Visualization tools can help synthetic biologists and molecular programmers understand the complex reactive pathways of nucleic acid reactions, which can be designed for many potential applications and can be modelled using a continuous-time Markov chain (CTMC). Here we present ViDa, a new visualization approach for DNA reaction trajectories that uses a 2D embedding of the secondary structure state space underlying the CTMC model. To this end, we integrate a scattering transform of the secondary structure adjacency, a variational autoencoder, and a nonlinear dimensionality reduction method. We augment the training loss with domain-specific supervised terms that capture both thermodynamic and kinetic features. We assess ViDa on two well-studied DNA hybridization reactions. Our results demonstrate that the domain-specific features lead to significant quality improvements over the state-of-the-art in DNA state space visualization, successfully separating different folding pathways and thus providing useful insights into dominant reaction mechanisms.
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There exist multiple regression applications in engineering and industry where the outcomes are not conditionally independent given the covariates, but where instead the covariates follow a sequential experimental design in which the next measurement depends on the previous outcomes, introducing dependence. Such designs are commonly employed for example for choosing test values when estimating the sensitivity of a material under physical stimulus. Apart from the extensive study of the Robbins--Monro procedure, virtually no attention has been given to verifying asymptotic normality of the maximum likelihood estimator in the general sequential setting, despite the wide use of such designs in industry since at least the 1940s. This is a considerable gap in the literature, since said properties underlie the construction of confidence intervals and hypothesis testing. In this paper we close this gap by establishing a large-sample theory for sequential experimental designs other than the Robbins--Monro procedure. First, we use martingale theory to prove a general result for when such asymptotic normality may be asserted. Second, we consider the special case where the covariate process forms a Markov chain. In doing so, we verify asymptotic normality for the widely applied Bruceton design and a proposed Markovian version of the Langlie design.
Immunotherapies and targeted therapies have gained popularity due to their promising therapeutic effects across multiple treatment areas. The focus of early phase dose-finding clinical trials has shifted from finding the maximum tolerated dose (MTD) to identifying the optimal biological dose (OBD), which aims to balance the toxicity and efficacy outcomes, thereby optimizing the risk-benefit trade-off. These trials often collect multiple pharmacokinetics (PK) outcomes to assess drug exposure, which has shown correlations with toxicity and efficacy outcomes but has not been utilized in the current dose-finding designs for OBD selection. Moreover, PK outcomes are usually available within days after initial treatment, much faster than toxicity and efficacy outcomes. To bridge this gap, we introduce the innovative model-assisted PKBOIN-12 design, which enhances the BOIN12 design by integrating PK information into both the dose-finding algorithm and the final OBD determination process. We further extend PKBOIN-12 to the TITE-PKBOIN-12 design to address the challenges of late-onset toxicity and efficacy outcomes. Simulation results demonstrate that the PKBOIN-12 design more effectively identifies the OBD and allocates a greater number of patients to it than BOIN12. Additionally, PKBOIN-12 decreases the probability of selecting inefficacious doses as the OBD by excluding those with low drug exposure. Comprehensive simulation studies and sensitivity analysis confirm the robustness of both PKBOIN-12 and TITE-PKBOIN-12 designs in various scenarios.
Adaptive first-order optimizers are fundamental tools in deep learning, although they may suffer from poor generalization due to the nonuniform gradient scaling. In this work, we propose AdamL, a novel variant of the Adam optimizer, that takes into account the loss function information to attain better generalization results. We provide sufficient conditions that together with the Polyak-Lojasiewicz inequality, ensure the linear convergence of AdamL. As a byproduct of our analysis, we prove similar convergence properties for the EAdam, and AdaBelief optimizers. Experimental results on benchmark functions show that AdamL typically achieves either the fastest convergence or the lowest objective function values when compared to Adam, EAdam, and AdaBelief. These superior performances are confirmed when considering deep learning tasks such as training convolutional neural networks, training generative adversarial networks using vanilla convolutional neural networks, and long short-term memory networks. Finally, in the case of vanilla convolutional neural networks, AdamL stands out from the other Adam's variants and does not require the manual adjustment of the learning rate during the later stage of the training.
Scientific claims gain credibility by replicability, especially if replication under different circumstances and varying designs yields equivalent results. Aggregating results over multiple studies is, however, not straightforward, and when the heterogeneity between studies increases, conventional methods such as (Bayesian) meta-analysis and Bayesian sequential updating become infeasible. *Bayesian Evidence Synthesis*, built upon the foundations of the Bayes factor, allows to aggregate support for conceptually similar hypotheses over studies, regardless of methodological differences. We assess the performance of Bayesian Evidence Synthesis over multiple effect and sample sizes, with a broad set of (inequality-constrained) hypotheses using Monte Carlo simulations, focusing explicitly on the complexity of the hypotheses under consideration. The simulations show that this method can evaluate complex (informative) hypotheses regardless of methodological differences between studies, and performs adequately if the set of studies considered has sufficient statistical power. Additionally, we pinpoint challenging conditions that can lead to unsatisfactory results, and provide suggestions on handling these situations. Ultimately, we show that Bayesian Evidence Synthesis is a promising tool that can be used when traditional research synthesis methods are not applicable due to insurmountable between-study heterogeneity.
