Mixed effects modeling to improve inference in dose response studies with plate variability

Music City Center 

Microtiter plate formats are a standard tool in laboratory experiments, allowing scientists to investigate physical, chemical, and biological reactions of test articles in various assays. We investigated data from a 384-well in-vitro study involving 18 test articles , which included 13 mixtures and an active product constituent, along with positive, negative, controls (e.g., vehicle controls). The experiment was conducted using two cell types, and two assays, with multiple replicates. Test articles were dosed in 10 concentrations in duplicate, spaced at equal log intervals. Despite normalization to vehicle controls, marked plate-to-plate variability was observed. Dose response curves were fitted for each replicate using the tcplfit2 library in R, selecting the best fitted model based on the lowest AIC. We focused on benchmark dose concentration as a key endpoint of the fitted curve. We applied a mixed-effects model with plate as a random effect to account for the observed plate-specific variability. This modeling approach provides a framework for addressing plate variability in dose response studies, enhancing reproducibility and accuracy.

Mixed effect model

in-vitro experiment

dose response modeling

Toxicology

Cell-based assays 

Biometrics Section