1 MRC Biostatistics Unit and Department of Medical Genetics, Cambridge.
2 Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge, UK.
SM Bird, Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge, UK. E-mail: sheila.bird{at}mrc-bsu.cam.ac.uk
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Abstract |
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Methods Simulation (from vCJD infections generated randomly from gender and age-specific dietary exposure intensities to BSE), constrained to equal the 47 and 64 vCJD onsets before 2001 in 19401969 and post-1969 birth cohorts, was used to estimate lognormal (and other) incubation mean and standard deviation which fitted the calendar year distribution of observed vCJD onsets; and to explore exponential decay in susceptibility to infection with age above 15 years.
Results For the post-1969 birth cohort, the best-fitting lognormal incubation period mean of 11 years (SD 1.5 years and 195 infections) was associated with 194 vCJD onsets (64 before 2001, 105 in 20012005, and 25 in 20062010). About one-fifth of simulated vCJD onsets before 2001 arose from infections in 19901996; age and gender of simulated and observed vCJD patients agreed closely. For the 19401969 birth cohort, well-fitting lognormal means ranged widely, the marginally best fitting being 26 years (SD 16.5 years and 382 infections; 47 vCJD onsets before 2001, 58 in 20012005, and 63 in 20062010). An age-dependent susceptibility function was required to match the age distribution of vCJD patients in the 19401969 birth cohort.
Conclusions About three-fifths of predicted vCJD onsets are expected to be in males, and nearly two-thirds of vCJD onsets in 20012005 are expected to be in post-1969 birth cohort according to best-fitting predictions.
Accepted 23 May 2003
Dietary exposure to the agent responsible for bovine spongiform encephalopathy (BSE) is the most likely primary cause of variant Creutzfeldt-Jakob disease (vCJD). Burgers, sausages, and other meat products have been implicated in human exposure to BSE through their use of beef mechanically recovered meat (MRM)15 and head meat.6 Beef MRM and head meat were potentially contaminated respectively with BSE infected spinal cord and dorsal root ganglia, and brain. Legislation ended UK production of beef MRM in December 1995 and of head meat in March 1996.
Published vCJD predictions have differed in five important aspects, the first of which is the differences in the assumed shape of human exposure intensity to BSE: specifically, whether79 and how1012 infectivity from clinical BSE and pre-clinical bovines was taken into consideration. Second are differences in the assumed impact of legislation, such as the 1989 Specified Bovine Offal (SBO) legislation, to prevent BSE infectivity from reaching consumers. The SBO legislation has commonly been assumed to have had a key role in reducing human exposure to BSE.79 Third, a range of unimodal vCJD incubation period distributions has been assumed. Typically, they have included the lognormal distribution,7,9,12 sometimes as a special case of a more flexible distribution.8,10 Fourth is variation in whether any plausibility constraints have been imposed on vCJD incubation period mean, such as less than 30 years,7,11,12 or on variation about a given mean.7,12 Whether, and how, age-dependencies, such as in exposure,10,11 susceptibility,8,9 and incubation,10,11 were introduced is the fifth aspect. In the absence of age-specific exposure intensities to BSE, age-dependencies cannot be distinguished.
Previously,46 we have estimated dietary exposure intensities to BSE through consumption of beef MRM and head meat in burgers, sausages, and other meat products by birth cohort (pre-1940, 19401969, and post-1969) and gender; and highlighted major sensitivity issues. We now use these directly estimated dietary exposure intensities to make short-term predictions of vCJD incidence in the 19401969 and post-1969 birth cohorts. No predictions are made for the pre-1940 birth cohort as there has only been one vCJD onset reported in a patient born before 1940. As all vCJD patients to date are of one particular genotype (homozygous for methionine at polymorphic residue 129 of the prion proteinwhich accounts for about 40% of the UK population13), short-term predictions of vCJD incidence apply only to this subpopulation.712
In addition to the dietary exposure intensities, our approach differs from previous models in: (1) we allow the incubation period distribution to differ between birth cohorts; (2) consider age-dependent susceptibility, based on the age-risk function of Valleron et al.;9 and (3) estimate the transmission barrier for individuals with the affected genotype.
