One of my students once asked me how to become a better researcher. “Great question!” I thought. Instead of a straight and clear answer, I heard myself babbling, as happens when you have no idea what you are talking about. Somewhat disappointed by my non answer, I turned to my colleagues and asked how they teach research. The answer ranged from embarrassed silence to politely switching topic. Strange, I thought, it is our responsibility as principal investigators to educate the junior researchers of our group, so we’d better have some idea of what we are doing.
We have a fairly good idea of how to teach skills, like mathematics, molecular biology etc. But I would argue that research is not a skill. I would argue that it is an attitude. So the real question is how to teach an attitude. There is no foolproof recipe, but here goes a subjective view that I gathered from reading, from discussions and from personal experience.
1. Motivate the change
Most students and junior scientists enter the lab with an open mind, ready to learn as many new things as possible. But most of them focus on learning technical skills (at...
“Thinking is classifying” wrote Georges Clémenceau*. This tells, in simple words, everything about the obsession of the human mind to keep things tidy. No surprise we ask computers a little help here and there. Is this email spam? Is this online user human? Is this text written by that author? Training machines to put things into the boxes created by our human mind is called supervised learning and it can be very lucrative. But what about the more philosophical cases where machines make their own boxes? Can we reverse the process and put things in boxes created by computers? Unsupervised learning, as it is called, creates a lot of interesting problems where we, humans, are left wondering whether the boxes make any sense.
The mother of all classification techniques is undisputedly Principal Component Analysis (PCA). But let me reassure those who hate PCA and those who never heard of it: I will just touch the surface, and then very briefly. PCA automatically arranges similar items close to each other on a plane. The rest is up to you. Similarity, in particular, depends on a bunch of arbitrary features, size, height, number of legs... In a classical introductory...
A couple of months ago, I posted an approximate formula for the longest match in the problem of DNA alignment. I recently used it to calibrate a seeding heuristic to map Illumina reads and I was surprised to see that it was not just bad, but epic bad. Upon closer inspection, I realized that the main assumption does not hold when the error rate is small (which is typically the case for Illumina reads). The formula was based on longest runs in Bernoulli trials. This time I present more accurate results with an approach based on a stick breaking process.
Stick breaking (spacings)
Inserting $(k)$ mutations at random in a sequencing read will produce $(k+1)$ (possibly empty) subsequences without errors. The process is analogous to inserting $(k)$ breaks at random in a stick of length 1, and we can approximate the distribution of the longest subsequence without error by that of the longest fragment when breaking the stick.
The example above illustrates this concept graphically. A sequencing read of 60 nucleotides contains 2 mutations highlighted in red and the longest error-free stretch is the central subsequence of 28 nucleotides. If mutations occur uniformly on the read...
The first thing you learn in statistics is that “correlation does not imply causation”. As obvious as it sounds, most human mistakes fall in this category, and not only in statistics. The major difficulty with this question is that it is fairly easy to define correlation, but it is much harder to define causation, let alone quantify it. No surprise many statisticians just avoid talking about causation to stay out of the danger zone.
I see no greater impediment to scientific progress than the prevailing practice of focusing all our mathematical resources on probabilistic and statistical inferences while leaving causal considerations to the mercy of intuition and good judgment.
This book lays the foundation of the now popular Bayesian networks. The key idea is that you can distinguish correlation from causation if you can observe several independent causes. For instance, suppose that patients suffering from a certain type of cancer are often immunodeficient. You wonder whether immunodeficiency is a cause or a consequence of this cancer type.
Say that variable A is whether patients have...
bioinformatics combines computer science, statistics, mathematics, and engineering to study and process biological data.
To see how the community defines itself, I downloaded the abstracts of Bioinformatics from 2014 (for a total around 1000 articles, extracted the most relevant keywords and put the top 100 terms in a word cloud where a word size shows its frequency*.
Obviously, bioinformatics is about data, mostly gene/protein sequences and expression. It is also good to know that bioinformatics likes genomes and networks, and that it has more affinities with structural biology than with evolution.
The favourite organism of bioinformaticians is Homo sapiens, actually it is the only one mentioned in the word cloud, and when bioinformaticians work on a disease, it is cancer.
When bioinformaticians describe their work, it is “novel” and “new”, and what they talk about is “biological”, “different”, “multiple” and “single” (the last two are usually followed by “sequence alignment” and “nucleotide polymorphism”). It is also “functional” and “available”, but somewhat less. I expected it to be “fast” and “accurate”, but...
