Limited-Angle Computed Tomography (LACT) is a nondestructive 3D imaging technique used in a variety of applications ranging from security to medicine. The limited angle coverage in LACT is often a dominant source of severe artifacts in the reconstructed images, making it a challenging imaging inverse problem. Diffusion models are a recent class of deep generative models for synthesizing realistic images using image denoisers. In this work, we present DOLCE as the first framework for integrating conditionally-trained diffusion models and explicit physical measurement models for solving imaging inverse problems. DOLCE achieves the SOTA performance in highly ill-posed LACT by alternating between the data-fidelity and sampling updates of a diffusion model conditioned on the transformed sinogram. We show through extensive experimentation that unlike existing methods, DOLCE can synthesize high-quality and structurally coherent 3D volumes by using only 2D conditionally pre-trained diffusion models. We further show on several challenging real LACT datasets that the same pretrained DOLCE model achieves the SOTA performance on drastically different types of images.

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: National Cancer Institute 60, ancer Therapeutics Response Portal (CTRP), Genomics of Drug Sensitivity in Cancer, Cancer Cell Line Encyclopedia and Genentech Cell Line Screening Initiative (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.

Structure-based Deep Fusion models were recently shown to outperform several physics- and machine learning-based protein-ligand binding affinity prediction methods. As part of a multi-institutional COVID-19 pandemic response, over 500 million small molecules were computationally screened against four protein structures from the novel coronavirus (SARS-CoV-2), which causes COVID-19. Three enhancements to Deep Fusion were made in order to evaluate more than 5 billion docked poses on SARS-CoV-2 protein targets. First, the Deep Fusion concept was refined by formulating the architecture as one, coherently backpropagated model (Coherent Fusion) to improve binding-affinity prediction accuracy. Secondly, the model was trained using a distributed, genetic hyper-parameter optimization. Finally, a scalable, high-throughput screening capability was developed to maximize the number of ligands evaluated and expedite the path to experimental evaluation. In this work, we present both the methods developed for machine learning-based high-throughput screening and results from using our computational pipeline to find SARS-CoV-2 inhibitors.