Large scale analysis of in vivo toxicology studies has been hindered by the lack of a standardized digital format for data analysis. The SEND standard enables the analysis of data from multiple studies performed by different laboratories. The objective of this work is to develop methods to transform, sort, and analyze data to automate cross study analysis of toxicology studies. Cross study analysis can be applied to use cases such as understanding a single compound’s toxicity profile across all studies performed and/or evaluating on- versus off-target toxicity for multiple compounds intended for the same pharmacological target. This collaborative work between BioCelerate and FDA involved development of data harmonization/transformation strategies and analytic techniques to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND data sets from the BioCelerate Toxicology Data Sharing module of DataCelerate® were used for the analyses. Toxicity profiles for key organ systems were developed for liver, kidney, male reproductive tract, endocrine system, and hematopoietic system using SEND domains. A Cross-Study Analysis dashboard with a built-in user-defined scoring system was created for custom cross-study analyses, including a series of radar plots enabling users to visualize and evaluate data at the organ system level and drill down into individual animal data. This data analysis provides the tools for scientists to compare toxicity profiles across multiple studies using SEND. A cross-study analysis of two different compounds intended for the same pharmacological target is described and the analyses indicate potential on-target effects to liver, kidney, and hematopoietic systems.

Deidentified SEND data was donated by companies participating in BioCelerate’s Toxicology Data Sharing Initiative (TDS module in DataCelerate^®).The data included 1-Month Rat and 1-Month Dog SEND datasets for two different compounds intended for the same pharmacological target. 

To facilitate cross-study analysis of toxicology studies, it is practical to categorize findings within organ systems to provide insights into target organ toxicity. In the proof-of-concept for this application, we focused on the target organs with compound-related effects, namely the kidney, liver, hematopoietic system, endocrine system, and reproductive tract (male). The body weights (BW), food and water consumption (FW), laboratory test results (LB), organ measurements (OM), and microscopic findings (MI) SEND domains were included in the analysis. Each parameter was then assigned to the relevant organ system(s) (Table 1) based on veterinary literature (Faqi 2017) (Stockham 2008), scientific literature on clinical pathology in toxicology, and both the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice (INHAND) project (goreni.org) and SENDIG MI code list for organ system MI diagnosis.

Process Flow

The SEND datasets (two studies per compound with one dog and one rat study) were normalized and scored to assemble disparate data into a cohesive framework for visualization and comparison. Body weight (BW), hematopoietic system, liver, kidney, endocrine system, and male reproductive tract, were transformed, scored, and summarized data for common toxicological outcomes. These groupings were created by separating relevant test outcomes into categories. For example, the hematopoietic system group includes bone marrow, thymus, and spleen specimen material types (MISPEC) from the SEND microscopic domain (MI).