Recent research in representation learning utilizes large databases of proteins or molecules to acquire knowledge of drug and protein structures through unsupervised learning techniques. These pre-trained representations have proven to significantly enhance the accuracy of subsequent tasks, such as predicting the affinity between drugs and target proteins. In this study, we demonstrate that by incorporating knowledge graphs from diverse sources and modalities into the sequences or SMILES representation, we can further enrich the representation and achieve state-of-the-art results on established benchmark datasets. We provide preprocessed and integrated data obtained from 7 public sources, which encompass over 30M triples. Additionally, we make available the pre-trained models based on this data, along with the reported outcomes of their performance on three widely-used benchmark datasets for drug-target binding affinity prediction found in the Therapeutic Data Commons (TDC) benchmarks. Additionally, we make the source code for training models on benchmark datasets publicly available. Our objective in releasing these pre-trained models, accompanied by clean data for model pretraining and benchmark results, is to encourage research in knowledge-enhanced representation learning.
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We study self-regulating processes modeling biological transportation networks as presented in \cite{portaro2023}. In particular, we focus on the 1D setting for Dirichlet and Neumann boundary conditions. We prove an existence and uniqueness result under the assumption of positivity of the diffusivity $D$. We explore systematically various scenarios and gain insights into the behavior of $D$ and its impact on the studied system. This involves analyzing the system with a signed measure distribution of sources and sinks. Finally, we perform several numerical tests in which the solution $D$ touches zero, confirming the previous hints of local existence in particular cases.
An increasingly common viewpoint is that protein dynamics data sets reside in a non-linear subspace of low conformational energy. Ideal data analysis tools for such data sets should therefore account for such non-linear geometry. The Riemannian geometry setting can be suitable for a variety of reasons. First, it comes with a rich structure to account for a wide range of geometries that can be modelled after an energy landscape. Second, many standard data analysis tools initially developed for data in Euclidean space can also be generalised to data on a Riemannian manifold. In the context of protein dynamics, a conceptual challenge comes from the lack of a suitable smooth manifold and the lack of guidelines for constructing a smooth Riemannian structure based on an energy landscape. In addition, computational feasibility in computing geodesics and related mappings poses a major challenge. This work considers these challenges. The first part of the paper develops a novel local approximation technique for computing geodesics and related mappings on Riemannian manifolds in a computationally feasible manner. The second part constructs a smooth manifold of point clouds modulo rigid body group actions and a Riemannian structure that is based on an energy landscape for protein conformations. The resulting Riemannian geometry is tested on several data analysis tasks relevant for protein dynamics data. It performs exceptionally well on coarse-grained molecular dynamics simulated data. In particular, the geodesics with given start- and end-points approximately recover corresponding molecular dynamics trajectories for proteins that undergo relatively ordered transitions with medium sized deformations. The Riemannian protein geometry also gives physically realistic summary statistics and retrieves the underlying dimension even for large-sized deformations within seconds on a laptop.
Medical studies for chronic disease are often interested in the relation between longitudinal risk factor profiles and individuals' later life disease outcomes. These profiles may typically be subject to intermediate structural changes due to treatment or environmental influences. Analysis of such studies may be handled by the joint model framework. However, current joint modeling does not consider structural changes in the residual variability of the risk profile nor consider the influence of subject-specific residual variability on the time-to-event outcome. In the present paper, we extend the joint model framework to address these two heterogeneous intra-individual variabilities. A Bayesian approach is used to estimate the unknown parameters and simulation studies are conducted to investigate the performance of the method. The proposed joint model is applied to the Framingham Heart Study to investigate the influence of anti-hypertensive medication on the systolic blood pressure variability together with its effect on the risk of developing cardiovascular disease. We show that anti-hypertensive medication is associated with elevated systolic blood pressure variability and increased variability elevates risk of developing cardiovascular disease.
