The Quetzal Coalescence template library: A C++ programmers resource for integrating distributional,demographic and coalescent models

Genetic samples can be used to understand and predict the behaviour of species living in a fragmented and temporally changing environment. In this regard, models of coalescence conditioned to an environment through an explicit modelling of population growth and migration have been developed in recent years, and simulators implementing these models have been developed, enabling biologists to estimate parameters of interest with Approximate Bayesian Computation techniques. However, model choice remains limited, and developing new coalescence simulators is extremely time consuming because code re‐use is limited. We present Quetzal, a C++ library composed of re‐usable components, which is sufficiently general to efficiently implement a wide range of spatially explicit coalescence‐based environmental models of population genetics and to embed the simulation in an Approximate Bayesian Computation framework. Quetzal is not a simulation program, but a toolbox for programming simulators aimed at the community of scientific coders and research software engineers in molecular ecology and phylogeography. This new code resource is open‐source and available at https://becheler.github.io/pages/quetzal.html along with other documentation resources.     

Spread of Q fever within dairy cattle herds: key parameters inferred using a Bayesian approach

Q fever is a worldwide zoonosis caused by Coxiella burnetii. Although ruminants are recognized as the most important source of human infection, no previous studies have focused on assessing the characteristics of the bacterial spread within a cattle herd and no epidemic model has been proposed in this context. We assess the key epidemiological parameters from field data in a Bayesian framework that takes into account the available knowledge, missing data and the uncertainty of the observation process owing to the imperfection of diagnostic tests. We propose an original individual-based Markovian model in discrete time describing the evolution of the infection for each animal. Markov chain Monte Carlo methodology is used to estimate parameters of interest from data consisting of individual health states of 217 cows of five chronically infected dairy herds sampled every week for a four-week period. Outputs are the posterior distributions of the probabilities of transition between health states and of the environmental bacterial load. Our findings show that some herds are characterized by a very low infection risk while others have a mild infection risk and a non-negligible intermittent shedding probability. Moreover, the antibody status seems to be a key point in the bacterial spread (shedders with antibodies shed for a longer period of time than shedders without antibodies). In addition to the biological insights, these estimates also provide information for calibrating simulation models to assess control strategies for C. burnetii infection.     

Prevalence of hepatitis C virus infection among recyclable waste collectors in Central-West Brazil

The prevalence of hepatitis C virus (HCV) in a population of recyclable waste collectors (n = 431) was assessed using a cross-sectional survey in all 15 cooperatives in the city of Goiânia, Central-West Brazil. The HCV prevalence was 1.6% (95% confidence interval: 0.6-3.6) and a history of sexually transmitted infections was independently associated with this infection. HCV RNA (corresponding to genotype 1; subtypes 1a and 1b) was detected in five/seven anti-HCV-positive samples. Although the study population reported a high rate (47.3%) of sharps and needle accidents, HCV infection was not more frequent in recyclable waste collectors than in the general Brazilian population.     

The decline in antibodies to hepatitis C virus during antiviral therapy

The goal of the study was to analyze B-cell response to hepatitis C virus during antiviral therapy among responders and non-responders. The content of antibodies to individual structural and non-structural HCV proteins was investigated during two years in three groups of patients: initial responders, non-responders and a reference group (without therapy). Treated patients in all groups exhibited the decrease in antibodies to analyzed HCV proteins, but with different patterns. The first statistically significant differences in the decline of the virus-specific antibodies between initial responders and non-responders were observed within the first three months after the beginning of therapy. Some treated patients demonstrated the decrease in antibody levels to HCV proteins after the end of therapy.     

Mutation patterns for two flaviviruses: hepatitis C virus and GB virus C/hepatitis G virus

We studied the mutation patterns of hepatitis C virus (HCV) and GB virus C/hepatitis G virus (HGV). Although the mutation patterns of the two viruses were similar to each other, they were quite different from that of HIV. In particular, the similarity of the patterns between HCV or HGV and human nuclear pseudogenes was statistically significant whereas there was no similarity between HIV and human nuclear pseudogenes. This finding suggests that the mutation patterns of HCV and HGV are similar to the patterns of spontaneous substitution mutations of human genes, implying that nucleotide analogues which are effective against HCV and HGV may have a side effect on the normal cells of humans.     

