Target-Free Compound Activity Prediction via Few-Shot Learning.

Predicting the activities of compounds against protein-based or phenotypic assays using only a few known compounds and their activities is a common task in target-free drug discovery. Existing few-shot learning approaches are limited to predicting binary labels (active/inactive). However, in real-world drug discovery, degrees of compound activity are highly relevant. We study Few-Shot Compound Activity Prediction (FS-CAP) and design a novel neural architecture to meta-learn continuous compound activities across large bioactivity datasets. Our model aggregates encodings generated from the known compounds and their activities to capture assay information. We also introduce a separate encoder for the unknown compound. We show that FS-CAP surpasses traditional similarity-based techniques as well as other state of the art few-shot learning methods on a variety of target-free drug discovery settings and datasets.

Scaling of an antibody validation procedure enables quantification of antibody performance in major research applications.

Antibodies are critical reagents to detect and characterize proteins. It is commonly understood that many commercial antibodies do not recognize their intended targets, but information on the scope of the problem remains largely anecdotal, and as such, feasibility of the goal of at least one potent and specific antibody targeting each protein in a proteome cannot be assessed. Focusing on antibodies for human proteins, we have scaled a standardized characterization approach using parental and knockout cell lines (Laflamme et al., 2019) to assess the performance of 614 commercial antibodies for 65 neuroscience-related proteins. Side-by-side comparisons of all antibodies against each target, obtained from multiple commercial partners, have demonstrated that: (i) more than 50% of all antibodies failed in one or more applications, (ii) yet, ~50-75% of the protein set was covered by at least one high-performing antibody, depending on application, suggesting that coverage of human proteins by commercial antibodies is significant; and (iii) recombinant antibodies performed better than monoclonal or polyclonal antibodies. The hundreds of underperforming antibodies identified in this study were found to have been used in a large number of published articles, which should raise alarm. Encouragingly, more than half of the underperforming commercial antibodies were reassessed by the manufacturers, and many had alterations to their recommended usage or were removed from the market. This first study helps demonstrate the scale of the antibody specificity problem but also suggests an efficient strategy toward achieving coverage of the human proteome; mine the existing commercial antibody repertoire, and use the data to focus new renewable antibody generation efforts.

Commercially produced antibodies are essential research tools. Investigators at universities and pharmaceutical companies use them to study human proteins, which carry out all the functions of the cells. Scientists usually buy antibodies from commercial manufacturers who produce more than 6 million antibody products altogether. Yet many commercial antibodies do not work as advertised. They do not recognize their intended protein target or may flag untargeted proteins. Both can skew research results and make it challenging to reproduce scientific studies, which is vital to scientific integrity. Using ineffective commercial antibodies likely wastes $1 billion in research funding each year. Large-scale validation of commercial antibodies by an independent third party could reduce the waste and misinformation associated with using ineffective commercial antibodies. Previous research testing an antibody validation pipeline showed that a commercial antibody widely used in studies to detect a protein involved in amyotrophic lateral sclerosis did not work. Meanwhile, the best-performing commercial antibodies were not used in research. Testing commercial antibodies and making the resulting data available would help scientists identify the best study tools and improve research reliability. Ayoubi et al. collaborated with antibody manufacturers and organizations that produce genetic knock-out cell lines to develop a system validating the effectiveness of commercial antibodies. In the experiments, Ayoubi et al. tested 614 commercial antibodies intended to detect 65 proteins involved in neurologic diseases. An effective antibody was available for about two thirds of the 65 proteins. Yet, hundreds of the antibodies, including many used widely in studies, were ineffective. Manufacturers removed some underperforming antibodies from the market or altered their recommended uses based on these data. Ayoubi et al. shared the resulting data on Zenodo, a publicly available preprint database. The experiments suggest that 20-30% of protein studies use ineffective antibodies, indicating a substantial need for independent assessment of commercial antibodies. Ayoubi et al. demonstrated their side-by-side antibody comparison methods were an effective and efficient way of validating commercial antibodies. Using this approach to test commercial antibodies against all human proteins would cost about $50 million. But it could save much of the $1 billion wasted each year on research involving ineffective antibodies. Independent validation of commercial antibodies could also reduce wasted efforts by scientists using ineffective antibodies and improve the reliability of research results. It would also enable faster, more reliable research that may help scientists understand diseases and develop new therapies to improve patient's lives.

