Drug holidays and losing resistance with replicator dynamics

A couple of weeks ago, before we all left Tampa, Pranav Warman, David Basanta and I frantically worked on refinements of our model of prostate cancer in the bone. One of the things that David and Pranav hoped to see from the model was conditions under which adaptive therapy (or just treatment interrupted with non-treatment holidays) performs better than solid blocks of treatment. As we struggled to find parameters that might achieve this result, my frustration drove me to embrace the advice of George Pólya: “If you can’t solve a problem, then there is an easier problem you can solve: find it.”

IMO6 LogoIn this case, I opted to remove all mentions of the bone and cancer. Instead, I asked a simpler but more abstract question: what qualitative features must a minimal model of the evolution of resistance have in order for drug holidays to be superior to a single treatment block? In this post, I want to set up this question precisely, show why drug holidays are difficult in evolutionary models, and propose a feature that makes drug holidays viable. If you find this topic exciting then you should consider registering for the 6th annual Integrated Mathematical Oncology workshop at the Moffitt Cancer Center.[1] This year’s theme is drug resistance.
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Argument is the midwife of ideas (and other metaphors)

In their classic book Metaphors We Live By, George Lakoff and Mark Johnson argue — very convincingly, and as I’ve reviewed before — that “[m]etaphor is one of our most important tools for trying to comprehend partially what cannot be comprehended totally” and that these conceptual metaphors are central to shaping our understanding of and interaction with the world we are embedded in. Based on the authors’ grounding in linguistics, part of their case proceeds by offering examples of, by my count, over 58 different metaphors and metonymies in our everyday language; and given their book’s intentions, they chose a particularly pertinent first case: ARGUMENT is WAR.[1]

They show this metaphor in action through some example of common usage (pg. 4):

What do you want me to do? LEAVE? Then they'll keep being wrong!Your claims are indefensible.
He attacked every weak point in my argument.
His criticisms were right on target.
I demolished his argument.
I’ve never won an argument with him.
You disagree? Okay, shoot!
If you use that strategy, he’ll wipe you out.
He shot down all my arguments.

Notice that the even the xkcd I borrowed for visual reinforcement is titled ‘Duty Calls’, an expression usually associated with a departure for war. With our awareness drawn to this militaristic structure, Lakoff and Johnson encourage the reader to ask themselves: how would discussions look if instead of structuring arguments adversarially, we structured them after a cooperative activity like dance?[2]

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Modeling influenza at ECMTB/SMB 2016

This week, I am at the University of Nottingham for the joint meeting of the Society of Mathematical Biology and the European Conference on Mathematical and Theoretical Biology — ECMTB/SMB 2016. It is a huge meeting, with over 800 delegates in attendance, 308 half-hour mini-symposium talks, 264 twenty-minute contributed talks, 190 posters, 7 prize talks, 7 plenary talks, and 1 public lecture. With seventeen to eighteen sessions running in parallel, it is impossible to see more than a tiny fraction of the content. And impossible for me to give you a comprehensive account of the event. However, I did want to share some moments from this week. If you are at ECMTB and want to share some of your highlights for TheEGG then let me know, and we can have you guest post.

I did not come to Nottingham alone. Above is a photo of all the current/recent Moffitteers that made their way to the meeting.

I did not come to Nottingham alone. Above is a photo of current/recent Moffitteers that made their way to the meeting this year.

On the train ride to Nottingham, I needed to hear some success stories of mathematical biology. One of the ones that Dan Nichol volunteered was the SIR-model for controlling the spread of infectious disease. This is a simple system of ODEs with three compartments corresponding to the infection status of individuals in the population: susceptible (S), infectious (I), recovered (R). It is given by the following equations

\begin{aligned}  \dot{S} & = - \beta I S \\  \dot{I} & = \beta I S - \gamma I \\  \dot{R} & = \gamma I,  \end{aligned}

where \beta and \gamma are usually taken to be constants dependent on the pathogen, and the total number of individuals N = S + I + R is an invariant of the dynamics.

As the replicator dynamics are to evolutionary game theory, the SIR-model is to epidemiology. And it was where Julia Gog opened the conference with her plenary on the challenges of modeling infectious disease. In this post, I will briefly touch on her extensions of the SIR-model and how she used it to look at the 2009 swine flu outbreak in the US.
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Systemic change, effective altruism and philanthropy

Keep your coins. I want change.The topics of effective altruism and social (in)justice have weighed heavy on my mind for several years. I’ve even touched on the latter occasionally on TheEGG, but usually in specific domains closer to my expertise, such as in my post on the ethics of big data. Recently, I started reading more thoroughly about effective altruism. I had known about the movement[1] for some time, but had conflicting feelings towards it. My mind is still in disarray on the topic, but I thought I would share an analytic linkdex of some texts that have caught my attention. This is motivated by a hope to get some guidance from you, dear reader. Below are three videos, two articles, two book reviews and one paper alongside my summaries and comments. The methods range from philosophy to comedy and from critical theory to social psychology. I reach no conclusions.

