Modeling survival of experimentally virus-infected laboratory animals

Although survival analysis is a well-established mathematical discipline, there seem to be almost no attempts in survival modeling for experimentally virus-infected laboratory animals. We have taken up a stochastic approach originally developed by Shortley in the sixties and have applied it to three different types of experimental data: to virus titer determination, to the dose dependence of the mean survival time and to single survival curves. Experience concerning parameter estimation is reported and new ways of working with the model parameters are proposed. A standard mean survival time is defined and suggested as a new quantitative measure of virulence. Moreover, for the comparison of two experiments for which the amount of virions inoculated is kept fixed, but for which other parameters may vary, a new scheme of systematizing survival data from experimentally virus-infected laboratory animals is proposed. It is very likely that the model can be also applied to cancer survival data or any other infectious pathogen.     

A bivariate quantitative genetic model for a threshold trait and a survival trait

Many of the functional traits considered in animal breeding can be analyzed as threshold traits or survival traits with examples including disease traits, conformation scores, calving difficulty and longevity. In this paper we derive and implement a bivariate quantitative genetic model for a threshold character and a survival trait that are genetically and environmentally correlated. For the survival trait, we considered the Weibull log-normal animal frailty model. A Bayesian approach using Gibbs sampling was adopted in which model parameters were augmented with unobserved liabilities associated with the threshold trait. The fully conditional posterior distributions associated with parameters of the threshold trait reduced to well known distributions. For the survival trait the two baseline Weibull parameters were updated jointly by a Metropolis-Hastings step. The remaining model parameters with non-normalized fully conditional distributions were updated univariately using adaptive rejection sampling. The Gibbs sampler was tested in a simulation study and illustrated in a joint analysis of calving difficulty and longevity of dairy cattle. The simulation study showed that the estimated marginal posterior distributions covered well and placed high density to the true values used in the simulation of data. The data analysis of calving difficulty and longevity showed that genetic variation exists for both traits. The additive genetic correlation was moderately favorable with marginal posterior mean equal to 0.37 and 95% central posterior credibility interval ranging between 0.11 and 0.61. Therefore, this study suggests that selection for improving one of the two traits will be beneficial for the other trait as well.     

Reaction of the organism to stress: The survival attractor concept

This paper outlines a phenomenological approach for describing physiological reactions occurring immediately after vital threats. This exemplified by data taken from previous studies relative to chemical intoxications of rats by a neurotoxical drug. The survival rate of the animals and the variations of their cerebral acetylcholinesterese activity are both reported as a function of the drug concentration, and with respect to their age. The collecting of the results may be described as the cusp, a bifurcation set of Thom's Catastrophe Theory.The young animals react by a vital burst which modifies the shape of the cusp. A new fold or pocket takes place, changing it to the butterfly bifurcation set. This pocket supports the survival attractor concept, which appears reactional, transitory and variable in its intensity.In the last part of the paper, an extension of this concept is proposed to the visual domain. Some of patients who have suddenly and partially lost their visual acuity can recover some visual capacity by developing a new ability to see in weak contrasts. This reaction may be described as a visual survival attractor.     

Assessing survival in a multi-population system: a case study on bat populations

In long-lived animals, adult survival is among the most important determinants of population dynamics. Although it may show considerable variation both in time and among populations and sites, a single survival estimate per species is often used in comparative evolutionary studies or in conservation management to identify threatened populations. We estimated adult survival of the isabelline serotine bat Eptesicus isabellinus using capture–recapture data collected on six maternity colonies scattered over a large area (distance 8–103 km) during periods varying from 8 to 26 years. We modelled temporal and inter-colony variations as random effects in a Bayesian framework and estimated mean annual adult survival of females on two scales and a single survival value across all colonies. On a coarse scale, we grouped colonies according to two different habitat types and investigated the effect on survival. A difference in adult survival was detected between the two habitat types [posterior mean of annual survival probability 0.71; 95% credible interval (CI) 0.51–0.86 vs. 0.60; 0.28–0.89], but it was not statistically supported. On a fine scale, survival of the six colonies ranged between 0.58 (95% CI 0.23–0.92) and 0.81 (0.73–0.88), with variation between only two colonies being statistically supported. Overall survival was 0.72 (95% CI 0.57–0.93) with important inter-colony variability (on a logit scale 0.98; 95% CI 0.00–8.16). Survival varied temporally in a random fashion across colonies. Our results show that inference based solely on single colonies should be treated with caution and that a representative unbiased estimate of survival for any species should ideally be based on multiple populations.     

