Estimation of the median infective and median diarrhea dose in a gnotobiotic pig model of Human Norovirus based on the area under the curve of virus shedding and diarrhea score

PARREÑO, V.; RAMESH, A.; YUAN, L.; MUNILLA, S.

Virtual

Congreso; 2nd Women in Bioinformatics & Data Science LA Conference; 2021

Women in Bioinformatics and Data Science

In the process of standardizing animal models in pre-clinical studies, which reproduceinfections by human pathogens, it is essential to know how infection and disease occuras the dose of the pathogen increases so that the animal model resembles the infectionin human. Dose-response models are mathematical functions that allow describing therelationship between the dose of a pathogen and the severity of the infection anddisease it generates in a given host. The methods applied to the estimation of theparameters of these curves have been developed for several decades on discretevariables rate of infected/ill overexpose individuals. Sigmoid regressions applied oncontinuous variables had been widely used in pharmacology and toxicology but not invirology for median dose estimation. The present study explores the dose-responseeffect and the estimation of the median infectious dose ID50%, and the mediandiarrhea dose, DD50% using a sigmoid three-parameter log-logistic distribution appliedon the continuous variables area under the curve of virus shedding, AUCS, and diarrheascore, AUCD, in a dose-response experiment in gnotobiotic pigs experimentallychallenged with increasing doses of human norovirus. The adjustment of a 3P L.L.model on the AUCS and AUCD yielded logID50%=3.85. and logDD50%=4.46 whichwere in the same order as those calculated based on the binary data using classicalmethods. The proposed method offers optimum precision and accuracy. In turn, itallows the analysis of data generated using non-equidistant dilutions and with anunbalanced number of experimental units between doses. The challenge dose of thehuman Norovirus evaluated in this study was established at 2 x 105 copies of the viralgenome, which reproduced in gnotobiotic pigs the incubation times, duration, andseverity of infection and diarrhea that occur in human volunteers. Precise estimates ofthe infection and disease parameters under robust statistical analysis contribute to thecorrect standardization of the gnotobiotic pig as a suitable animal model for pre-clinicalstudies of human Norovirus.