A model of pulldown alignments from SssI-treated DNA improves DNA methylation prediction.

BACKGROUND: Protein pulldown using Methyl-CpG binding domain (MBD) proteins followed by high-throughput sequencing is a common method to determine DNA methylation. Algorithms have been developed to estimate absolute methylation level from read coverage generated by affinity enrichment-based techniques, but the most accurate one for MBD-seq data requires additional data from an SssI-treated Control experiment. RESULTS: Using our previous characterizations of Methyl-CpG/MBD2 binding in the context of an MBD pulldown experiment, we build a model of expected MBD pulldown reads as drawn from SssI-treated DNA. We use the program BayMeth to evaluate the effectiveness of this model by substituting calculated SssI Control data for the observed SssI Control data. By comparing methylation predictions against those from an RRBS data set, we find that BayMeth run with our modeled SssI Control data performs better than BayMeth run with observed SssI Control data, on both 100 bp and 10 bp windows. Adapting the model to an external data set solely by changing the average fragment length, our calculated data still informs the BayMeth program to a similar level as observed data in predicting methylation state on a pulldown data set with matching WGBS estimates. CONCLUSION: In both internal and external MBD pulldown data sets tested in this study, BayMeth used with our modeled pulldown coverage performs better than BayMeth run without the inclusion of any estimate of SssI Control pulldown, and is comparable to - and in some cases better than - using observed SssI Control data with the BayMeth program. Thus, our MBD pulldown alignment model can improve methylation predictions without the need to perform additional control experiments.

Teleradiology as a foundation for an enterprise-wide health care delivery system.

An effective, integrated telemedicine system has been developed that allows (a) teleconsultation between local primary health care providers (primary care physicians and general radiologists) and remote imaging subspecialists and (b) active patient participation related to his or her medical condition and patient education. The initial stage of system development was a traditional teleradiology consultation service between general radiologists and specialists; this established system was expanded to include primary care physicians and patients. The system was developed by using a well-defined process model, resulting in three integrated modules: a patient module, a primary health care provider module, and a specialist module. A middle agent layer enables tailoring and customization of the modules for each specific user type. Implementation by using Java and the Common Object Request Broker Architecture standard facilitates platform independence and interoperability. The system supports (a) teleconsultation between a local primary health care provider and an imaging subspecialist regardless of geographic location and (b) patient education and online scheduling. The developed system can potentially form a foundation for an enterprise-wide health care delivery system. In such a system, the role of radiologist specialists is enhanced from that of a diagnostician to the management of a patient's process of care.

Affinity in paired event probability.

It is shown that a general parametric functional generates the conditional and joint probabilities of event pairs when the order within paired events is irrelevant. The parameters represent affinities or associations between single events. If the marginal probabilities of the single events are known, then these parameters specify a hypersurface on which all the joint probabilities of event pairs must lie. Examples are presented, and applications in probability, ecology, epidemiology, genetics, and distribution theory are offered.

Heterogeneous sexual mixing in populations with arbitrarily connected multiple groups.

"A simple procedure for constructing [social/sexual] mixing models for arbitrarily classified (e.g. by sex, age, geographical location, sexual preference) populations is outlined, including a scheme for finding the number of independent mixing parameters required, and a simple (linear algebra) means for finding the values of the dependent mixing parameters. Various worked examples are presented, including the two-sex problem and structured and selective mixing." The use of the models for analyzing mixing structures for AIDS transmission is assessed. (SUMMARY IN FRE)

Empirical methods for the estimation of the mixing probabilities for socially structured populations from a single survey sample.

"The role of variability of sexual behavior in the transmission dynamics of HIV and AIDS has been illustrated, through the use of mathematical models, by several investigators.... In this paper we describe some practical methods for estimating the deviations from random mixing from a single survey sample.... We include a description of the role of the estimated mixing probabilities in models for the spread of HIV, a discussion of alternatives and possible extensions of the methods described in this article, and an outline of future directions of research." (SUMMARY IN FRE)

Toward a unified theory of sexual mixing and pair formation.

Sexually transmitted diseases such as gonorrhea, syphilis, herpes, and AIDS are driven and maintained in populations by epidemiological and sociological factors that are not completely understood. One such factor is the way in which people mix sexually. In this paper, we outline a unified approach to modeling sexual mixing structures, where such structures are defined in terms of a set of axioms for a finite number of distinct groups of people. Theorems for homosexual, heterosexual, and arbitrary group mixing are presented, leading to a representation of all mixing structures defined by the axioms. The representation and its parameters are interpreted in terms of intergroup affinities for sexual mixing. The use of the approach in sexually transmitted disease modeling is discussed.

Like-with-like preference and sexual mixing models.

Two new general methods for incorporating like-with-like preference into one-sex mixing models in epidemiology are presented. The first is a generalization of the preferred mixing equation, while the second comprises a transformation of a general preference function for partners of similar sexual activity levels. Both methods satisfy the constraints implicit in a mixing model. The behavior of the transformation preference method is illustrated, and it is compared with the standard proportionate mixing model.

