Evaluation using latent class models of the diagnostic performances of three ELISA tests commercialized for the serological diagnosis of Coxiella burnetii infection in domestic ruminants.

ELISA methods are the diagnostic tools recommended for the serological diagnosis of Coxiella burnetii infection in ruminants but their respective diagnostic performances are difficult to assess because of the absence of a gold standard. This study focused on three commercial ELISA tests with the following objectives (1) assess their sensitivity and specificity in sheep, goats and cattle, (2) assess the between- and within-herd seroprevalence distribution in these species, accounting for diagnostic errors, and (3) estimate optimal sample sizes considering sensitivity and specificity at herd level. We comparatively tested 1413 cattle, 1474 goat and 1432 sheep serum samples collected in France. We analyzed the cross-classified test results with a hierarchical zero-inflated beta-binomial latent class model considering each herd as a population and conditional dependence as a fixed effect. Potential biases and coverage probabilities of the model were assessed by simulation. Conditional dependence for truly seropositive animals was high in all species for two of the three ELISA methods. Specificity estimates were high, ranging from 94.8% [92.1; 97.8] to 99.2% [98.5; 99.7], whereas sensitivity estimates were generally low, ranging from 39.3 [30.7; 47.0] to 90.5% [83.3; 93.8]. Between- and within-herd seroprevalence estimates varied greatly among geographic areas and herds. Overall, goats showed higher within-herd seroprevalence levels than sheep and cattle. The optimal sample size maximizing both herd sensitivity and herd specificity varied from 3 to at least 20 animals depending on the test and ruminant species. This study provides better interpretation of three widely used commercial ELISA tests and will make it possible to optimize their implementation in future studies. The methodology developed may likewise be applied to other human or animal diseases.

Impact of heat and cold waves on female cattle mortality beyond the effect of extreme temperatures.

Although heat and cold temperatures are known to have an impact on cattle mortality, no study has evidenced and quantified the influence of the prolonged exposure to extreme temperatures beyond the single effect of daily temperatures. We defined a heat (or cold) wave by a continuous variable indicating the number of successive days with temperatures above (or below) a given threshold. For heat wave, the threshold was set to the 95th or 99th percentile of the mean daily temperature distribution and for cold wave to the 1st or 5th percentile. We collected female cattle mortality data by type of production and age classes between 2001 and 2015 for 100 iso-hygro-thermal areas in France. We used time-series analyses to estimate the area-specific heat wave- and cold wave-mortality relationships. Then, we applied meta-analyses to pool area-specific effects at the country level for each definition of heat and cold wave. For each type of production and age classes, our models predicted symmetrical relationships between temperature and mortality, with a temperature range of minimum mortality located approximately between 15 and 20 °CTHI in most categories. Outside that range, relative risks between 1.3 and 2.5 were estimated for extreme cold temperatures and relative risks between 1.1 and 1.5 were estimated for extreme hot temperatures depending on age categories and production type. Our results indicated that a prolonged exposure to high (or low) temperatures caused a significant increase on mortality (up to 40% during heat waves and 23% for cold waves, depending on type of production and age classes), in addition to the effect of extreme temperature alone. This additional mortality risk increased along with the duration and intensity of the exposure. Our results suggest that not discriminating the effect of the prolonged exposure to extreme temperature, may overestimate the effect of temperature alone on mortality.

Individual factors associated with L- and H-type Bovine Spongiform encephalopathy in France.