Scaling of an antibody validation procedure enables quantification of antibody performance in major research applications.

Antibodies are critical reagents to detect and characterize proteins. It is commonly understood that many commercial antibodies do not recognize their intended targets, but information on the scope of the problem remains largely anecdotal, and as such, feasibility of the goal of at least one potent and specific antibody targeting each protein in a proteome cannot be assessed. Focusing on antibodies for human proteins, we have scaled a standardized characterization approach using parental and knockout cell lines (Laflamme et al., 2019) to assess the performance of 614 commercial antibodies for 65 neuroscience-related proteins. Side-by-side comparisons of all antibodies against each target, obtained from multiple commercial partners, demonstrates that: i) more than 50% of all antibodies failed in one or more tests, ii) yet, ~50-75% of the protein set was covered by at least one high-performing antibody, depending on application, suggesting that coverage of human proteins by commercial antibodies is significant; and iii) recombinant antibodies performed better than monoclonal or polyclonal antibodies. The hundreds of underperforming antibodies identified in this study were found to have been used in a large number of published articles, which should raise alarm. Encouragingly, more than half of the underperforming commercial antibodies were reassessed by the manufacturers, and many had alterations to their recommended usage or were removed from the market. This first such study helps demonstrate the scale of the antibody specificity problem but also suggests an efficient strategy toward achieving coverage of the human proteome; mine the existing commercial antibody repertoire, and use the data to focus new renewable antibody generation efforts.

PreprintMatch: A tool for preprint to publication detection shows global inequities in scientific publication.

Preprints, versions of scientific manuscripts that precede peer review, are growing in popularity. They offer an opportunity to democratize and accelerate research, as they have no publication costs or a lengthy peer review process. Preprints are often later published in peer-reviewed venues, but these publications and the original preprints are frequently not linked in any way. To this end, we developed a tool, PreprintMatch, to find matches between preprints and their corresponding published papers, if they exist. This tool outperforms existing techniques to match preprints and papers, both on matching performance and speed. PreprintMatch was applied to search for matches between preprints (from bioRxiv and medRxiv), and PubMed. The preliminary nature of preprints offers a unique perspective into scientific projects at a relatively early stage, and with better matching between preprint and paper, we explored questions related to research inequity. We found that preprints from low income countries are published as peer-reviewed papers at a lower rate than high income countries (39.6% and 61.1%, respectively), and our data is consistent with previous work that cite a lack of resources, lack of stability, and policy choices to explain this discrepancy. Preprints from low income countries were also found to be published quicker (178 vs 203 days) and with less title, abstract, and author similarity to the published version compared to high income countries. Low income countries add more authors from the preprint to the published version than high income countries (0.42 authors vs 0.32, respectively), a practice that is significantly more frequent in China compared to similar countries. Finally, we find that some publishers publish work with authors from lower income countries more frequently than others.

The Antibody Registry: ten years of registering antibodies.

Antibodies are ubiquitous key biological research resources yet are tricky to use as they are prone to performance issues and represent a major source of variability across studies. Understanding what antibody was used in a published study is therefore necessary to repeat and/or interpret a given study. However, antibody reagents are still frequently not cited with sufficient detail to determine which antibody was used in experiments. The Antibody Registry is a public, open database that enables citation of antibodies by providing a persistent record for any antibody-based reagent used in a publication. The registry is the authority for antibody Research Resource Identifiers, or RRIDs, which are requested or required by hundreds of journals seeking to improve the citation of these key resources. The registry is the most comprehensive listing of persistently identified antibody reagents used in the scientific literature. Data contributors span individual authors who use antibodies to antibody companies, which provide their entire catalogs including discontinued items. Unlike many commercial antibody listing sites which tend to remove reagents no longer sold, registry records persist, providing an interface between a fast-moving commercial marketplace and the static scientific literature. The Antibody Registry (RRID:SCR_006397) https://antibodyregistry.org.

LIMO: Latent Inceptionism for Targeted Molecule Generation.