The approach to analysing compositional data has been dominated by the use of logratio transformations, to ensure exact subcompositional coherence and, in some situations, exact isometry as well. A problem with this approach is that data zeros, found in most applications, have to be replaced to allow the logarithmic transformation. An alternative new approach, called the `chiPower' transformation, which allows data zeros, is to combine the standardization inherent in the chi-square distance in correspondence analysis, with the essential elements of the Box-Cox power transformation. The chiPower transformation is justified because it} defines between-sample distances that tend to logratio distances for strictly positive data as the power parameter tends to zero, and are then equivalent to transforming to logratios. For data with zeros, a value of the power can be identified that brings the chiPower transformation as close as possible to a logratio transformation, without having to substitute the zeros. Especially in the area of high-dimensional data, this alternative approach can present such a high level of coherence and isometry as to be a valid approach to the analysis of compositional data. Furthermore, in a supervised learning context, if the compositional variables serve as predictors of a response in a modelling framework, for example generalized linear models, then the power can be used as a tuning parameter in optimizing the accuracy of prediction through cross-validation. The chiPower-transformed variables have a straightforward interpretation, since they are each identified with single compositional parts, not ratios.
Bayesian linear mixed-effects models and Bayesian ANOVA are increasingly being used in the cognitive sciences to perform null hypothesis tests, where a null hypothesis that an effect is zero is compared with an alternative hypothesis that the effect exists and is different from zero. While software tools for Bayes factor null hypothesis tests are easily accessible, how to specify the data and the model correctly is often not clear. In Bayesian approaches, many authors use data aggregation at the by-subject level and estimate Bayes factors on aggregated data. Here, we use simulation-based calibration for model inference applied to several example experimental designs to demonstrate that, as with frequentist analysis, such null hypothesis tests on aggregated data can be problematic in Bayesian analysis. Specifically, when random slope variances differ (i.e., violated sphericity assumption), Bayes factors are too conservative for contrasts where the variance is small and they are too liberal for contrasts where the variance is large. Running Bayesian ANOVA on aggregated data can - if the sphericity assumption is violated - likewise lead to biased Bayes factor results. Moreover, Bayes factors for by-subject aggregated data are biased (too liberal) when random item slope variance is present but ignored in the analysis. These problems can be circumvented or reduced by running Bayesian linear mixed-effects models on non-aggregated data such as on individual trials, and by explicitly modeling the full random effects structure. Reproducible code is available from \url{//osf.io/mjf47/}.
Deep generative chemistry models emerge as powerful tools to expedite drug discovery. However, the immense size and complexity of the structural space of all possible drug-like molecules pose significant obstacles, which could be overcome with hybrid architectures combining quantum computers with deep classical networks. As the first step toward this goal, we built a compact discrete variational autoencoder (DVAE) with a Restricted Boltzmann Machine (RBM) of reduced size in its latent layer. The size of the proposed model was small enough to fit on a state-of-the-art D-Wave quantum annealer and allowed training on a subset of the ChEMBL dataset of biologically active compounds. Finally, we generated 2331 novel chemical structures with medicinal chemistry and synthetic accessibility properties in the ranges typical for molecules from ChEMBL. The presented results demonstrate the feasibility of using already existing or soon-to-be-available quantum computing devices as testbeds for future drug discovery applications.