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Methods |
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Simulation of vCJD incidence |
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To estimate the calendar years of infection for the n infected individuals, we made the strong assumption that vCJD infections predominantly resulted from exposure to BSE in beef MRM and head meat, and that we had successfully modelled this exposure.46 Consequently, we generated the calendar times of infection for the n infected individuals from their birth cohorts dietary exposure intensity to BSE by assuming that the number of infections in calendar year y (during exposure period 19801996) was proportional to the birth cohorts dietary exposure to BSE in year y. For each infected individual, we then randomly assigned a week within their calendar year of infection when the event occurred. The age at infection (and hence year of birth) and gender of an infected individual were estimated in accordance with the age- and gender-specific exposure within the birth cohort in calendar year y. Infectivity option 1 was assumed for the main simulations, but simulations were repeated for infectivity option 2.
To estimate the incubation periods for the n infected individuals, we assumed a lognormal distribution7,9,12,15 and searched for the best-fitting standard deviation for a given mean (see Incubation period distribution, below). Simulations were repeated assuming gamma and Weibull distributions for the incubation period.7,16 For each infected individual, after generating their incubation period, we derived their calendar time of onset and age at onset. Finally, we used age- and gender-specific UK life tables17 to estimate whether the infected individuals survived to vCJD onset.
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Incubation period distribution |
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The chosen range of incubation means was guided by the incubation means for other human transmissible spongiform encephalopathies (TSE).16,18,19 In the absence of a species barrier, Collinge19 suggested an incubation mean of about 1015 years (range: at least 440 years) for human TSE after peripheral innoculation or oral exposure, which may result in a longer incubation mean.
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Goodness-of-fit criterion |
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Expected vCJD simulated onsets were estimated by the mean number of simulated onsets for the 100 simulation runs (note: Tables give median). To compare the expected vCJD onsets with those observed before 1996, in 1996, 1997, 1998, 1999, and 2000, we used a standard 2 measure of goodness-of-fit on 5 degrees of freedom (d.f.). If the goodness-of-fit test statistic exceeded 11.07, the 95% critical value for the
25 distribution, the simulated expectations were not consistent with the observed incidence. For the combined 19401969 and post-1969 birth cohorts, the simulation was required to reproduce the 111 onsets in the combined birth cohorts (the model constraint) and the goodness-of-fit test statistic on 11 d.f. measured agreement by birth cohort between expected vCJD simulated onsets and those observed before 1996, and in 1996, 1997, 1998, 1999, and 2000.
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Transmission barrier |
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transmission barrier =total dietary exposure to BSE*0.4
n
However, such an estimate depends to a great extent on the estimates of bovine tissue-specific infectivity used in the estimation of the dietary exposure intensities, about which there is uncertainty.2022 The route of infection is also critical: the oral route of infection is known to be the least effective.22 Despite the hazards of interpretation, we estimated the transmission barrier for each simulation model to investigate whether the transmission barrier is similar for the best-fitting models of the 19401969 and post-1969 birth cohorts. As the above definition of the transmission barrier does not take into account the infective dose or the number of individuals exposed who do not become infected (not estimated by the model), the transmission barrier is different from the species barrier.19
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Age-dependent susceptibility |
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Results |
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For the 19401969 and post-1969 birth cohorts separately, Table 1 lists the best fitting standard deviation for lognormal incubation means of 1030 years and associated
2 goodness-of-fit test statistic. The
2 test statistic was not significant for any of the models, indicating that their expected simulated vCJD onsets were consistent with the observed onsets. The
2 test statistic had a distinct minimum value for the post-1969 birth cohort at an incubation period of 11 years (SD 1.5 years). For the 19401969 birth cohort, the
2 test statistic was relatively flat around the minimum value at an incubation mean of 26 years (SD 16.5 years) and remained at about this level even with an incubation mean of 60 years.
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For infectivity option 2, the best-fitting models assuming a lognormal incubation period distribution had identical incubation period parameters as infectivity option 1 for the post-1969 birth cohort and an incubation mean of 16 years (SD 9 years) for the 19401969 birth cohort. The 2 test statistic was again not significant for any of the models and relatively flat for the 19401969 birth cohort models. Expected transmission barrier for the post-1969 birth cohort (770; 5th95th percentiles: 652902) was 0.6 times lower than that of the 19401969 birth cohort (1310; 5th95th percentiles: 11201578). With similar or shorter incubation means, the birth cohort specific transmission barriers were necessarily higher for infectivity option 2 than for infectivity option 1.
As summarized in Table 5, when incubation mean ranged from 10 to 30 years, simulated vCJD infections ranged from 80 to 1140 for the 19401969 birth cohort and from 155 to 6585 for the post-1969 birth cohort, dependent on assumed incubation distribution and infectivity option. The transmission barrier ranged from 15 to over 2500. However, constraints on incubation mean (maximum of 20 years) or transmission barrier (between 201 and 800) dramatically reduced the prediction range for both birth cohorts.
