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Cancer drug response prediction (DRP) models present a promising approach towards precision oncology, tailoring treatments to individual patient profiles. While deep learning (DL) methods have shown great potential in this area, models that can be successfully translated into clinical practice and shed light on the molecular mechanisms underlying treatment response will likely emerge from collaborative research efforts. This highlights the need for reusable and adaptable models that can be improved and tested by the wider scientific community. In this study, we present a scoring system for assessing the reusability of prediction DRP models, and apply it to 17 peer-reviewed DL-based DRP models. As part of the IMPROVE (Innovative Methodologies and New Data for Predictive Oncology Model Evaluation) project, which aims to develop methods for systematic evaluation and comparison DL models across scientific domains, we analyzed these 17 DRP models focusing on three key categories: software environment, code modularity, and data availability and preprocessing. While not the primary focus, we also attempted to reproduce key performance metrics to verify model behavior and adaptability. Our assessment of 17 DRP models reveals both strengths and shortcomings in model reusability. To promote rigorous practices and open-source sharing, we offer recommendations for developing and sharing prediction models. Following these recommendations can address many of the issues identified in this study, improving model reusability without adding significant burdens on researchers. This work offers the first comprehensive assessment of reusability and reproducibility across diverse DRP models, providing insights into current model sharing practices and promoting standards within the DRP and broader AI-enabled scientific research community., Comment: 12 pages, 2 figures

Human cancers present a significant public health challenge and require the discovery of novel drugs through translational research. Transcriptomics profiling data that describes molecular activities in tumors and cancer cell lines are widely utilized for predicting anti-cancer drug responses. However, existing AI models face challenges due to noise in transcriptomics data and lack of biological interpretability. To overcome these limitations, we introduce VETE (Variational and Explanatory Transcriptomics Encoder), a novel neural network framework that incorporates a variational component to mitigate noise effects and integrates traceable gene ontology into the neural network architecture for encoding cancer transcriptomics data. Key innovations include a local interpretability-guided method for identifying ontology paths, a visualization tool to elucidate biological mechanisms of drug responses, and the application of centralized large scale hyperparameter optimization. VETE demonstrated robust accuracy in cancer cell line classification and drug response prediction. Additionally, it provided traceable biological explanations for both tasks and offers insights into the mechanisms underlying its predictions. VETE bridges the gap between AI-driven predictions and biologically meaningful insights in cancer research, which represents a promising advancement in the field.

Informed selection of drug candidates for laboratory experimentation provides an efficient means of identifying suitable anti-cancer treatments. The advancement of artificial intelligence has led to the development of computational models to predict cancer cell line response to drug treatment. It is important to analyze the false positive rate (FPR) of the models, to increase the number of effective treatments identified and to minimize unnecessary laboratory experimentation. Such analysis will also aid in identifying drugs or cancer types that require more data collection to improve model predictions. This work uses an attention based neural network classification model to identify responsive/non-responsive drug treatments across multiple types of cancer cell lines. Two data filtering techniques have been applied to generate 10 data subsets, including removing samples for which dose response curves are poorly fitted and removing samples whose area under the dose response curve (AUC) values are marginal around 0.5 from the training set. One hundred trials of 10-fold cross-validation analysis is performed to test the model prediction performance on all the data subsets and the subset with the best model prediction performance is selected for further analysis. Several error analysis metrics such as the false positive rate (FPR), and the prediction uncertainty are evaluated, and the results are summarized by cancer type and drug mechanism of action (MoA) category. The FPR of cancer type spans between 0.262 and 0.5189, while that of drug MoA category spans almost the full range of [0, 1]. This study identifies cancer types and drug MoAs with high FPRs. Additional drug screening data of these cancer and drug categories may improve response modeling. Our results also demonstrate that the two data filtering approaches help improve the drug response prediction performance.

Efficient delivery of current from PCB to point-of-load (POL) is a primary concern in modern high-power high-density integrated systems. Traditionally, a 48 V power signal is converted to the low, POL voltage at the board and/or package level. As interconnect has become the dominant power loss component, minimizing voltage drop across the laterally routed portions of the board-to-die interconnect (referred to as horizontal interconnect) is a promising approach to enhance the efficiency of the power delivery system. Delivering lower current vertically, at a higher voltage should therefore be considered. High-power conversion near POL, however, results in higher switching and inductor losses, exhibiting an undesired power efficiency tradeoff. To address this problem, four vertical power delivery architectures are proposed in this paper, considering state-of-the-art power converter topologies, integration levels, and voltage conversion schemes. Embedding Silicon (Si) and Gallium Nitride (GaN) power devices and inductors on top of and/or within the interposer is investigated. Integrating GaN power devices on a dedicated power die is also discussed. Various multi-stage 48V-to-1V power conversion schemes are examined and state-of-the-art power conversion circuits are reviewed. Power delivery characteristics with these architectures are determined for a high power (1 kW) high-current density (2 A/mm$^2$) system.