BACKGROUND: Cattle with L-type (L-BSE) and H-type (H-BSE) atypical Bovine Spongiform encephalopathy (BSE) were identified in 2003 in Italy and France respectively before being identified in other countries worldwide. As of December 2011, around 60 atypical BSE cases have currently been reported in 13 countries, with over one third in France. While the epidemiology of classical BSE (C-BSE) has been widely described, atypical BSEs are still poorly documented, but appear to differ from C-BSE. We analysed the epidemiological characteristics of the 12 cases of L-BSE and 11 cases of H-BSE detected in France from January 2001 to late 2009 and looked for individual risk factors. As L-BSE cases did not appear to be homogeneously distributed throughout the country, two complementary methods were used: spatial analysis and regression modelling. L-BSE and H-BSE were studied separately as both the biochemical properties of their pathological prion protein and their features differ in animal models. RESULTS: The median age at detection for L-BSE and H-BSE cases was 12.4 (range 8.4-18.7) and 12.5 (8.3-18.2) years respectively, with no significant difference between the two distributions. However, this median age differed significantly from that of classical BSE (7.0 (range 3.5-15.4) years). A significant geographical cluster was detected for L-BSE. Among animals over eight years of age, we showed that the risk of being detected as a L-BSE case increased with age at death. This was not the case for H-BSE. CONCLUSION: To the best of our knowledge this is the first study to describe the epidemiology of the two types of atypical BSE. The geographical cluster detected for L-BSE could be partly due to the age structure of the background-tested bovine population. Our regression analyses, which adjusted for the effect of age and birth cohort showed an age effect for L-BSE and the descriptive analysis showed a particular age structure in the area where the cluster was detected. No birth cohort effect was evident. The relatively small number of cases of atypical BSE and the few individual data available for the tested population limited our analysis to the investigation of age and cohort effect only. We conclude that it is essential to maintain BSE surveillance to further elucidate our findings.

Joint assessment of temporal segmentation, time unit and detection algorithms in syndromic surveillance.

The choice of the aggregation that defines the temporal unit of epidemiological surveillance is part of the more theoretical framework of the modifiable temporal unit problem (MTUP). It has been demonstrated that this choice influences temporal cluster detection and may lead to false-positive results and poor estimation of regression model parameters. In syndromic surveillance (SyS), despite the choice of which temporal aggregation to use being crucial, it has not yet been addressed in the literature. In most SyS systems, this choice is driven by the frequency of the data collection and/or human resources available, although neither the temporal unit's influence on the performance of anomaly detection algorithms nor on the efficiency of the SyS are known.The main objective of our study was to analyze the influence of the temporal aggregation unit on the performances of SyS detection algorithms used routinely, according to the characteristics of specific syndromes and outbreaks. Simulating daily time series of various syndromes, we tested three different time series aggregation methods. For each of four anomaly detection algorithms and their variants, we calculated seven performance indicators and multi-criteria scores to guide epidemiologists in their choice of which temporal aggregation of surveillance to use. From 19,200 analyzed time series, we observed an effect of temporal aggregation on the performance of the detection algorithms tested. Results also showed that the time aggregation unit was linked to the detection algorithm used, and that strong aggregation-algorithm interactions need to be taken into account when deciding on which aggregation-algorithm pair to use. Using theoretical data, our study also showed that no one ideal aggregation-algorithm pair exists for all contexts when deciding on which temporal unit of surveillance to use, and that the choice depends on several parameters.Our results can help public health practitioners choose the most appropriate time series aggregation and algorithm according to their specific needs. Finally, the present work enabled us to develop recommendations for a One Health project where the same time aggregation type and detection method could be used for both human and animal syndromic surveillance data.

How far away do you keep your equines? Estimation of the equine population's spatial distribution in France.

It is essential to have an accurate picture of the spatial distribution of equines to be able to monitor equine health events effectively. In France, this information is only available for certain categories of live equines kept in professional structures and for dead equines removed by renderers. This limits the surveillance, prevention and control methods able to be used to prevent the spread of equine diseases. Our study aimed to provide a realistic estimate of the spatial distribution of the French equine population at the detailed scale of the French commune (France's smallest administrative unit). For this purpose, we adapted the Bayesian method used by Lo Lacono et al., based on the distance between the owner's location and the location of his/her equines, and on the percentage of urban coverage. To assess whether the location of dead equines could be representative of the location of live equines, the distribution of distances between equines and owners was calculated from a sample of live equines on the one hand, and a sample of dead equines on the other, both accurately located. We also tested two different assignment methods for locating equines: Method 1 assigned to each owner a single holding commune, while Method 2 allowed more variability in holding communes for owners associated with multiple equines. A marked difference was observed between Methods 1 and 2 regardless of the sample used, with only 2.4% and 4.3% respectively of the communes having the same number of equines. Conversely, little difference was observed in the results whether the live or dead equine sample was used, with approximately 45% of the communes having the same number of equines. Regarding differences in spatial distribution, Method 1 based on the live equine sample estimated higher local densities of equines without considering urban areas. In contrast, Method 2 provided more dispersed maps, with low densities in the densest urban areas. In conclusion, dead equines appeared to be representative of live equines and some of our estimates are consistent with the information collected by the French horse and riding institute (IFCE). These results now have to be compared with field data to test their relevance.

