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Deep Learning (DL) has recently enabled unprecedented advances in one of the grand challenges in computational biology: the half-century-old problem of protein structure prediction. In this paper we discuss recent advances, limitations, and future perspectives of DL on five broad areas: protein structure prediction, protein function prediction, genome engineering, systems biology and data integration, and phylogenetic inference. We discuss each application area and cover the main bottlenecks of DL approaches, such as training data, problem scope, and the ability to leverage existing DL architectures in new contexts. To conclude, we provide a summary of the subject-specific and general challenges for DL across the biosciences.

 

Deep Neural Networks (DNNs) trained for classification tasks are vulnerable to adversarial attacks. But not all the classes are equally vulnerable. Adversarial training does not make all classes or groups equally robust as well. For example, in classification tasks with long-tailed distributions, classes are asymmetrically affected during adversarial training, with lower robust accuracy for less frequent classes. In this regard, we propose a provable robustness method by leveraging the continuous piecewise-affine (CPA) nature of DNNs. Our method can impose linearity constraints on the decision boundary, as well as the DNN CPA partition, without requiring any adversarial training. Using such constraints, we show that the margin between the decision boundary and minority classes can be increased in a provable manner. We also present qualitative and quantitative validation of our method for class-specific robustness. Our code is available at https: //github.com/Josuelmet/CROP 

Current Deep Network (DN) visualization and inter-pretability methods rely heavily on data space visualizations such as scoring which dimensions of the data are responsible for their associated prediction or generating new data features or samples that best match a given DN unit or representation. In this paper, we go one step further by developing the first provably exact method for computing the geometry of a DN's mapping - including its decision boundary - over a specified region of the data space. By lever-aging the theory of Continuous Piece- Wise Linear (CPWL) spline DNs, SplineCam exactly computes a DN's geometry without resorting to approximations such as sampling or architecture simplification. SplineCam applies to any DN architecture based on CPWL activation nonlinearities, including (leaky) ReLU, absolute value, maxout, and max-pooling and can also be applied to regression DNs such as implicit neural representations. Beyond decision boundary visualization and characterization, SplineCam enables one to compare architectures, measure generalizability, and sample from the decision boundary on or off the data manifold. Project website: bit.ly/splinecam. 

Generating new molecules with specified chemical and biological properties via generative models has emerged as a promising direction for drug discovery. However, existing methods require extensive training/fine-tuning with a large dataset, often unavailable in real-world generation tasks. In this work, we propose a new retrieval-based framework for controllable molecule generation. We use a small set of exemplar molecules, i.e., those that (partially) satisfy the design criteria, to steer the pre-trained generative model towards synthesizing molecules that satisfy the given design criteria. We design a retrieval mechanism that retrieves and fuses the exemplar molecules with the input molecule, which is trained by a new self-supervised objective that predicts the nearest neighbor of the input molecule. We also propose an iterative refinement process to dynamically update the generated molecules and retrieval database for better generalization. Our approach is agnostic to the choice of generative models and requires no task-specific fine-tuning. On various tasks ranging from simple design criteria to a challenging real-world scenario for designing lead compounds that bind to the SARS-CoV-2 main protease, we demonstrate our approach extrapolates well beyond the retrieval database, and achieves better performance and wider applicability than previous methods. 

The first step toward investigating the effectiveness of a treatment via a randomized trial is to split the population into control and treatment groups then compare the average response of the treatment group receiving the treatment to the control group receiving the placebo. To ensure that the difference between the two groups is caused only by the treatment, it is crucial that the control and the treatment groups have similar statistics. Indeed, the validity and reliability of a trial are determined by the similarity of two groups’ statistics. Covariate balancing methods increase the similarity between the distributions of the two groups’ covariates. However, often in practice, there are not enough samples to accurately estimate the groups’ covariate distributions. In this article, we empirically show that covariate balancing with the standardized means difference (SMD) covariate balancing measure, as well as Pocock and Simon’s sequential treatment assignment method, are susceptible to worst case treatment assignments. Worst case treatment assignments are those admitted by the covariate balance measure, but result in highest possible ATE estimation errors. We developed an adversarial attack to find adversarial treatment assignment for any given trial. Then, we provide an index to measure how close the given trial is to the worst case. To this end, we provide an optimization-based algorithm, namely adversarial treatment assignment in treatment effect trials (ATASTREET), to find the adversarial treatment assignments. 