Importance of determining the climatic domains of sheep breeds

The main purpose of the study was to compare the capacity of the major sheep breeds in Morocco to cope with climate changes through the ranges of several climate parameters in which they can be found. We first delimitated the climatic ‘domains’ of each breed by constructing a database including altitude and climatic parameters (minima mean of the coldest month, maxima mean of the hottest month, annual rainfall, pluviothermic coefficient of Emberger Q₂, annual minima mean and annual maxima mean) on a 30-year period using the representative stations of each breed distribution. The overlap between each breed combination was quantified through a canonical analysis that extracted the most discriminant parameters. The variance analysis of each climatic parameter evidenced two breeds remarkable by their tolerance. The first one is the Timahdite, mainly settled in areas over 1100 m, which can tolerate the greatest variations in annual rainfall and pluviothermic coefficient. In spite of this feature, this breed is endangered owing to the decreasing quality of pastures. The second one is the D’man which apparently can support high variations in extreme temperatures. In fact, this breed is not well adapted to pastures and requires a special microclimate offered by oases. The information reported in this study will be the basis for the establishment of characterization and selection strategies for Moroccan sheep.     

Diseases, parasites and survival of coyotes in south-central Georgia.

Serologic testing, radio-telemetry and post-mortem diagnostic evaluations were used to investigate survival and causes of mortality among 17 coyotes (Canis latrans) in south-central Georgia (USA). Prevalence of canine heartworm (Dirofilaria immitis) microfilariae was lower (P = 0.057) among fall-captured (22%) than among winter-captured (75%) coyotes. Prevalence of heartworm was higher among adults than juveniles in the fall, but no significant difference was detected between animals captured in winter. Antibodies were found against canine parvovirus (65%), canine parainfluenza virus (59%), infectious canine hepatitis virus (41%), and Toxoplasma gondii (18%). Antibodies were not found to Brucella canis, canine coronavirus, five serovars of Leptospira interrogans, or canine distemper virus. Seroprevalence of canine parvovirus was lower (P = 0.009) among fall-captured animals (33%) than winter-captured animals (100%). The Kaplan-Meier estimate of annual survival was 0.500 for all animals. Juvenile survival did not differ (P = 0.79) from adult survival, but male survival (S = 0.217) was lower (P = 0.11) than female survival (S = 0.804). Two of nine (22%) mortalities were human-caused, one was due to concurrent canine parvovirus and canine distemper virus infections, one animal died of trauma, two were considered natural mortalities of unknown cause, and no cause of death could be determined for the remaining three animals. Natural mortality may be significant for coyotes in south-central Georgia, although there was no apparent link between exposure to pathogens and the animals' subsequent fate in our small sample.     

Genetic parameters for social effects on survival in cannibalistic layers: Combining survival analysis and a linear animal model

Background

Mortality due to cannibalism in laying hens is a difficult trait to improve genetically, because censoring is high (animals still alive at the end of the testing period) and it may depend on both the individual itself and the behaviour of its group members, so-called associative effects (social interactions). To analyse survival data, survival analysis can be used. However, it is not possible to include associative effects in the current software for survival analysis. A solution could be to combine survival analysis and a linear animal model including associative effects. This paper presents a two-step approach (2STEP), combining survival analysis and a linear animal model including associative effects (LAM).

Methods

Data of three purebred White Leghorn layer lines from Institut de Sélection Animale B.V., a Hendrix Genetics company, were used in this study. For the statistical analysis, survival data on 16,780 hens kept in four-bird cages with intact beaks were used. Genetic parameters for direct and associative effects on survival time were estimated using 2STEP. Cross validation was used to compare 2STEP with LAM. LAM was applied directly to estimate genetic parameters for social effects on observed survival days.

Results

Using 2STEP, total heritable variance, including both direct and associative genetic effects, expressed as the proportion of phenotypic variance, ranged from 32% to 64%. These results were substantially larger than when using LAM. However, cross validation showed that 2STEP gave approximately the same survival curves and rank correlations as LAM. Furthermore, cross validation showed that selection based on both direct and associative genetic effects, using either 2STEP or LAM, gave the best prediction of survival time.

