Kathleen M. Jagodnik

Enrichr: a comprehensive gene set enrichment analysis web server 2016 update

Enrichment analysis is a popular method for analyzing gene sets generated by genome-wide experiments. Here we present a significant update to one of the tools in this domain called Enrichr. Enrichr currently contains a large collection of diverse gene set libraries available for analysis and download. In total, Enrichr currently contains 180 184 annotated gene sets from 102 gene set libraries. New features have been added to Enrichr including the ability to submit fuzzy sets, upload BED files, improved application programming interface and visualization of the results as clustergrams. Overall, Enrichr is a comprehensive resource for curated gene sets and a search engine that accumulates biological knowledge for further biological discoveries. Enrichr is freely available at: http://amp.pharm.mssm.edu/Enrichr.

Extraction and analysis of signatures from the Gene Expression Omnibus by the crowd.

Gene expression data are accumulating exponentially in public repositories. Reanalysis and integration of themed collections from these studies may provide new insights, but requires further human curation. Here we report a crowdsourcing project to annotate and reanalyse a large number of gene expression profiles from Gene Expression Omnibus (GEO). Through a massive open online course on Coursera, over 70 participants from over 25 countries identify and annotate 2,460 single-gene perturbation signatures, 839 disease versus normal signatures, and 906 drug perturbation signatures. All these signatures are unique and are manually validated for quality. Global analysis of these signatures confirms known associations and identifies novel associations between genes, diseases and drugs. The manually curated signatures are used as a training set to develop classifiers for extracting similar signatures from the entire GEO repository. We develop a web portal to serve these signatures for query, download and visualization.

Data Portal for the Library of Integrated Network-based Cellular Signatures (LINCS) program: Integrated access to diverse large-scale cellular perturbation response data

Abstract The Library of Integrated Network-based Cellular Signatures (LINCS) program is a national consortium funded by the NIH to generate a diverse and extensive reference library of cell-based perturbation-response signatures, along with novel data analytics tools to improve our understanding of human diseases at the systems level. In contrast to other large-scale data generation efforts, LINCS Data and Signature Generation Centers (DSGCs) employ a wide range of assay technologies cataloging diverse cellular responses. Integration of, and unified access to LINCS data has therefore been particularly challenging. The Big Data to Knowledge (BD2K) LINCS Data Coordination and Integration Center (DCIC) has developed data standards specifications, data processing pipelines, and a suite of end-user software tools to integrate and annotate LINCS-generated data, to make LINCS signatures searchable and usable for different types of users. Here, we describe the LINCS Data Portal (LDP) (http://lincsportal.ccs.miami.edu/), a unified web interface to access datasets generated by the LINCS DSGCs, and its underlying database, LINCS Data Registry (LDR). LINCS data served on the LDP contains extensive metadata and curated annotations. We highlight the features of the LDP user interface that is designed to enable search, browsing, exploration, download and analysis of LINCS data and related curated content.

Developing a framework for digital objects in the Big Data to Knowledge (BD2K) commons: Report from the Commons Framework Pilots workshop

The volume and diversity of data in biomedical research have been rapidly increasing in recent years. While such data hold significant promise for accelerating discovery, their use entails many challenges including: the need for adequate computational infrastructure, secure processes for data sharing and access, tools that allow researchers to find and integrate diverse datasets, and standardized methods of analysis. These are just some elements of a complex ecosystem that needs to be built to support the rapid accumulation of these data. The NIH Big Data to Knowledge (BD2K) initiative aims to facilitate digitally enabled biomedical research. Within the BD2K framework, the Commons initiative is intended to establish a virtual environment that will facilitate the use, interoperability, and discoverability of shared digital objects used for research. The BD2K Commons Framework Pilots Working Group (CFPWG) was established to clarify goals and work on pilot projects that address existing gaps toward realizing the vision of the BD2K Commons. This report reviews highlights from a two-day meeting involving the BD2K CFPWG to provide insights on trends and considerations in advancing Big Data science for biomedical research in the United States.

smartAPI: Towards a more intelligent network of Web APIs

Data science increasingly employs cloud-based Web application programming interfaces (APIs). However, automatically discovering and connecting suitable APIs for a given application is difficult due to the lack of explicit knowledge about the structure and datatypes of Web API inputs and outputs. To address this challenge, we conducted a survey to identify the metadata elements that are crucial to the description of Web APIs and subsequently developed the smartAPI metadata specification and associated tools to capture their domain-related and structural characteristics using the FAIR (Findable, Accessible, Interoperable, Reusable) principles. This paper presents the results of the survey, provides an overview of the smartAPI specification and a reference implementation, and discusses use cases of smartAPI. We show that annotating APIs with smartAPI metadata is straightforward through an extension of the existing Swagger editor. By facilitating the creation of such metadata, we increase the automated interoperability of Web APIs. This work is done as part of the NIH Commons Big Data to Knowledge (BD2K) API Interoperability Working Group.

GEN3VA: aggregation and analysis of gene expression signatures from related studies

BackgroundGenome-wide gene expression profiling of mammalian cells is becoming a staple of many published biomedical and biological research studies. Such data is deposited into data repositories such as the Gene Expression Omnibus (GEO) for potential reuse. However, these repositories currently do not provide simple interfaces to systematically analyze collections of related studies.ResultsHere we present GENE Expression and Enrichment Vector Analyzer (GEN3VA), a web-based system that enables the integrative analysis of aggregated collections of tagged gene expression signatures identified and extracted from GEO. Each tagged collection of signatures is presented in a report that consists of heatmaps of the differentially expressed genes; principal component analysis of all signatures; enrichment analysis with several gene set libraries across all signatures, which we term enrichment vector analysis; and global mapping of small molecules that are predicted to reverse or mimic each signature in the aggregate. We demonstrate how GEN3VA can be used to identify common molecular mechanisms of aging by analyzing tagged signatures from 244 studies that compared young vs. old tissues in mammalian systems. In a second case study, we collected 86 signatures from treatment of human cells with dexamethasone, a glucocorticoid receptor (GR) agonist. Our analysis confirms consensus GR target genes and predicts potential drug mimickers.ConclusionsGEN3VA can be used to identify, aggregate, and analyze themed collections of gene expression signatures from diverse but related studies. Such integrative analyses can be used to address concerns about data reproducibility, confirm results across labs, and discover new collective knowledge by data reuse. GEN3VA is an open-source web-based system that is freely available at: http://amp.pharm.mssm.edu/gen3va.

