A queueing model for chronic recurrent conditions under panel observation

In many chronic conditions, subjects alternate between an active and an inactive state, and sojourns into the active state may involve multiple lesions, infections, or other recurrences with different times of onset and resolution. We present a biologically interpretable model of such chronic recurrent conditions based on a queueing process. The model has a birth-death process describing recurrences and a semi-Markov process describing the alternation between active and inactive states, and can be fit to panel data that provide only a binary assessment of the active or inactive state at a series of discrete time points using a hidden Markov approach. We accommodate individual heterogeneity and covariates using a random effects model, and simulate the posterior distribution of unknowns using a Markov chain Monte Carlo algorithm. Application to a clinical trial of genital herpes shows how the method can characterize the biology of the disease and estimate treatment efficacy.     

Clinical and Virologic Course of Herpes Simplex Genitalis

The clinical and virologic course of herpes simplex genitalis in women and men was examined in order to identify measurements useful in antiviral trials. Factors influencing the clinical course included initial disease versus recurrent disease, wet-skin versus dry-skin lesions, female versus male sex. Women with initial genital herpes had higher mean peak lesion virus titers than those with recurrent disease (10^4.5 pfu compared with 10^2.5 pfu) and excreted virus longer (13 to 15 days compared with 6 to 8 days). Men with recurrent lesions had higher mean peak virus titers than women (10^4.0 pfu compared with 10^2.5 pfu), but the duration of virus excretion was shorter (three to four days compared with six to eight days). There was pronounced variation in the clinical and virologic course of recurrent lesions among different patients and even within the same patient. These observations indicate several difficulties that must be considered in conducting careful antiviral trials in patients with herpes simplex genitalis.     

An age dependent stochastic model of periodic screening: Basic properties

An age dependent stochastic model for the periodic screening of a progressive chronic disease is developed in this paper by combining results from previous modeling efforts. The basic concepts used are the random variables describing the disease free state and preclinical state sojourn times and the age at screening or observation, as well as generations of individuals defined according to time of entry into the preclinical state. At discrete time points, the model characterizes the density functions for individuals who are healthy, have preclinical disease, or have clinical disease. The joint density functions of age and sojourn times for cases detected by a periodic screening program and for cases which surface clinically between screens are derived as functions of screening interval, false negative rate, and disease natural history.     

The cotton rat provides a novel model to study genital herpes infection and to evaluate preventive strategies

Prevention of genital herpes and other sexually transmitted infections (STI) is a critical health priority because of the overwhelming impact on women and infants and the epidemiological association with human immunodeficiency virus (HIV)/AIDS. Small animal models are essential for evaluating strategies for prevention or treatment of STI. Neither the murine nor the guinea pig model of genital herpes fully recapitulates human disease. We demonstrate that herpes simplex virus type 2 (HSV-2) readily infects inbred cotton rats (Sigmodon hispidus). Consistent infection does not require pretreatment with medroxyprogesterone, and primary disease resembles that observed in humans. The animals develop genital lesions and fully recover. During primary infection, viral DNA is also detected in liver, lungs, brain, and kidneys. Clinical self-limited recurrences occur spontaneously but may also be induced by dexamethasone. Pretreatment of cotton rats with PRO 2000 gel, a candidate vaginal microbicide being evaluated in clinical trials to prevent HSV and HIV, protects cotton rats from HSV. Together, these studies suggest that the cotton rat may provide an excellent model to study genital herpes and to evaluate preventive strategies.     

Bayesian modeling of multiple episode occurrence and severity with a terminating event

An individual's health condition can affect the frequency and intensity of episodes that can occur repeatedly and that may be related to an event time of interest. For example, bleeding episodes during pregnancy may indicate problems predictive of preterm delivery. Motivated by this application, we propose a joint model for a multiple episode process and an event time. The frequency of occurrence and severity of the episodes are characterized by a latent variable model, which allows an individual's episode intensity to change dynamically over time. This latent episode intensity is then incorporated as a predictor in a discrete time model for the terminating event. Time-varying coefficients are used to distinguish among effects earlier versus later in gestation. Formulating the model within a Bayesian framework, prior distributions are chosen so that conditional posterior distributions are conjugate after data augmentation. Posterior computation proceeds via an efficient Gibbs sampling algorithm. The methods are illustrated using bleeding episode and gestational length data from a pregnancy study.     

