Azra C. Ghani

Predicted vCJD mortality in Great Britain

There is continued speculation about the likely number of cases of variant Creutzfeldt–Jakob disease (vCJD) that will occur in Great Britain in the wake of the BSE epidemic in cattle and in light of a recent cluster of vCJD cases in Leicestershire, England. We show here that the current mortality data are consistent with between 63 and 136,000 cases among the population known to have a susceptible genotype (about 40% of the total population), with on average less than two cases of vCJD arising from the consumption of one infected bovine.

Implications of BSE infection screening data for the scale of the British BSE epidemic and current European infection levels

The incidence of confirmed clinical cases of bovine spongiform encephalopathy (BSE) in Great Britain continues to decline, but the recent discovery of cases in previously unaffected countries (including Israel, Japan, Poland, Slovenia and Spain) has heightened concerns that BSE transmission was more intense and widespread than previously thought. We use back–calculation methods to undertake an integrated analysis of data on infection prevalence in apparently healthy cattle and the incidence of confirmed clinical disease. The results indicate substantial underascertainment of clinical cases over the course of the British epidemic, and consequently that two– to fourfold more animals were infected than previously estimated. Upper bounds on the predicted size of the new variant Creutzfeldt–Jakob Disease (vCJD) epidemic are unaffected, as the prediction methods employed fit to observed vCJD mortality data, and are not sensitive to estimates of the absolute magnitude of past human exposure to BSE–infected cattle, only to relative changes in exposure through time. We also estimate the per–head incidence of infection in cattle born between 1993 and 1997 in other European Union countries, using data on the testing of apparently healthy cattle slaughtered for consumption. Infection incidence for cattle born after mid–1996 was highest in Greece, Italy and Belgium, with Spain and The Netherlands having intermediate levels, and estimates for Great Britain, Germany and France being comparably low.

Estimating the human health risk from possible BSE infection of the British sheep flock

Following the controversial failure of a recent study and the small numbers of animals yet screened for infection, it remains uncertain whether bovine spongiform encephalopathy (BSE) was transmitted to sheep in the past via feed supplements and whether it is still present. Well grounded mathematical and statistical models are therefore essential to integrate the limited and disparate data, to explore uncertainty, and to define data-collection priorities. We analysed the implications of different scenarios of BSE spread in sheep for relative human exposure levels and variant Creutzfeldt–Jakob disease (vCJD) incidence. Here we show that, if BSE entered the sheep population and a degree of transmission occurred, then ongoing public health risks from ovine BSE are likely to be greater than those from cattle, but that any such risk could be reduced by up to 90% through additional restrictions on sheep products entering the food supply. Extending the analysis to consider absolute risk, we estimate the 95% confidence interval for future vCJD mortality to be 50 to 50,000 human deaths considering exposure to bovine BSE alone, with the upper bound increasing to 150,000 once we include exposure from the worst-case ovine BSE scenario examined.

Epidemiological determinants of the pattern and magnitude of the vCJD epidemic in Great Britain

Understanding the epidemiology and aetiology of new–variant Creutzfeldt–Jakob (vCJD) disease in humans has become increasingly important given the scientific evidence linking it to bovine spongiform encephalopathy (BSE) in cattle and hence the wide exposure of the population of Great Britain (GB) to potentially infectious tissue. The recent analysis undertaken to determine the risk to the population from dorsal route ganglia illustrated the danger in presenting point estimates rather than ranges of scenarios in the face of uncertainty. We present a mathematical template that relates the past pattern of the BSE epidemic in cattle to the future course of any vCJD epidemic in humans, and use extensive scenario analysis to explore the wide range of possible outcomes given the uncertainty in epidemiological determinants. We demonstrate that the average number of humans infected by one infectious bovine and the incubation period distribution are the two epidemiological factors that have the greatest impact on epidemic size and duration. Using the time–series of the BSE epidemic and the cases seen to date, we show that the minimum length of the incubation period is approximately nine years and that at least 20% of the cases diagnosed to date were exposed prior to 1986. We also demonstrate that the current age distribution of vCJD cases can only arise if younger people were either exposed to a greater extent, more susceptible to infection, or have shorter incubation periods. Extensive scenario analyses show that given the information currently available, the very high degree of uncertainty in the future size of the epidemic will remain for the next 3–5 years. Furthermore, we demonstrate that this uncertainty is unlikely to be reduced by mass screening for late–stage infection.

Retrospective study of prion-protein accumulation in tonsil and appendix tissues

To identify individuals who could be at high risk of developing vCJD, a sensitive immunohistochemical technique was used to detect prion protein in a retrospective series of over 3000 tonsil and appendix specimens. No positives were detected but further studies are required to help reduce uncertainties about possible future numbers of vCJD cases in the UK.

