The main contribution of [Understanding the difficulty of training deep feedforward neural networks](http://jmlr.org/proceedings/papers/v9/glorot10a/glorot10a.pdf) by Glorot et al. is a **normalized weight initialization**

$$W \sim U \left [  - \frac{\sqrt{6}}{\sqrt{n_j + n_{j+1}}}, \frac{\sqrt{6}}{\sqrt{n_j + n_{j+1}}} \right ]$$

where $n_j \in \mathbb{N}^+$ is the number of neurons in the layer $j$.

Showing some ways **how to debug neural networks** might be another reason to read the paper.

The paper analyzed standard multilayer perceptrons (MLPs) on a artificial dataset of $32 \text{px} \times 32 \text{px}$ images with either one or two of the 3 shapes: triangle, parallelogram and ellipse. The MLPs varied in the activation function which was used (either sigmoid, tanh or softsign).

However, no regularization was used and many mini-batch epochs were learned. It might be that batch normalization / dropout might change the influence of initialization very much.

Questions that remain open for me:

* [How is weight initialization done today?](https://www.reddit.com/r/MLQuestions/comments/4jsge9)
* Figure 4: Why is this plot not simply completely dependent on the data?
* Is softsign still used? Why not?
* If the only advantage of softsign is that is has the plateau later, why doesn't anybody use $\frac{1}{1+e^{-0.1 \cdot x}}$ or something similar instead of the standard sigmoid activation function?

This paper from 2016 introduced a new k-mer based method to estimate isoform abundance from RNA-Seq data called kallisto.  The method provided a significant improvement in speed and memory usage compared to the previously used methods while yielding similar accuracy.   In fact, kallisto is able to quantify expression in a matter of minutes instead of hours.

The standard (previous) methods for quantifying expression rely on mapping, i.e. on the alignment of a transcriptome sequenced reads to a genome of reference.  Reads are assigned to a position in the genome and the gene or isoform expression values are derived by counting the number of reads overlapping the features of interest. 

The idea behind kallisto is to rely on a pseudoalignment which does not attempt to identify the positions of the reads in the transcripts, only the potential transcripts of origin. Thus,  it avoids doing an alignment of each read to a reference genome. In fact, kallisto only uses the transcriptome sequences (not the whole genome) in its first step which is the generation of  the kallisto index.  Kallisto builds a colored de Bruijn graph (T-DBG) from all the k-mers found in the transcriptome.  Each node of the graph corresponds to a k-mer (a short sequence of k nucleotides) and retains the information about the transcripts in which they can be found in the form of a color.  Linear stretches having the same coloring in the graph correspond to transcripts. Once the T-DBG is built, kallisto stores a hash table mapping each k-mer to its transcript(s) of origin along with the position within the transcript(s).  This step is done only once and is dependent on a provided annotation file (containing the sequences of all the transcripts in the transcriptome).  
  
Then for a given sequenced sample, kallisto decomposes each read into its k-mers and uses those k-mers to find a path covering in the T-DBG.  This path covering of the transcriptome graph, where a path corresponds to a transcript, generates k-compatibility classes for each k-mer, i.e. sets of potential transcripts of origin on the nodes.   The potential transcripts of origin for a read can be obtained using the intersection of its k-mers k-compatibility classes. To make the pseudoalignment faster, kallisto removes redundant k-mers since neighboring k-mers often belong to the same transcripts. Figure1, from the paper, summarizes these different steps.

https://i.imgur.com/eNH2kuO.png

**Figure1**. Overview of kallisto. The input consists of a reference transcriptome and reads from an RNA-seq experiment. (a) An example of a read (in black) and three overlapping transcripts with exonic regions as shown. (b) An index is constructed by creating the transcriptome de Bruijn Graph (T-DBG) where nodes (v1, v2, v3, ... ) are k-mers, each transcript corresponds to a colored path as shown and the path cover of the transcriptome induces a k-compatibility class for each k-mer. (c) Conceptually, the k-mers of a read are hashed (black nodes) to find the k-compatibility class of a read. (d) Skipping (black dashed lines) uses the information stored in the T-DBG to skip k-mers that are redundant because they have the same k-compatibility class. (e) The k-compatibility class of the read is determined by taking the intersection of the k-compatibility classes of its constituent k-mers.[From Bray et al. Near-optimal probabilistic RNA-seq quantification, Nature Biotechnology, 2016.]