Successful treatment of herpes labialis with topical acyclovir.

A double blind, placebo controlled trial of 5% acyclovir cream, applied topically five times a day for five days, was carried out in 49 patients with recurrent herpes labialis. These patients had a total of 74 episodes, 34 of which were treated with the 5% acyclovir cream and 40 with matching placebo. First episodes and all episodes treated with acyclovir cream had significantly shorter times to formation of ulcer or crust and to complete healing (p less than 0.05 for all variables). The duration of all symptoms and proportion of patients developing itching was also reduced by acyclovir cream in first episodes, though the difference was not significant. When the patient started treatment early in the course of a first episode acyclovir cream significantly reduced the percentage of lesions progressing beyond the papular stage (p less than 0.05). Acyclovir cream is well tolerated and effective for the treatment of recurrent herpes labialis.     

Human genetic susceptibility and infection with Leishmania peruviana.

Racial differences, familial clustering, and murine studies are suggestive of host genetic control of Leishmania infections. Complex segregation analysis has been carried out by use of the programs POINTER and COMDS and data from a total population survey, comprising 636 nuclear families, from an L. peruviana endemic area. The data support genetic components controlling susceptibility to clinical leishmaniasis, influencing severity of disease and resistance to disease among healthy individuals. A multifactorial model is favored over a sporadic model. Two-locus models provided the best fit to the data, the optimal model being a recessive gene (frequency .57) plus a modifier locus. Individuals infected at an early age and with recurrent lesions are genetically more susceptible than those infected with a single episode of disease at a later age. Among people with no lesions, those with a positive skin-test response are genetically less susceptible than those with a negative response. The possibility of the involvement of more than one gene together with environmental effects has implications for the design of future linkage studies.     

Efficacy of therapeutic and prophylactic actions of ultralow doses of antibodies to gamma-interferon in experimental murine model of herpes virus]

The process of the disease due to herpes simplex virus types 1 and 2 (HSV-1 and 2) was studied on white uninbred mice weighing 10 to 12 g. The animals were infected intracerebrally or intraperitoneally. Intraperitoneal contamination of the animals with MS strain of HSV-2 was used for the experimental model of the herpes simplex infection. The prophylactic antiherpes action of ultralow doses of the human gamma-interferon antibodies (ULD of anti-IFN-gamma) at a course of its intragastral administration was evaluated. The preparation was shown to have a significant (p < 0.05) protective effect in a dose of 10 LD50, evident from a 10-fold decrease of the HSV-2 accumulation in the brain, a lower percentage of the animal deaths and an increase of the average lifespan of the animals by 3.3 days. The study of the therapeutic action of ULD of anti-IFN-gamma at a course of its intragastral administration showed that the preparation had no significant positive effect on the disease process in the animals infected with HSV-2 in a dose of 10 LD50. However, a positive effect associated with delayed virus replication in the brain was observed in the study on the therapeutic effect of ULD of anti-IFN-gamma after its intragastral administration to the mice infected with a sublethal dose of the virus.     