Generation of drug-like molecules with high binding affinity to target proteins remains a difficult and resource-intensive task in drug discovery. Existing approaches primarily employ reinforcement learning, Markov sampling, or deep generative models guided by Gaussian processes, which can be prohibitively slow when generating molecules with high binding affinity calculated by computationally-expensive physics-based methods. We present Latent Inceptionism on Molecules (LIMO), which significantly accelerates molecule generation with an inceptionism-like technique. LIMO employs a variational autoencoder-generated latent space and property prediction by two neural networks in sequence to enable faster gradient-based reverse-optimization of molecular properties. Comprehensive experiments show that LIMO performs competitively on benchmark tasks and markedly outperforms state-of-the-art techniques on the novel task of generating drug-like compounds with high binding affinity, reaching nanomolar range against two protein targets. We corroborate these docking-based results with more accurate molecular dynamics-based calculations of absolute binding free energy and show that one of our generated drug-like compounds has a predicted K D (a measure of binding affinity) of 6 · 10-14 M against the human estrogen receptor, well beyond the affinities of typical early-stage drug candidates and most FDA-approved drugs to their respective targets. Code is available at https://github.com/Rose-STL-Lab/LIMO.

Is the future of peer review automated?

The rising rate of preprints and publications, combined with persistent inadequate reporting practices and problems with study design and execution, have strained the traditional peer review system. Automated screening tools could potentially enhance peer review by helping authors, journal editors, and reviewers to identify beneficial practices and common problems in preprints or submitted manuscripts. Tools can screen many papers quickly, and may be particularly helpful in assessing compliance with journal policies and with straightforward items in reporting guidelines. However, existing tools cannot understand or interpret the paper in the context of the scientific literature. Tools cannot yet determine whether the methods used are suitable to answer the research question, or whether the data support the authors' conclusions. Editors and peer reviewers are essential for assessing journal fit and the overall quality of a paper, including the experimental design, the soundness of the study's conclusions, potential impact and innovation. Automated screening tools cannot replace peer review, but may aid authors, reviewers, and editors in improving scientific papers. Strategies for responsible use of automated tools in peer review may include setting performance criteria for tools, transparently reporting tool performance and use, and training users to interpret reports.

Establishing Institutional Scores With the Rigor and Transparency Index: Large-scale Analysis of Scientific Reporting Quality.

BACKGROUND: Improving rigor and transparency measures should lead to improvements in reproducibility across the scientific literature; however, the assessment of measures of transparency tends to be very difficult if performed manually. OBJECTIVE: This study addresses the enhancement of the Rigor and Transparency Index (RTI, version 2.0), which attempts to automatically assess the rigor and transparency of journals, institutions, and countries using manuscripts scored on criteria found in reproducibility guidelines (eg, Materials Design, Analysis, and Reporting checklist criteria). METHODS: The RTI tracks 27 entity types using natural language processing techniques such as Bidirectional Long Short-term Memory Conditional Random Field-based models and regular expressions; this allowed us to assess over 2 million papers accessed through PubMed Central. RESULTS: Between 1997 and 2020 (where data were readily available in our data set), rigor and transparency measures showed general improvement (RTI 2.29 to 4.13), suggesting that authors are taking the need for improved reporting seriously. The top-scoring journals in 2020 were the Journal of Neurochemistry (6.23), British Journal of Pharmacology (6.07), and Nature Neuroscience (5.93). We extracted the institution and country of origin from the author affiliations to expand our analysis beyond journals. Among institutions publishing >1000 papers in 2020 (in the PubMed Central open access set), Capital Medical University (4.75), Yonsei University (4.58), and University of Copenhagen (4.53) were the top performers in terms of RTI. In country-level performance, we found that Ethiopia and Norway consistently topped the RTI charts of countries with 100 or more papers per year. In addition, we tested our assumption that the RTI may serve as a reliable proxy for scientific replicability (ie, a high RTI represents papers containing sufficient information for replication efforts). Using work by the Reproducibility Project: Cancer Biology, we determined that replication papers (RTI 7.61, SD 0.78) scored significantly higher (P<.001) than the original papers (RTI 3.39, SD 1.12), which according to the project required additional information from authors to begin replication efforts. CONCLUSIONS: These results align with our view that RTI may serve as a reliable proxy for scientific replicability. Unfortunately, RTI measures for journals, institutions, and countries fall short of the replicated paper average. If we consider the RTI of these replication studies as a target for future manuscripts, more work will be needed to ensure that the average manuscript contains sufficient information for replication attempts.