ancestors, and between the species a presence of a hierarchy of complexity with humans — as always — on top. A common example of this is the rationality fetish that views Bayesian learning as a fixed point of evolution, or ranks species based on intelligence or levels-of-consciousness. This is then coupled with an insistence on progress, and gives them the what to be explained: the arc of evolution is long, but it bends towards complexity.

In the early months of TheEGG, Julian Xue turned to explaining the why behind the evolution of complexity with ideas like irreversible evolution as the steps up the ladder of life.[2] One of Julian’s strongest examples of such an irreversible step up has been the transition from prokaryotes to eukaryotes through the acquisition of membrane-bound organelles like mitochondria. But as an honest and dedicated scholar, Julian is always on the lookout for falsifications of his theories. This morning — with an optimistic “there goes my theory” — he shared the new Kamkowska et al. (2016) paper showing a surprising what to add to our natural history: a eukaryote without mitochondria. An apparent example of a eukaryote stepping down a rung in complexity by losing its membrane-bound ATP powerhouse.
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Radicalization, expertise, and skepticism among doctors & engineers: the value of philosophy in education

This past Friday was a busy day for a lot of the folks in Integrated Mathematical Oncology here at the Moffitt Cancer Center. Everybody was rushing around to put the final touches on a multi-million dollar research center grant application to submit to the National Cancer Institute. Although the time was not busy for me, I still stopped by Jacob Scott’s office towards the end of the day to celebrate. Let me set the scene for you: it is a corner office down the hall from me; its many windows are scribbled over with graphs, equations, and biological interaction networks; two giant screens crowd a standing desk, and another screen is hidden in the corner; the only non-glass wall has scribbles in pencil for the carpenters: paint blackboard here. There are too many chairs — Jake is a connector, so his office is always open to guests.

A different celerbation in Jake's office. The view is from his desk towards the wall that needs to be replaced by a blackboard.

A different celerbation in Jake’s office. The view is from his desk towards the wall that needs to be replaced by a blackboard.

In addition to the scientific and administrative stress of grant-writing, Jake was also covering for his friend as the doc-of-the-day for radiation oncology. So as I rambled on: “If we consider nodes of degree three or higher in this model, we would break up contingent blocks of mutants and result in the domain of our probability distribution going from n^2 to 2^n“, scribbling more math on his wall, we would get interrupted by phone calls. His resident calling to tell him that the neurosurgeons have scheduled a consultation for an acute myeloid leukemia patient who is recovering from surgery earlier that day.

“Only on a Friday afternoon do you get this kind of consult!” Jake fires off, “He’s still in surgery! We can’t do anything for at least a few days – schedule him for Monday.”

The call was on speakerphone, but I could not keep up with the conversation. After years of training and experience, this was an effortless context-shift for Jake. He went from the heavy skepticism of a scientist staring at a blackboard to the certainty of a doctor that needed to get shit done, and back, in moments. I couldn’t imagine having this sort of confidence in my judgements, mostly because I have no training in medicine, but also because I am not expected to be certain. That is why I lean towards using abductive models versus insilications for clinial research; I have more confidence in machine learning than in my own physical and biological intuitions about cancer. Even if that approach might produce less understanding.

In recent weeks, I’ve noticed a theme in some of the (news and blog) articles I’ve been reading. In this post, I wanted to provide an annotated collection of some of these links, along with my reflections on what they say about the tension between expertise and skepticism and how that can radicalize us, both in mundane ways and in drastic ones. And what role philosophy can play in helping us cope. I will end up touching on recent events and politics as a source context, but hopefully we can keep the overall conversation more or less detached from current events.
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False memories and journalism

We like to think of ourselves as a collection of our memories, and of each memory as a snapshot of an event in our lives. Sure, we all know that our minds aren’t as sturdy as our computer’s hard-drive, so these snapshots decay over time, especially the boring ones — that’s why most of us can’t remember what we had for breakfast 12 years ago. We are even familiar with old snapshots rearranging their order and losing context, but we don’t expect to generate vivid and certain memories of events that didn’t occur. How could we have a snapshot of something that didn’t happen?

This view of memory is what makes Brian Williams’ recent fib about being on board a helicopter that was hit by two rockets and small arms fire in Iraq 12 years ago, so hard to believe. There was indeed a helicopter that was forced to land on that day, but the downed aircraft’s crew reports that Williams was actually on a helicopter about an hour behind the three that came under fire. Williams has apologized for his story, saying he conflated his helicopter with the downed one. To this, Erik Wemple voices the popular skepticism that “‘conflating’ the experience of taking incoming fire with the experience of not taking incoming fire seems verily impossible.”

But research into false memories suggests that such constructed memories as Williams’ do occur. In this post, I want to discuss these sort of false memories, share a particularly interesting example, and then discuss what this might mean for journalism.

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Space and stochasticity in evolutionary games

Two of my goals for TheEGG this year are to expand the line up of contributors and to extend the blog into a publicly accessible venue for active debate about preliminary, in-progress, and published projects; a window into the everyday challenges and miracles of research. Toward the first goal, we have new contributions from Jill Gallaher late last year and Alexander Yartsev this year with more posts taking shape as drafts from Alex, Marcel Montrey, Dan Nichol, Sergio Graziosi, Milo Johnson, and others. For the second goal, we have an exciting debate unfolding that was started when my overview of Archetti (2013,2014) prompted an objection from Philip Gerlee in the comments and Philipp Altrock on twitter. Subsequently, Philip and Philipp combined their objections into a guest post that begat an exciting comment thread with thoughtful discussion between David Basanta, Robert Vander Velde, Marc Harper, and Philip. Last Thursday, I wrote about how my on-going project with Robert, David, and Jacob Scott is expanding on Archetti’s work and was surprised to learn that Philip has responded on twitter with the same criticism as before. I was a little flabbergast by this because I thought that I had already addressed Philip’s critique in my original comment response and that he was reiterating the same exact text in his guest post simply for completeness and record, not because he thought it was still a fool-proof objection.

My biggest concern now is the possibility that Philip and I are talking past each other instead of engaging in a mutually beneficial dialogue. As such, I will use this post to restate (my understand of the relevant parts of) Philip and Philipp’s argument and extend it further, providing a massive bibliography for readers interested in delving deeper into this. In a future post, I will offer a more careful statement of my response. Hopefully Philip or other readers will clarify any misunderstandings or misrepresentations in my summary or extension. Since this discussion started in the context of mathematical oncology, I will occasionally reference cancer, but the primary point at issue is one that should be of interest to all evolutionary game theorists (maybe even most mathematical modelers): the model complexity versus simplicity tension that arises from the stochastic to deterministic transition and the discrete to continuous transition.

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