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Discussion |
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Separate simulation models for the 19401969 and post-1969 birth cohorts suggested that the incubation period was shorter for the post-1969 birth cohort. However, there was greater uncertainty about the incubation period for the 19401969 birth cohort. Previous work has reported a very severe incubation period parameter identifiability problem.8
The age-dependent susceptibility function was required to match the age distribution of vCJD patients in the 19401969 birth cohort. The simple formulation proposed by Valleron et al.9 of exponential decay in susceptibility after 15 years of age worked well.
Our simulation models make low predictions of vCJD incidence in methionine homozygotes. Short-term predictions from the best fitting models for the 19401969 and post-1969 birth cohorts respectively were 58 (5th95th percentiles: 4279) and 105 (5th95th percentiles: 85140) onsets in 20012005. In the short-term, the predicted low incidence will make it hard to distinguish between incubation periods. For instance, expected vCJD incidence in 20012005 for the 19401969 birth cohort ranged only between 36 and 52 for incubation means ranging from 11 to 35 years.
We have assumed that the primary sources of exposure to BSE were through the consumption of meat products containing beef MRM and head meat. Other global and local sources of exposure to BSE have not been ruled out, but may be unquantifiable. The cluster of five vCJD patients from Queniborough in Leicestershire raised the spectre of localized sources of exposure to BSE. The investigation into the cluster revealed that traditional practices of local butchers were likely to have resulted in the contamination of bovine carcass meat with BSE.23 Had such localized exposures occurred throughout the UK the cluster of patients from Queniborough would have stood out less from the other vCJD patients. Predictions of vCJD incidence based on global exposure intensities to BSE need to consider that vCJD patients from Queniborough could have succumbed to local exposure. Practically, this would suggest the exclusion of vCJD patients from Queniborough from those for whom any global exposure intensity to BSE was responsible. The exclusion of the vCJD patients from Queniborough did not change our results.
More recent findings of the BSE Pathogenesis Experiment have resulted in a shift from 10 Bo ID50 units,20 as assumed in our estimation of the dietary exposure intensities to BSE,5,6 to 50 Bo ID50 units per gram of brain, spinal cord, and dorsal root ganglia of a clinical BSE bovine.14 This has only a multiplicative effect on our dietary exposure intensities to BSE.
The strength of the method used in this paper is that calendar times of infection and infected patient characteristics are derived directly from dietary exposure intensities to BSE. We used a transparent simulation model with a single constraint and, for each birth cohort, had only to estimate the two incubation period parameters and the exponential decay in the age-dependent susceptibility function. Clearly, the simulation model can be extended to include more flexible incubation period distributions and different age-dependent susceptibility functions.
Considerable uncertainty about the incubation period will remain for a number of years, particularly for the 19401969 birth cohort. Despite this incubation period uncertainty, overall low predictions of vCJD incidence within the subpopulation of the UK with the affected genotype are made. According to the best-fitting models, almost two-thirds of predicted vCJD patients in 20012005 are expected to be in the post-1969 birth cohort, whose vCJD incidence is predicted to peak in this calendar period and to outnumber (about 1.5 times more onsets) those in the 19401969 birth cohort. Very few onsets are predicted to occur after 2010 in the post-1969 birth cohort. In contrast, for the 19401969 birth cohort, almost half of onsets are predicted to occur after 2010. About three-fifths of vCJD patients are expected to be male.
The dietary exposure intensities to BSE show that the age distribution of observed vCJD patients can only arise if younger individuals have a shorter incubation period and/or are more susceptible to infection. There is remarkable similarity between the age distribution and gender of simulated and observed vCJD patients, which supports (but does not prove) our assumption about the primary sources of exposure to BSE. In contrast to other predictions of vCJD incidence, our predictions are testable by the number, birth cohort, age, and gender of future vCJD patients.
As all vCJD patients tested have been homozygous for methionine at polymorphic residue 129 of the prion protein, it is premature to make extrapolations from vCJD incidence in individuals with the affected genotype to individuals with other genotypes. A number of biological processes, including species barrier19 and incubation period,8 may be dependent on genotype. For instance, other genotypes may be absolutely protected, relatively less susceptible, or equally susceptible but with substantially longer incubation periods. Transmission studies, however, argue against absolute protection.24
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Acknowledgements |
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KEY MESSAGE
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