Construction of a chimeric hepatitis C virus replicon based on a strain isolated from a chronic hepatitis C patient

Subgenomic replicons of hepatitis C virus (HCV) have been widely used for studying HCV replication. Here, we report a new subgenomic replicon based on a strain isolated from a chronically infected patient. The coding sequence of HCV was recovered from a Chinese chronic hepatitis C patient displaying high serum HCV copy numbers. A consensus sequence designated as CCH strain was constructed based on the sequences of five clones and this was classified by sequence alignment as belonging to genotype 2a. The subgenomic replicon of CCH was replication-deficient in cell culture, due to dysfunctions in NS3 and NS5B. Various JFH1/CCH chimeric replicons were constructed, and specific mutations were introduced. The introduction of mutations could partially restore the replication of chimeric replicons. A replication-competent chimeric construct was finally obtained by the introduction of NS3 from JFH1 into the backbone of the CCH strain.     

Coalescent inference for infectious disease: meta-analysis of hepatitis C

Genetic analysis of pathogen genomes is a powerful approach to investigating the population dynamics and epidemic history of infectious diseases. However, the theoretical underpinnings of the most widely used, coalescent methods have been questioned, casting doubt on their interpretation. The aim of this study is to develop robust population genetic inference for compartmental models in epidemiology. Using a general approach based on the theory of metapopulations, we derive coalescent models under susceptible–infectious (SI), susceptible–infectious–susceptible (SIS) and susceptible–infectious–recovered (SIR) dynamics. We show that exponential and logistic growth models are equivalent to SI and SIS models, respectively, when co-infection is negligible. Implementing SI, SIS and SIR models in BEAST, we conduct a meta-analysis of hepatitis C epidemics, and show that we can directly estimate the basic reproductive number (R₀) and prevalence under SIR dynamics. We find that differences in genetic diversity between epidemics can be explained by differences in underlying epidemiology (age of the epidemic and local population density) and viral subtype. Model comparison reveals SIR dynamics in three globally restricted epidemics, but most are better fit by the simpler SI dynamics. In summary, metapopulation models provide a general and practical framework for integrating epidemiology and population genetics for the purposes of joint inference.     

Autoregressive models for capture-recapture data: a Bayesian approach

In this article, we incorporate an autoregressive time-series framework into models for animal survival using capture-recapture data. Researchers modeling animal survival probabilities as the realization of a random process have typically considered survival to be independent from one time period to the next. This may not be realistic for some populations. Using a Gibbs sampling approach, we can estimate covariate coefficients and autoregressive parameters for survival models. The procedure is illustrated with a waterfowl band recovery dataset for northern pintails (Anas acuta). The analysis shows that the second lag autoregressive coefficient is significantly less than 0, suggesting that there is a triennial relationship between survival probabilities and emphasizing that modeling survival rates as independent random variables may be unrealistic in some cases. Software to implement the methodology is available at no charge on the Internet.     

Putative hepatitis C virus cell receptors

Virus entry into a host cell comprises the first step of the viral life cycle. Blockage of this process can stop or prevent the rise of the infection. Development of compounds exhibiting directed blocking activity requires information about host cell and viral molecules, which are involved into reciprocal recognition resulting in the virus entry into the cell. This review is devoted to the problems of the identification of plasma membrane molecules, involved in binding of hepatitis C virus and its subsequent transfer inside the cells. The putative role of these molecules as hepatitis C virus receptors and co-receptors in the beginning and development of the infection is discussed.     

