Scrapie is a neuro-degenerative transmissible disease, known since the 18th
century, that affects small ruminants and belongs to the group of transmissible spongiform encephalopathies (TSEs). Diseases of this group are characterized by the accumulation in the brain of an anomalous form of the prion protein (PrP), that induces nervous clinical signs leading to death. Bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease are two other members of this group that respectively affect cattle and human. BSE was first described in 1987 [1
]. In the following year, field studies allowed epidemiologists to identify its major transmission mode, meat and bone meal [2
], and a first set of control measures were taken to break the transmission cycle. Ten years later, laboratory studies and epidemiological features showed that BSE agent was the probable cause of a new form of Creutzfeldt-Jakob disease in human [3
], and a second set of control measures were taken, for public health protection. During BSE epidemic, European sheep were probably exposed to food contaminated by the BSE agent. Experimental studies have shown that sheep may be infected by BSE agent [5
], and that the clinical signs are then identical to those of scrapie [6
]. Furthermore, transmission experiments have shown the possibility of an horizontal transmission of BSE agent among sheep [7
If sheep flocks have been exposed to BSE agent, a "sheep BSE" could thus exist and propagate silently, clinical cases being identified as scrapie cases [9
]. The potential threat for public health induced by such a propagation led European animal health authorities to launch screening programmes for detecting BSE cases in small ruminants. To date, these programmes failed to detect BSE in sheep, but allowed to identify a TSE case in a goat, the agent signature of which could not be distinguished from that of BSE [10
]. Distribution of pathological changes in the brain as well as western blot profiles allow to distinguish two scrapie types: classical scrapie and atypical scrapie. Epidemiological studies suggest that the aetiology and epidemiology of these two scrapie types are different, the infectious nature of atypical scrapie being uncertain [11
]. The present study is specifically dedicated to classical scrapie, and the word 'scrapie' will be used below for 'classical scrapie'.
Genetic variations of susceptibility to scrapie have been described in numerous studies [12
]. These variations are associated with the polymorphism of PrP gene, and individual susceptibility to scrapie may be characterized by three codons of this gene [14
]. Despite available data are sparse, genetic susceptibility profiles to BSE in sheep seem similar to those of scrapie. Selection programmes have thus been launched in several European countries, that aim at eliminating the most susceptible alleles to decrease circulation of scrapie agent as well as the potential circulation of BSE agent in sheep [15
Besides large abattoir or fallen stock screening programmes (which are very costly) and genetic selection programmes (the effects of which appear slowly in the general population), an intermediate approach centred on the flock may be proposed. As for other transmissible diseases, existence of a procedure to substantiate flock freedom from scrapie would allow defining objectively a subset of population considered as scrapie-free, a distinction that could be the basis of measures oriented towards public health or animal health. If a circulation of BSE agent in sheep flocks were demonstrated, such a qualification procedure would probably become mandatory, and form the basis of scrapie eradication plans, similar to those dedicated to other transmissible diseases such as tuberculosis or brucellosis.
However, a first particularity of scrapie is that unlike other transmissible diseases, no live animals tests are currently used in the EU for routine diagnostic, as tests are performed on brain samples. Therefore, scrapie can only be routinely diagnosed on slaughtered or dead animals. For other transmissible diseases, the status of a herd can be determined by testing all the animals living in that herd. But for scrapie, the status of a flock can only be based upon test results obtained from animals leaving the flock, that represent the remaining animals.
A second particularity of scrapie is that evidence of freedom from disease can not only be based on negative test results obtained on a sample of animals from the flock, but also on genetic data. Knowledge of the genotypes of the tested animals is necessary to interpret results of diagnostic tests: a negative result obtained from a genetically susceptible animal brings more evidence of scrapie freedom than a negative result obtained from a genetically resistant animal (because even if the flock were infected, this animal would probably have remained negative). Ideally, if live animals tests could be routinely used and if a full knowledge of flock genetics were available, animals of the most susceptible genotypes should be tested first to detect disease presence. However, in practice, it is not the case, and this situation leads to a paradox for flocks with a majority of genetically resistant animals: while in such flocks, the probability to be free from scrapie should be considered as high even if no animal has been tested for disease detection, performing diagnostic tests on the flock animals does not bring significant evidence of scrapie freedom as these animals are genetically resistant. Substantiating scrapie freedom through disease detection surveys would then be more difficult in resistant flocks than in susceptible flocks.
The objective of this study was to propose a framework for solving the preceding paradox, that allowed defining and comparing several practical approaches (termed below "qualification strategies") for substantiating scrapie freedom in a flock. These took into account scrapie specificities and differed according to how results of diagnostic tests were combined with genetic data to provide evidence of freedom from scrapie. Two sources of genetic data were considered: genotyping exams that may be performed on some of the flock animals, and flock pedigree (the set of parent-child relationships for the flock animals) that may also allow to derive genotype-associated probabilities for non-genotyped animals [16
Feasibility of the proposed qualification strategies was quantified, in terms of probability for a scrapie-free simulated flock to be classified as such within a reasonable time. The corresponding durations were evaluated, as well as the associated costs: numbers of diagnostic tests and genotyping exams performed. The strategy for which the associated cost is the lowest was finally determined, as well as how this one varies according to the unitary costs of genotyping exams and diagnostic tests.