# Modeling omics dose-response at the pathway level with DoseRider

## TL;DR

DoseRider is a tool for modeling dose-response relationships at the pathway level using omics data, helping to determine biological exposure limits.

## Contribution

Introduces DoseRider, a web application and R package for pathway-level dose-response modeling using generalized mixed effect models.

## Key findings

- DoseRider allows analysis of RNA sequencing and metabolomics data with pathway annotations from multiple species.
- The tool introduces trend change doses (TCDs) as a new numerical descriptor for complex dose-response curves.
- Application to BPAF treatment data showed a BMD of 0.2 µM and a TCD1 of 0.003 µM for estrogen-upregulated genes in breast cancer.

## Abstract

The generation of omics data sets has become an important approach in modern pharmacological and toxicological research as it can provide mechanistic and quantitative information on a large scale. Analyses of these data frequently revealed a non-linear dose-response relationship underscoring the importance of the modeling process to infer biological exposure limits. A number of tools have been developed for dose-response modeling and various thresholds have been defined as a quantitative representation of the effect of a substance, such as effective concentrations or benchmark doses (BMD). Here we present DoseRider an easy-to-use web application and a companion R package for linear and non-linear dose-response modeling and assessment of BMD at the level of biological pathways or signatures using generalized mixed effect models. This approach allows to analyze custom or provided multi-omics data such as RNA sequencing or metabolomics data and its annotation of a collection of pathways and gene sets from various species. Moreover, we introduce the concept of the trend change doses (TCDs) as a numerical descriptor of effects derived from complex dose-response curves. The usability of DoseRider was demonstrated by analyses of RNA sequencing data of bisphenol AF (BPAF) treatment of a human breast cancer cell line (MCF-7) at 8 different concentrations using gene sets for chemical and genetic perturbations (MSigDB). The BMD for BPAF and a set of genes upregulated by estrogen in breast cancer was 0.2 µM (95 %-CI 0.1–0.5 µM) and the lowest TCD (TCD1) was 0.003 µM (95 %-CI 0.0006–0.01 µM). The comprehensive presentation of the results underlines the suitability of the system for pharmacogenomics, toxicogenomics, and applications beyond.