Using expert knowledge to incorporate uncertainty in cause-of-death assignments for modeling of cause-specific mortality.

Implicit and explicit use of expert knowledge to inform ecological analyses is becoming increasingly common because it often represents the sole source of information in many circumstances. Thus, there is a need to develop statistical methods that explicitly incorporate expert knowledge, and can successfully leverage this information while properly accounting for associated uncertainty during analysis. Studies of cause-specific mortality provide an example of implicit use of expert knowledge when causes-of-death are uncertain and assigned based on the observer's knowledge of the most likely cause. To explicitly incorporate this use of expert knowledge and the associated uncertainty, we developed a statistical model for estimating cause-specific mortality using a data augmentation approach within a Bayesian hierarchical framework. Specifically, for each mortality event, we elicited the observer's belief of cause-of-death by having them specify the probability that the death was due to each potential cause. These probabilities were then used as prior predictive values within our framework. This hierarchical framework permitted a simple and rigorous estimation method that was easily modified to include covariate effects and regularizing terms. Although applied to survival analysis, this method can be extended to any event-time analysis with multiple event types, for which there is uncertainty regarding the true outcome. We conducted simulations to determine how our framework compared to traditional approaches that use expert knowledge implicitly and assume that cause-of-death is specified accurately. Simulation results supported the inclusion of observer uncertainty in cause-of-death assignment in modeling of cause-specific mortality to improve model performance and inference. Finally, we applied the statistical model we developed and a traditional method to cause-specific survival data for white-tailed deer, and compared results. We demonstrate that model selection results changed between the two approaches, and incorporating observer knowledge in cause-of-death increased the variability associated with parameter estimates when compared to the traditional approach. These differences between the two approaches can impact reported results, and therefore, it is critical to explicitly incorporate expert knowledge in statistical methods to ensure rigorous inference.

Experimental infection of meadow voles (Microtus pennsylvanicus) with sheep scrapie.

Meadow voles (Microtus pennsylvanicus) are permissive to chronic wasting disease (CWD) infection, but their susceptibility to other transmissible spongiform encephalopathies (TSEs) is poorly characterized. In this initial study, we intracerebrally challenged 6 meadow voles with 2 isolates of sheep scrapie. Three meadow voles acquired a TSE after the scrapie challenge and an extended incubation period. The glycoform profile of proteinase K-resistant prion protein (PrP(res)) in scrapie-sick voles remained similar to the sheep inocula, but differed from that of voles clinically affected by CWD. Vacuolization patterns and disease-associated prion protein (PrP(Sc)) deposition were generally similar in all scrapie-affected voles, except in the hippocampus, where PrP(Sc) staining varied markedly among the animals. Our results demonstrate that meadow voles can acquire a TSE after intracerebral scrapie challenge and that this species could therefore prove useful for characterizing scrapie isolates.

Les campagnols des champs (Microtus pennsylvanicus) sont permissifs à l'infection par l'agent de la maladie débilitante chronique (MDC), mais leur susceptibilité aux autres encéphalopathies spongiformes transmissibles (EST) est peu caractérisée. Dans cette première étude, six campagnols ont été inoculés par voie intracérébrale avec deux isolats de l'agent de la tremblante du mouton. Trois campagnols ont présenté une EST suite à l'inoculation de l'agent de la tremblante après une période d'incubation prolongée. Le profil glycoforme de la protéine prion résistante à la protéinase K (PrPres) chez les campagnols atteints demeura similaire à celui de l'inoculum ovin, mais différait de celui des campagnols affectés cliniquement de MDC. Les patrons de vacuolisation et le dépôt de protéine prion associée à la maladie (PrPSc) étaient généralement similaires chez tous les campagnols affectés de tremblante, à l'exception de l'hippocampe, où la coloration de PrPSc variait de façon marquée parmi les animaux. Ces résultats démontrent que les campagnols peuvent souffrir d'EST après inoculation intracérébrale de l'agent de la tremblante et que cette espèce pourrait s'avérer utile pour caractériser les isolats de l'agent de la tremblante.(Traduit par Docteur Serge Messier).

Integrated survival analysis using an event-time approach in a Bayesian framework.

