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Abstract:
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A change in estrous cycling is a reproductive parameter that can indicate adverse effects in response to chemical exposure. We present a novel application of a continuous-time Markov chain (CTMC) model to evaluate estrous cycling in rodent-based toxicology studies. Our method is evaluated by analyzing data from the National Toxicology Program (NTP). Using daily vaginal lavage samples, estrous stages are identified over 2-3 week periods for 40 animals in four dose groups. Our results are compared with the current NTP analysis method and other methods from the reproductive toxicology literature. The CTMC model can be applied using an existing R package that is widely cited and regularly maintained. The CTMC model holds a number of advantages over previous approaches; it can account for intra-animal dependence, missed days, littermate status, and other covariates. By modeling the biological process in continuous time, the model provides additional insight into estrous cycle dynamics and characterizes cycle disruptions with appropriate measures of uncertainty. Our results suggest existing methods may be overly sensitive to some common features of vaginal cytology data.
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