Conclusion

It can be concluded that 2STEP can be used to estimate genetic parameters for direct and associative effects on survival time in laying hens. Using 2STEP increased the heritable variance in survival time. Cross validation showed that social genetic effects contribute to a large difference in survival days between two extreme groups. Genetic selection targeting both direct and associative effects is expected to reduce mortality due to cannibalism in laying hens.     

Marginal habitats provide unexpected survival benefits to the alpine marmot

Age-specific survival trajectories can vary significantly among wild populations. Identifying the environmental conditions associated with such variability is of primary importance to understand the dynamics of free-ranging populations. In this study, we investigated survival variations among alpine marmot (Marmota marmota) families living in areas with opposite environmental characteristics: the typical habitat of the species (alpine meadow) and a marginal area bordering the forest. We used data collected during an 11-year study in the Gran Paradiso National Park (Italy) and performed a Bayesian survival trajectory analysis on marked individuals. Furthermore, we investigated, at a territorial level, the relationships among demographic parameters and habitat variables by using a path analysis approach. Contrary to our expectations, for most of the marmot's lifespan, survival rate was higher in the marginal site closer to the forest and with lower visibility than in the alpine meadow site. Path analysis indicated that the number of families living close to each other negatively affected the stability of the dominant couple, which in turn affected both juvenile survival and reproduction. Given the lower number of neighboring families which inhabited the marginal site and the potentially different predation pressure by the most effective predator in the area (Aquila chrysaetos), our results suggest that species adapted to live in open habitats may benefit from living in a marginal habitat. This study highlights the importance of habitats bordering the forest in the conservation of alpine marmots.     

Plasma viremia in macaques infected with simian immunodeficiency virus: plasma viral load early in infection predicts survival.

A reliable method for the quantitation of plasma viremia in nonhuman primates infected with simian immunodeficiency virus (SIV) and related viruses is described. This method is based on an established quantitative-competitive PCR format and includes a truncated control for internal assay calibration. Optimization of assay conditions has significantly improved amplification specificity, and interassay variability is comparable to that of commercially available assays for human immunodeficiency virus (HIV) quantitation. This procedure was used to monitor viral loads in a group of Macaca mulatta animals that were infected with SIVsmE660 for over 2 years. Highly diverse profiles of plasma viremia were observed among animals, and high viral loads were associated with more rapid disease progression. Spearman rank correlation analyses were done for survival versus three parameters of viral load: plasma viremia, p27 core antigen, and frequency of infected peripheral blood mononuclear cells. Plasma viremia had the strongest overall correlation and was significantly (P < 0.05 to P < 0.01) associated with survival at 10 of the 13 time points examined. Plasma viremia did not correlate with survival during the primary viremia phase; however, the strength of this correlation increased with time postinfection and, remarkably, viremia levels as early as week 6 postinfection were highly predictive (P < 0.01) of relative survival. These findings are consistent with the available clinical data concerning viral load correlates early in HIV infection, and they provide further support for the view that disease outcome in lentiviral infection may be largely determined by events that occur shortly after infection.     

Delayed transmission selects for increased survival of vesicular stomatitis virus

Life-history theory predicts that traits for survival and reproduction cannot be simultaneously maximized in evolving populations. For this reason, in obligate parasites such as infectious viruses, selection for improved between-host survival during transmission may lead to evolution of decreased within-host reproduction. We tested this idea using experimental evolution of RNA virus populations, passaged under differing transmission times in the laboratory. A single ancestral genotype of vesicular stomatitis virus (VSV), a negative-sense RNA Rhabdovirus, was used to found multiple virus lineages evolved in either ordinary 24-h cell-culture passage, or in delayed passages of 48 h. After 30 passages (120 generations of viral evolution), we observed that delayed transmission selected for improved extracellular survival, which traded-off with lowered viral fecundity (slower exponential population growth and smaller mean plaque size). To further examine the confirmed evolutionary trade-off, we obtained consensus whole-genome sequences of evolved virus populations, to infer phenotype–genotype associations. Results implied that increased virus survival did not occur via convergence; rather, improved virion stability was gained via independent mutations in various VSV structural proteins. Our study suggests that RNA viruses can evolve different molecular solutions for enhanced survival despite their limited genetic architecture, but suffer generalized reproductive trade-offs that limit overall fitness gains.     