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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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Hadza hunter-gatherers, social networks, and models of cooperation

At the heart of the Great Lakes region of East Africa is Tanzania — a republic comprised of 30 mikoa, or provinces. Its border is marked off by the giant lakes Victoria, Tanganyika, and Malawi. But the lake that interests me the most is an internal one: 200 km from the border with Kenya at the junction of mikao Arusha, Manyara, Simiyu and Singed is Lake Eyasi. It is a temperamental lake that can dry up almost entirely — becoming crossable on foot — in some years and in others — like the El Nino years — flood its banks enough to attract hippos from the Serengeti.

For the Hadza, it is home.

The Hadza number around a thousand people, with around 300 living as traditional nomadic hunter-gatherers (Marlow, 2002; 2010). A life style that is believed to be a useful model of societies in our own evolutionary heritage. An empirical model of particular interest for the evolution of cooperation. But a model that requires much more effort to explore than running a few parameter settings on your computer. In the summer of 2010, Coren Apicella explored this model by traveling between Hadza camps throughout the Lake Eyasi region to gain insights into their social network and cooperative behavior.

Here is a video abstract where Coren describes her work:

The data she collected with her colleagues (Apicella et al., 2012) provides our best proxy for the social organization of early humans. In this post, I want to talk about the Hadza, the data set of their social network, and how it can inform other models of cooperation. In other words, I want to freeride on Apicella et al. (2012) and allow myself and other theorists to explore computational models informed by the empirical Hadza model without having to hike around Lake Eyasi for ourselves.

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A year in books: Neanderthals to the National Cancer Act to now

A tradition I started a couple of years ago is to read at least one non-fiction book per month and then to share my thoughts on the reading at the start of the following year. Last year, my dozen books were mostly on philosophy, psychology, and political economy. My brief comments on them ended up running a long 3.2 thousand words. This time the list had expanded to around 19 books. So I will divide the summaries into thematic sets. For the first theme, I will start with a subject that is new for my idle reading: cancer.

As a new researcher in mathematical oncology — and even though I am located in a cancer hospital — my experience with cancer has been mostly confined to the remote distance of replicator dynamics. So above all else these three books — Nelson’s (2013) Anarchy in the Organism, Mukherjee’s (2010) The Emperor of All Maladies, and Leaf’s (2014) The Truth in Small Doses — have provided me with insights into the personal experiences of the patient and doctor.

I hope that based on these reviews and the ones to follow, you can suggest more books for me to read in 2016. Better yet, maybe my comments will help you choose your next book. Much of what I read in 2015 came from suggestions made by my friends and readers, as well as articles, blogs, and reviews I’ve stumbled across.[1] In fact, each of these cancer books was picked for me by someone else.

If you’ve been to a restaurant with me then you know that I hate choosing between close-to-equivalent options. To avoid such discomfort, I outsourced the choosing of my February book to G+ and Nelson’s Anarchy in the Organism beat out Problems of the Self by a narrow margin to claim a spot on the reading list. As I was finishing up Nelson’s book — which I will review last in this post — David Basanta dropped off The Emperor of All Maladies on my desk. So I continued my reading on cancer. Finally, Leaf’s book came towards the end of the year based on a recommendation from Jacob Scott. It helped reinvigorate me after a summer away from the Moffitt Cancer Center.
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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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Operationalizing the local environment for replicator dynamics

Recently, Jake Taylor-King arrived in Tampa and last week we were brainstorming some projects to work on together. In the process, I dug up an old idea I’ve been playing with as my understanding of the Ohtsuki-Nowak transform matured. The basic goal is to work towards an operational account of spatial structure without having to commit ourselves to a specific model of space. I will take replicator dynamics and work backwards from them, making sure that each term we use can be directly measured in a single system or abducted from the other measurements. The hope is that if we start making such measurements then we might see some empirical regularities which will allow us to link experimental and theoretical models more closely without having to make too many arbitrary assumptions. In this post, I will sketch the basic framework and then give an example of how some of the spatial features can be measured from a sample histology.
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Short history of iterated prisoner’s dilemma tournaments

Nineteen Eighty — if I had to pick the year that computational modeling invaded evolutionary game theory then that would be it. In March, 1980 — exactly thirty-five years ago — was when Robert Axelrod, a professor of political science at University of Michigan, published the results of his first tournament for iterated prisoner’s dilemma in the Journal of Conflict Resolution. Game theory experts, especially those specializing in Prisoner’s dilemma, from the disciplines of psychology, political science, economics, sociology, and mathematics submitted 14 FORTRAN programs to compete in a round-robin tournament coded by Axelrod and his research assistant Jeff Pynnonen. If you want to relive these early days of evolutionary game theory but have forgotten FORTRAN and only speak Python then I recommend submitting a strategy to an analogous tournament by Vincent Knight on GitHub. But before I tell you more about submitting, dear reader, I want to celebrate the anniversary of Axelrod’s paper by sharing more about the original tournament.

Maybe it will give you some ideas for strategies.
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