Then, kallisto optimizes the following RNA-Seq likelihood function using the expectation-maximization (EM) algorithm.  

$$L(\alpha) \propto \prod_{f \in F} \sum_{t \in T} y_{f,t} \frac{\alpha_t}{l_t} = \prod_{e \in E}\left(  \sum_{t \in e} \frac{\alpha_t}{l_t} \right )^{c_e}$$

In this function,  $F$ is the set of fragments (or reads), $T$ is the set of transcripts, $l_t$ is the (effective) length of transcript $t$ and **y**$_{f,t}$ is a compatibility matrix defined as 1 if  fragment $f$ is compatible with $t$ and 0 otherwise.  The parameters $α_t$ are the probabilities of selecting reads from a transcript $t$.  These $α_t$ are the parameters of interest since they represent the isoforms abundances or relative expressions.

To make things faster, the compatibility matrix is collapsed (factorized) into equivalence classes. An equivalent class consists of all the reads compatible with the same subsets of transcripts. The EM algorithm is applied to equivalence classes (not to reads).  Each $α_t$ will be optimized to maximise the likelihood of transcript abundances given observations of the equivalence classes. The speed of the method makes it possible to evaluate the uncertainty of the  abundance estimates for each RNA-Seq sample using a bootstrap technique.  For a given sample containing $N$ reads, a bootstrap sample is generated from the sampling of $N$ counts from a multinomial distribution over the equivalence classes derived from the original sample.  The EM algorithm is applied on those sampled equivalence class counts to estimate transcript abundances. The bootstrap information is then used in downstream analyses such as determining which genes are differentially expressed.

Practically, we can illustrate the different steps involved in kallisto using a small example.  Starting from a tiny genome with 3 transcripts, assume that the RNA-Seq experiment produced 4 reads as depicted in the image below.

https://i.imgur.com/5JDpQO8.png

The first step is to build the T-DBG graph and the kallisto index.  All transcript sequences are decomposed into k-mers (here k=5) to construct the colored de Bruijn graph. Not all nodes are represented in the following drawing.  The idea is that each different transcript will lead to a different path in the graph.  The strand is not taken into account, kallisto is strand-agnostic.

https://i.imgur.com/4oW72z0.png

Once the index is built, the four reads of the sequenced sample can be analysed.  They are decomposed into k-mers (k=5 here too) and the pre-built index is used to determine the k-compatibility class of each k-mer. Then, the k-compatibility class of each read is computed. For example, for read 1, the intersection of all the k-compatibility classes of its k-mers suggests that it might come from transcript 1 or transcript 2.

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

This is done for the four reads enabling the construction of the compatibility matrix  **y**$_{f,t}$ which is part of the RNA-Seq likelihood function.  In this equation, the $α_t$ are the parameters that we want to estimate.

https://i.imgur.com/Hp5QJvH.png

The EM algorithm being too slow to be applied on millions of reads, the compatibility matrix **y**$_{f,t}$ is factorized into equivalence classes and a count is computed for each class (how many reads are represented by this equivalence class). The EM algorithm uses this collapsed information to maximize the new equivalent RNA-Seq likelihood function and optimize the $α_t$.

https://i.imgur.com/qzsEq8A.png

The EM algorithm stops when for every transcript $t$, $α_tN$ > 0.01 changes less than 1%, where $N$ is the total number of reads. 