Is the French SIRE equine information system a good basis for surveillance and epidemiological research? Quality assessment using two surveys.

Accurate demographic knowledge of the equine population is needed to assess and model equine health events. France is one of the few European countries with an operational centralized database (SIRE) recording individual data on all declared equines living in France and on their owners and keepers. Our study aimed to assess SIRE database quality concerning the updating of information by equine owners and keepers with a view to its improvement and use in surveillance and research. Two online surveys were conducted with the participation of 6244 registered keepers and 13,869 owners. Results showed some inconsistencies between SIRE records and survey responses. The inconsistency rate for equines whose castration and death were not registered in the database was 28.7% and 5.9% respectively. Concerning owners, 11% of respondents did not own the reference equine selected considered by the survey, 33% had changed address without updating it in the SIRE. Concerning premises hosting equines, the keeper survey's inconsistency rate was 7.3%, of which 57 respondents had closed and 32 had opened premises without reporting it. Comparatively, the owner survey's inconsistency rate was 40.7% including respondents who owned and hosted an equine without reporting these equine premises, and owners who did not keep any equines on their premises. In conclusion, the SIRE database proved to be a valuable and reliable source for epidemiological research as long as some bias is taken into account. On the contrary, its use in surveillance is currently limited due some shortcomings in updating and/or reporting by owners and keepers.

Home Sweet Home: New Insights Into the Location of Equine Premises in France and Keeping Habits to Inform Health Prevention and Disease Surveillance.

Identifying and tracking equines are key activities in equine health prevention. France is one of the few European countries with an operational centralized database that records information on equines, owners, and keepers but not on the location and keeping conditions of equines. The objective of our study was to collect information on keeping habits of equines and the relative location of a wide range of equines, owners, and keepers and discuss their implication for surveillance and control of outbreak improvement. A national email survey was conducted among the 1.9% of people registered as owners and 8.2% of people registered as keepers in the French national equine identification database having given their agreement to be contacted by email. It led to the collection of information from 728 owners, 121 keepers, and 2,669 owner-keepers. Most of them housed their equines in a single commune (smallest geographic administrative unit in France) at their home as private individuals. The distance between the communes of residence and of holding was, in most cases (including 79% of owners in the owner survey, 89.5% of the keepers in the keeper survey, and about 94% of the owner-keepers in both surveys), less than 30 km. More than half of the keepers kept a maximum of five equines and the majority with two different uses/destinations together, mostly leisure-retirement, leisure-breeding, leisure-sport, and sport-breeding. The main limitation of the study was that a relatively limited number of people (n = 3518) were reachable due to the low availability of an email address and contact agreement. Nonetheless, the findings provide an overview of how equines are kept by non-professional owners and keepers and complements information usually collected by the French riding institute. Additionally, information collected is very helpful to determine a realistic estimate of the spatial distribution of equines in France. This information is very important for the equine sector, for demographic knowledge and also improvement of surveillance plans and control measures and for the management and monitoring of health events to limit the spread of diseases.

Modelling BSE trend over time in Europe, a risk assessment perspective.

