From: TSS (216-119-136-132.ipset16.wt.net)
Subject: Quantative understanding of transmissable spongiform encephalopathies such as BSE and CJD
Date: November 11, 2003 at 10:03 am PST
Statistical Methods in Medical Research
Quantative understanding of transmissable spongiform encephalopathies such as BSE and CJD
Volume 12 Number 3 2003
Editorial
Dedication, yet uncertainty
175
Sheila M. Bird; Robert G. Will
Review articles
Extending backcalculation to analyse BSE data
177
CA Donnelly; NM Ferguson; AC Ghani; RM Anderson
Title: Extending backcalculation to analyse BSE data
Author(s): CA Donnelly1; NM Ferguson2; AC Ghani3; RM Anderson4
Source: Statistical Methods in Medical Research Volume: 12 Number: 3 Page: 177 -- 190
DOI: 10.1191/0962280203sm337ra
Publisher: Arnold
Abstract: We review the origins of backcalculation (or back projection) methods developed for the analysis of AIDS (acquired immunodeficiency syndrome) incidence data. These techniques have been used extensively for >15 years to deconvolute clinical case incidence, given knowledge of the incubation period distribution, to obtain estimates of past HIV (human immunodeficiency virus) infection incidence and short-term predictions of future AIDS incidence. Adaptations required for the analysis of bovine spongiform encephalopathy (BSE) incidence included: stratification of BSE incidence by age as well as birth cohort; allowance for incomplete survival between infection and the onset of clinical signs of disease; and decomposition of the age-and time-related infection incidence into a time-dependent feed risk component and an age-dependent exposure/ susceptibility function. The most recent methodological developments focus on the incorporation of data from clinically unaffected cattle screened using recently developed tests for preclinical BSE infection. Backcalculation-based predictions of future BSE incidence obtained since 1996 are examined. Finally, future directions of epidemiological analysis of BSE epidemics are discussed taking into account ongoing developments in the science of BSE and possible changes in BSE-related policies.
© Arnold 2003
Reference Links: 50
Affiliations: 1: Department of Infectious Disease Epidemiology, Imperial College London, UK ; 2: Department of Infectious Disease Epidemiology, Imperial College London, UK ; 3: Department of Infectious Disease Epidemiology, Imperial College London, UK ; 4: Department of Infectious Disease Epidemiology, Imperial College London, UK
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Short-term projections for variant Creutzfeldt-Jakob disease onsets
191
Azra C Ghani; Neil M Ferguson; Christl A Donnelly; Roy M Anderson
Title: Short-term projections for variant Creutzfeldt-Jakob disease onsets
Author(s): Azra C Ghani1; Neil M Ferguson2; Christl A Donnelly3; Roy M Anderson4
Source: Statistical Methods in Medical Research Volume: 12 Number: 3 Page: 191 -- 201
DOI: 10.1191/0962280203sm327ra
Publisher: Arnold
Abstract: Projections of both the short- and long-term course of the variant Creutzfeldt-Jakob disease (vCJD) epidemic in Great Britain have demonstrated great uncertainty due to the lack of knowledge of key aspects of the biology and epidemiology of this new disease. Such projections are sensitive to assumptions made regarding the pattern of exposure to BSE-infected animals, the effectiveness of control measures introduced in 1989 and 1996 in reducing this exposure, the functional form of the incubation period distribution and patterns of age-dependent susceptibility/exposure. This paper provides short-term projections for vCJD onsets using the time- and age-distributed onset data to the end of 2000, with results that are directly comparable to the other papers in this issue. These results demonstrate the continued uncertainty in the future scale of this disease.
© Arnold 2003
Reference Links: 22
Affiliations: 1: Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College, London, UK ; 2: Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College, London, UK ; 3: Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College, London, UK ; 4: Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College, London, UK
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The predictability of the epidemic of variant Creutzfeldt-Jakob disease by back-calculation methods
203
Jéroôme N Huillard d'Aignaux; Simon N Cousens; Peter G Smith
Title: The predictability of the epidemic of variant Creutzfeldt-Jakob disease by back-calculation methods
Author(s): Jéroôme N Huillard d'Aignaux1; Simon N Cousens2; Peter G Smith3
Source: Statistical Methods in Medical Research Volume: 12 Number: 3 Page: 203 -- 220
DOI: 10.1191/0962280203sm328ra
Publisher: Arnold
Abstract: We present a back-calculation analysis of the variant Creutzfeldt-Jakob (vCJD) epidemic in the UK to estimate the number of infected individuals and to explore the likely future incidence of the disease. The main features of the model are that the hazard of infection was assumed proportional to the incidence of BSE in the UK with allowance for precautionary control measures taken in 1988 and in 1996, and that the incubation period distribution of vCJD follows an offset generalized F distribution. Our results indicate that current the numbers of cases with onset up to 31 December 2000 data are broadly compatible with numbers of primary infections ranging from a few hundred to several million. However, if a very large number of persons were infected, the model suggests that the mean incubation period is likely to be well beyond the human lifespan, resulting in a disease epidemic of much smaller size (maximum several thousand). A sensitivity analysis indicates that our results are sensitive to the underreporting of vCJD cases before 1996. Finally, we show that, in the absence of a reliable test for asymptomatic infection, uncertainty in estimates of the total number of infections is likely to remain for at least several years, even if the number of clinical cases remains low.