I never planned to do bioinformatics. It just happened because I liked to spend time in front of my computer and my boss was OK with it. Still, as every sane individual, I sometimes think that I should do something else with my life, and I wonder whether I am doing the right thing. On this topic, I recently came across the famous farewell to bioinformatics by Frederick J. Ross, which is worth reading, and from which the most emblematic quote is the now celebrated aphorism
Fuck you, bioinformatics. Eat shit and die.
There is nothing to agree or disagree in this quote, but Frederick gives further detail about his point of view in the post. In short, bioinformaticians are bad programmers, and community-level obfuscation maintains the illusion.
By making the tools unusable, by inventing file format after file format, by seeking out the most brittle techniques and the slowest languages, by not publishing their algorithms and making their results impossible to replicate, the field managed to reduce its productivity by at least 90%, probably closer to 99%.
There are indeed many issues in the bioinformatics community and I am on Frederick’s side regarding file formats...
1. Cars would have nice names
Here is what an abstract describing a car would look like.
Transporting people to defined locations of interest is a challenge of significant economic importance. To achieve this goal, people usually use cars or public transport. However, these solutions are suboptimal in several conditions. For instance, when people are extremely close to their target location, both cars and public transport are inappropriate, which limits their practical use. Here we present CaЯ (vehiCle for chAnging geo-cooЯdinates), a fast and accurate tool as an alternative to existing vehicles.
2. Cars would be fast and accurate
Bioinformaticians develop fast and accurate software. Their cars would be just the same. Here is what a typical benchmark sections would look like.
To show that CaЯ is faster and more accurate than existing alternatives, we benchmarked CaЯ against Volvo XC90 and Ferrari F430. In the first series of tests, we measured the time to lower the front windows of the vehicles. The average run duration was 2.3 seconds for CaЯ, 3.1 seconds for Volvo XC90 and 3.9 seconds for Ferrari F430, which demonstrates that CaЯ is substantially faster than Volvo XC90 and Ferrari...
The problem of sequence alignment gets a lot of attention from bioinformaticians (the list of alignment software counts more than 200 entries). Yet, the statistical aspect of the problem is often neglected. In the post Once upon a BLAST, David Lipman explained that the breakthrough of BLAST was not a new algorithm, but the careful calibration of a heuristic by a sound statistical framework.
Inspired by this idea, I wanted to work out the probability of identifying best hits in the problem of long read alignments. Since this is a fairly general result and that it may be useful for many similar applications, I post it here for reference.
Longest runs of 1s
I start with generalities on...
Before you rush to the comments and express your opinion about this title, let me make something clear. I do not expect anybody to erase their operating system and install Linux after reading this post. Actually, I do not care whether you use Linux or another operating system. All I want is to share what I have learned by using Linux, and why it made me a better scientist.
The mouse that infects your brain
About a year after I started to use Linux, I was surprised to realize how uncomfortable working on Mac and Windows had become. I could not quite pinpoint the problem, but I had the vague feeling that something was missing. Yet everything seemed to be there. When I could finally formulate it, I realized that what was bugging me was the discomfort that all the possible options had been preconceived for me. I could click on option A, I could click on option B, and if I liked neither of those, there was no option C.
But most surprising was that I had never realized this before, because I had no idea of all the things you can do with your computer. I...
A recent Nature editorial entitled “Code share” discusses an update in Nature’s policy regarding the use of software. Interestingly, the subtitle is
Papers in Nature journals should make computer code accessible where possible.
Yes, finally! The last decade was a transition period, which, in the history of bioinformatics will probably be known as the “bioinformatics revolution”. Following the completion of the first genome projects, the demand for bioinformatics rose steadily, to the detriment of biochemistry and genetics, which have now fallen from grace. Something as traumatic cannot happen in a day, and it cannot happen without pain. Actually, the transition is still ongoing and this regularly causes difficulties of all kinds in biology.
One of the most perverse effects of the massive popularization of bioinformatics is that senior scientists were not properly trained for it. This led to an implicit view that bioinformatics is a tool, somewhat like a microscope or a FACS. This explains why the materials and methods section of the first papers using bioinformatics was often reduced to something like “all the bioinformatics analysis were performed using R”. In other words, “we got some bioinformatics software and asked a qualified technician to use it...