A Markov formulation of the repair-misrepair model of cell survival

Tobias' repair-misrepair (RMR) model of cell survival is formulated as a Markov process, a sequence of discrete repair steps occurring at random times, and the probability of a sequence of viable repairs is calculated. The Markov formulation describes the time evolution of the probability distribution for the number of lesions in a cell. The probability of cell survival is calculated from the distribution of the initial number of lesions and the probabilities of the repair events. The production of lesions is formulated in accordance with the principles of microdosimetry, and the distribution of the initial number of lesions is obtained as an approximation for high and low linear energy transfer cases. The Markov formulation of the RMR model uses the same biological hypotheses as the original version with two statistical approximations deleted. These approximations are the neglect of the effect of statistical fluctuations in calculating the average rate of repair of lesions and the assumption that the final number of unrepaired and lethally misrepaired lesions has a Poisson distribution. The quantitative effect of these approximations is calculated, and a basis is provided for an alternative approach to calculating survival probabilities.     

On the relation between recovery from potential lethal and sublethal radiation lesions of yeast cells

Summary Tetraploid yeast cells were used to study the time course of recovery from potential lethal lesions by delayed plating after a single dose of gamma-radiation and recovery from sublethal lesions by using two fraction dose technique. The mean lifetime of potential lethal and sublethal lesions in comparable conditions are the same. The elimination of lethals in the first steps of recovery process is accompanied by transition of lethally damaged cells into sublethally damaged ones.Sublethals are in principle completely reversible. As potential lethals consist of sublethals the number of which are critical the former immediately after irradiation also are complete reversible in principle. In a time course a definite fraction of potential lethals is fixed into true irreversible lethals. This pattern is in close agreement with the common model of formation of two-hit chromosome aberration.     

Clinical immunological characteristics of herpes zoster]

Changes of antibody formation of 96 patients with various clinical forms of herpes zoster were traced by indirect hemagglutination inhibition test. Four variants of the immunological response were distinguished; clinical characteristics of each of these groups is presented. The initial antibody level failed to determine the severity of the course of the disease in herpes zoster.     

Detection of potential enzyme targets by metabolic modelling and optimization: application to a simple enzymopathy

MOTIVATION: A very promising approach in drug discovery involves the integration of available biomedical data through mathematical modelling and data mining. We have developed a method called optimization program for drug discovery (OPDD) that allows new enzyme targets to be identified in enzymopathies through the integration of metabolic models and biomedical data in a mathematical optimization program. The method involves four steps: (i) collection of the necessary information about the metabolic system and disease; (ii) translation of the information into mathematical terms; (iii) computation of the optimization programs prioritizing the solutions that propose the inhibition of a reduced number of enzymes and (iv) application of additional biomedical criteria to select and classify the solutions. Each solution consists of a set of predicted values for metabolites, initial substrates and enzyme activities, which describe a biologically acceptable steady state of the system that shifts the pathologic state towards a healthy state. RESULTS: The OPDD was used to detect target enzymes in an enzymopathy, the human hyperuricemia. An existing S-system model and bibliographic information about the disease were used. The method detected six single-target enzyme solutions involving dietary modification, one of them coinciding with the conventional clinical treatment using allopurinol. The OPDD detected a large number of possible solutions involving two enzyme targets. All except one contained one of the previously detected six enzyme targets. The purpose of this work was not to obtain solutions for direct clinical implementation but to illustrate how increasing levels of biomedical information can be integrated together with mathematical models in drug discovery. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

Exploratory Bayesian model selection for serial genetics data

Characterizing the process by which molecular and cellular level changes occur over time will have broad implications for clinical decision making and help further our knowledge of disease etiology across many complex diseases. However, this presents an analytic challenge due to the large number of potentially relevant biomarkers and the complex, uncharacterized relationships among them. We propose an exploratory Bayesian model selection procedure that searches for model simplicity through independence testing of multiple discrete biomarkers measured over time. Bayes factor calculations are used to identify and compare models that are best supported by the data. For large model spaces, i.e., a large number of multi-leveled biomarkers, we propose a Markov chain Monte Carlo (MCMC) stochastic search algorithm for finding promising models. We apply our procedure to explore the extent to which HIV-1 genetic changes occur independently over time.     

