A normalization technique for next generation sequencing experiments

Next generation sequencing (NGS) are these days one of the key technologies in biology. NGS' cost effectiveness and capability of finding the smallest variations in the genome makes them increasingly popular. For studies aiming at genome assembly, differences in read count statistics do not affect the outcome. However, these differences bias the outcome if the goal is to identify structural DNA characteristics like copy number variations (CNVs). Thus a normalization step must removed such random read count variations subsequently read counts from different experiments are comparable. Especially after normalization the commonly used assumption of Poisson read count distribution in windows on the chromosomes is more justified. Strong deviations of read counts from the estimated mean Poisson distribution indicate CNVs

Principled Weight Initialisation for Input-Convex Neural Networks

Input-Convex Neural Networks (ICNNs) are networks that guarantee convexity in their input-output mapping. These networks have been successfully applied for energy-based modelling, optimal transport problems and learning invariances. The convexity of ICNNs is achieved by using non-decreasing convex activation functions and non-negative weights. Because of these peculiarities, previous initialisation strategies, which implicitly assume centred weights, are not effective for ICNNs. By studying signal propagation through layers with non-negative weights, we are able to derive a principled weight initialisation for ICNNs. Concretely, we generalise signal propagation theory by removing the assumption that weights are sampled from a centred distribution. In a set of experiments, we demonstrate that our principled initialisation effectively accelerates learning in ICNNs and leads to better generalisation. Moreover, we find that, in contrast to common belief, ICNNs can be trained without skip-connections when initialised correctly. Finally, we apply ICNNs to a real-world drug discovery task and show that they allow for more effective molecular latent space exploration.Comment: Presented at NeurIPS 202

Fr\'echet ChemNet Distance: A metric for generative models for molecules in drug discovery

The new wave of successful generative models in machine learning has increased the interest in deep learning driven de novo drug design. However, assessing the performance of such generative models is notoriously difficult. Metrics that are typically used to assess the performance of such generative models are the percentage of chemically valid molecules or the similarity to real molecules in terms of particular descriptors, such as the partition coefficient (logP) or druglikeness. However, method comparison is difficult because of the inconsistent use of evaluation metrics, the necessity for multiple metrics, and the fact that some of these measures can easily be tricked by simple rule-based systems. We propose a novel distance measure between two sets of molecules, called Fr\'echet ChemNet distance (FCD), that can be used as an evaluation metric for generative models. The FCD is similar to a recently established performance metric for comparing image generation methods, the Fr\'echet Inception Distance (FID). Whereas the FID uses one of the hidden layers of InceptionNet, the FCD utilizes the penultimate layer of a deep neural network called ChemNet, which was trained to predict drug activities. Thus, the FCD metric takes into account chemically and biologically relevant information about molecules, and also measures the diversity of the set via the distribution of generated molecules. The FCD's advantage over previous metrics is that it can detect if generated molecules are a) diverse and have similar b) chemical and c) biological properties as real molecules. We further provide an easy-to-use implementation that only requires the SMILES representation of the generated molecules as input to calculate the FCD. Implementations are available at: https://www.github.com/bioinf-jku/FCDComment: Implementations are available at: https://www.github.com/bioinf-jku/FC

Identifying Copy Number Variations based on Next Generation Sequencing Data by a Mixture of Poisson Model

Next generation sequencing (NGS) technologies have profoundly impacted biological research and are becoming more and more popular due to cost effectiveness and their speed. NGS can be utilized to identify DNA structural variants, namely copy number variations (CNVs) which showed association with diseases like HIV, diabetes II, or cancer.

There have been first approaches to detect CNVs in NGS data, where most of them detect a CNV by a significant difference of read counts within neighboring windows at the chromosome. However these methods suffer from systematical variations of the underlying read count distributions along the chromosome due to biological and technical noise. In contrast to these global methods, we locally model the read count distribution characteristics by a mixture of Poissons which allows to incorporate a linear dependence between copy numbers and read counts. Model selection is performed in a Bayesian framework by maximizing the posterior through an EM algorithm. We define a CNV call which indicates a deviation of the Poisson mixture parameters from the null hypothesis represented by the prior which is a model for constant copy number across the samples. A CNV call requires sufficient information in the data to push the model away from the null hypothesis given by the prior.

We test our approach on the HapMap cohort where we rediscovered previously found CNVs which validates our approach. It is then tested on the tumor genome data set where we are able to considerably increase the detection while reducing the false discoveries.
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Quantification of Uncertainty with Adversarial Models

Quantifying uncertainty is important for actionable predictions in real-world applications. A crucial part of predictive uncertainty quantification is the estimation of epistemic uncertainty, which is defined as an integral of the product between a divergence function and the posterior. Current methods such as Deep Ensembles or MC dropout underperform at estimating the epistemic uncertainty, since they primarily consider the posterior when sampling models. We suggest Quantification of Uncertainty with Adversarial Models (QUAM) to better estimate the epistemic uncertainty. QUAM identifies regions where the whole product under the integral is large, not just the posterior. Consequently, QUAM has lower approximation error of the epistemic uncertainty compared to previous methods. Models for which the product is large correspond to adversarial models (not adversarial examples!). Adversarial models have both a high posterior as well as a high divergence between their predictions and that of a reference model. Our experiments show that QUAM excels in capturing epistemic uncertainty for deep learning models and outperforms previous methods on challenging tasks in the vision domain

VN-EGNN: E(3)-Equivariant Graph Neural Networks with Virtual Nodes Enhance Protein Binding Site Identification

Being able to identify regions within or around proteins, to which ligands can potentially bind, is an essential step to develop new drugs. Binding site identification methods can now profit from the availability of large amounts of 3D structures in protein structure databases or from AlphaFold predictions. Current binding site identification methods heavily rely on graph neural networks (GNNs), usually designed to output E(3)-equivariant predictions. Such methods turned out to be very beneficial for physics-related tasks like binding energy or motion trajectory prediction. However, the performance of GNNs at binding site identification is still limited potentially due to the lack of dedicated nodes that model hidden geometric entities, such as binding pockets. In this work, we extend E(n)-Equivariant Graph Neural Networks (EGNNs) by adding virtual nodes and applying an extended message passing scheme. The virtual nodes in these graphs are dedicated quantities to learn representations of binding sites, which leads to improved predictive performance. In our experiments, we show that our proposed method VN-EGNN sets a new state-of-the-art at locating binding site centers on COACH420, HOLO4K and PDBbind2020