© Arnold 2003
Reference Links: 19
Affiliations: 1: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK ; 2: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK ; 3: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
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Modelling the epidemic of variant Creutzfeldt-Jakob disease in the UK based on age characteristics: updated, detailed analysis
221
Pierre-yves Boëlle; Guy Thomas; Alain-Jacques Valleron; Jean-Yves Cesbron; Robert Will
Title: Modelling the epidemic of variant Creutzfeldt-Jakob disease in the UK based on age characteristics: updated, detailed analysis
Author(s): Pierre-yves Boëlle1; Guy Thomas2; Alain-Jacques Valleron3; Jean-Yves Cesbron4; Robert Will5
Source: Statistical Methods in Medical Research Volume: 12 Number: 3 Page: 221 -- 233
DOI: 10.1191/0962280203sm329ra
Publisher: Arnold
Abstract: Incubation period of the new variant Creutzfeldt-Jakob disease (vCJD)from infection to clinical onset and the eventual impact of the disease remain major concerns. Based on i) epidemiological conceptualization of human exposure to BSE contaminated material, ii) exponentially decreasing susceptibility after 15 years of age, and iii) typical incubation period (IP)distributions for time from infection to onset, we have previously estimated mean incubation period and projected number of vCJD cases. In this paper, we investigate the robustness of these estimates with respect to i-iii using the UK's 113 vCJD cases with clinical onset before December 2000. Mean incubation period was estimated at 16.4 years (95% CI 11.4-24.8), 15.9 years (95% CI 11.4-22.0), 14.1 years (95% CI 10.4-24.2) with the log-normal, Gamma and Weibull distributions respectively. Corresponding predictions for the total size of the epidemic ranged from 183 to 304. Maximal susceptibility to infection between 1.3 and 15.9 years and decreasing by 15% per year of age thereafter yielded the best fit. The shape of the IP distribution did not affect the predictions. In summary, within a set of reasonable assumptions, mean incubation period for vCJD ranged from 15 to 20 years, and the eventual impact of vCJD was a few hundred patients.
© Arnold 2003
Reference Links: 16
Affiliations: 1: Epidémiologie et Sciences de l'Information, INSERM U444, Assistance Publique, Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France ; 2: Epidémiologie et Sciences de l'Information, INSERM U444, Assistance Publique, Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France ; 3: Epidémiologie et Sciences de l'Information, INSERM U444, Assistance Publique, Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France ; 4: Immunité Anti-Infectieuse JE 2236, UFR de Médecine de Grenoble, Université Joseph Fourier, Grenoble, France ; 5: National Creutzfeldt-Jacob Disease Surveillance Unit, Western General Hospital, Edinburgh, UK
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The geographical distribution of variant Creutzfeldt-Jakob disease cases in the UK: what can we learn from it?
235
Simon Cousens; Dawn Everington; Hester JT Ward; Jerome Huillard; Robert G Will; Peter G Smith
Title: The geographical distribution of variant Creutzfeldt-Jakob disease cases in the UK: what can we learn from it?
Author(s): Simon Cousens1; Dawn Everington2; Hester JT Ward3; Jerome Huillard4; Robert G Will5; Peter G Smith6
Source: Statistical Methods in Medical Research Volume: 12 Number: 3 Page: 235 -- 246
DOI: 10.1191/0962280203sm332ra
Publisher: Arnold
Abstract: The causative agents of variant Creutzfeldt-Jakob disease (vCJD) and of bovine spongiform encephalopathy (BSE) are currently indistinguishable. However, the route(s) by which humans became infected remain unknown. The path by which humans were infected with the BSE agent might impact on the geographical distribution of cases and we therefore sought evidence of regional variation and local clustering of vCJD cases. With the notable exception of a group of five cases in Leicestershire, the absence of local clustering of vCJD cases is compatible with most human exposure to the vCJD agent arising through routes that result in the risk of infection being similar over wide geographical areas, rather than through small-scale local events. Infection through the consumption of mechanically recovered meat (MRM) contaminated with the BSE agent was a potential route for such widespread exposure. An ecological analysis relating the regional incidence of vCJD to historical dietary data does not provide a clear evidence that humans became infected through consumption of MRM.