Chimpanzees in hepatitis C virus research: 1998–2007

Background  Chimpanzees have been widely used in hepatitis C virus (HCV) research, but their endangered status and high financial and ethical costs have prompted a closer review.
Methods  One hundred and nine articles published in 1998–2007 were analyzed for the number of chimpanzees involved, experimental procedures, objectives and other relevant issues.
Results  The articles described the use of 852 chimpanzees, but accounting for likely multiple uses, the number of individual chimpanzees involved here is estimated to be approximately 500. Most articles addressed immunology and inoculation studies. A significant portion of studies lasted for several months or years. Approximately one half of the individual chimpanzees were each used in 2–10 studies.
Conclusions  Significant financial and scientific resources have been expended in these chimpanzee HCV studies. Discussion addresses troublesome questions presented by some of the reviewed articles, including statistical validity, repeatability, and biological relevance of this model. These concerns merit attention as future approaches to HCV research and research priorities are considered.     

Assembly of hepatitis C virus particles

Infection with hepatitis C virus (HCV) is a major risk factor for chronic hepatitis, cirrhosis and hepatocellular carcinoma. Once robust cell culture systems for production of recombinant infectious HCV became available, evidence on molecular mechanisms underlying assembly and release of the virus particles began to accumulate. Recent studies have demonstrated that lipid droplets and viral nonstructural proteins play key roles in HCV morphogenesis. This review considers the current knowledge about maturation of HCV structural proteins and production of viral infectious particles.     

Pathology of hepatitis C

Abstract: The basic morphological patterns of acute or chronic viral hepatitides are very similar, irrespective of the causative hepatitis viruses A, B, C, D or E. In addition, however, acute and chronic hepatitis C shows characteristic, although not pathognomonic histological changes. These consist of lymphoid aggregates in portal tracts, sometimes with germinal centers, damage of bile duct epithelium, and micro- or macrovesicular steatosis of hepatocytes. A combination of two of these three characteristic alterations is seen in over half of the patients with chronic hepatitis C and is helpful in the histological diagnosis of the disease.     

Non-human primate surrogate model of hepatitis C virus infection

More than 170 million people worldwide are chronically infected by HCV, which is the causative agent of chronic hepatitis C, cirrhosis, and finally liver cancer. Although animal models of viral hepatitis are a prerequisite for the evaluation of antiviral and vaccine efficacy, the restricted host range of HCV has hampered the development of a suitable small animal model of HCV infection. Use of the chimpanzee, the only animal known to be susceptible to HCV infection, is limited by ethical and financial restrictions. In this regard GBV-B, being closely related to HCV, appears to be a promising non-human surrogate model for the study of HCV infection. This review describes the characteristic of GBV-B infection of New World monkeys, and discusses current issues concerning the GBV-B model and its future directions.     

The joint allele frequency spectrum of multiple populations: a coalescent theory approach

The allele frequency spectrum is a series of statistics that describe genetic polymorphism, and is commonly used for inferring population genetic parameters and detecting natural selection. Population genetic theory on the allele frequency spectrum for a single population has been well studied using both coalescent theory and diffusion equations. Recently, the theory was extended to the joint allele frequency spectrum (JAFS) for three populations using diffusion equations and was shown to be very useful in inferring human demographic history. In this paper, I show that the JAFS can be analytically derived with coalescent theory for a basic model of two isolated populations and then extended to multiple populations and various complex scenarios, such as those involving population growth and bottleneck, migration, and positive selection. Simulation study is used to demonstrate the accuracy and applicability of the theoretical model. The coalescent theory-based approach for the JAFS can characterize the demographic history with comprehensive statistical models as the diffusion approach does, and in addition gains several novel advantages: the computational complexity of calculating the JAFS with coalescent theory is reduced, and thus it is feasible to analytically obtain the JAFS for multiple populations; the hitchhiking effect can be efficiently modeled in coalescent theory, enabling the development of methodologies for detecting selection via multi-population polymorphism data. As an alternative to the diffusion approximation approach, the coalescent theory for the JAFS also provides a foundation for population genetic inference with the advent of large-scale genomic polymorphism data.     