Cancer claims millions of lives yearly worldwide. While many therapies have been made available in recent years, by in large cancer remains unsolved. Exploiting computational predictive models to study and treat cancer holds great promise in improving drug development and personalized design of treatment plans, ultimately suppressing tumors, alleviating suffering, and prolonging lives of patients. A wave of recent papers demonstrates promising results in predicting cancer response to drug treatments while utilizing deep learning methods. These papers investigate diverse data representations, neural network architectures, learning methodologies, and evaluations schemes. However, deciphering promising predominant and emerging trends is difficult due to the variety of explored methods and lack of standardized framework for comparing drug response prediction models. To obtain a comprehensive landscape of deep learning methods, we conducted an extensive search and analysis of deep learning models that predict the response to single drug treatments. A total of 60 deep learning-based models have been curated and summary plots were generated. Based on the analysis, observable patterns and prevalence of methods have been revealed. This review allows to better understand the current state of the field and identify major challenges and promising solution paths.

We analyze the regression accuracy of convolutional neural networks assembled from encoders, decoders and skip connections and trained with multifidelity data. Besides requiring significantly less trainable parameters than equivalent fully connected networks, encoder, decoder, encoder-decoder or decoder-encoder architectures can learn the mapping between inputs to outputs of arbitrary dimensionality. We demonstrate their accuracy when trained on a few high-fidelity and many low-fidelity data generated from models ranging from one-dimensional functions to Poisson equation solvers in two-dimensions. We finally discuss a number of implementation choices that improve the reliability of the uncertainty estimates generated by Monte Carlo DropBlocks, and compare uncertainty estimates among low-, high- and multifidelity approaches.

Patient-derived xenografts (PDXs) are an appealing platform for preclinical drug studies because the in vivo environment of PDXs helps preserve tumor heterogeneity and usually better mimics drug response of patients with cancer compared to CCLs. We investigate multimodal neural network (MM-Net) and data augmentation for drug response prediction in PDXs. The MM-Net learns to predict response using drug descriptors, gene expressions (GE), and histology whole-slide images (WSIs) where the multi-modality refers to the tumor features. We explore whether the integration of WSIs with GE improves predictions as compared with models that use GE alone. We use two methods to address the limited number of response values: 1) homogenize drug representations which allows to combine single-drug and drug-pairs treatments into a single dataset, 2) augment drug-pair samples by switching the order of drug features which doubles the sample size of all drug-pair samples. These methods enable us to combine single-drug and drug-pair treatments, allowing us to train multimodal and unimodal neural networks (NNs) without changing architectures or the dataset. Prediction performance of three unimodal NNs which use GE are compared to assess the contribution of data augmentation methods. NN that uses the full dataset which includes the original and the augmented drug-pair treatments as well as single-drug treatments significantly outperforms NNs that ignore either the augmented drug-pairs or the single-drug treatments. In assessing the contribution of multimodal learning based on the MCC metric, MM-Net statistically significantly outperforms all the baselines. Our results show that data augmentation and integration of histology images with GE can improve prediction performance of drug response in PDXs.

Novel Magnetic Resonance (MR) imaging modalities can quantify hemodynamics but require long acquisition times, precluding its widespread use for early diagnosis of cardiovascular disease. To reduce the acquisition times, reconstruction methods from undersampled measurements are routinely used, that leverage representations designed to increase image compressibility. Reconstructed anatomical and hemodynamic images may present visual artifacts. Although some of these artifact are essentially reconstruction errors, and thus a consequence of undersampling, others may be due to measurement noise or the random choice of the sampled frequencies. Said otherwise, a reconstructed image becomes a random variable, and both its bias and its covariance can lead to visual artifacts; the latter leads to spatial correlations that may be misconstrued for visual information. Although the nature of the former has been studied in the literature, the latter has not received as much attention. In this study, we investigate the theoretical properties of the random perturbations arising from the reconstruction process, and perform a number of numerical experiments on simulated and MR aortic flow. Our results show that the correlation length remains limited to two to three pixels when a Gaussian undersampling pattern is combined with recovery algorithms based on $\ell_1$-norm minimization. However, the correlation length may increase significantly for other undersampling patterns, higher undersampling factors (i.e., 8x or 16x compression), and different reconstruction methods.

