A Brief History Of Bioinformatics, 1996-2011

That's from an interesting article by Christos Ouzounis. Here he discusses the "adolescence" period:

One factor in policymakers' high expectations might have been a certain lack of milestones: due to the field's dual nature, that of science and engineering, computational biology rarely has the “eureka” moment of a scientist's discovery and is grounded in the laborious yet inspired process of an engineer's invention. 

And there's this bit, too:

The notion of computing in biology, virtually a religious argument just 10 years ago, is now enthroned as the pillar of new biology.

So why has "bioinformatics" become less discussed? In part, because it has been so successful. 

Schelling Points And Bioinformatics

A lot of what think about when I do bioinformatics is how to set parameters non-arbitrarily. Basically I am looking for Schelling points: round, clear numbers that are easy to justify. The classic case is setting a p-value threshold to 0.05, which has been around for over eighty years and is still going strong, despite the haters. Other examples are setting e-value thresholds to 0.01 and setting Bayes factor thresholds of 10 as the first to indicate "strong" evidence. Like any threshold, these are arbitrary, but following the paradigm of statistics as rhetoric, their staying power make sense insofar as scientists need to be able to resort to standard procedures to settle debates. Anyway, I have no profound point here, I just think it's cool that a seemingly esoteric topic affects what I actually do on a day-to-day basis.

Is It Possible, In Principle, To Do Methodologically Sound Research?

In a paper published 31 years ago, Joseph McGrath argues (html, pdf) that the answer is no. Specifically, he claims that any research design faces two trade-offs: 1) being obtrusive vs unobstrusive (which maps to my terminology as acquiring info vs altering subject), and 2) being generalizable vs context-cognizant (which maps to my terminology as precision vs simplicity).

In his terminology, these trade-offs allow for the optimization of three distinct values (generalizability of samples to populations; precision in measuring variables; and context realism for the participants). Initially, I disagreed with this. To me, intuition suggests that there should be four points which maximize certain qualities when you are considering the intersection of two-trade offs: one in each corner of the 2-d space.

One way to get around this is if you claim that, in the context of this decision (study design), the trade-offs are not independent. For example, it might be very difficult for a design to be both highly generalizable and highly obstrusive.

Below I've drawn an example. Think of the dots as realizations of actually feasible study designs sampled from someone's mental generation process; i.e., they are probably not at the absolute extremes of the theoretical distribution, but with enough realizations, would come close.

I'm not sure that I agree with this exact distribution, and it would need some justification, but it seems like the only way to justify his three-pronged rather than four-pronged set-up.

The Valiant Never Taste Death But Once

After reading this interesting excerpted article from Dick Teresi's book The Undead, which discusses the difficulties in defining death by a single, consistent set of criteria and the social qualms that stirs, I decided to check out the Amazon reviews. The associated ratings were (and still are) quite shockingly bad! They follow the classic "so bad it's good" distribution, with 5 5-star ratings, 1 3-star rating, and 33 1-star ratings. So, given that I am always up for a good controversy, I decided to read and review it myself. Ultimately I mostly side with the critics, giving it two stars. If you are interested in the subject matter, I'd suggest instead Kenneth Iserson's Death to Dust, which is a bit older but much more level-headed and thorough treatment of similar issues. 

What Makes Phrases Memorable

For 1000 movies, this study compared lines included on imdb's memorable quotes page to those that were not. People who hadn't seen the movies were able to pick the correct one 78% of the time, although, caveat lector, that's with only n = 68.

What features allow this above chance classification? The authors suggest 1) distinctiveness (i.e., a lower likelihood of coming from samples of standard English text), 2) generality (fewer personal pronouns, more present tense), and 3) complexity (words with more syllables and fewer coordinating conjunctions like "for" and "and").

Interestingly, their best support vector machine only correctly classified examples 64% of the time, so either the human data is somehow biased, or there are plenty more subtleties for machines to learn before they can best us humans in recognizing literary wit. 

Indexing Wikipedia Article Submissions On Pubmed

I have complained before about few academics writing Wikipedia pages and instead writing reviews that few people will read. So, I feel compelled to admit that this is really cool:

We suggest a principal reason for this limited breadth and depth of coverage of topics in computational biology is one that affects a number of disciplines: reward. Authors in the biomedical sciences get academic reward for publishing papers in reputable journals that are indexed in PubMed and have associated digital object identifiers (DOIs).... 

Topic Pages are the version of record of a page to be posted to (the English version of) Wikipedia. In other words, PLoS Computational Biology publishes a version that is static, includes author attributions, and is indexed in PubMed. In addition, we intend to make the reviews and reviewer identities of Topic Pages available to our readership. Our hope is that the Wikipedia pages subsequently become living documents that will be updated and enhanced by the Wikipedia community...

