Scrapie infections initiated at varying doses: an analysis of 117 titration experiments

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Abstract
An analysis of 117 titration experiments in the murine scrapie model is presented. The experiments encompass 30 years' work and a wide range of experimental conditions. To check that the experimental designs were reasonably consistent over time, comparisons were made of size, duration, source of inoculum, etc., in each experiment. These comparisons revealed no systematic trends that would render invalid comparisons across experiments. For 114 of the experiments it was possible to calculate the dose at which half of the challenged animals were infected (the ID 50 ). These 114 experiments were then combined on the basis of relative dose (i.e. tenfold dilution relative to the ID 50 ). This created a data set in which over 4000 animals were challenged with doses of scrapie ranging from four orders of magnitude below to five orders of magnitude above the ID 50 . Analysis of this data reveals that mean incubation periods rise linearly with logarithmic decreases in dose. A one unit increase in relative dose (i.e. a tenfold increase in actual dose) will, on average, decrease the incubation period by 25 days. At ID 50 the average incubation period in this data set is 300 days. Within a single dose, in a single experimental model, incubation periods have a distribution close to normal. Variability in incubation period also rises linearly as dose decreases. There is no age or sex effect upon the probability of infection, but female mice have incubation periods that are, on average, nine days shorter than their male counterparts and young mice have incubation periods that are longer by seven days. Although many of these patterns are apparent in the results of single titration curves, they can be more rigorously investigated by considering the outcome for thousands of mice.