BSE is a zoonotic disease that caused the emergence of variant Creuzfeldt-Jakob disease in the mid 1990s. The trend of the BSE epidemic in seven European countries was assessed and compared, using Age-Period-Cohort and Reproduction Ratio modelling applied to surveillance data 2001-2007. A strong decline in BSE risk was observed for all countries that applied control measures during the 1990s, starting at different points in time in the different countries. Results were compared with the type and date of the BSE control measures implemented between 1990 and 2001 in each country. Results show that a ban on the feeding of meat and bone meal (MBM) to cattle alone was not sufficient to eliminate BSE. The fading out of the epidemic started shortly after the complementary measures targeted at controlling the risk in MBM. Given the long incubation period, it is still too early to estimate the additional effect of the ban on the feeding of animal protein to all farm animals that started in 2001. These results provide new insights in the risk assessment of BSE for cattle and Humans, which will especially be useful in the context of possible relaxing BSE surveillance and control measures.

Time trends in exposure of cattle to bovine spongiform encephalopathy and cohort effect in France and Italy: value of the classical Age-Period-Cohort approach.

BACKGROUND: The Age-Period-Cohort (APC) analysis is routinely used for time trend analysis of cancer incidence or mortality rates, but in veterinary epidemiology, there are still only a few examples of this application. APC models were recently used to model the French epidemic assuming that the time trend for BSE was mainly due to a cohort effect in relation to the control measures that may have modified the BSE exposure of cohorts over time. We used a categorical APC analysis which did not require any functional form for the effect of the variables, and examined second differences to estimate the variation of the BSE trend. We also reanalysed the French epidemic and performed a simultaneous analysis of Italian data using more appropriate birth cohort categories for comparison. RESULTS: We used data from the exhaustive surveillance carried out in France and Italy between 2001 and 2007, and comparatively described the trend of the epidemic in both countries. At the end, the shape and irregularities of the trends were discussed in light of the main control measures adopted to control the disease. In Italy a decrease in the epidemic became apparent from 1996, following the application of rendering standards for the processing of specific risk material (SRM). For the French epidemic, the pattern of second differences in the birth cohorts confirmed the beginning of the decrease from 1995, just after the implementation of the meat and bone meal (MBM) ban for all ruminants (1994). CONCLUSION: The APC analysis proved to be highly suitable for the study of the trend in BSE epidemics and was helpful in understanding the effects of management and control of the disease. Additionally, such an approach may help in the implementation of changes in BSE regulations.

Utility of examining fallen stock data to monitor health-related events in equids: Application to an outbreak of West Nile Virus in France in 2015.

Few studies about the use of quantitative equine mortality data for monitoring purposes are available. Our study evaluated the utility of monitoring emerging equine diseases using mortality data collected by rendering plants. We used approaches involving modelling of historical mortality fluctuations and detection algorithm methods to analyse changes in equine mortality in connection with the West Nile Virus (WNV) outbreak that occurred between July and September 2015 along the Mediterranean coast of France. Two weeks after the first equine WNV case was detected by clinical surveillance, detection algorithms identified excess mortality. The temporal distribution of this excess mortality suggested that it was related to the WNV outbreak, which may helped to assess the impact of the WNV epizootic on equine mortality. The results suggest that real-time follow-up of mortality could be a useful tool for equine health surveillance.

Designing a Syndromic Bovine Mortality Surveillance System: Lessons Learned From the 1-Year Test of the French OMAR Alert Tool.