Event-time or continuous-time statistical approaches have been applied throughout the biostatistical literature and have led to numerous scientific advances. However, these techniques have traditionally relied on knowing failure times. This has limited application of these analyses, particularly, within the ecological field where fates of marked animals may be unknown. To address these limitations, we developed an integrated approach within a Bayesian framework to estimate hazard rates in the face of unknown fates. We combine failure/survival times from individuals whose fates are known and times of which are interval-censored with information from those whose fates are unknown, and model the process of detecting animals with unknown fates. This provides the foundation for our integrated model and permits necessary parameter estimation. We provide the Bayesian model, its derivation, and use simulation techniques to investigate the properties and performance of our approach under several scenarios. Lastly, we apply our estimation technique using a piece-wise constant hazard function to investigate the effects of year, age, chick size and sex, sex of the tending adult, and nesting habitat on mortality hazard rates of the endangered mountain plover (Charadrius montanus) chicks. Traditional models were inappropriate for this analysis because fates of some individual chicks were unknown due to failed radio transmitters. Simulations revealed biases of posterior mean estimates were minimal (≤ 4.95%), and posterior distributions behaved as expected with RMSE of the estimates decreasing as sample sizes, detection probability, and survival increased. We determined mortality hazard rates for plover chicks were highest at <5 days old and were lower for chicks with larger birth weights and/or whose nest was within agricultural habitats. Based on its performance, our approach greatly expands the range of problems for which event-time analyses can be used by eliminating the need for having completely known fate data.

Using auxiliary information to improve wildlife disease surveillance when infected animals are not detected: a Bayesian approach.

There are numerous situations in which it is important to determine whether a particular disease of interest is present in a free-ranging wildlife population. However adequate disease surveillance can be labor-intensive and expensive and thus there is substantial motivation to conduct it as efficiently as possible. Surveillance is often based on the assumption of a simple random sample, but this can almost always be improved upon if there is auxiliary information available about disease risk factors. We present a Bayesian approach to disease surveillance when auxiliary risk information is available which will usually allow for substantial improvements over simple random sampling. Others have employed risk weights in surveillance, but this can result in overly optimistic statements regarding freedom from disease due to not accounting for the uncertainty in the auxiliary information; our approach remedies this. We compare our Bayesian approach to a published example of risk weights applied to chronic wasting disease in deer in Colorado, and we also present calculations to examine when uncertainty in the auxiliary information has a serious impact on the risk weights approach. Our approach allows "apples-to-apples" comparisons of surveillance efficiencies between units where heterogeneous samples were collected.

A method for quantifying blood flow distribution among the alveoli of the lung.

This article describes a method for quantifying blood flow distribution among lung alveoli. Our method is based on analysis of trapping patterns of small diameter (4 µm) fluorescent latex particles infused into lung capillaries. Trapping patterns are imaged using confocal microscopy, and the images are analyzed statistically using SAS subroutines. The resulting plots provide a quantifiable way of assessing interalveolar perfusion distribution in a way that has not previously been possible. Methods for using this technique are described, and the SAS routines are included. This technique can be an important tool for learning how this critical vascular bed performs in health and disease.

Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrP(TSE)) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrP(TSE) in tissues and blood. Macaque vCJD PrP(TSE) did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrP(TSE). The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrP(TSE). Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrP(TSE) was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrP(TSE) demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrP(TSE) was more permissive than human PrP(TSE) in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrP(TSE) from brains of humans and macaques with vCJD. PrP(TSE) signals were reproducibly detected by Western blot in dilutions through 10⁻¹² of vCJD-infected 10% brain homogenates. This is the first report showing PrP(TSE) from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrP(TSE) in vCJD-infected human and macaque blood.

The effect of swab sample choice on the detection of avian influenza in apparently healthy wild ducks.

Historically, avian influenza viruses have been isolated from cloacal swab specimens, but recent data suggest that the highly pathogenic avian influenza (HPAI) H5N1 virus can be better detected from respiratory tract specimens. To better understand how swab sample type affects the detection ability of low pathogenic avian influenza (LPAI) viruses we collected and tested four swab types: oropharyngeal swabs (OS), cloacal swabs (CS), the two swab types combined in the laboratory (LCS), and the two swab types combined in the field (FCS). A total of 1968 wild waterfowl were sampled by each of these four methods and tested for avian influenza virus using matrix gene reverse-transcription (RT)-PCR. The highest detection rate occurred with the FCS (4.3%) followed by the CS (4.0%). Although this difference did not achieve traditional statistical significance, Bayesian analysis indicated that FCS was superior to CS with an 82% probability. The detection rates for both the LCS (2.4%) and the OS (0.4%) were significantly different from the FCS. In addition, every swab type that was matrix RT-PCR positive was also tested for recovery of viable influenza virus. This protocol reduced the detection rate, but the ordering of swab types remained the same: 1.73% FCS, 1.42% CS, 0.81% LCS, and 0% OS. Our data suggest that the FCS performed at least as well as any other swab type for detecting LPAI viruses in the wild ducks tested. When considering recent studies showing that HPAI H5N1 can be better detected in the respiratory tract, the FCS is the most appropriate sample to collect for HPAI H5N1 surveillance while not compromising LPAI studies.