Autoimmune hepatitis and hepatititis C virus infection

Abstract: The identification of the hepatitis C virus (HCV) and the availability of serological tests for the identification of its infection has deeply changed our view of autoimmune hepatitis. In fact, we have learned that autoantibodies such as anti-nuclear, anti-smooth muscle and anti-liver kidney microsomes, cannot be considered specific any longer for the diagnosis, of autoimmune hepatitis, since they are frequently found in association with HCV. The new clinical entity characterized by the association of autoantibodies with signs of HCV infection is presently under evaluation. This, in order to understand what is the prevalent mechanism, viral or autoimmune, operating in these patients and to chose the best treatment regimen.     

Modeling a Poisson forest in variable elevations: a nonparametric Bayesian approach

A nonparametric Bayesian formulation is given to the problem of modeling nonhomogeneous spatial point patterns influenced by concomitant variables. Only incomplete information on the concomitant variables is assumed, consisting of a relatively small number of point measurements. Residual variation, caused by other unmeasured influential factors, is modeled in terms of a spatially varying baseline intensity function. A Markov chain Monte Carlo scheme is proposed for the simultaneous nonparametric estimation of each unknown function in the model. The suggested method is illustrated by reanalysing a data set in Rathbun (1996, Biometrics 52, 226-242), and the estimated models are compared with those obtained by Rathbun.     

Interferon therapy in chronic hepatitis C virus infection

Abstract: Antiviral treatment of chronic hepatitis C with interferon is reviewed. Alpha-interferon, both recombinant alpha-2a, -2b and human lymphoblastoid interferon given at a dose of ≥3MU t.i.w. for 6–12 months will result in normalisation of ALT levels complete response) in some 50–60% of treated patients with chronic hepatitis C virus (HCV) infection. Approximately half of the complete responders to interferon will relapse within 6 months once treatment is withdrawn (non-sustained response). Longer treatment schedules (6 vs. 12 months) seem to diminish the relapse rate and increase the percentage of sustained response. In patients with sustained response to interferon treatment with continuously normal ALT levels ≥6 months after treatment stop a concomitant eradication of the viraemia is usually seen, whereas a non-sustained or non-response to interferon usually will indicate a continuous viraemia. Factors predictive of a favourable response are low pretreatment HCV RNA levels in serum, genotypes other than type II according to Okamoto, short disease duration, female gender and less pronounced liver damage, whereas high serum HCV RNA levels, having genotype II and cirrhosis, are predictive of a less favourable response. Patients with a sustained response and eradication of the viraemia will also improve their liver inflammation with diminishing scores for portal inflammation, piecemeal necrosis, lobular inflammation and also fibrosis after treatment. For non-responders and non-sustained responders to interferon, ribavirin especially in combination with interferon will offer some hope for the future.     

Increased frequency of micronuclei in the lymphocytes of patients chronically infected with hepatitis B or hepatitis C virus

In this study, we analysed the frequency of micronuclei (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) and evaluated mutagen-induced sensitivity in the lymphocytes of patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). In total, 49 patients with chronic viral hepatitis (28 HBV-infected and 21 HCV-infected patients) and 33 healthy, non-infected blood donor controls were investigated. The frequencies (‰) of MN, NPBs and NBUDs in the controls were 4.41 ± 2.15, 1.15 ± 0.97 and 2.98 ± 1.31, respectively. The frequencies of MN and NPBs were significantly increased (p < 0.0001) in the patient group (7.01 ± 3.23 and 2.76 ± 2.08, respectively) compared with the control group. When considered separately, the HBV-infected patients (7.18 ± 3.57) and HCV-infected patients (3.27 ± 2.40) each had greater numbers of MN than did the controls (p < 0.0001). The HCV-infected patients displayed high numbers of NPBs (2.09 ± 1.33) and NBUDs (4.38 ± 3.28), but only the HBV-infected patients exhibited a significant difference (NPBs = 3.27 ± 2.40, p < 0.0001 and NBUDs = 4.71 ± 2.79, p = 0.03) in comparison with the controls. Similar results were obtained for males, but not for females, when all patients or the HBV-infected group was compared with the controls. The lymphocytes of the infected patients did not exhibit sensitivity to mutagen in comparison with the lymphocytes of the controls (p = 0.06). These results showed that the lymphocytes of patients who were chronically infected with HBV or HCV presented greater chromosomal instability.