Between May 2018 and 2019, a syndromic bovine mortality surveillance system (OMAR) was tested in 10 volunteer French départements (French intermediate-level administrative unit) to assess its performance in real conditions, as well as the human and financial resources needed to ensure normal functioning. The system is based on the automated weekly analysis of the number of cattle deaths reported by renderers in the Fallen Stock Data Interchange Database established in January 2011. In our system, every Thursday, the number of deaths is grouped by ISO week and small surveillance areas and then analyzed using traditional time-series analysis steps (cleaning, prediction, signal detection). For each of the five detection algorithms implemented (i.e., the exponentially weighted moving average chart, cumulative sum chart, Shewhart chart, Holt-Winters, and historical limits algorithms), seven detection limits are applied, giving a signal score from 1 (low excess mortality) to 7 (high excess mortality). The severity of excess mortality (alarm) is then classified into four categories, from very low to very high, by combining the signal scores, the relative excess mortality, and the persistence of the signal(s) over the previous 4 weeks. Detailed and interactive weekly reports and a short online questionnaire help pilot départements and the OMAR central coordination cell assess the performance of the system. During the 1-year test, the system showed highly variable sensitivity among départements. This variability was partly due not only to the demographic distribution of cattle (very few signals in low-density areas) but also to the renderer's delay in reporting to the Fallen Stock Data Interchange Database (on average, only 40% of the number of real deaths had been transmitted within week, with huge variations among départements). As a result, in the pilot départements, very few alarms required on-farm investigation and excess mortality often involved a small number of farms already known to have health or welfare problems. Despite its perfectibility, the system nevertheless proved useful in the daily work of animal health professionals for collective and individual surveillance. The test is still ongoing for a second year in nine départements to evaluate the effectiveness of the improvements agreed upon at the final meeting.

Swab cloths as a tool for revealing environmental contamination by Q fever in ruminant farms.

Q fever is a zoonotic abortive disease of ruminants mostly transmitted by inhalation of aerosols contaminated by Coxiella burnetii. Clusters of cases or even epidemics regularly occur in humans but, to date, there is no consensus about the best way to carry out outbreak investigations in order to identify potential farms at risk. Although environmental samples might be useful during such investigations, there are few baseline data on the presence of C. burnetii in the environment of ruminant farms. We thus investigated dust samples from cattle, sheep and goat farm buildings in order to (a) estimate C. burnetii detection frequency and bacterial loads in the environment, and (b) determine whether this environmental contamination is associated with series of abortions attributed to Q fever. We considered 113 herds with a recent abortive episode potentially related (n = 60) or not (n = 53) to C. burnetii. Dust was sampled using a swab cloth and tested by a quantitative PCR method targeting the IS1111 gene. Coxiella burnetii DNA was detected on 9 of 50 cattle farms, 13 of 19 goat farms and 30 of 40 sheep farms. On 16 cloths, bacterial loads were higher than 108 genome equivalents, levels as high as in infectious materials such as placentas and aborted foetuses. Overall, the probability of detecting C. burnetii DNA was higher on small ruminant farms than cattle farms, in herds suspected of Q fever and in large herds. We conclude that swab cloths are a putative indicator of contamination of ruminant farms by C. burnetii.

Assessment of fallen equine data in France and their usefulness for epidemiological investigations.

Quantitative information about equine mortality is relatively scarce, yet it could be of great value for epidemiology purposes. Several European projects based on the exploitation of data from rendering plants have been developed to improve livestock surveillance. Similar data are available for equines in France but have never been studied to date. The objective of this research was to evaluate the potential of the French Ministry of Agriculture's Fallen Stock Data Interchange (FSDI) database to provide quantitative mortality information on the French equine population. The quality of FSDI equine data from 2011 to 2014 was assessed using complementary data registered in the French equine census database, SIRE. Despite a perfectible quality, the FSDI database proved to be a valuable source for studying the basal patterns of mortality over time in the French equine population as illustrated by the spatial representation of the number of deaths. However, improvements in the FSDI database are needed, in particular regarding the registration of animal identification numbers, in order to detail equine mortality for epidemiology purposes.

Evaluation of a Multivariate Syndromic Surveillance System for West Nile Virus.