Alteration of the chronic wasting disease species barrier by in vitro prion amplification.

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids now detected in 19 states of the United States, three Canadian provinces, and South Korea. Whether noncervid species can be infected by CWD and thereby serve as reservoirs for the infection is not known. To investigate this issue, we previously used serial protein misfolding cyclic amplification (sPMCA) to demonstrate that CWD prions can amplify in brain homogenates from several species sympatric with cervids, including prairie voles (Microtus ochrogaster) and field mice (Peromyscus spp.). Here, we show that prairie voles are susceptible to mule deer CWD prions in vivo and that sPMCA amplification of CWD prions in vole brain enhances the infectivity of CWD for this species. Prairie voles inoculated with sPMCA products developed clinical signs of TSE disease approximately 300 days prior to, and more consistently than, those inoculated with CWD prions from deer brain. Moreover, the deposition patterns and biochemical properties of protease-resistant form of PrP (PrP(RES)) in the brains of affected voles differed from those in cervidized transgenic (CerPrP) mice infected with CWD. In addition, voles inoculated orally with sPMCA products developed clinical signs of TSE and were positive for PrP(RES) deposition, whereas those inoculated orally with deer-origin CWD prions did not. These results demonstrate that transspecies sPMCA of CWD prions can enhance the infectivity and adapt the host range of CWD prions and thereby may be useful to assess determinants of prion species barriers.

Modeling routes of chronic wasting disease transmission: environmental prion persistence promotes deer population decline and extinction.

Chronic wasting disease (CWD) is a fatal disease of deer, elk, and moose transmitted through direct, animal-to-animal contact, and indirectly, via environmental contamination. Considerable attention has been paid to modeling direct transmission, but despite the fact that CWD prions can remain infectious in the environment for years, relatively little information exists about the potential effects of indirect transmission on CWD dynamics. In the present study, we use simulation models to demonstrate how indirect transmission and the duration of environmental prion persistence may affect epidemics of CWD and populations of North American deer. Existing data from Colorado, Wyoming, and Wisconsin's CWD epidemics were used to define plausible short-term outcomes and associated parameter spaces. Resulting long-term outcomes range from relatively low disease prevalence and limited host-population decline to host-population collapse and extinction. Our models suggest that disease prevalence and the severity of population decline is driven by the duration that prions remain infectious in the environment. Despite relatively low epidemic growth rates, the basic reproductive number, R(0), may be much larger than expected under the direct-transmission paradigm because the infectious period can vastly exceed the host's life span. High prion persistence is expected to lead to an increasing environmental pool of prions during the early phases (i.e. approximately during the first 50 years) of the epidemic. As a consequence, over this period of time, disease dynamics will become more heavily influenced by indirect transmission, which may explain some of the observed regional differences in age and sex-specific disease patterns. This suggests management interventions, such as culling or vaccination, will become increasingly less effective as CWD epidemics progress.

Elodontoma in captive southern red-backed voles (Myodes gapperi).

Five southern red-backed voles (Myodes gapperi) of the first generation of a wild-caught breeding colony were presented with lesions at the maxillary incisors consistent with elodontoma. The affected animals had a history of chronic weight loss, were >16 months of age, and were siblings. Radiographs of the head showed multiglobular to irregularly outlined mineral opacity masses at the apices of the maxillary incisors. On necropsy, maxillary incisor teeth were not grossly visible, and a gingival ulceration was observed at the expected site of eruption. Microscopically, the apical region of the maxillary incisors was thickened or replaced by irregular dental tissue masses consistent with elodontoma. This is the first report to describe elodontoma in red-backed voles.

Mapping brucellosis increases relative to elk density using hierarchical Bayesian models.

