DS5: An Open-Source Framework for Standardized High-Throughput Drug Screening Data Storage, Analysis, and Drug Prioritization

Background. High-throughput drug screening (HTS) is increasingly used in precision oncology across cell lines, patient-derived models such as organoids (PDO) and xenograft organoids (PDxO), and ex vivo patient samples, with multiple active clinical trials incorporating HTS for individualizing treatment. Yet HTS efforts predominantly rely on ad hoc, spreadsheet-based workflows, with no standardized infrastructure for storing, analyzing, and comparing screens across patients, cohorts, or institutions, limiting reproducibility and slowing clinical data exchange. Existing tools address isolated pieces of the workflow, handling either data management or analysis and visualization, but none integrate standardized storage, reproducible dose-response analysis, individualized drug prioritization, and clinician and molecular tumor board friendly reporting in a single open-source framework. Results. We present DS5, an open-source Python framework that operates on an HDF5-based DS5 file format that unifies standardized storage, quality control, dose-response analysis, cohort-level drug prioritization, and automated reporting in a single lightweight package. DS5 enforces raw-data immutability, integrates RxNorm-based drug name standardization, and scales from small clinical cohorts to large pharmacogenomics datasets on a standard laptop. We validated DS5 against two public benchmarks spanning over 428,000 drug, cell line pairs, recovering published LN IC50 values from GDSC2 (Pearson r = 0.973) and Emax values from CTRP (r = 0.961). Using a published breast cancer PDxO dataset (45 compounds by 16 models), we reproduced GR-based profiles via a custom-metric extension and used DS5's cohort-level prioritization to predict in vivo tumor response with ROC AUC = 0.907 across 30 drug PDX pairs. Finally, we demonstrate the utilities of DS5 in an ongoing pediatric brain tumor precision oncology initiative, where its cohort-normalized drug rankings and automated reports directly support molecular tumor board discussions. Conclusion. DS5 provides the cancer basic and translational research community with a standardized file format and reproducible computational analysis methods to support functional drug screening experiments; and its reporting features facilitate bridging raw drug screening measurements to translational decisions. DS5 is released open-source under the permissible MIT license.