We prove that in the non-orientable setting, the minimal stretch factor of a pseudo-Anosov homeomorphism of a surface of genus $g$ with a fixed number of punctures is asymptotically on the order of $\frac{1}{g}$. Our result adapts the work of Yazdi to non-orientable surfaces. We include the details of Thurston's theory of fibered faces for non-orientable 3-manifolds., Comment: Accepted to Algebraic and Geometric Topology. Statement (1) on page 11 is revised, typos corrected

We propose a benchmark to study surrogate model accuracy for protein-ligand docking. We share a dataset consisting of 200 million 3D complex structures and 2D structure scores across a consistent set of 13 million "in-stock" molecules over 15 receptors, or binding sites, across the SARS-CoV-2 proteome. Our work shows surrogate docking models have six orders of magnitude more throughput than standard docking protocols on the same supercomputer node types. We demonstrate the power of high-speed surrogate models by running each target against 1 billion molecules in under a day (50k predictions per GPU seconds). We showcase a workflow for docking utilizing surrogate ML models as a pre-filter. Our workflow is ten times faster at screening a library of compounds than the standard technique, with an error rate less than 0.01\% of detecting the underlying best scoring 0.1\% of compounds. Our analysis of the speedup explains that to screen more molecules under a docking paradigm, another order of magnitude speedup must come from model accuracy rather than computing speed (which, if increased, will not anymore alter our throughput to screen molecules). We believe this is strong evidence for the community to begin focusing on improving the accuracy of surrogate models to improve the ability to screen massive compound libraries 100x or even 1000x faster than current techniques.

To enable personalized cancer treatment, machine learning models have been developed to predict drug response as a function of tumor and drug features. However, most algorithm development efforts have relied on cross validation within a single study to assess model accuracy. While an essential first step, cross validation within a biological data set typically provides an overly optimistic estimate of the prediction performance on independent test sets. To provide a more rigorous assessment of model generalizability between different studies, we use machine learning to analyze five publicly available cell line-based data sets: NCI60, CTRP, GDSC, CCLE and gCSI. Based on observed experimental variability across studies, we explore estimates of prediction upper bounds. We report performance results of a variety of machine learning models, with a multitasking deep neural network achieving the best cross-study generalizability. By multiple measures, models trained on CTRP yield the most accurate predictions on the remaining testing data, and gCSI is the most predictable among the cell line data sets included in this study. With these experiments and further simulations on partial data, two lessons emerge: (1) differences in viability assays can limit model generalizability across studies, and (2) drug diversity, more than tumor diversity, is crucial for raising model generalizability in preclinical screening., Comment: Accepted by Briefings in Bioinformatics

The race to meet the challenges of the global pandemic has served as a reminder that the existing drug discovery process is expensive, inefficient and slow. There is a major bottleneck screening the vast number of potential small molecules to shortlist lead compounds for antiviral drug development. New opportunities to accelerate drug discovery lie at the interface between machine learning methods, in this case developed for linear accelerators, and physics-based methods. The two in silico methods, each have their own advantages and limitations which, interestingly, complement each other. Here, we present an innovative infrastructural development that combines both approaches to accelerate drug discovery. The scale of the potential resulting workflow is such that it is dependent on supercomputing to achieve extremely high throughput. We have demonstrated the viability of this workflow for the study of inhibitors for four COVID-19 target proteins and our ability to perform the required large-scale calculations to identify lead antiviral compounds through repurposing on a variety of supercomputers.

Totally symmetric sets are a recently introduced tool for studying homomorphisms between groups. In this paper, we give full classifications of totally symmetric sets in certain families of groups and bound their sizes in others. As a consequence, we derive restrictions on possible homomorphisms between these groups. One sample application of our results is that any homomorphism of a braid group to a direct product of solvable groups must have cyclic image., Comment: 11 pages

Motivated by the size of cell line drug sensitivity data, researchers have been developing machine learning (ML) models for predicting drug response to advance cancer treatment. As drug sensitivity studies continue generating data, a common question is whether the proposed predictors can further improve the generalization performance with more training data. We utilize empirical learning curves for evaluating and comparing the data scaling properties of two neural networks (NNs) and two gradient boosting decision tree (GBDT) models trained on four drug screening datasets. The learning curves are accurately fitted to a power law model, providing a framework for assessing the data scaling behavior of these predictors. The curves demonstrate that no single model dominates in terms of prediction performance across all datasets and training sizes, suggesting that the shape of these curves depends on the unique model-dataset pair. The multi-input NN (mNN), in which gene expressions and molecular drug descriptors are input into separate subnetworks, outperforms a single-input NN (sNN), where the cell and drug features are concatenated for the input layer. In contrast, a GBDT with hyperparameter tuning exhibits superior performance as compared with both NNs at the lower range of training sizes for two of the datasets, whereas the mNN performs better at the higher range of training sizes. Moreover, the trajectory of the curves suggests that increasing the sample size is expected to further improve prediction scores of both NNs. These observations demonstrate the benefit of using learning curves to evaluate predictors, providing a broader perspective on the overall data scaling characteristics. The fitted power law curves provide a forward-looking performance metric and can serve as a co-design tool to guide experimental biologists and computational scientists in the design of future experiments., Comment: 14 pages, 7 figures