The relationship between host density and parasite transmission is central to the effectiveness of many disease management strategies. Few studies, however, have empirically estimated this relationship particularly in large mammals. We applied hierarchical Bayesian methods to a 19-year dataset of over 6400 brucellosis tests of adult female elk (Cervus elaphus) in northwestern Wyoming. Management captures that occurred from January to March were over two times more likely to be seropositive than hunted elk that were killed in September to December, while accounting for site and year effects. Areas with supplemental feeding grounds for elk had higher seroprevalence in 1991 than other regions, but by 2009 many areas distant from the feeding grounds were of comparable seroprevalence. The increases in brucellosis seroprevalence were correlated with elk densities at the elk management unit, or hunt area, scale (mean 2070 km(2); range = [95-10237]). The data, however, could not differentiate among linear and non-linear effects of host density. Therefore, control efforts that focus on reducing elk densities at a broad spatial scale were only weakly supported. Additional research on how a few, large groups within a region may be driving disease dynamics is needed for more targeted and effective management interventions. Brucellosis appears to be expanding its range into new regions and elk populations, which is likely to further complicate the United States brucellosis eradication program. This study is an example of how the dynamics of host populations can affect their ability to serve as disease reservoirs.

Chronic wasting disease (CWD) susceptibility of several North American rodents that are sympatric with cervid CWD epidemics.

Chronic wasting disease (CWD) is a highly contagious always fatal neurodegenerative disease that is currently known to naturally infect only species of the deer family, Cervidae. CWD epidemics are occurring in free-ranging cervids at several locations in North America, and other wildlife species are certainly being exposed to infectious material. To assess the potential for transmission, we intracerebrally inoculated four species of epidemic-sympatric rodents with CWD. Transmission was efficient in all species; the onset of disease was faster in the two vole species than the two Peromyscus spp. The results for inocula prepared from CWD-positive deer with or without CWD-resistant genotypes were similar. Survival times were substantially shortened upon second passage, demonstrating adaptation. Unlike all other known prion protein sequences for cricetid rodents that possess asparagine at position 170, our red-backed voles expressed serine and refute previous suggestions that a serine in this position substantially reduces susceptibility to CWD. Given the scavenging habits of these rodent species, the apparent persistence of CWD prions in the environment, and the inevitable exposure of these rodents to CWD prions, our intracerebral challenge results indicate that further investigation of the possibility of natural transmission is warranted.

Further development of raccoon poxvirus-vectored vaccines against plague (Yersinia pestis).

In previous studies, we demonstrated protection against plague in mice and prairie dogs using a raccoon pox (RCN) virus-vectored vaccine that expressed the F1 capsular antigen of Yersinia pestis. In order to improve vaccine efficacy, we have now constructed additional RCN-plague vaccines containing two different forms of the lcrV (V) gene, including full-length (Vfull) and a truncated form (V307). Mouse challenge studies with Y. pestis strain CO92 showed that vaccination with a combination of RCN-F1 and the truncated V construct (RCN-V307) provided the greatest improvement (P=0.01) in protection against plague over vaccination with RCN-F1 alone. This effect was mediated primarily by anti-F1 and anti-V antibodies and both contributed independently to increased survival of vaccinated mice.

Genetic susceptibility to chronic wasting disease in free-ranging white-tailed deer: complement component C1q and Prnp polymorphisms.

The genetic basis of susceptibility to chronic wasting disease (CWD) in free-ranging cervids is of great interest. Association studies of disease susceptibility in free-ranging populations, however, face considerable challenges including: the need for large sample sizes when disease is rare, animals of unknown pedigree create a risk of spurious results due to population admixture, and the inability to control disease exposure or dose. We used an innovative matched case-control design and conditional logistic regression to evaluate associations between polymorphisms of complement C1q and prion protein (Prnp) genes and CWD infection in white-tailed deer from the CWD endemic area in south-central Wisconsin. To reduce problems due to admixture or disease-risk confounding, we used neutral genetic (microsatellite) data to identify closely related CWD-positive (n=68) and CWD-negative (n=91) female deer to serve as matched cases and controls. Cases and controls were also matched on factors (sex, location, age) previously demonstrated to affect CWD infection risk. For Prnp, deer with at least one Serine (S) at amino acid 96 were significantly less likely to be CWD-positive relative to deer homozygous for Glycine (G). This is the first characterization of genes associated with the complement system in white-tailed deer. No tests for association between any C1q polymorphism and CWD infection were significant at p<0.05. After controlling for Prnp, we found weak support for an elevated risk of CWD infection in deer with at least one Glycine (G) at amino acid 56 of the C1qC gene. While we documented numerous amino acid polymorphisms in C1q genes none appear to be strongly associated with CWD susceptibility.