© Arnold 2003
Reference Links: 15
Affiliations: 1: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK ; 2: National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK ; 3: National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK ; 4: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK ; 5: National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK ; 6: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
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Estimation of the exposure of the French population to the BSE agent: comparison of the 1980-95 consumption of beef products containing mechanically recovered meat in France and the UK, by birth cohort and gender
247
Marc Chadeau-Hyam; Alexandra Tard; Sheila Bird; Solenn Le Guennec; Nawel Bemrah; Jean-Luc Volatier; Annick Alpérovitch
Title: Estimation of the exposure of the French population to the BSE agent: comparison of the 1980-95 consumption of beef products containing mechanically recovered meat in France and the UK, by birth cohort and gender
Author(s): Marc Chadeau-Hyam1; Alexandra Tard2; Sheila Bird3; Solenn Le Guennec4; Nawel Bemrah5; Jean-Luc Volatier6; Annick Alpérovitch7
Source: Statistical Methods in Medical Research Volume: 12 Number: 3 Page: 247 -- 260
DOI: 10.1191/0962280203sm330ra
Publisher: Arnold
Abstract: Assuming that human exposure to BSE was through beef mechanically recovered meat (MRM) consumed as burgers and other meat products, we estimated the French consumption of different food items containing beef MRM, and compared these consumptions for French and British populations. To estimate consumption of meat products containing bovine MRM, we used dietary data from national individual and household food surveys conducted between 1980 and 1995. After reconciliation of consumption data between the available surveys and calendar year adjustments, we simulated consumption of one-thousandth of the French population. Consumption was estimated by birth cohort and gender, and for the periods 1980-89 and 1990-95 separately. Data showed that burgers (including manufactured minced meat) represented around 75-80% of the individual consumption of meat products containing MRM, and that consumption of burgers increased by 40% over the 1980-95 period. In all age groups, consumption was higher in males than in females. In both genders, the 1940-69 birth cohort had the highest mean consumption of burgers and other beef products containing MRM. Similar findings have been reported for the UK population. Estimated consumption of bovine MRM per calendar year increased markedly over the study period, concomitantly with an increase of bovine carcasses imported from the UK. Comparison of the 1980-1995 pattern of bovine MRM consumption in the UK and France indicated that this consumption peaked later in France than in the UK. This difference might result in different temporal pattern of vCJD incidence.
© Arnold 2003
Reference Links: 3
Affiliations: 1: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche Epidémiologique sur les Maladies Neurologiques, Paris, France ; 2: Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Direction de l'Evaluation des Risques Nutritionnels et Sanitaires, Maisons-Alfort, France ; 3: Medical Research Council (MRC), Biostatistics Unit, Cambridge, UK ; 4: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche Epidémiologique sur les Maladies Neurologiques, Paris, France ; 5: Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Direction de l'Evaluation des Risques Nutritionnels et Sanitaires, Maisons-Alfort, France ; 6: Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Direction de l'Evaluation des Risques Nutritionnels et Sanitaires, Maisons-Alfort, France ; 7: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche Epidémiologique sur les Maladies Neurologiques, Paris, France
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European Union's rapid TSE testing in adult cattle and sheep: implementation and results in 2001 and 2002
261
Sheila M Bird
Title: European Union's rapid TSE testing in adult cattle and sheep: implementation and results in 2001 and 2002
Author(s): Sheila M Bird1
Source: Statistical Methods in Medical Research Volume: 12 Number: 3 Page: 261 -- 278
DOI: 10.1191/0962280203sm331ra
Publisher: Arnold
Abstract: After the discovery of variant Creutzfeldt-Jakob disease (vCJD), scientific advances quickly led to postmortem tests to identify late-stage bovine spongiform encephalopathy (BSE) disease. These were first used in Switzerland in 1999 for active BSE surveillance of a) fallen and emergency-slaughter bovines (risk stock) and b) 5% sample of routinely slaughtered cattle over 30 months of age. In 1999 and 2000, Switzerland's estimated 103 BSE positives per 1 000 000 adult cattle put it in the same BSE risk classification as UKand Portugal. In July2000, the European Union's Scientific Steering Committee published its methodology (and first vetted results) for geographical BSE risk (GBR) assessment in cattle. Member states with no BSE cases found themselves, on rational assessment, classified as GBR III (BSE