DOI: 10.5061/dryad.s1rn8pkgr
title: Data for: Cross study analyses of SEND data: toxicity profile classification

description: 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.
description: Deidentified SEND data was donated by companies participating in
 BioCelerate’s Toxicology Data Sharing Initiative (TDS module in
 DataCelerate<sup>®</sup>).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).
description: # Dataset for Cross Study Analyses of SEND Data: Toxicity Profile
 Classification
 [https://doi.org/10.5061/dryad.s1rn8pkgr](https://doi.org/10.5061/dryad.s1rn8pkgr) The data included 1-Month Rat and 1-Month Dog SEND datasets for two different compounds (Compound A and Compound B) intended for the same pharmacological target.  ## Description of the data and file structure The files contain data from toxicology studies performed in rats and dogs to support clinical development for two different drugs intended for the same pharmacological target. The studies were donated by the pharmaceutical companies involved in development of the compounds. All proprietary and identifying information has been removed and deidentified.   The toxicology data is organized based on the CDISC - Standard for Exchange of Nonclinical Data (SEND) data standard ([https://www.cdisc.org/standards/foundational/send/sendig-v3-1](https://www.cdisc.org/standards/foundational/send/sendig-v3-1)) and stored in .json and .xpt files. The two letter code used to name the files is the SEND data domain abbreviation and are defined in the SENDIG link provided above. The SENDIG provides specific domain models, assumptions, business rules, and examples for preparing standard nonclinical tabulation datasets. SEND is designed to support data typically found in single-dose general toxicology, repeat-dose general toxicology, and carcinogenicity studies, as well as respiratory and cardiovascular testing done during safety pharmacology studies. Note that SEND is an exchange standard, rather than a presentation format; it is assumed that tabulation data will be transformed by software tools to better support viewing and analysis. The .json files can be opened with publicly available programs (e.g., JSON Viewer) and .xpt files can be viewed in SAS. Both file types can be converted to .csv or .xml files for use with Excel and the data structure will be maintained. There are a number of commercially available programs (e.g., SEND Explorer) that can also read the .xpt files for viewing and analysis. The table below matches the trial identifier with the study type for ease of reference. | 35449 | 1 month dog- Compound B | | :---- | :---------------------- | | 43066 | 1 month dog- Compound A | | 87497 | 1 month rat- Compound B | | 96298 | 1 month rat- Compound A | ## Sharing/Access information Data was derived from the following sources: * Deidentified SEND data was donated by companies participating in BioCelerate’s Toxicology Data Sharing Initiative (TDS module in DataCelerate®). ## Code/Software A Shiny App dashboard was created to facilitate data analysis. The user first selects the analysis criteria and the number of studies to analyze on the main dashboard shown in Figure 2. There are three main categories of information to select from before the analysis can begin: 1) General information, including study numbers, dose groups, and sex(es) to analyze; 2) Organs or systems of interest and which study domains/parameters to include; and 3) Scoring criteria/logic to normalize study results versus concurrent control. Therefore, the interface facilitates user flexibility in selecting toxicity profile study inputs, parameters, and weight/emphasis given to changes in study parameters versus control values. Preset default values are built into the Cross-Study Analysis App, but these may be modified by the user.  All R code (R Core Team, 2022) used in this analysis can be found in BioCelerate/cross-study at master · PHUSE-org/BioCelerate (github.com) GitHub repository ([https://github.com/phuse-org/BioCelerate](https://github.com/phuse-org/BioCelerate)