The drug discovery process currently employed in the pharmaceutical industry typically requires about 10 years and $2-3 billion to deliver one new drug. This is both too expensive and too slow, especially in emergencies like the COVID-19 pandemic. In silicomethodologies need to be improved to better select lead compounds that can proceed to later stages of the drug discovery protocol accelerating the entire process. No single methodological approach can achieve the necessary accuracy with required efficiency. Here we describe multiple algorithmic innovations to overcome this fundamental limitation, development and deployment of computational infrastructure at scale integrates multiple artificial intelligence and simulation-based approaches. Three measures of performance are:(i) throughput, the number of ligands per unit time; (ii) scientific performance, the number of effective ligands sampled per unit time and (iii) peak performance, in flop/s. The capabilities outlined here have been used in production for several months as the workhorse of the computational infrastructure to support the capabilities of the US-DOE National Virtual Biotechnology Laboratory in combination with resources from the EU Centre of Excellence in Computational Biomedicine.

A machine learning (ML) design framework is proposed for adaptively adjusting clock frequency based on propagation delay of individual instructions. A random forest model is trained to classify propagation delays in real time, utilizing current operation type, current operands, and computation history as ML features. The trained model is implemented in Verilog as an additional pipeline stage within a baseline processor. The modified system is experimentally tested at the gate level in 45 nm CMOS technology, exhibiting a speedup of 70% and energy reduction of 30% with coarse-grained ML classification. A speedup of 89% is demonstrated with finer granularities with 15.5% reduction in energy consumption., Comment: 12 pages, 8 figures, 5 tables, IEEE transaction on computers. arXiv admin note: substantial text overlap with arXiv:2006.07450

A machine learning (ML) design framework is proposed for dynamically adjusting clock frequency based on propagation delay of individual instructions. A Random Forest model is trained to classify propagation delays in real-time, utilizing current operation type, current operands, and computation history as ML features. The trained model is implemented in Verilog as an additional pipeline stage within a baseline processor. The modified system is simulated at the gate-level in 45 nm CMOS technology, exhibiting a speed-up of 68% and energy reduction of 37% with coarse-grained ML classification. A speed-up of 95% is demonstrated with finer granularities at additional energy costs.

Transfer learning has been shown to be effective in many applications in which training data for the target problem are limited but data for a related (source) problem are abundant. In this paper, we apply transfer learning to the prediction of anti-cancer drug response. Previous transfer learning studies for drug response prediction focused on building models that predict the response of tumor cells to a specific drug treatment. We target the more challenging task of building general prediction models that can make predictions for both new tumor cells and new drugs. We apply the classic transfer learning framework that trains a prediction model on the source dataset and refines it on the target dataset, and extends the framework through ensemble. The ensemble transfer learning pipeline is implemented using LightGBM and two deep neural network (DNN) models with different architectures. Uniquely, we investigate its power for three application settings including drug repurposing, precision oncology, and new drug development, through different data partition schemes in cross-validation. We test the proposed ensemble transfer learning on benchmark in vitro drug screening datasets, taking one dataset as the source domain and another dataset as the target domain. The analysis results demonstrate the benefit of applying ensemble transfer learning for predicting anti-cancer drug response in all three applications with both LightGBM and DNN models. Compared between the different prediction models, a DNN model with two subnetworks for the inputs of tumor features and drug features separately outperforms LightGBM and the other DNN model that concatenates tumor features and drug features for input in the drug repurposing and precision oncology applications. In the more challenging application of new drug development, LightGBM performs better than the other two DNN models.

By combining various cancer cell line (CCL) drug screening panels, the size of the data has grown significantly to begin understanding how advances in deep learning can advance drug response predictions. In this paper we train >35,000 neural network models, sweeping over common featurization techniques. We found the RNA-seq to be highly redundant and informative even with subsets larger than 128 features. We found the inclusion of single nucleotide polymorphisms (SNPs) coded as count matrices improved model performance significantly, and no substantial difference in model performance with respect to molecular featurization between the common open source MOrdred descriptors and Dragon7 descriptors. Alongside this analysis, we outline data integration between CCL screening datasets and present evidence that new metrics and imbalanced data techniques, as well as advances in data standardization, need to be developed.