Although deep learning techniques have shown significant achievements, they frequently depend on extensive amounts of hand-labeled data and tend to perform inadequately in few-shot scenarios. The objective of this study is to devise a strategy that can improve the model's capability to recognize biomedical entities in scenarios of few-shot learning. By redefining biomedical named entity recognition (BioNER) as a machine reading comprehension (MRC) problem, we propose a demonstration-based learning method to address few-shot BioNER, which involves constructing appropriate task demonstrations. In assessing our proposed method, we compared the proposed method with existing advanced methods using six benchmark datasets, including BC4CHEMD, BC5CDR-Chemical, BC5CDR-Disease, NCBI-Disease, BC2GM, and JNLPBA. We examined the models' efficacy by reporting F1 scores from both the 25-shot and 50-shot learning experiments. In 25-shot learning, we observed 1.1% improvements in the average F1 scores compared to the baseline method, reaching 61.7%, 84.1%, 69.1%, 70.1%, 50.6%, and 59.9% on six datasets, respectively. In 50-shot learning, we further improved the average F1 scores by 1.0% compared to the baseline method, reaching 73.1%, 86.8%, 76.1%, 75.6%, 61.7%, and 65.4%, respectively. We reported that in the realm of few-shot learning BioNER, MRC-based language models are much more proficient in recognizing biomedical entities compared to the sequence labeling approach. Furthermore, our MRC-language models can compete successfully with fully-supervised learning methodologies that rely heavily on the availability of abundant annotated data. These results highlight possible pathways for future advancements in few-shot BioNER methodologies.
Characterizing shapes of high-dimensional objects via Ricci curvatures plays a critical role in many research areas in mathematics and physics. However, even though several discretizations of Ricci curvatures for discrete combinatorial objects such as networks have been proposed and studied by mathematicians, the computational complexity aspects of these discretizations have escaped the attention of theoretical computer scientists to a large extent. In this paper, we study one such discretization, namely the Ollivier-Ricci curvature, from the perspective of efficient computation by fine-grained reductions and local query-based algorithms. Our main contributions are the following. (a) We relate our curvature computation problem to minimum weight perfect matching problem on complete bipartite graphs via fine-grained reduction. (b) We formalize the computational aspects of the curvature computation problems in suitable frameworks so that they can be studied by researchers in local algorithms. (c) We provide the first known lower and upper bounds on queries for query-based algorithms for the curvature computation problems in our local algorithms framework. En route, we also illustrate a localized version of our fine-grained reduction. We believe that our results bring forth an intriguing set of research questions, motivated both in theory and practice, regarding designing efficient algorithms for curvatures of objects.
Artificial neural networks thrive in solving the classification problem for a particular rigid task, acquiring knowledge through generalized learning behaviour from a distinct training phase. The resulting network resembles a static entity of knowledge, with endeavours to extend this knowledge without targeting the original task resulting in a catastrophic forgetting. Continual learning shifts this paradigm towards networks that can continually accumulate knowledge over different tasks without the need to retrain from scratch. We focus on task incremental classification, where tasks arrive sequentially and are delineated by clear boundaries. Our main contributions concern 1) a taxonomy and extensive overview of the state-of-the-art, 2) a novel framework to continually determine the stability-plasticity trade-off of the continual learner, 3) a comprehensive experimental comparison of 11 state-of-the-art continual learning methods and 4 baselines. We empirically scrutinize method strengths and weaknesses on three benchmarks, considering Tiny Imagenet and large-scale unbalanced iNaturalist and a sequence of recognition datasets. We study the influence of model capacity, weight decay and dropout regularization, and the order in which the tasks are presented, and qualitatively compare methods in terms of required memory, computation time, and storage.
Graph representation learning for hypergraphs can be used to extract patterns among higher-order interactions that are critically important in many real world problems. Current approaches designed for hypergraphs, however, are unable to handle different types of hypergraphs and are typically not generic for various learning tasks. Indeed, models that can predict variable-sized heterogeneous hyperedges have not been available. Here we develop a new self-attention based graph neural network called Hyper-SAGNN applicable to homogeneous and heterogeneous hypergraphs with variable hyperedge sizes. We perform extensive evaluations on multiple datasets, including four benchmark network datasets and two single-cell Hi-C datasets in genomics. We demonstrate that Hyper-SAGNN significantly outperforms the state-of-the-art methods on traditional tasks while also achieving great performance on a new task called outsider identification. Hyper-SAGNN will be useful for graph representation learning to uncover complex higher-order interactions in different applications.
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