Spatial and temporal patterns of chronic wasting disease: fine-scale mapping of a wildlife epidemic in Wisconsin.

Emerging infectious diseases threaten wildlife populations and human health. Understanding the spatial distributions of these new diseases is important for disease management and policy makers; however, the data are complicated by heterogeneities across host classes, sampling variance, sampling biases, and the space-time epidemic process. Ignoring these issues can lead to false conclusions or obscure important patterns in the data, such as spatial variation in disease prevalence. Here, we applied hierarchical Bayesian disease mapping methods to account for risk factors and to estimate spatial and temporal patterns of infection by chronic wasting disease (CWD) in white-tailed deer (Odocoileus virginianus) of Wisconsin, U.S.A. We found significant heterogeneities for infection due to age, sex, and spatial location. Infection probability increased with age for all young deer, increased with age faster for young males, and then declined for some older animals, as expected from disease-associated mortality and age-related changes in infection risk. We found that disease prevalence was clustered in a central location, as expected under a simple spatial epidemic process where disease prevalence should increase with time and expand spatially. However, we could not detect any consistent temporal or spatiotemporal trends in CWD prevalence. Estimates of the temporal trend indicated that prevalence may have decreased or increased with nearly equal posterior probability, and the model without temporal or spatiotemporal effects was nearly equivalent to models with these effects based on deviance information criteria. For maximum interpretability of the role of location as a disease risk factor, we used the technique of direct standardization for prevalence mapping, which we develop and describe. These mapping results allow disease management actions to be employed with reference to the estimated spatial distribution of the disease and to those host classes most at risk. Future wildlife epidemiology studies should employ hierarchical Bayesian methods to smooth estimated quantities across space and time, account for heterogeneities, and then report disease rates based on an appropriate standardization.

Estimating cause-specific mortality rates using recovered carcasses.

Stranding networks, in which carcasses are recovered and sent to diagnostic laboratories for necropsy and determination of cause of death, have been developed to monitor the health of marine mammal and bird populations. These programs typically accumulate comprehensive, long-term datasets on causes of death that can be used to identify important sources of mortality or changes in mortality patterns that lead to management actions. However, the utility of these data in determining cause-specific mortality rates has not been explored. We present a maximum likelihood-based approach that partitions total mortality rate, estimated by independent sources, into cause-specific mortality rates. We also demonstrate how variance estimates are derived for these rates. We present examples of the method using mortality data for California sea otters (Enhydra lutris nereis) and Florida manatees (Trichechus manatus latirostris).

Using amplified fragment length polymorphism analysis to differentiate isolates of Pasteurella multocida serotype 1.

Avian cholera, an infectious disease caused by the bacterium Pasteurella multocida, kills thousands of North American wild waterfowl annually. Pasteurella multocida serotype 1 isolates cultured during a laboratory challenge study of Mallards (Anas platyrhynchos) and collected from wild birds and environmental samples during avian cholera outbreaks were characterized using amplified fragment length polymorphism (AFLP) analysis, a whole-genome DNA fingerprinting technique. Comparison of the AFLP profiles of 53 isolates from the laboratory challenge demonstrated that P. multocida underwent genetic changes during a 3-mo period. Analysis of 120 P. multocida serotype 1 isolates collected from wild birds and environmental samples revealed that isolates were distinguishable from one another based on regional and temporal genetic characteristics. Thus, AFLP analysis had the ability to distinguish P. multocida isolates of the same serotype by detecting spatiotemporal genetic changes and provides a tool to advance the study of avian cholera epidemiology. Further application of AFLP technology to the examination of wild bird avian cholera outbreaks may facilitate more effective management of this disease by providing the potential to investigate correlations between virulence and P. multocida genotypes, to identify affiliations between bird species and bacterial genotypes, and to elucidate the role of specific bird species in disease transmission.

Acute hypoxia does not alter inter-alveolar perfusion distribution in unanesthetized rats.