Assessment of the prevalence of vCJD through testing tonsils and appendices for abnormal prion protein

The objective of this study was to determine the age group or groups which will provide the most information on the potential size of the vCJD epidemic in Great Britain via the sampling of tonsil and appendix material to detect the presence of abnormal prion protein (PrPSc). A subsidiary aim was to determine the degree to which such an anonymous age‐stratified testing programme will reduce current uncertainties in the size of the epidemic in future years. A cohort‐ and time‐stratified model was used to generate epidemic scenarios consistent with the observed vCJD case incidence. These scenarios, together with data on the age distribution of tonsillectomies and appendectomies, were used to evaluate the optimal age group and calendar time for undertaking testing and to calculate the range of epidemic sizes consistent with different outcomes. The analyses suggested that the optimal five‐year age group to test is 25–29 years, although a random sample of appendix tissue from all age groups is nearly as informative. A random sample of tonsil tissue from all age groups is less informative, but the information content is improved if sampling is restricted to tissues removed from those over ten years of age. Based on the assumption that the test is able to detect infection in the last 75% of the incubation period, zero detected infections in an initial random sample of 1000 tissues would suggest that the epidemic will be less than 870 000 cases. If infections are detected, then the model prediction suggests that both relatively small epidemics (800+ cases if one is detected or 8300+ if two are detected) and larger epidemics (21000+ cases if three or more are detected) are possible. It was concluded that testing will be most informative if undertaken using appendix tissues or tonsil tissues removed from those over ten years of age. Large epidemics can only be excluded if a small number of infections are detected and the test is able to detect infection early in the incubation period.

Factors determining the pattern of the variant Creutzfeldt-Jakob disease (vCJD) epidemic in the UK.

Following the emergence of a new variant of Creutzfeldt-Jakob disease (vCJD) 6 years ago, and the gradual rise in clinical cases, there has been increased speculation regarding the overall magnitude of this epidemic in Great Britain. In this paper, we explore the epidemiological factors and uncertainties determining the scale of this epidemic in light of the most recent data on reported vCJD mortality. Our results demonstrate that, while the magnitude of the uncertainty has decreased dramatically since 1996, it is still not possible to predict with any degree of accuracy the final magnitude of this epidemic, with the 95% confidence interval for future cases being from 10 to 7000 deaths. However, short-term projections show that it is unlikely that a dramatic increase in case numbers will be observed in the next 2–5 years (95% confidence interval for 2 years: 10–80 cases, for 5 years: 10–200 cases). The results confirm significant age-dependent susceptibility/exposure to infection, with the likelihood profile demonstrating that those aged between 10 and 20 years are at highest risk of infection. We also demonstrate how projections based on onset data may be substantially biased, and explore the sensitivity of results to assumptions concerning the exposure to bovine spongiform encephalopathy (BSE) and the incubation-period distribution.

Analysis of the Bovine Spongiform Encephalopathy Maternal Cohort Study: Evidence for Direct Maternal Transmission

SUMMARY In an initial exploratory analysis of the bovine spongiform encephalopathy (BSE) maternal cohort study data we demonstrate several confounding effects in the study design. Given these effects, we assess a variety of statistical models to determine the relative contributions of direct maternal transmission of the aetiological agent of BSE and of genetic susceptibility to the observed maternally enhanced risk of BSE in the offspring of affected dams. To control for the substantial between-herd variation in the risk of exposure to the BSE agent, it is essential that analyses take into account the matched pair structure of the data. Maternal exposure is estimated to be most important in animals born within 150 days of disease onset in their dams. The analysis of a full survival likelihood model indicates that the hypothesis of maternal transmission with no genetic variation in susceptibility fits the data significantly better than the hypothesis of genetically variable susceptibility with no maternal transmission. However, models incorporating both maternal transmission and genetically variable susceptibility fit the data significantly better than pure maternal transmission models. Although genetic susceptibility cannot be excluded as the cause of the cohort study results in the absence of detailed genotyping, the analysis of these study data suggest that low level maternal transmission of BSE is, at least in part, responsible for the significantly enhanced risk of BSE in the offspring of affected dams. Similar results indicating significant maternal transmission in the later stages of the dam incubation period are obtained from the independent analysis of data on the dam-offspring relationships among confirmed BSE cases.

Predicting the size of the epidemic of the new variant of Creutzfeldt‐Jakob disease

In response to a paper published in a previous issue of British Food Journal, it criticises the methodology of the previous research. Examines the earlier findings on the projected epidemic size of the new variant of Creutzfeldt‐Jakob Disease (vCJD) in humans. Argues that the earlier research is flawed and there exists no data which can provide adequate predictions for the extent of the vCJD epidemic.

Scrapie in Britain during the BSE years.

The experimental transmission of bovine spongiform encephalopathy (BSE) to sheep raised the possibility that some sheep in the United Kingdom could have been infected during the 1980s after exposure to BSE-contaminated feed. In contrast to new diseases that have appeared in a number of feline species and wild ungulates, the symptoms of BSE in sheep are very similar to another transmissible spongiform encephalopathy called scrapie, which has been endemic in Britain for over 200 years. Although so far no cases of BSE in sheep have been found, these may have been misdiagnosed as scrapie. Here we present data describing the historical changes in scrapie incidence, and find no evidence for a peak in scrapie incidence before, during or after the BSE outbreak, making it unlikely that a substantial epidemic of BSE has occurred in the sheep population.