Grey matter lesions in MS

Although multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the white matter (WM) of the central nervous system, several pathological and magnetic resonance imaging (MRI) studies have shown that a large amount of lesions are located in the cortical and deep gray matter. The histopathological and immunological characteristics of cortical lesions differ significantly from those located in the WM, which suggests a location-dependent expression of the MS immunopathological process. More recently, the availability of not-conventional MRI sequences having higher sensitivity for the gray matter has allowed to depict in vivo a portion of such lesions. The available MRI data obtained on large cohorts of patients, having different clinical forms of the disease, indicate that cortical lesions can be detected early in the disease course, sometimes even before the appearance of WM lesions, and correlate with the severity of physical disability and cognitive impairment, and with the evolution of the disease toward the secondary progressive phase. This review provides a summary of the main histopathological and MRI findings of cortical lesions in MS and discusses their possible clinical implications.     

A Pseudo-Markov Model for Series of Neuronal Spike Events

Spike trains of spontaneous neuronal activity in the rabbit brain are submitted to statistical analyses based on the following pseudo-Markov model. The nerve cell is supposed to alternate between a bursting and a resting state. The numbers of consecutive spikes within each state are assumed to be independent integer-valued random variables with discrete probability distributions. Given the state, the interspike intervals are independent real-valued random variables. The two state semi-Markov model is obtained as a special case when the discrete distributions are geometrical. Statistical second-order properties of recorded spike trains are compared with those predicted by the model on the basis of known first-order properties. For that purpose, serial correlation coefficients and intensity functions for spike trains produced by the model are computed. A comparison between observed and predicted results for the spontaneous activity of 17 brain cells yields a good fit in eight cells and discloses some salient features of the statistical structure in the activity of six other cells. By making it feasible to compute theoretical correlograms, the model may advance the understanding of empirical correlograms. The possibilities for integrating this statistical model of spike trains with a model of the mechanism of spike train production are discussed.     

Immunodominant epitopes in herpes simplex virus type 2 glycoprotein D are recognized by CD4 lymphocytes from both HSV-1 and HSV-2 seropositive subjects

In human recurrent cutaneous herpes simplex, there is a sequential infiltrate of CD4 and then CD8 lymphocytes into lesions. CD4 lymphocytes are the major producers of the key cytokine IFN-gamma in lesions. They recognize mainly structural proteins and especially glycoproteins D and B (gD and gB) when restimulated in vitro. Recent human vaccine trials using recombinant gD showed partial protection of HSV seronegative women against genital herpes disease and also, in placebo recipients, showed protection by prior HSV1 infection. In this study, we have defined immunodominant peptide epitopes recognized by 8 HSV1(+) and/or 16 HSV2(+) patients using (51)Cr-release cytotoxicity and IFN-gamma ELISPOT assays. Using a set of 39 overlapping 20-mer peptides, more than six immunodominant epitopes were defined in gD2 (two to six peptide epitopes were recognized for each subject). Further fine mapping of these responses for 4 of the 20-mers, using a panel of 9 internal 12-mers for each 20-mers, combined with MHC II typing and also direct in vitro binding assay of these peptides to individual DR molecules, showed more than one epitope per 20-mers and promiscuous binding of individual 20-mers and 12-mers to multiple DR types. All four 20-mer peptides were cross-recognized by both HSV1(+)/HSV2(-) and HSV1(-)/HSV2(+) subjects, but the sites of recognition differed within the 20-mers where their sequences were divergent. This work provides a basis for CD4 lymphocyte cross-recognition of gD2 and possibly cross-protection observed in previous clinical studies and in vaccine trials.     