Effects of hypoxic vasoconstriction on inter-alveolar perfusion distribution (< or =1000 alveoli) have not been studied. To address this, we measured inter-alveolar perfusion distribution in the lungs of unanesthetized rats breathing 10% O(2). Perfusion distributions were measured by analyzing the trapping patterns of 4 microm diameter fluorescent latex particles infused into the pulmonary circulation. The trapping patterns were statistically quantified in confocal images of the dried lungs. Trapping patterns were measured in lung volumes that ranged between less than 1 and 1300 alveoli, and were expressed as the log of the dispersion index (logDI). A uniform (statistically random) perfusion distribution corresponds to a logDI value of zero. The more this value exceeds zero, the more the distribution is clustered (non-random). At the largest tissue volume (1300 alveoli) logDI reached a maximum value of 0.68+/-0.42 (mean+/-s.d.) in hypoxic rats (n = 6), 0.50+/-0.38 in hypercapnic rats (n.s.) and 0.48+/-0.25 in air-breathing controls (n.s.). Our results suggest that acute hypoxia did not cause significant changes in inter-alveolar perfusion distribution in unanesthetized, spontaneously breathing rats.

Hemorrhage progressively disturbs interalveolar perfusion in the lungs of rats.

Acute hemorrhage is often followed by devastating lung injury. However, why blood loss should lead to lung injury is not known. One possibility is that hemorrhage rapidly disturbs the distribution of microvascular perfusion at the alveolar level, which may be a triggering event for subsequent injury. We showed previously that a 30% blood loss in rats caused significant maldistribution of interalveolar perfusion within 45 min (J Trauma 60:158, 2006). In this report, we describe results of further exploration of this phenomenon. We wanted to know if perfusion distribution was disturbed at 15 min, when vascular pressures were significantly reduced by the blood loss, compared with those at 45 min, when the pressures had returned substantially toward normal. We hemorrhaged rats by removing 30% of their blood volume. We quantified interalveolar perfusion distribution by statistically analyzing the trapping patterns of 4-microm-diameter fluorescent latex particles infused into the pulmonary circulation 15 (red particles) and 45 min (green particles) after blood removal. We used confocal fluorescence microscopy to digitally image the trapping patterns in sections of the air-dried lungs and used pattern analysis to quantify the patterns in tissue image volumes that ranged from 1,300 alveoli to less than 1 alveolus. LogDI, a measure of perfusion maldistribution, increased from 1.00 +/- 0.15 at 15 min after blood loss to 1.62 +/- 0.24 at 45 min (P < 0.001). These values were 0.86 +/- 0.22 (15 min) and 1.12 +/- 0.24 (45 min) in control rats (P = 0.03). Hemorrhage caused the green (45 min)-to-red (15 min) particle distance to decrease from 35.9 +/- 6.5 to 28.0 +/- 5.1 microm (P = 0.024) and the red-to-green particle distance to remain unchanged (30.2 +/- 5.7 microm [red]; 31.5 +/- 10.0 microm [green] [n.s.]). We conclude that hemorrhage caused a progressive increase in interalveolar perfusion maldistribution over 45 min that did not correspond to reduced arterial pressures or altered blood gases. Our particle distance measurements led us to further conclude that this maldistribution occurred in areas that were perfused at 15 min rather than in previously unperfused areas .

The fitting of general force-of-infection models to wildlife disease prevalence data.

Researchers and wildlife managers increasingly find themselves in situations where they must deal with infectious wildlife diseases such as chronic wasting disease, brucellosis, tuberculosis, and West Nile virus. Managers are often charged with designing and implementing control strategies, and researchers often seek to determine factors that influence and control the disease process. All of these activities require the ability to measure some indication of a disease's foothold in a population and evaluate factors affecting that foothold. The most common type of data available to managers and researchers is apparent prevalence data. Apparent disease prevalence, the proportion of animals in a sample that are positive for the disease, might seem like a natural measure of disease's foothold, but several properties, in particular, its dependency on age structure and the biasing effects of disease-associated mortality, make it less than ideal. In quantitative epidemiology, the "force of infection," or infection hazard, is generally the preferred parameter for measuring a disease's foothold, and it can be viewed as the most appropriate way to "adjust" apparent prevalence for age structure. The typical ecology curriculum includes little exposure to quantitative epidemiological concepts such as cumulative incidence, apparent prevalence, and the force of infection. The goal of this paper is to present these basic epidemiological concepts and resulting models in an ecological context and to illustrate how they can be applied to understand and address basic epidemiological questions. We demonstrate a practical approach to solving the heretofore intractable problem of fitting general force-of-infection models to wildlife prevalence data using a generalized regression approach. We apply the procedures to Mycobacterium bovis (bovine tuberculosis) prevalence in bison (Bison bison) in Wood Buffalo National Park, Canada, and demonstrate strong age dependency in the force of infection as well as an increased mortality hazard in positive animals.