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

An analysis of 117 titration experiments in the murine scrapie model is pre sented. The experiments encompass 30 years' work and a wide range of experi mental conditions. To check that the experimental designs were reasonably c onsistent over time, comparisons were made of size, duration, source of ino culum, etc., in each experiment. These comparisons revealed no systematic t rends 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 ID50). These 114 experiments were the n combined on the basis of relative dose (i.e. tenfold dilution relative to the ID50) This created a data set in which over 4000 animals were challeng ed with doses of scrapie ranging from four orders of magnitude below to fiv e orders of magnitude above the ID50. Analysis of this data reveals that me an incubation periods rise linearly with logarithmic decreases in dose. A o ne unit increase in relative dose (i.e. a tenfold increase in actual dose) will, on average, decrease the incubation period by 25 days. At ID50 the av erage incubation period in this data set is 300 days. Within a single dose, in a single experimental model, incubation periods have a distribution clo se 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 sh orter than their male counterparts and young mice have incubation periods t hat are longer by seven days. Although many of these patterns are apparent in the results of single titration curves, they can be more rigorously inve stigated by considering the outcome for thousands of mice.