likely but not confirmed, or confirmed at a lower level). Because of Europe's thus highly assessed BSE risks, active BSE surveillance of adult cattle in all member states began in January2001 using one of three validated post-mortem tests. Implementation was variable across member states in January to March 2001 but, where operational, active surveillance was typically achieved for around 13 300 routinely slaughtered and 1000 risk stock per month per 1 000 000 adult cattle; BSE positive rates were 60 and 600 per 1 000 000 routinely slaughtered and risk cattle, respectively. By the second half of 2001, active BSE surveillance was operating reasonably in most member states, although anomalies persisted. Performance and results for July to December 2001 and for January to June 2002 are considered in detail. The BSE positive rate decreased substantially in UK, Portugal and Ireland between semesters, whereas Spain's rates increased for both routinely slaughtered and risk bovines. Based on 1 450 000 routinely slaughtered and 135 000 risk stock as standard, France could have expected 153 BSE positives in July to December 2001 (109 in January to June 2002); Italy 154 (67); and Germany only 39 (48). When sample-based surveillance data were scaled up and combined with clinical BSE cases, Great Britain's BSE positives were estimated at around 400 per 1 000 000 adult cattle in 2002 compared with over 1000 per 1 000 000 adult cattle in 2000. Age distributions for cattle subject to active BSE surveillance have been underexploited. The major transmissible spongiform encephalopathy (TSE) which affects sheep and goats is scrapie. Passive surveillance of scrapie is associated with substantial under-reporting. Susceptibility to scrapie depends strongly on sheep genotype; but resistance to scrapie does not necessarily confer resistance of sheep to BSE. Because of uncertainty about the true prevalence of scrapie-infected adult sheep and concern that BSE in sheep may be missed, the European Union pre-empted its planned evaluation of rapid post-mortem TSE tests in sheep by requiring the rapid TSE testing of small ruminants from April 2002 with one of the three cattle-validated tests. Basic requirements for active TSE surveillance in sheep were: random sample of 6000 fallen sheep and of 60 000 routinely slaughtered adult native sheep to be tested per member state by end March 2003. Lower surveillance targets were set for countries with under 1 000 000 adult sheep. Adequately to map scrapie-susceptible genotypes and identify resistant genotypes, a random sample of 500 routinely slaughtered native adult sheep was to be genotyped, together with each TSE rapid test positive adult sheep and two sets of three suitably sampled controls. By the end of August 2002, when 41% of the initial surveillance time had elapsed, only 20% of the European joint target for routinely slaughtered adult sheep had been completed, but that for fallen sheep was exceeded. Except in Ireland, the upper 95% confidence bound on TSE prevalence exceeded 500 per 1 000 000 routinely slaughtered adult sheep in reporting-compliant countries with more than 1 000 000 adult sheep. The UK, Greece, Italy and France were likely to approach the goal of 100 TSE rapid test positives on completion of their assigned first-year surveillance target for sheep. Results from the recommended genotyping of TSE positive adult sheep and controls for use in inferring differential TSE-positive susceptibility by genotype are awaited. Only by genotyping 5000-50 000 TSE-positive adult sheep, a massive undertaking even on the European scale, will it become clear whether scrapie resistance is relative rather than absolute. This paper details Europe's quantitative evolution in TSE surveillance.
© Arnold 2003
Reference Links: 17
Affiliations: 1: MRC Biostatistics Unit, Cambridge, UK
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TSE risk assessments: a decision support tool
279
Philip J Comer; Paul J Huntly
Title: TSE risk assessments: a decision support tool
Author(s): Philip J Comer1; Paul J Huntly2
Source: Statistical Methods in Medical Research Volume: 12 Number: 3 Page: 279 -- 291
DOI: 10.1191/0962280203sm333ra
Publisher: Arnold
Abstract: The paper presents a practical approach to assessing the risks of exposure to the infective agents from transmissible spongiform encephalopathies. Current data on the infectivity of bovine tissues have been reviewed and values for use in risk assessment studies proposed for the infectivity of central nervous system and other tissues, the development of infectivity through the incubation period and the cattle-human species barrier. A study to assess the risk of exposure to BSE infectivity in cattle disposed of during the 2001 foot and mouth epidemic in the UK by burning in pyres or burial is used to illustrate the application of TSE risk assessment and the way in which it can be used as an input to decision making.
© Arnold 2003
Reference Links: 25
Affiliations: 1: DNV Consulting, London, UK ; 2: DNV Consulting, London, UK
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