The transmission dynamics of the human immunodeficiency virus type 1 in the male homosexual community in the United Kingdom: the influence of changes in sexual behaviour.

This paper examines the transmission dynamics of human immune deficiency virus type 1 (HIV-1) in the male homosexual population in the U.K. via numerical studies employing a mathematical model representing the principal epidemiological process. The model is based on an assumption of proportionate mixing between different sexual-activity classes (defined by the rate of sexual partner change per unit of time) and incorporates heterogeneity in sexual activity, distributed infection and incubation periods and the recruitment of susceptibles to the sexually active population. The sensitivity of model predictions to various assumptions and parameter assignments is examined. Numerical studies of model behaviour focus on the influence of changes in the magnitudes of the transmission parameters, associated with three periods of infectiousness during the incubation period of acquired immune deficiency syndrome (AIDS), on the magnitude and duration of the epidemic and on the level of the endemic equilibrium state. Predicted temporal trends in the incidence of AIDS are shown to be particularly sensitive to changes in the intensities and durations of the stages of infectiousness. Most of the paper addresses the influence of changes in sexual behaviour on the magnitude and duration of the epidemic. Numerical simulations show that the manner in which behavioural changes occur and who is influenced by such changes (i.e. infecteds or susceptibles, the sexually active population or new recruits to this population) have a major impact on the future timecourse of the epidemic. The greatest reduction in the incidence of AIDS over the coming decades is induced by changes in the rate of sexual-partner change among the sexually active population, particularly those currently infected. The time periods at which changes in behaviour occur, in relation to the starting point of the epidemic (assumed to be 1979), are also of particular significance to the future pattern of the incidence of disease and infection. Changes in behaviour early on in the timecourse of the epidemic have a much greater impact than equivalent changes at latter time points. On the basis of limited data on the pattern of change in sexual behaviour among the male homosexual community in the U.K., numerical studies of model behaviour tentatively suggest that the epidemic is at, or near to, a period of peak incidence of the disease AIDS. Analyses suggest that, following the peak in incidence, there will be a period of slow decline over many decades provided recent changes in behaviour are maintained in the coming years.(ABSTRACT TRUNCATED AT 400 WORDS)

Pulmonary antigen challenge in rats passively sensitized with a monoclonal IgE antibody induces immediate but not late changes in airway mechanics.

Pulmonary antigen challenge in sensitized individuals results in isolated immediate, isolated late, or dual reactions consisting of both an immediate and late change in airway function. The immediate response appears to be dependent on the presence of IgE antibody and mast cell mediator release. Although the late phase of dual responses is considered to be related to or a continuum of the immediate hypersensitivity response, its precise pathogenesis remains to be determined. To increase both the sensitivity and specificity of analyzing the pathogenesis of IgE-dependent pulmonary responses, we have used a Sprague-Dawley rat model system in which rats are passively sensitized with a murine monoclonal IgE anti-dinitrophenol (DNP) antibody prior to challenge with DNP-bovine serum albumin (DNP-BSA). Pathogen-free rats were injected with IgE or saline in a randomized blinded protocol, and in 24 to 48 h were anesthetized with urethane (1.2 g/kg intraperitoneally) and instrumented to measure lung resistance (RL) and dynamic compliance (Cdyn). Rats were then challenged with aerosolized DNP-BSA (10 mg/ml), and RL and Cdyn monitored through 7 h after challenge. Both RL (0.30 +/- 0.10 versus 0.13 +/- 0.02 cm H2O/ml.sec-1) and Cdyn (0.41 +/- 0.10 versus 0.25 +/- 0.08 ml/cm H2O) were significantly different (p less than 0.05) in sensitized rats compared to control rats immediately after challenge. No late changes were observed in either the treated or control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Variable infectiousness in HIV transmission models.

Two different approaches to the encapsulation of temporal variation in the infectiousness of HIV-infected persons, and variability in the incubation period of the disease AIDS, in simple homogeneous mixing models of viral transmission in male homosexual communities are described. The first approach is based on the division of the infected population into a series of subclasses with differing levels of infectivity and different durations of occupancy. The second approach is more mechanistic in character and is based on an attempt to relate changes in viral abundance within an infected person to the likelihood that the disease AIDS develops. Variable incubation is induced by variation in the rate of change of viral abundance in the infected population. Numerical projections of changes in the incidence of AIDS through time, generated from both types of model, are compared with projections based on the assumption of constant infectivity throughout the incubation period of AIDS. Model formulation highlights areas in which more detailed quantitative epidemiological studies are required. Methods of parameter estimation and future research needs are discussed.

Distributed incubation and infectious periods in models of the transmission dynamics of the human immunodeficiency virus (HIV).