Effects of sexual differences of age at maturity and survival on population sex ratio

Summary Five demographical factors influencing the sex ratio of a population are classically considered. The influence of two of them is dependent on the longevity of individuals in the population. The effect of differential age at maturity between males and females is higher for animals with low annual survival, whereas the effect of differential annual survival between males and females is higher for animals with high annual survival. Such a conclusion applied to turtles, which are long life-span animals, allows us to retain differential survival between sexes as a major factor influencing the population sex ratio.     

Virus survival as a seasonal factor in influenza and poliomyelitis

Summary The influence of temperature and humidity on the survival of airborne viruses was studied in a static system. Preliminary experiments with a bacteriophage showed that relative humidity was more important than temperature and absolute humidity. The effect of relative humidity was not dependent on the composition of the medium surrounding the virus particles. The survival of influenza and poliomyelitis virus are sharply influenced by relative humidity but in an opposite way. Influenza virus survives much better at lower humidities, poliomyelitis virus at higher humidities. In countries with moderate climates the period of increasing morbility for influenza, in winter, coincides with indoor conditions of relative humidity which are optimal to virus survival. For poliomyelitis the same is true during summer (Fig. 7). Indoor relative humidity is considered an important “seasonal factor” in the epidemiology of poliomyelitis and influenza and probably of other diseases.     

Richards-like two species population dynamics model

The two-species population dynamics model is the simplest paradigm of inter- and intra-species interaction. Here, we present a generalized Lotka–Volterra model with intraspecific competition, which retrieves as particular cases, some well-known models. The generalization parameter is related to the species habitat dimensionality and their interaction range. Contrary to standard models, the species coupling parameters are general, not restricted to non-negative values. Therefore, they may represent different ecological regimes, which are derived from the asymptotic solution stability analysis and are represented in a phase diagram. In this diagram, we have identified a forbidden region in the mutualism regime, and a survival/extinction transition with dependence on initial conditions for the competition regime. Also, we shed light on two types of predation and competition: weak, if there are species coexistence, or strong, if at least one species is extinguished.     

Generalized F accelerated failure time model for mapping survival trait loci

As the two most popular models in survival analysis, the accelerated failure time (AFT) model can more easily fit survival data than the Cox proportional hazards model (PHM). In this study, we develop a general parametric AFT model for identifying survival trait loci, in which the flexible generalized F distribution, including many commonly used distributions as special cases, is specified as the baseline survival distribution. EM algorithm for maximum likelihood estimation of model parameters is given. Simulations are conducted to validate the flexibility and the utility of the proposed mapping procedure. In analyzing survival time following hyperoxic acute lung injury (HALI) of mice in an F(2) mating population, the generalized F distribution performed best among the six competing survival distributions and detected four QTLs controlling differential HALI survival.     

Ranking: a closer look on globalisation methods for normalisation of gene expression arrays

Data from gene expression arrays are influenced by many experimental parameters that lead to variations not simply accessible by standard quantification methods. To compare measurements from gene expression array experiments, quantitative data are commonly normalised using reference genes or global normalisation methods based on mean or median values. These methods are based on the assumption that (i) selected reference genes are expressed at a standard level in all experiments or (ii) that mean or median signal of expression will give a quantitative reference for each individual experiment. We introduce here a new ranking diagram, with which we can show how the different normalisation methods compare, and how they are influenced by variations in measurements (noise) that occur in every experiment. Furthermore, we show that an upper trimmed mean provides a simple and robust method for normalisation of larger sets of experiments by comparative analysis.     

The simulation of 137Cs distribution in forest ecosystems and prediction of its accumulation by forest products

A mathematical model of 137Cs migration in forest ecosystem is presented, which describes the behaviour of this radionuclide in the forest litter-soil system, trees, understory and forest animals. The model's parameters for different types of forest ecosystems are estimated and model's adequacy is tested through the use of independent experimental data. The sensitivity of the model's output variables is analyzed to variations in the most significant parameters. The differences in the seasonal and mean annual dynamics of 137Cs concentration in muscles of roe deers and mooses are shown to be defined by specific features of the diets of these animals and variations in 137Cs content in the main diet components.     