Abstract We develop new theoretical results on matrix perturbation to shed light on the impact of architecture on the performance of a deep network. In particular, we explain analytically what deep learning practitioners have long observed empirically: the parameters of some deep architectures (e.g., residual networks, ResNets, and Dense networks, DenseNets) are easier to optimize than others (e.g., convolutional networks, ConvNets). Building on our earlier work connecting deep networks with continuous piecewise-affine splines, we develop an exact local linear representation of a deep network layer for a family of modern deep networks that includes ConvNets at one end of a spectrum and ResNets, DenseNets, and other networks with skip connections at the other. For regression and classification tasks that optimize the squared-error loss, we show that the optimization loss surface of a modern deep network is piecewise quadratic in the parameters, with local shape governed by the singular values of a matrix that is a function of the local linear representation. We develop new perturbation results for how the singular values of matrices of this sort behave as we add a fraction of the identity and multiply by certain diagonal matrices. A direct application of our perturbation results explains analytically why a network with skip connections (such as a ResNet or DenseNet) is easier to optimize than a ConvNet: thanks to its more stable singular values and smaller condition number, the local loss surface of such a network is less erratic, less eccentric, and features local minima that are more accommodating to gradient-based optimization. Our results also shed new light on the impact of different nonlinear activation functions on a deep network’s singular values, regardless of its architecture. 

Is overparameterization a privacy liability? In this work, we study the effect that the number of parameters has on a classifier's vulnerability to membership inference attacks. We first demonstrate how the number of parameters of a model can induce a privacy--utility trade-off: increasing the number of parameters generally improves generalization performance at the expense of lower privacy. However, remarkably, we then show that if coupled with proper regularization, increasing the number of parameters of a model can actually simultaneously increase both its privacy and performance, thereby eliminating the privacy--utility trade-off. Theoretically, we demonstrate this curious phenomenon for logistic regression with ridge regularization in a bi-level feature ensemble setting. Pursuant to our theoretical exploration, we develop a novel leave-one-out analysis tool to precisely characterize the vulnerability of a linear classifier to the optimal membership inference attack. We empirically exhibit this "blessing of dimensionality" for neural networks on a variety of tasks using early stopping as the regularizer. 

We develop a measure for evaluating the performance of generative networks given two sets of images. A popular performance measure currently used to do this is the Fréchet Inception Distance (FID). FID assumes that images featurized using the penultimate layer of Inception-v3 follow a Gaussian distribution, an assumption which cannot be violated if we wish to use FID as a metric. However, we show that Inception-v3 features of the ImageNet dataset are not Gaussian; in particular, every single marginal is not Gaussian. To remedy this problem, we model the featurized images using Gaussian mixture models (GMMs) and compute the 2-Wasserstein distance restricted to GMMs. We define a performance measure, which we call WaM, on two sets of images by using Inception-v3 (or another classifier) to featurize the images, estimate two GMMs, and use the restricted 2-Wasserstein distance to compare the GMMs. We experimentally show the advantages of WaM over FID, including how FID is more sensitive than WaM to imperceptible image perturbations. By modelling the non-Gaussian features obtained from Inception-v3 as GMMs and using a GMM metric, we can more accurately evaluate generative network performance. 

Implicit neural representations (INRs) have recently advanced numerous vision-related areas. INR performance depends strongly on the choice of activation function employed in its MLP network. A wide range of nonlinearities have been explored, but, unfortunately, current INRs designed to have high accuracy also suffer from poor robustness (to signal noise, parameter variation, etc.). Inspired by harmonic analysis, we develop a new, highly accurate and robust INR that does not exhibit this tradeoff. Our Wavelet Implicit neural REpresentation (WIRE) uses as its activation function the complex Gabor wavelet that is well-known to be optimally concentrated in space–frequency and to have excellent biases for representing images. A wide range of experiments (image denoising, image inpainting, super-resolution, computed tomography reconstruction, image overfitting, and novel view synthesis with neural radiance fields) demonstrate that WIRE defines the new state of the art in INR accuracy, training time, and robustness.