This paper focuses on the application of deep learning to the docking problem within rational drug design. The overall objective of drug design or discovery is to build predictive models of how well a candidate compound (or "ligand") will bind with a target protein, to help inform the decision of what compounds are promising enough to be worth testing in a wet lab. Protein binding prediction is important because many small-molecule drugs, which are designed to be small enough to get through cell membranes, act by binding to a specific protein within a disease pathway, and thus blocking that protein's mechanism. 

The formulation of the docking problem, as best I understand it, is: 

1. A "docking program," which is generally some model based on physical and chemical interactions, takes in a (ligand, target protein) pair, searches over a space of ways the ligand could orient itself within the binding pocket of the protein (which way is it facing, where is it twisted, where does it interact with the protein, etc), and ranks them according to plausibility 
2. A scoring function takes in the binding poses (otherwise known as binding modes) ranked the highest, and tries to predict the affinity strength of the resulting bond, or the binary of whether a bond is "active". 

The goal of this paper was to interpose modern machine learning into the second step, as alternative scoring functions to be applied after the pose generation . Given the complex data structure that is a highly-ranked binding pose, the hope was that deep learning would facilitate learning from such a complicated raw data structure, rather than requiring hand-summarized features. They also tested a similar model structure on the problem of predicting whether a highly ranked binding pose was actually the empirically correct one, as determined by some epsilon ball around the spatial coordinates of the true binding pose. Both of these were binary tasks, which I understand to be 

1. Does this ranked binding pose in this protein have sufficiently high binding affinity to be "active"? This is known as the "virtual screening" task, because it's the relevant task if you want to screen compounds in silico, or virtually, before doing wet lab testing. 
2. Is this ranked binding pose the one that would actually be empirically observed? This is known as the "binding mode prediction" task

The goal of this second task was to better understand biases the researchers suspected existed in the underlying dataset, which I'll explain later in this post. 

The researchers used a graph convolution architecture. At a (very) high level, graph convolution works in a way similar to normal convolution - in that it captures hierarchies of local patterns, in ways that gradually expand to have visibility over larger areas of the input data. The distinction is that normal convolution defines kernels over a fixed set of nearby spatial coordinates, in a context where direction (the pixel on top vs the pixel on bottom, etc) is meaningful, because photos have meaningful direction and orientation. By contrast, in a graph, there is no "up" or "down", and a given node doesn't have a fixed number of neighbors (whereas a fixed pixel in 2D space does), so neighbor-summarization kernels have to be defined in ways that allow you to aggregate information from 1) an arbitrary number of neighbors, in 2) a manner that is agnostic to orientation. Graph convolutions are useful in this problem because both the summary of the ligand itself, and the summary of the interaction of the posed ligand with the protein, can be summarized in terms of graphs of chemical bonds or interaction sites. 

Using this as an architectural foundation, the authors test both solo versions and ensembles of networks: 

https://i.imgur.com/Oc2LACW.png

1. "L" - A network that uses graph convolution to summarize the ligand itself, with no reference to the protein it's being tested for binding affinity with 
2. "LP" - A network that uses graph convolution on the interaction points between the ligand and protein under the binding pose currently being scored or predicted
3. "R" - A simple network that takes into account the rank assigned to the binding pose by the original docking program (generally used in combination with one of the above). 

The authors came to a few interesting findings by trying different combinations of the above model modules. First, they found evidence supporting an earlier claim that, in the dataset being used for training, there was a bias in the positive and negative samples chosen such that you could predict activity of a ligand/protein binding using *ligand information alone.* This shouldn't be possible if we were sampling in an unbiased way over possible ligand/protein pairs, since even ligands that are quite effective with one protein will fail to bind with another, and it shouldn't be informationally possible to distinguish the two cases without protein information. Furthermore, a random forest on hand-designed features was able to perform comparably to deep learning, suggesting that only simple features are necessary to perform the task on this (bias and thus over-simplified)

Specifically, they found that L+LP models did no better than models of L alone on the virtual screening task. However, the binding mode prediction task offered an interesting contrast, in that, on this task, it's impossible to predict the output from ligand information alone, because by construction each ligand will have some set of binding modes that are not the empirically correct one, and one that is, and you can't distinguish between these based on ligand information alone, without looking at the actual protein relationship under consideration. In this case, the LP network did quite well, suggesting that deep learning is able to learn from ligand-protein interactions when it's incentivized to do so. Interestingly, the authors were only able to improve on the baseline model by incorporating the rank output by the original docking program, which you can think of an ensemble of sorts between the docking program and the machine learning model. 