Population size and survival of the Brazilian Torrent Frog Hylodes heyeri (Anura,Hylodidae)

Population dynamics are influenced by environmental variability and understanding the abundance and persistence of individuals and populations is a fundamental goal of population ecology. Thus, estimating demographic parameters to identify the factors important for population variability is required to understand temporal and spatial dynamics. The stream-living diurnal frog Hylodes heyeri is endemic to the Atlantic Forest of Brazil in the states of Paraná, São Paulo and Santa Catarina. Here we use capture-mark-recapture methods to estimate survival rates and population size of this Brazilian Torrent Frog in Pico do Marumbi State Park, Paraná. We used CJS models for an open population to estimate apparent survival, capturability and population size in two streams. The number of captures during each session was positively correlated with the minimum weekly temperature. Despite that correlation, the most parsimonious model of survival and capturability was the constant model for both parameters, resulting in a monthly survival rate of 0.38 (95% CI = 0.30–0.46). Thus, only the abundance of the frog differed in the two streams (79 vs. 36), with the population size estimate of 187 individuals. Reproduction is seasonal in the Brazilian Torrent Frog and so the low monthly survival rate suggests that animals move over time rather than die, because 38% month⁻¹ survival should result in <1% of the population remaining after 5 months. Thus, researchers must recognize that populations are labile and individuals often move or are washed downstream during heavy rainfall, generating apparently rapid local turnover that is unlikely to reflect true mortality.     

Estimating survival of a streamside salamander: importance of temporary emigration,capture response,and location

Estimating survival for highly secretive aquatic animals, such as stream salamanders, presents numerous challenges. Salamanders often spend a considerable time in refugia where they are difficult to capture. Few studies have calculated vital rates for stream salamanders, yet the need is substantial as they are threatened by a wide range of land-use stressors, especially urban development. In this study, we used 34 months of continuous field samples collected at an urban and undisturbed stream and robust design mark-recapture analysis to evaluate the importance of temporary emigration, capture response, and location on survival estimates of the salamander Desmognathus fuscus. We constructed a set of candidate models incorporating combinations of time- and location-varying capture and recapture probabilities, capture responses, temporary emigration, and survival estimates and ranked models using Akaike’s Information Criterion. We found strong support for month-specific capture probabilities, recapture probabilities, temporary emigration and a negative behavioral response to capture in the majority of months. We found no support for variation in capture probabilities, recapture probabilities, and temporary emigration between locations. However, we found that location strongly influenced survival estimates. Specifically, survival estimates were significantly higher at the undisturbed site than at the urban site. Our results emphasize the importance of estimating capture probabilities, recapture probabilities, capture response, and temporary emigration when evaluating survival in highly secretive aquatic animals. Failure to account for these population parameters will likely yield biased estimates of survival in freshwater animal populations.     

The initial part of the survival curve: does it predict the outcome of fractionated radiotherapy?

The publication of a number of single-cell survival curves in vitro has stimulated radiobiologists and radiotherapists to analyze the survival characteristics of these curves for their ability to be predictive of the radioresponses of the tumors from which they were derived. Parameters of interest have been the steepness of the initial slope, the single-dose survival at 2 Gy, the mean inactivation dose, and the extrapolation number along with the D0 dose. An assessment of these correlations shows considerable overlap between the values of particular survival parameters even when tumors thought to be the most responsive are compared to those thought to be the least responsive. The importance of the full repair of sublethal damage in the analysis is noted, and a number of factors which may limit effective correlations between cell survival parameters and tumor response are discussed.     

Early control of viral load by favipiravir promotes survival to Ebola virus challenge and prevents cytokine storm in non-human primates

Ebola virus has been responsible for two major epidemics over the last several years and there has been a strong effort to find potential treatments that can improve the disease outcome. Antiviral favipiravir was thus tested on non-human primates infected with Ebola virus. Half of the treated animals survived the Ebola virus challenge, whereas the infection was fully lethal for the untreated ones. Moreover, the treated animals that did not survive died later than the controls. We evaluated the hematological, virological, biochemical, and immunological parameters of the animals and performed proteomic analysis at various timepoints of the disease. The viral load strongly correlated with dysregulation of the biological functions involved in pathogenesis, notably the inflammatory response, hemostatic functions, and response to stress. Thus, the management of viral replication in Ebola virus disease is of crucial importance in preventing the immunopathogenic disorders and septic-like shock syndrome generally observed in Ebola virus-infected patients.