Human-Like Rewards to Train a Reinforcement Learning Controller for Planar Arm Movement

High-level spinal cord injury (SCI) in humans causes paralysis below the neck. Functional electrical stimulation (FES) technology applies electrical current to nerves and muscles to restore movement, and controllers for upper extremity FES neuroprostheses calculate stimulation patterns to produce desired arm movement. However, currently available FES controllers have yet to restore natural movements. Reinforcement learning (RL) is a reward-driven control technique; it can employ user-generated rewards, and human preferences can be used in training. To test this concept with FES, we conducted simulation experiments using computer-generated “pseudo-human” rewards. Rewards with varying properties were used with an actor-critic RL controller for a planar two-degree-of-freedom biomechanical human arm model performing reaching movements. Results demonstrate that sparse, delayed pseudo-human rewards permit stable and effective RL controller learning. The frequency of reward is proportional to learning success, and human-scale sparse rewards permit greater learning than exclusively automated rewards. Diversity of training task sets did not affect learning. Long-term stability of trained controllers was observed. Using human-generated rewards to train RL controllers for upper-extremity FES systems may be useful. Our findings represent progress toward achieving human-machine teaming in control of upper-extremity FES systems for more natural arm movements based on human user preferences and RL algorithm learning capabilities.

Datasets2Tools, repository and search engine for bioinformatics datasets, tools and canned analyses

Biomedical data repositories such as the Gene Expression Omnibus (GEO) enable the search and discovery of relevant biomedical digital data objects. Similarly, resources such as OMICtools, index bioinformatics tools that can extract knowledge from these digital data objects. However, systematic access to pre-generated ‘canned’ analyses applied by bioinformatics tools to biomedical digital data objects is currently not available. Datasets2Tools is a repository indexing 31,473 canned bioinformatics analyses applied to 6,431 datasets. The Datasets2Tools repository also contains the indexing of 4,901 published bioinformatics software tools, and all the analyzed datasets. Datasets2Tools enables users to rapidly find datasets, tools, and canned analyses through an intuitive web interface, a Google Chrome extension, and an API. Furthermore, Datasets2Tools provides a platform for contributing canned analyses, datasets, and tools, as well as evaluating these digital objects according to their compliance with the findable, accessible, interoperable, and reusable (FAIR) principles. By incorporating community engagement, Datasets2Tools promotes sharing of digital resources to stimulate the extraction of knowledge from biomedical research data. Datasets2Tools is freely available from: http://amp.pharm.mssm.edu/datasets2tools.

Training an Actor-Critic Reinforcement Learning Controller for Arm Movement Using Human-Generated Rewards

Functional Electrical Stimulation (FES) employs neuroprostheses to apply electrical current to the nerves and muscles of individuals paralyzed by spinal cord injury to restore voluntary movement. Neuroprosthesis controllers calculate stimulation patterns to produce desired actions. To date, no existing controller is able to efficiently adapt its control strategy to the wide range of possible physiological arm characteristics, reaching movements, and user preferences that vary over time. Reinforcement learning (RL) is a control strategy that can incorporate human reward signals as inputs to allow human users to shape controller behavior. In this paper, ten neurologically intact human participants assigned subjective numerical rewards to train RL controllers, evaluating animations of goal-oriented reaching tasks performed using a planar musculoskeletal human arm simulation. The RL controller learning achieved using human trainers was compared with learning accomplished using human-like rewards generated by an algorithm; metrics included success at reaching the specified target; time required to reach the target; and target overshoot. Both sets of controllers learned efficiently and with minimal differences, significantly outperforming standard controllers. Reward positivity and consistency were found to be unrelated to learning success. These results suggest that human rewards can be used effectively to train RL-based FES controllers.

An optimized proportional-derivative controller for the human upper extremity with gravity.

When Functional Electrical Stimulation (FES) is used to restore movement in subjects with spinal cord injury (SCI), muscle stimulation patterns should be selected to generate accurate and efficient movements. Ideally, the controller for such a neuroprosthesis will have the simplest architecture possible, to facilitate translation into a clinical setting. In this study, we used the simulated annealing algorithm to optimize two proportional-derivative (PD) feedback controller gain sets for a 3-dimensional arm model that includes musculoskeletal dynamics and has 5 degrees of freedom and 22 muscles, performing goal-oriented reaching movements. Controller gains were optimized by minimizing a weighted sum of position errors, orientation errors, and muscle activations. After optimization, gain performance was evaluated on the basis of accuracy and efficiency of reaching movements, along with three other benchmark gain sets not optimized for our system, on a large set of dynamic reaching movements for which the controllers had not been optimized, to test ability to generalize. Robustness in the presence of weakened muscles was also tested. The two optimized gain sets were found to have very similar performance to each other on all metrics, and to exhibit significantly better accuracy, compared with the three standard gain sets. All gain sets investigated used physiologically acceptable amounts of muscular activation. It was concluded that optimization can yield significant improvements in controller performance while still maintaining muscular efficiency, and that optimization should be considered as a strategy for future neuroprosthesis controller design.