I continue to be impressed by the innovation from the PLoS suite. 

Why Does Speed Variability Create Congestion?

Above are the results from one trial of an experiment designed to answer this question. Participants were randomly assigned to one of two groups, each with its own walking direction and color.

The authors defined "clusters" as groups of people walking in basically the same path, with some leeway. They then did simulations to determine the average lifetime of a cluster as a function of the group's variability in walking speed. As you can see, the greater the variability, the shorter the lifetime of the clusters.

N = the number of pedestrians in the simulation

This trend fits with their experimental results. Here's how the authors explain it:

[T]hose moving faster catch up with those walking slower, leaving an empty zone in front of the slow walkers ... [P]edestrians who are willing to walk faster than others make use of density gaps to overtake the slow walkers in front of them. By doing so, faster pedestrians move away from their lane, and meet the opposite flow head-on a few seconds later. This initial perturbation often triggers a complex sequence of avoidance maneuvers that results in the observed global instabilities. 

So here's a situation where more diversity, defined as inter-individual variability, leads to worse outcomes. Of course, as the authors mention, there are many other situations, such as collective decision making, where inter-individual variability is actually quite helpful.

Perhaps more diversity generally serves the function of pushing a group out of local optima. So you can think of diversity as shifting a group more towards the "explore" side of the exploration-exploitation trade-off. This would hurt in situations with a clearly defined goal, such as pedestrians walking in a circle as quickly as possible. But it might help in more complex situations.

Comp Exams For Each Course

The solution I propose is comprehensive exams at the end of each course, much like Advanced Placement exams, that thoroughly and objectively distinguish students on merit alone. The emphasis in each classroom would then shift from fighting the teacher for high grades to cooperating with the teacher to learn the material necessary to perform on the exam.

That's from Andrew Knight, in an essay discussing problems that will not be new to anyone who is or has recently been in school; more here. This is exactly what I wanted during most of my science and math courses. The alternative is to place a greater emphasis on big standardized tests like the SAT, but there can be so much variability in results from just one day.

One question is whether such exams could be a part of classes that are less fact-based, such as history and english. There is actually a machine learning competition for automated essay grading going on right now. I don't pretend to know the answer to this question, but even if it is currently infeasible, that shouldn't stop the tests from being used in math, science, and foreign language classes. 

Snub City At The Oscars

Of the Best Picture nominees, The Artist is currently the highest rated on imdb, at 8.4, though it will drop. A good comparison is Avatar, because both movies are technically adventurous, and they both have terrifyingly trite plots.

The main difference between Avatar and The Artist is that the latter is about the past, triggering nostalgia, whereas the former is about one possible version of the future, and is thus discomforting. This is why The Artist will win Best Picture and Avatar didn't come close. (No movie set in at any point in the future has ever won the award.)

But of course, the best movie of the past year is A Separation. The fact that it wasn't even nominated just showcases the Academy's striking anti-foreign film bias.

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It is obviously very fun to hate on the Academy, and there are many good reasons to do so, but as imdb user Fish_Beauty reminds us, this year is highly unlikely to go down as the biggest black mark of all time. Here are the lowest rated Best Picture winners:

Around the World in Eighty Days (1956) 6.8/10 9,106 (which won over the amazing The Killing)
The Greatest Show on Earth (1952) 6.7/10 5,177 (which won over High Noon)
The Broadway Melody (1929) 6.4/10 2,459
Cavalcade (1933) 6.3/10 1,421
Cimarron (1931) 6.1/10 1,739 (which won over the best silent film ever, City Lights)

These are truly embarrassingly bad films.

Tuesday Statisticz: Pick Your Poison At Starbucks

Every healthy drink is the same, every unhealthy drink is unhealthy in its own way. That's my conclusion upon analyzing this data set containing nutrition info of Starbucks drinks from the data set aggregator Factual. 

It turns out that there's an inverse, non-linear relationship between the sodium and sugar content of a drink. Drinks with very little sodium tend to have lots of sugar. These are mainly things like lemonade and iced tea. (Of course, it's controversial whether salt is bad for you, but the prevailing evidence points to yes.) 

normalized to the number of calories, filtered for >50 calories only; code

Surely this is not a universal trade-off, but it seems to indicate that in order to survive as a popular drink, you have to offer consumers something that they'll enjoy. 

Inspiration To Be Better

There's always someone whose monster won't go to sleep, no matter what Molotov cocktail of drugs and poison the medical miracle-makers can concoct to throw at it. Good people, better than I, are doomed to such a fate. The thought of it just seems to drain all of the air out of the room. But it makes me want to be better. I know those people won't stop fighting until that final breath, and that's a lifetime's worth of inspiration for me. I will forever hesitate to take a simple moment in this life for granted, though it will probably take some getting used to, because I've never lived that way before. But, having thought about it, there's really no other way to live. It's all just too fleeting and too ephemeral to fail to take the time we do have here to try and be better. I'm going to be better to myself, more forgiving of my mistakes, better to those around me and to those close to me, because they deserve it. We all deserve it...