Overall, the authors' takeaways from this paper were that (1) we need to be more careful about constructing datasets, so as to not leak information through biases, and (2) that graph convolutional models are able to perform well, but (3) seem to be capturing different things than physics-based models, since ensembling the two together provides marginal value.

The goal of this work is to edit the model’s weights given new edit pairs ($x_e, y_e$) at test time. They achieve this by learning a "model editor network" that takes a fine tuning gradient computed from ($x_e, y_e$) and transforms this into a weight update. 

$$ f(\nabla W_l) \rightarrow \tilde\nabla W_l$$ 

The editor network is parameterized by the layer that it is predicting using a FiLM style scale and shift.

The editor network is trained on a small set of examples ($D^{tr}_{edit}$). The paper states that this dataset contains edits that are similar to the "the types of edits that will be made." which is interesting because it introduces generalization limitations to the potential edits.

An extra loss term is used to prevent unintended changes for other inputs to the model (called $x_{loc}$). This is achieved with the following loss that will maintain the predictions to be the same value.
$$L_{loc} = KL(p_{\theta_W}(\cdot | x_{loc}) \| p_{\theta_\tilde{W}}(\cdot | x_{loc}))$$
 

Some intuition for why this works is editor network $f$ approximates full dataset gradient from just a single example so it is more efficient. It can reduce the change of elements of the weight matrix which were disruptive to the loss when it was trained, information that requires many training examples to uncover.

Cheney et al. study the robustness of deep neural networks, especially AlexNet, with regard to randomly dropping or perturbing weights. In particular, the authors consider three types of perturbations: synapse knockouts set random weights to zero, node knockouts set all weights corresponding to a set of neurons to zero, and weight perturbations add random Gaussian noise to the weights of a specific layer. These perturbations are studied on AlexNet, considering the top-5 accuracy on ImageNet; perturbations are considered per layer. For example, Figure 1 (left) shows the influence on accuracy when knocking out synapses. As can be seen, the lower layers, especially the first convolutional layer, are impacted significantly by these perturbations. Similar observations, Figure 1 (right) are made for random perturbations of weights; although the impact is less significant. Especially high-level features, i.e., the corresponding layers, seem to be robust to these kind of perturbations. The authors also provide evidence that these results extend to the top-1 accuracy, as well as other architectures. For VGG, however, the impact is significantly less pronounced which may also be due to the employed dropout layers.

https://i.imgur.com/78T6Gg2.png
Figure 1: Left: Influence of setting weights in the corresponding layers to zero. Right: Influence of randomly perturbing weights of specific layers. Experiments are on ImageNet using AlexNet.

Also find this summary at [davidstutz.de](https://davidstutz.de/category/reading/).

This paper suggests a novel explanation for why dropout training is helpful: because it corresponds to an adaptive data augmentation method. Indeed, the authors point out that, when sampling a mask of the hidden units in a network (effectively setting the corresponding units to 0), the same effect would have been obtained by feeding as input an example tailored to yield activations of 0 for these units and otherwise the same activation for all other units. Since this "ghost" example will have to be different from the original example, and since each different mask would correspond to a different "ghost" example, then effectively mask sampling is similar to data augmentation.

While in practice finding a ghost example that replicates exactly the same dropout hidden activations might not be possible, the authors show that finding an "approximate" ghost example that minimizes a distance between the target dropout activation and the deterministic activation of the ghost example works well. Indeed, they show that training a deep neural net on additional data generated by this procedure yields results that are at least as good as regular dropout on MNIST and CIFAR-10 (actually, the deterministic neural net still uses regular dropout at the input layer, however they do show that the additional ghost examples are necessary to match the neural net trained with dropout at all layers).

Then the authors use that interpretation to justify a variation of dropout where the dropout rate isn't fixed, but itself is randomly sampled in some range for each example. Indeed, if we think of dropout at a fixed rate as a specific class of ghost data being added, varying the dropout rate corresponds to enriching even more the ghost data pool. The experiments show that this can help, though not by much.