BACKGROUND: Various methods are currently used for the early detection of West Nile virus (WNV) but their outputs are not quantitative and/or do not take into account all available information. Our study aimed to test a multivariate syndromic surveillance system to evaluate if the sensitivity and the specificity of detection of WNV could be improved. METHODS: Weekly time series data on nervous syndromes in horses and mortality in both horses and wild birds were used. Baselines were fitted to the three time series and used to simulate 100 years of surveillance data. WNV outbreaks were simulated and inserted into the baselines based on historical data and expert opinion. Univariate and multivariate syndromic surveillance systems were tested to gauge how well they detected the outbreaks; detection was based on an empirical Bayesian approach. The systems' performances were compared using measures of sensitivity, specificity, and area under receiver operating characteristic curve (AUC). RESULTS: When data sources were considered separately (i.e., univariate systems), the best detection performance was obtained using the data set of nervous symptoms in horses compared to those of bird and horse mortality (AUCs equal to 0.80, 0.75, and 0.50, respectively). A multivariate outbreak detection system that used nervous symptoms in horses and bird mortality generated the best performance (AUC = 0.87). CONCLUSIONS: The proposed approach is suitable for performing multivariate syndromic surveillance of WNV outbreaks. This is particularly relevant, given that a multivariate surveillance system performed better than a univariate approach. Such a surveillance system could be especially useful in serving as an alert for the possibility of human viral infections. This approach can be also used for other diseases for which multiple sources of evidence are available.

Was the French clinical surveillance system of bovine brucellosis influenced by the occurrence and surveillance of other abortive diseases?

The bovine brucellosis clinical surveillance system implemented in France aims to detect early any case of bovine brucellosis, a disease of which the country has been declared free since 2005. It relies on the mandatory notification of every bovine abortion. Following the spread of the Schmallenberg virus (SBV) in France in 2012 and 2013, and the implementation in 2012 of a clinical surveillance programme of Q fever based on abortion notifications in ten pilot départements, our objective was to study whether these two events influenced the brucellosis clinical surveillance system. The proportion of notifying farmers was analyzed over each semester from June 1, 2009 to June 30, 2013 according to the size and production type of herds, SBV status of départements and the implementation of the Q fever surveillance. Our analysis showed a slight increase in the proportion of notifying farmers as départements became infected by SBV, and after the implementation of Q fever surveillance (during the first semester of 2013). These variations might be explained by an increase in abortion occurrence (congenital deformities in newborns, due to SBV) and/or by an increase in farmers' and veterinarians' awareness (due to the spread of SBV and the implementation of the Q fever surveillance). These results highlight the difficulties in interpreting variations in the proportion of notifying farmers as a consequence of an increase in abortion occurrence. As bovine abortion surveillance can play an important role in the early warning for several diseases, there is a need to explore other ways to monitor abortions in cattle, such as syndromic surveillance using the dates of artificial insemination or calving data.

Modelling the trend of bovine spongiform encephalopathy prevalence in France: Use of restricted cubic spline regression in age-period-cohort models to estimate the efficiency of control measures.

An age-period-cohort (APC) analysis was used to assess the trend in prevalence of bovine spongiform encephalopathy (BSE) in France over time in relation to the control measures adopted since onset of the epidemic. Restricted cubic regression splines were used to model the functional forms of the non-linear effects of age at screening, birth cohort and date of diagnosis of the tested animals. The data of the 2001-2007 period of surveillance was analysed using 1-year categorisation. A categorical analysis was performed as control to check the accuracy of the sets of knots in the spline models, which were selected according to the Akaike Information Criterion (AIC). Knot selection was based on a priori knowledge of the disease and the dates of implementation of the five main BSE control measures. It was assumed that disease prevalence was a function of exposure to BSE and that changes in the exposure of cattle to BSE were mainly due to the control measures. The effects of the five main control measures were discussed in relation to the trend in BSE risk for the successive birth cohorts. The six selected models confirmed that all measures participated in disease control. However, characterization of the respective effect of individual measures was not straightforward due to the very low disease prevalence, incompletely tested cohorts and probably cumulative and overlapping effects of successive measures. The ban of importation of meat and bone meal (MBM) from the UK and the ban of use of MBM in bovines were insufficient to control the epidemic. The decline in the BSE epidemic more likely originated from implementation of the ban of MBM use in all ruminants in 1994, whose effect was probably reinforced by the evolution in perception of the BSE risk following evidence of BSE transmission to humans. Finally, the respective effects of the last two measures (prohibition of the use of specific risk material in 1996 and total MBM ban in 2000) could not be characterized as they were implemented when the disease trend was already in strong decline.