On a temporal model for the Chikungunya disease: modeling, theory and numerics

Reunion Island faced two episodes of Chikungunya, a vector-borne disease, in 2005 and in 2006. The latter was of unprecedented magnitude: one third of the population was infected. Until the severe episode of 2006, our knowledge of Chikungunya was very limited. The principal aim of our study is to propose a model, including human and mosquito compartments, that is associated to the time course of the first epidemic of Chikungunya. By computing the basic reproduction number R(0), we show there exists a disease-free equilibrium that is locally asymptotically stable if the basic reproduction number is less than 1. Moreover, we give a necessary condition for global asymptotic stability of the disease-free equilibrium. Then, we propose a numerical scheme that is qualitatively stable and present several simulations as well as numerical estimates of the basic reproduction number for some cities of Reunion Island. For the episode of 2005, R(0) was less than one, which partly explains why no outbreak appeared. Using recent entomological results, we investigate links between the episode of 2005 and the outbreak of 2006. Finally, our work shows that R(0) varied from place to place on the island, indicating that quick and focused interventions, like the destruction of breeding sites, may be effective for controlling the disease.     

Inferring complex DNA substitution processes on phylogenies using uniformization and data augmentation

A new method is developed for calculating sequence substitution probabilities using Markov chain Monte Carlo (MCMC) methods. The basic strategy is to use uniformization to transform the original continuous time Markov process into a Poisson substitution process and a discrete Markov chain of state transitions. An efficient MCMC algorithm for evaluating substitution probabilities by this approach using a continuous gamma distribution to model site-specific rates is outlined. The method is applied to the problem of inferring branch lengths and site-specific rates from nucleotide sequences under a general time-reversible (GTR) model and a computer program BYPASSR is developed. Simulations are used to examine the performance of the new program relative to an existing program BASEML that uses a discrete approximation for the gamma distributed prior on site-specific rates. It is found that BASEML and BYPASSR are in close agreement when inferring branch lengths, regardless of the number of rate categories used, but that BASEML tends to underestimate high site-specific substitution rates, and to overestimate intermediate rates, when fewer than 50 rate categories are used. Rate estimates obtained using BASEML agree more closely with those of BYPASSR as the number of rate categories increases. Analyses of the posterior distributions of site-specific rates from BYPASSR suggest that a large number of taxa are needed to obtain precise estimates of site-specific rates, especially when rates are very high or very low. The method is applied to analyze 45 sequences of the alpha 2B adrenergic receptor gene (A2AB) from a sample of eutherian taxa. In general, the pattern expected for regions under negative selection is observed with third codon positions having the highest inferred rates, followed by first codon positions and with second codon positions having the lowest inferred rates. Several sites show exceptionally high substitution rates at second codon positions that may represent the effects of positive selection.     

Further observations on clinical, histopathological, and immunological features of borderline disseminated cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis

Leishmania (Leishmania) amazonensis has for some time been considered as the causative agent of two distinct forms of American cutaneous leishmaniasis (ACL): localized cutaneous leishmaniasis (LCL), and anergic diffuse cutaneous leishmaniasis (ADCL). Recently, a new intermediate form of disease, borderline disseminated cutaneous leishmaniasis (BDCL), was introduced into the clinical spectrum of ACL caused by this parasite, and in this paper we record the clinical, histopathological, and immunological features of eight more BDCL patients from Brazilian Amazonia, who acquired the disease in the Pará state, North Brazil. Seven of them had infections of one to two years' evolution and presented with primary skin lesions and the occurrence of metastases at periods varying from six to 12 months following appearance of the first lesion. Primary skin lesions ranged from 1-3 in number, and all had the aspect of an erythematous, infiltrated plaque, variously located on the head, arms or legs. There was lymphatic dissemination of infection, with lymph node enlargement in seven of the cases, and the delayed hypersensitivity skin-test (DTH) was negative in all eight patients prior to their treatment. After that, there was a conversion of DTH to positive in five cases re-examined. The major histopathological feature was a dermal mononuclear infiltration, with a predominance of heavily parasitized and vacuolated macrophages, together with lymphocytes and plasma cells. In one case, with similar histopathology, the patient had acquired his infection seven years previously and he presented with the largest number of disseminated cutaneous lesions. BDCL shows clinical and histopathological features which are different from those of both LCL and ADCL, and there is a good prognosis of cure which is generally not so in the case of frank ADCL.