A community effort to optimize sequence-based deep learning models of gene regulation.

A systematic evaluation of how model architectures and training strategies impact genomics model performance is needed. To address this gap, we held a DREAM Challenge where competitors trained models on a dataset of millions of random promoter DNA sequences and corresponding expression levels, experimentally determined in yeast. For a robust evaluation of the models, we designed a comprehensive suite of benchmarks encompassing various sequence types. All top-performing models used neural networks but diverged in architectures and training strategies. To dissect how architectural and training choices impact performance, we developed the Prix Fixe framework to divide models into modular building blocks. We tested all possible combinations for the top three models, further improving their performance. The DREAM Challenge models not only achieved state-of-the-art results on our comprehensive yeast dataset but also consistently surpassed existing benchmarks on Drosophila and human genomic datasets, demonstrating the progress that can be driven by gold-standard genomics datasets.