Many interesting physical problems described by systems of hyperbolic conservation laws are stiff, and thus impose a very small time-step because of the restrictive CFL stability condition. In this case, one can exploit the superior stability properties of implicit time integration which allows to choose the time-step only from accuracy requirements, and thus avoid the use of small time-steps. We discuss an efficient framework to devise high order implicit schemes for stiff hyperbolic systems without tailoring it to a specific problem. The nonlinearity of high order schemes, due to space- and time-limiting procedures which control nonphysical oscillations, makes the implicit time integration difficult, e.g.~because the discrete system is nonlinear also on linear problems. This nonlinearity of the scheme is circumvented as proposed in (Puppo et al., Comm.~Appl.~Math.~\& Comput., 2023) for scalar conservation laws, where a first order implicit predictor is computed to freeze the nonlinear coefficients of the essentially non-oscillatory space reconstruction, and also to assist limiting in time. In addition, we propose a novel conservative flux-centered a-posteriori time-limiting procedure using numerical entropy indicators to detect troubled cells. The numerical tests involve classical and artificially devised stiff problems using the Euler's system of gas-dynamics.
As in many fields of medical research, survival analysis has witnessed a growing interest in the application of deep learning techniques to model complex, high-dimensional, heterogeneous, incomplete, and censored medical data. Current methods often make assumptions about the relations between data that may not be valid in practice. In response, we introduce SAVAE (Survival Analysis Variational Autoencoder), a novel approach based on Variational Autoencoders. SAVAE contributes significantly to the field by introducing a tailored ELBO formulation for survival analysis, supporting various parametric distributions for covariates and survival time (as long as the log-likelihood is differentiable). It offers a general method that consistently performs well on various metrics, demonstrating robustness and stability through different experiments. Our proposal effectively estimates time-to-event, accounting for censoring, covariate interactions, and time-varying risk associations. We validate our model in diverse datasets, including genomic, clinical, and demographic data, with varying levels of censoring. This approach demonstrates competitive performance compared to state-of-the-art techniques, as assessed by the Concordance Index and the Integrated Brier Score. SAVAE also offers an interpretable model that parametrically models covariates and time. Moreover, its generative architecture facilitates further applications such as clustering, data imputation, and the generation of synthetic patient data through latent space inference from survival data.
Text normalization is a crucial technology for low-resource languages which lack rigid spelling conventions or that have undergone multiple spelling reforms. Low-resource text normalization has so far relied upon hand-crafted rules, which are perceived to be more data efficient than neural methods. In this paper we examine the case of text normalization for Ligurian, an endangered Romance language. We collect 4,394 Ligurian sentences paired with their normalized versions, as well as the first open source monolingual corpus for Ligurian. We show that, in spite of the small amounts of data available, a compact transformer-based model can be trained to achieve very low error rates by the use of backtranslation and appropriate tokenization.
Machine learning algorithms often contain many hyperparameters (HPs) whose values affect the predictive performance of the induced models in intricate ways. Due to the high number of possibilities for these HP configurations and their complex interactions, it is common to use optimization techniques to find settings that lead to high predictive performance. However, insights into efficiently exploring this vast space of configurations and dealing with the trade-off between predictive and runtime performance remain challenging. Furthermore, there are cases where the default HPs fit the suitable configuration. Additionally, for many reasons, including model validation and attendance to new legislation, there is an increasing interest in interpretable models, such as those created by the Decision Tree (DT) induction algorithms. This paper provides a comprehensive approach for investigating the effects of hyperparameter tuning for the two DT induction algorithms most often used, CART and C4.5. DT induction algorithms present high predictive performance and interpretable classification models, though many HPs need to be adjusted. Experiments were carried out with different tuning strategies to induce models and to evaluate HPs' relevance using 94 classification datasets from OpenML. The experimental results point out that different HP profiles for the tuning of each algorithm provide statistically significant improvements in most of the datasets for CART, but only in one-third for C4.5. Although different algorithms may present different tuning scenarios, the tuning techniques generally required few evaluations to find accurate solutions. Furthermore, the best technique for all the algorithms was the IRACE. Finally, we found out that tuning a specific small subset of HPs is a good alternative for achieving optimal predictive performance.
The remarkable practical success of deep learning has revealed some major surprises from a theoretical perspective. In particular, simple gradient methods easily find near-optimal solutions to non-convex optimization problems, and despite giving a near-perfect fit to training data without any explicit effort to control model complexity, these methods exhibit excellent predictive accuracy. We conjecture that specific principles underlie these phenomena: that overparametrization allows gradient methods to find interpolating solutions, that these methods implicitly impose regularization, and that overparametrization leads to benign overfitting. We survey recent theoretical progress that provides examples illustrating these principles in simpler settings. We first review classical uniform convergence results and why they fall short of explaining aspects of the behavior of deep learning methods. We give examples of implicit regularization in simple settings, where gradient methods lead to minimal norm functions that perfectly fit the training data. Then we review prediction methods that exhibit benign overfitting, focusing on regression problems with quadratic loss. For these methods, we can decompose the prediction rule into a simple component that is useful for prediction and a spiky component that is useful for overfitting but, in a favorable setting, does not harm prediction accuracy. We focus specifically on the linear regime for neural networks, where the network can be approximated by a linear model. In this regime, we demonstrate the success of gradient flow, and we consider benign overfitting with two-layer networks, giving an exact asymptotic analysis that precisely demonstrates the impact of overparametrization. We conclude by highlighting the key challenges that arise in extending these insights to realistic deep learning settings.
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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