Finally, the authors propose an explanation of a property of dropout: that it tends to generate hidden representations that are sparser. Again, the authors rely on their interpretation of dropout as data augmentation. The explanation goes as follows. Training on the ghost data distribution might imply that the classification problem has become significantly harder. Specifically, it is quite possible that the addition of new ghost examples generates new isolated class clusters in input space that the model most now learn to  discriminate. And they hypothesize that the generation of such additional clusters would encourage sparsity. To test this hypothesis, the authors synthetically simulate this scenario, by sampling data on a circle, which is clustered in small arcs each assigned to one of 10 possible classes in cycling order. Decreasing the arc length thus increases the number of arcs, i.e. class clusters. They show that training deep networks on datasets with increasing number of class clusters does yield representations that are increasingly sparser. This thus suggests that dropout might indeed be equivalent to modifying the input distribution by adding such isolated class-specific clusters in input space. 

One assumption behind this analysis is that the sparsity patterns (i.e. the set of non-zero dimensions) play an important role in classification and incorporate most of the discriminative class information. This assumption is also confirmed in experiments, where converting the ReLU activation function by a binary activation (that is 1 if the pre-activation is positive and 0 otherwise) after training still yields a network with good performance (though slightly worse).


#### My two cents

This is a really original and thought provoking paper. One interpretation I make of these results is that the inductive bias corresponding to using a deep neural network with ReLU activations is more valuable than one might have thought, and that the usefulness of deep neural networks goes beyond just being black boxes that can learn data-dependent representations. Otherwise, it's not clear to me why the ghost data implicitly generated by the architecture would be useful at all. This also suggests an experiment where such ghost samples would be fed to  another type of classifier, such as an SVM, to test whether the data augmentation is useful in itself and reflects meaningful structure in the data, as opposed to being somehow useful only for neural nets.

I note that the results are mostly specific to architectures based on ReLU activations (not that this is a problem, but one should keep this in mind).

I'd really like to see what the ghost samples look like. Do they correspond to interpretable images? The authors also mention that exploring how the samples change with training would be interesting to investigate, and I agree.

Finally, I think there might be a typo in Figure 1. While the labels of a) and b) states that the arc length is smaller for a) than b), the plot clearly show otherwise.

A very simple (but impractical) discrete model of subclonal evolution would include the following events:

* Division of a cell to create two cells:
    * **Mutation** at a location in the genome of the new cells
* Cell death at a new timestep
* Cell survival at a new timestep

Because measurements of mutations are usually taken at one time point, this is taken to be at the end of a time series of these events, where a tiny of subset of cells are observed and a **genotype matrix** $A$ is produced, in which mutations and cells are arbitrarily indexed such that $A_{i,j} = 1$ if mutation $j$ exists in cell $i$. What this matrix allows us to see is the proportion of cells which *both have mutation $j$*.

Unfortunately, I don't get to observe $A$, in practice $A$ has been corrupted by IID binary noise to produce $A'$. This paper focuses on difference inference problems given $A'$, including *inferring $A$*, which is referred to as **`noise_elimination`**. The other problems involve inferring only properties of the matrix $A$, which are referred to as:

* **`noise_inference`**: predict whether matrix $A$ would satisfy the *three gametes rule*, which asks if a given genotype matrix *does not describe a branching phylogeny* because a cell has inherited mutations from two different cells (which is usually assumed to be impossible under the infinite sites assumption). This can be computed exactly from $A$.
* **Branching Inference**: it's possible that all mutations are inherited between the cells observed; in which case there are *no branching events*. The paper states that this can be computed by searching over permutations of the rows and columns of $A$. The problem is to predict from $A'$ if this is the case.

In both problems inferring properties of $A$, the authors use fully connected networks with two hidden layers on simulated datasets of matrices. For **`noise_elimination`**, computing $A$ given $A'$, the authors use a network developed for neural machine translation called a [pointer network][pointer]. They also find it necessary to map $A'$ to a matrix $A''$, turning every element in $A'$ to a fixed length row containing the location, mutation status and false positive/false negative rate.

Unfortunately, reported results on real datasets are reported only for branching inference and are limited by the restriction on input dimension. The inferred branching probability reportedly matches that reported in the literature.

[pointer]: https://arxiv.org/abs/1409.0473