My friend Jon passed away a couple of days ago. Much of his writing, including the above, can be found here. I have many memories of our time together, and I cherish them. He will be missed. 

Trade-Offs In Evolvability

"[T]he main and broadly applicable effect of fluctuating selection on the evolution of gene regulatory networks that allow for a feedback loop is selection for specific system dynamics that confer an increased evolvability. Increased evolvability mainly results from evolution of system parameters controlling the feedback loop, into a nonlinear regime, where both phenotypic diversity and the amount of phenotypic shift caused by individual mutations are increased."

More here. To the extent that you expect your environment to change a lot (i.e., undergo "fluctuating selection"), you should prefer meta-level approaches which allow you to change your object-level strategy more quickly and less costly. To the extent that you expect your environment to remain constant, this ability and propensity to change will be a hindrance.

A Separation

Finally it has come out in Bethesda! Spoiler alert, you can view it as a delectable set of plausible moral quandaries wrapped up in a family drama. You can also view it as a demonstration of how external stressors are what really kill relationships. My favorite line was, naturally, "what is wrong is wrong, no matter who said it or where it's written."

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Completely unrelated, this is the funniest thing I've read so far this calendar year. Anything for science. 

Seven Ideas From 2011

One Idea For Trepidation

1) U.S. Life Expectancies Stagnate: In more than 20% of counties, life expectancies for women declined between 1997 and 2007, driven largely by increased rates of smoking and high blood pressure. In some senses this is not unexpected, as the century-long gains in lifespan in developed nations have been more a story of asymptotically approaching the maximum human lifespan rather than pushing it back. And healthiness during one's lifespan is to some people the most important measure. Still, this is a major worry, and all of the other ideas on this list must be tainted by this one. (see here and here for more)

county-wide change in life expectancies over recent decades, left is males and right is females, green is positive and red is negative; doi:10.1371/journal.pmed.0050066 

Four Ideas For Optimism

2) Chip-Based Neuronal Nets: Memristors are circuit elements that can "remember" their resistance state even in the absence of curent. They open up a wealth of potential applications, including directly mimicking synaptic learning rules. The first implementation of the memristor is now slated for commercial release in less than two years. (see here, here, and here for more)

certain memristor architectures can store the topology of a maze in the state of its switches and thus allow all of the memristors to participate in the path calculation at once; http://arxiv.org/pdf/1103.0021v2

3) Altering DNA More Precisely. Zinc finger nucleases are proteins that can be engineered to target and cut a particular DNA sequence, thus allowing for manipulation of (human) genomes. This year a set of breakthroughs were announced which allow for researchers to query the specificity of ZFN's across the genome. This is crucial, because you really want to minimize any chance for error when you might accidentally mutate a tumor suppressor gene. The only clinical trial I know of with these is for HIV, which seems to have had some promising albeit highly preliminary results. (see here, here, and here for more)

a model of a zinc finger nuclease; doi:10.1186/1471-2164-12-83

4) Downloadable Sneakers. What will be the "killer app" of 3D printing that makes everybody want one as badly as they first wanted a personal computer? It's unclear, but the initial spread of the tech is already upon us, and the events of this year have me more convinced that it will prove similarly disruptive. (see here and here for more)

photo by photon

5) The End Of Drunk Driving. What if your smartphone could double as your chauffeur? Amazingly, we already have the basic autonomous driving capabilities. The most important reasons to care about this are a) the number of lives it could save and b) the amount of time it could free up. Yes, there are plenty of downsides, but they must be weighed at every step against these upsides. (see here, here, and here for more)

photo by jurvetson

Two Ideas To Think About

6) The Dimensions Of The DSM-5. To what extent will the dimensional approach to mental disorders make it into the next draft of the bible of psychiatry? This is not purely academic. Rating patients by the significance of their disorder would help eliminate arbitrary thresholds between the healthy and pathological. But if the switch is made too soon, before the levels can be validated, then it could turn into a bonanza of overmedication. (see here and here for more)

photo by ecstaticist

7) The Apogee Of The Corporation. As self-employment rises and technology advances, a smaller and smaller chunk of economic activity is being dictated by firms. Our very notions of the corporation and the employee seem to be on their way out, and perhaps they will be replaced by something that makes more sense for the society of tomorrow. (see here and here for more)

a network representation of strongly connected transnational corporations;  doi:10.1371/journal.pone.0025995; how long can or will they last?