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Background: Gene set enrichment analysis and overrepresentation analyses are commonly used methods to determine the biological processes affected by a differential expression experiment. This approach requires biologically relevant gene sets, which are currently curated manually, limiting their availability and accuracy in many organisms without extensively curated resources. New feature learning approaches can now be paired with existing data collections to directly extract functional gene sets from big data. Results: Here we introduce a method to identify perturbed processes. In contrast with methods that use curated gene sets, this approach uses signatures extracted from public expression data. We first extract expression signatures from public data using ADAGE, a neural network-based feature extraction approach. We next identify signatures that are differentially active under a given treatment. Our results demonstrate that these signatures represent biological processes that are perturbed by the experiment. Because these signatures are directly learned from data without supervision, they can identify uncurated or novel biological processes. We implemented ADAGE signature analysis for the bacterial pathogen Pseudomonas aeruginosa. For the convenience of different user groups, we implemented both an R package (ADAGEpath) and a web server (http://adage.greenelab.com) to run these analyses. Both are open-source to allow easy expansion to other organisms or signature generation methods. We applied ADAGE signature analysis to an example dataset in which wild-type and Δanr mutant cells were grown as biofilms on the Cystic Fibrosis genotype bronchial epithelial cells. We mapped active signatures in the dataset to KEGG pathways and compared with pathways identified using GSEA. The two approaches generally return consistent results; however, ADAGE signature analysis also identified a signature that revealed the molecularly supported link between the MexT regulon and Anr. Conclusions: We designed ADAGE signature analysis to perform gene set analysis using data-defined functional gene signatures. This approach addresses an important gap for biologists studying non-traditional model organisms and those without extensive curated resources available. We built both an R package and web server to provide ADAGE signature analysis to the community. [ABSTRACT FROM AUTHOR]

High-throughput experiments are becoming increasingly common, and scientists must balance hypothesis-driven experiments with genome-wide data acquisition. We sought to predict novel genes involved in Drosophila learning and long-term memory from existing public high-throughput data. We performed an analysis using PILGRM, which analyzes public gene expression compendia using machine learning. We evaluated the top prediction alongside genes involved in learning and memory in IMP, an interface for functional relationship networks. We identified Grunge/Atrophin (Gug/Atro), a transcriptional repressor, histone deacetylase, as our top candidate. We find, through multiple, distinct assays, that Gug has an active role as a modulator of memory retention in the fly and its function is required in the adult mushroom body. Depletion of Gug specifically in neurons of the adult mushroom body, after cell division and neuronal development is complete, suggests that Gug function is important for memory retention through regulation of neuronal activity, and not by altering neurodevelopment. Our study provides a previously uncharacterized role for Gug as a possible regulator of neuronal plasticity at the interface of memory retention and memory extinction. [ABSTRACT FROM AUTHOR]

The Kipoi repository provides a home for trained machine-learning models that facilitates their sharing and reuse. [ABSTRACT FROM AUTHOR]

Motivation Most models can be fit to data using various optimization approaches. While model choice is frequently reported in machine-learning-based research, optimizers are not often noted. We applied two different implementations of LASSO logistic regression implemented in Python's scikit-learn package, using two different optimization approaches (coordinate descent, implemented in the liblinear library, and stochastic gradient descent, or SGD), to predict mutation status and gene essentiality from gene expression across a variety of pan-cancer driver genes. For varying levels of regularization, we compared performance and model sparsity between optimizers. Results After model selection and tuning, we found that liblinear and SGD tended to perform comparably. liblinear models required more extensive tuning of regularization strength, performing best for high model sparsities (more nonzero coefficients), but did not require selection of a learning rate parameter. SGD models required tuning of the learning rate to perform well, but generally performed more robustly across different model sparsities as regularization strength decreased. Given these tradeoffs, we believe that the choice of optimizers should be clearly reported as a part of the model selection and validation process, to allow readers and reviewers to better understand the context in which results have been generated. Availability and implementation The code used to carry out the analyses in this study is available at https://github.com/greenelab/pancancer-evaluation/tree/master/01%5fstratified%5fclassification. Performance/regularization strength curves for all genes in the Vogelstein et al.  (2013) dataset are available at https://doi.org/10.6084/m9.figshare.22728644. [ABSTRACT FROM AUTHOR]