Distributions describing variation in the incubation and infectious periods of the human immunodeficiency virus (HIV) are derived from a series of risk or hazard functions. Four possible forms of the probability density function are considered, namely, exponential, Weibull, Erlang/gamma, and rectangular, and the properties and underlying risk functions are compared and contrasted. Models of the transmission dynamics of the virus, encapsulating different assumptions concerning the distributed incubation and infectious periods, are analysed, and their properties compared by steady-state and local-stability analyses and numerical methods.

Heterogeneous sexual activity models of HIV transmission in male homosexual populations.

A proportionate mixing one-sex model of sexual transmission of HIV is described, in which sexual activity (new partners per unit time) is defined as a continuous variable in a set of integro-partial-differential equations. A discrete activity-class approximation is developed by matching equilibrium state and rate variables as closely as possible with the continuous-variable model, and consists only of ordinary differential equations. Activity-class boundaries are arbitrary, and each class is characterized by a single level of activity. If there are N classes, the level of activity in N - 1 of them is such that the steady-state susceptible class sub-population is equal to the population in the equivalent section of the continuous model. The activity level for the remaining class is chosen such that the condition for endemicity of the infection in the approximation is equal to that for the equivalent continuous-variable model; this minimizes errors in the steady-state population. The relationship between the discrete and continuous-variable models is explored, via numerical and analytical studies, in order to evaluate the accuracy of the approximation.

Is it possible to predict the minimum size of the acquired immunodeficiency syndrome (AIDS) epidemic in the United Kingdom?

A mathematical model of the dynamics of transmission of human immunodeficiency virus within the male homosexual population in the United Kingdom demonstrates that even the minimum size of the acquired immunodeficiency syndrome (AIDS) epidemic in the United Kingdom (based upon the assumption that all transmission ceased at the end of 1986) is difficult to predict. Model predictions are particularly sensitive to assumptions about the distributed incubation period of the disease, differences in frequency and patterns of sexual activity, and the proportion of infected people in whom AIDS later develops. More accurate predictions will depend on the collection of data on the incubation period of the disease, the infectiousness of infected persons, and on the numbers of new sexual partners of each sex per person and the duration of each partnership.

IgE antibody mediated inflammation of rat lung: histologic and bronchoalveolar lavage assessment.

Pulmonary antigen challenge in sensitized individuals elicits immediate and late phase responses (LPR). While mast cells and tissue inflammation are thought to be vital to the development of the LPR, the precise pathogenesis of these responses remains under investigation. Using the Sprague-Dawley rat as a model to study cutaneous LPR, we have previously demonstrated that rat cutaneous LPR are mast cell-dependent and are histologically characterized by early (1-8 h) neutrophil-rich and late (8-24 h) mononuclear cell-rich infiltrates. To compare and contrast this cutaneous response with IgE-dependent pulmonary inflammatory responses, we performed bronchoalveolar lavage (BAL) analyses of pulmonary inflammation following specific antigen challenge in actively immunized [IgE anti-ovalbumin (OA) antibody] and BAL and histologic analyses in passively sensitized [mouse hybridoma anti-dinitrophenyl (DNP) IgE antibody] rats. Following direct insufflation of OA into the trachea, actively sensitized animals demonstrated an increased number of polymorphonuclear leukocytes (PMNs) at 4 h in BAL fluid. These cell numbers were significantly increased over controls by 24 h following challenge. In addition, rats passively sensitized for 72 h with anti-DNP IgE hybridoma antibody (PCA = 1:10,000) were challenged with DNP-BSA aerosols. Examination of BAL fluid 1 to 2 h following challenge revealed significantly increased numbers of PMNs which returned to normal levels by 24 h. Numbers of lymphocytes and macrophages were unchanged compared to controls. Microscopic examination of lung tissue revealed alveolar and interstitial edema at 2 h following challenge and a focal peribronchiolitis characterized by a predominantly mononuclear cell infiltrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Stage-structure models of populations with distinct growth and development processes.

We extend the repertoire of stage-structure models which can be described in terms of delay-differential equations, by analysing models where the processes of growth and development within a stage are distinct. This permits the use of delay-differential equation models in situations where both population numbers and total biomass are dynamically significant.

Advances in the diagnosis and management of cystic fibrosis.

Cystic fibrosis (CF), the most common lethal genetic disease affecting Caucasians, is a multi-system illness, most frequently characterized by childhood chronic obstructive pulmonary disease, pancreatic exocrine insufficiency, and abnormal sweat electrolyte concentrations. The diagnosis of CF is based on a combination of the above clinical findings and/or a positive family history of the illness in conjunction with an abnormal sweat test. The quantitative pilocarpine iontophoresis test is the sole acceptable method for diagnostic confirmation of the clinical suspicion of CF. A recent advance in the diagnosis of CF has been in the development of methods for neonatal detection. The immunoreactive trypsinogen (IRT) detection test is practical, adaptable to large scale screening of dried neonatal blood spots, relatively inexpensive, and promising for the detection of newborns with CF who have pancreatic insufficiency. However, the reliability and validity of this method have not yet been adequately established. Major advances in the treatment of patients with CF have emerged in the last decades, particularly in supportive pulmonary and nutritional care.