Tag Archives: programming

Slow and steady improvements in the prediction of one-dimensional protein features

What do you do when you have a big, complex problem whose solution is not necessarily trivial? You break the problem into smaller, easier to solve parts,  solve each of these sub-problems and merge the results to find the solution of the original, bigger problem. This is an algorithm design paradigm known as the divide and conquer approach.

In protein informatics, we use divide and conquer strategies to deal with a plethora of large and complicated problems. From protein structure prediction to protein-protein interaction networks, we have a wide range of sub and sub-sub problems whose solutions are supposed to help us with the bigger picture.

In particular, prediction of the so called one-dimensional protein features are fundamental sub-problems with a wide range of applications such as protein structure modelling,  homology detection, functional characterization and others. Here, one-dimensional protein features refer to secondary structure, backbone dihedral and C-alpha angles, and solvent accessible surface area.

In this week’s group meeting, I discussed the latest advancements in prediction of one-dimensional features as described in an article published by Heffernan R. and colleagues in Scientific Reports (2015):

“Improving prediction of secondary structure, local backbone angles, and solvent accessible surface area of proteins by iterative deep learning.”

In this article, the authors describe the implementation of SPIDER2, a deep learning approach to predict secondary structure, solvent accessible surface area, and four backbone angles (the traditional dihedrals phi and psi, and the recently explored theta and tau).

“Deep learning” is the buzzword (buzz-two-words or buzzsentence, maybe?) of the moment. For those of you who have no idea what I am talking about, deep learning is an umbrella term for a series of convoluted machine learning methods. The term deep comes from the multiple hidden layers of neurons used during learning.

Deep learning is a very fashionable term for a reason. These methods have been shown to produce state-of-the-art results for a wide range of applications in several fields, including bioinformatics. As a matter of fact, one of the leading methods for contact prediction (previously introduced in this blog post), uses a deep learning approach to improve the precision of predicted protein contacts.

Machine learning has already been explored to predict one-dimensional protein features, showing promising (and more importantly, useful) results. With the emergence of new, more powerful machine learning techniques such as deep learning, previous software are now becoming obsolete.

Based on this premise, Heffernan R. and colleagues implemented and applied their deep learning approach to improve the prediction of one-dimensional protein features. Their training process was rigorous: they performed a 10-fold cross validation using their training set of ~4500 proteins and, on top of that, they also had two independent test sets (a ~1200 protein test set and a set based on the targets of CASP11).  Proteins in all sets did not share more than 25% (30% sequence identity for the CASP set) to any other protein in any of the sets.

The method described in the paper, SPIDER2, was thoroughly compared with state-of-the art prediction software for each of the one-dimensional protein features that it  is capable of predicting. Results show that SPIDER2 achieves a small, yet significant improvement compared to other methods.

It is just like they say, slow and steady wins the race, right? In this case, I am not so sure. It would be interesting to see how much the small increments in precision obtained by SPIDER2 can improve the bigger picture, whichever your bigger picture is. The thing about divide and conquer is that if you become marginally better at solving one of the parts, that doesn’t necessarily imply that you will improve the solution of the bigger, main problem.

If we think about it, during the “conquer” stage (that is, when you are merging the solution of the smaller parts to get to the bigger picture),  you may make compromises that completely disregard any minor improvements for the sub-problems. For instance, in my bigger picture, de novo protein structure prediction, predicted local properties can be sacrificed to ensure a more globally consistent model. More than that, most methods that perform de novo structure prediction already account for a certain degree of error or uncertainty for, say, secondary structure prediction. This is particularly important for the border regions between secondary structure elements (i.e. where an alpha-helix ends and a loop begins). Therefore, even if you improve the precision of your predictions for those border regions, the best approach for structure prediction may still consider those slightly more precise border predictions as unreliable.

The other moral of this story is far more pessimistic. If you think about it, there were significant advancements in machine learning, which led to the creation of ever-more-so complicated neural network architectures. However, when we look back to how much improvement we observed when these highly elaborate techniques were applied to an old problem (prediction of one-dimensional protein features), it seems that the pay-off wasn’t as significant (at least as I would expect). Maybe, I am a glass half-empty kind of guy, but given the buzz surrounding deep learning, I think minor improvements is a bit of a let down. Not to take any credit away from the authors. Their work was rigorous and scientifically very sound. It is just that maybe we are reaching our limits when it comes to applying machine learning to predict secondary structure. Maybe when the next generation of buzzword-worthy machine learning techniques appear, we will observe an even smaller improvement to secondary structure prediction. Which leaves a very bitter unanswered question in all our minds: if machine learning is not the answer, what is?

aRrrrgh! or how to apply a fitted model to new data

Recently I’ve been battling furiously with R while analysing some loop modelling accuracy data. The idea was simple:

  1. Fit a general linear model to some data
  2. Get out a formula to predict a variable (let’s call it “accuracy”) based on some input parameters
  3. Apply this formula to new data and see how well the predictor does

It turns out, it’s not that simple to actually implement. Fitting a general linear model in R produces coefficients in a vector.

model <- glm(accuracy ~ param1 + param2 * param3, data=trainingset)
            (Intercept)                  param1                  param2 
            0.435395087            -0.093295388             0.148154339 
                 param3           param2:param3
            0.024399530             0.021100300

There seems to be no easy way to insert these coefficients into your formula and apply the resulting equation to new data. The only easy thing to do is to plot the fitted values against the variable we’re trying to predict, i.e. plot our predictions on the training set itself:

plot(model$fitted.values, trainingset$accuracy, xlab="score", ylab="accuracy", main="training set")

I’m sure there must be a better way of doing this, but many hours of Googling led me nowhere. So here is how I did it. I ended up writing my own parser function, which works only on very simple formulae using the + and * operators and without any R code inside the formula.

coefapply <- function(coefficients, row)
  result <- 0
  for (i in 1:length(coefficients))
    subresult <- as.numeric(coefficients[i])
    if (!is.na(subresult))
      name <- names(coefficients[i])
      if (name != "(Intercept)")
        subnames <- strsplit(name, ":", fixed=TRUE)[[1]]
        for (n in subnames)
          subresult <- subresult * as.numeric(row[n])
      result <- result + subresult

calculate_scores <- function(data, coefficients)
  scores <- vector(mode="numeric", length=nrow(data))
  for (i in 1:nrow(data))
    row <- data[i,]
    scores[i] <- coefapply(coefficients, row)

Now we can apply our formula to a new dataset and plot the accuracy achieved on the new data:

model_coef <- coef(model)

# Test if our scores are the same values as the model's fitted values
training_scores <- calculate_scores(model_coef, trainingset)
sum((training_scores - model$fitted.values) < 0.000000000001) / length(scores)

# Calculate scores for our test set and plot them
test_scores <- calculate_scores(model_coef, testset)
plot(test_scores, testset$accuracy, xlab="score", ylab="accuracy", main="test set")

It works for my purpose. Maybe one day someone will see this post, chuckle, and then enlighten me with their perfectly simple and elegant alternative.