Molecular “fingerprints” encoding structural information are the workhorse of cheminformatics and machine learning in drug discovery applications. However, fingerprint representations necessarily emphasize particular aspects of the molecular structure while ignoring others, rather than allowing the model to make data-driven decisions. We describe molecular graph convolutions, a machine learning architecture for learning from undirected graphs, specifically small molecules. Graph convolutions use a simple encoding of the molecular graph—atoms, bonds, distances, etc.—which allows the model to take greater advantage of information in the graph structure. Although graph convolutions do not outperform all fingerprint-based methods, they (along with other graph-based methods) represent a new paradigm in ligand-based virtual screening with exciting opportunities for future improvement.

Microscopy is a central method in life sciences. Many popular methods, such as antibody labeling, are used to add physical fluorescent labels to specific cellular constituents. However, these approaches have significant drawbacks, including inconsistency; limitations in the number of simultaneous labels because of spectral overlap; and necessary perturbations of the experiment, such as fixing the cells, to generate the measurement. Here, we show that a computational machine-learning approach, which we call "in silico labeling" (ISL), reliably predicts some fluorescent labels from transmitted-light images of unlabeled fixed or live biological samples. ISL predicts a range of labels, such as those for nuclei, cell type (e.g., neural), and cell state (e.g., cell death). Because prediction happens in silico, the method is consistent, is not limited by spectral overlap, and does not disturb the experiment. ISL generates biological measurements that would otherwise be problematic or impossible to acquire.

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Image-based screening is a powerful technique to reveal how chemical, genetic, and environmental perturbations affect cellular state. Its potential is restricted by the current analysis algorithms that target a small number of cellular phenotypes and rely on expert-engineered image features. Newer algorithms that learn how to represent an image are limited by the small amount of labeled data for ground-truth, a common problem for scientific projects. We demonstrate a sensitive and robust method for distinguishing cellular phenotypes that requires no additional ground-truth data or training. It achieves state-of-the-art performance classifying drugs by similar molecular mechanism, using a Deep Metric Network that has been pre-trained on consumer images and a transformation that improves sensitivity to biological variation. However, our method is not limited to classification into predefined categories. It provides a continuous measure of the similarity between cellular phenotypes that can also detect subtle differences such as from increasing dose. The rich, biologically-meaningful image representation that our method provides can help therapy development by supporting high-throughput investigations, even exploratory ones, with more sophisticated and disease-relevant models.

This paper reports on a new approach to solving a subset-based points-to analysis for Java using Binary Decision Diagrams (BDDs). In the model checking community, BDDs have been shown very effective for representing large sets and solving very large verification problems. Our work shows that BDDs can also be very effective for developing a points-to analysis that is simple to implement and that scales well, in both space and time, to large programs. The paper first introduces BDDs and operations on BDDs using some simple points-to examples. Then, a complete subset-based points-to algorithm is presented, expressed completely using BDDs and BDD operations. This algorithm is then refined by finding appropriate variable orderings and by making the algorithm incremental, in order to arrive at a very efficient algorithm. Experimental results are given to justify the choice of variable ordering, to demonstrate the improvement due to incrementalization, and to compare the performance of the BDD-based solver to an efficient hand-coded graph-based solver. Finally, based on the results of the BDD-based solver, a variety of BDD-based queries are presented, including the points-to query.