We want to find two matrices $W$ and $H$ such that $V = WH$. Often a goal is to determine underlying patterns in the relationships between the concepts represented by each row and column. $W$ is some $m$ by $n$ matrix and we want the inner dimension of the factorization to be $r$. So 

$$\underbrace{V}_{m \times n} = \underbrace{W}_{m \times r} \underbrace{H}_{r \times n}$$

Let's consider an example matrix where of three customers (as rows) are associated with three movies (the columns) by a rating value.

$$
V = \left[\begin{array}{c c c}
5 & 4 & 1  \\\\
4 & 5 & 1 \\\\
2 & 1 & 5
\end{array}\right]
$$


We can decompose this into two matrices with $r = 1$. First lets do this without any non-negative constraint using an SVD reshaping matrices based on removing eigenvalues:


$$
W = \left[\begin{array}{c c c}
-0.656 \\\
 -0.652 \\\
 -0.379
\end{array}\right],
H = \left[\begin{array}{c c c}
-6.48 & -6.26 & -3.20\\\\
\end{array}\right]
$$

We can also decompose this into two matrices with $r = 1$ subject to the constraint that $w_{ij} \ge 0$ and  $h_{ij} \ge 0$. (Note: this is only possible when $v_{ij} \ge 0$):

$$
W = \left[\begin{array}{c c c}
0.388 \\\\
0.386 \\\\
0.224
\end{array}\right],
H = \left[\begin{array}{c c c}
11.22 & 10.57 & 5.41  \\\\
\end{array}\right]
$$

Both of these $r=1$ factorizations reconstruct matrix $V$ with the same error. 

$$
V \approx WH = \left[\begin{array}{c c c}
4.36 & 4.11 & 2.10 \\\
4.33 & 4.08 & 2.09 \\\
2.52 & 2.37 & 1.21 \\\
\end{array}\right]
$$


If they both yield the same reconstruction error then why is a non-negativity constraint useful? We can see above that it is easy to observe patterns in both factorizations such as similar customers and similar movies. `TODO: motivate why NMF is better`



#### Paper Contribution 

This paper discusses two approaches for iteratively creating a non-negative $W$ and $H$ based on random initial matrices. The paper discusses a multiplicative update rule where the elements of $W$ and $H$ are iteratively transformed by scaling each value such that error is not increased. 

The multiplicative approach is discussed in contrast to an additive gradient decent based approach where small corrections are iteratively applied. The multiplicative approach can be reduced to this by setting the learning rate ($\eta$) to a ratio that represents the magnitude of the element in $H$ to the scaling factor of $W$ on $H$.



### Still a draft

The paper discusses a number of extensions to the Skip-gram model previously proposed by Mikolov et al (citation [7] in the paper): which learns linear word embeddings that are particularly useful for analogical reasoning type tasks. The extensions proposed (namely, negative sampling and sub-sampling of high frequency words) enable extremely fast training of the model on large scale datasets. This also results in significantly improved performance as compared to previously proposed techniques based on neural networks. The authors also provide a method for training phrase level embeddings by slightly tweaking the original training algorithm. 

This paper proposes 3 improvements for the skip-gram model which allows for learning embeddings for words. The first improvement is subsampling frequent word, the second is the use of a simplified version of noise constrastive estimation (NCE) and finally they propose a method to learn idiomatic phrase embeddings. In all three cases the improvements are somewhat ad-hoc. In practice, both the subsampling and negative samples help to improve generalization substantially on an analogical reasoning task. The paper reviews related work and furthers the interesting topic of additive compositionality in embeddings. 

The article does not propose any explanation as to why the negative sampling produces better results than NCE which it is suppose to loosely approximate. In fact it doesn't explain why besides the obvious generalization gain the negative sampling scheme should be preferred to NCE since they achieve similar speeds. 

The authors have a dataset of 780 electronic health records and they use it to detect various medical events such as adverse drug events, drug dosage, etc. The task is done by assigning a label to each word in the document.

https://i.imgur.com/bZ7yM0z.png

Annotation statistics for the corpus of health records.

They look at CRFs, LSTMs and GRUs. Both LSTMs and GRUs outperform the CRF, but the best performance is achieved by a GRU trained on whole documents.