Efficiencies of experimental designs for an illness-death model

Disease development is described by the progressive Markov illness-death model with one disease. The efficiencies of four experimental designs are discussed: the simple survival experiment, serial sacrifice, periodic diagnosis and complete observation. The discussion is based on the 'semiparametric' assumption of piecewise-constant intensities. Simple survival experiments are shown to have very low efficiency, serial sacrifice experiments to be moderately efficient, and periodic diagnosis to be almost as efficient as complete observation. An application to the analysis of the development of leukaemia in laboratory mice is given.     

Culling Dogs in Scenarios of Imperfect Control: Realistic Impact on the Prevalence of Canine Visceral Leishmaniasis

Background

Visceral leishmaniasis belongs to the list of neglected tropical diseases and is considered a public health problem worldwide. Spatial correlation between the occurrence of the disease in humans and high rates of canine infection suggests that in the presence of the vector, canine visceral leishmaniasis is the key factor for triggering transmission to humans. Despite the control strategies implemented, such as the sacrifice of infected dogs being put down, the incidence of American visceral leishmaniasis remains high in many Latin American countries.

Methodology/Principal Findings

Mathematical models were developed to describe the transmission dynamics of canine leishmaniasis and its control by culling. Using these models, imperfect control scenarios were implemented to verify the possible factors which alter the effectiveness of controlling this disease in practice.

Conclusions/Significance

A long-term continuous program targeting both asymptomatic and symptomatic dogs should be effective in controlling canine leishmaniasis in areas of low to moderate transmission (R₀ up to 1.4). However, the indiscriminate sacrifice of asymptomatic dogs with positive diagnosis may jeopardize the effectiveness of the control program, if tests with low specificity are used, increasing the chance of generating outrage in the population, and leading to lower adherence to the program. Therefore, culling must be planned accurately and implemented responsibly and never as a mechanical measure in large scale. In areas with higher transmission, culling alone is not an effective control strategy.     

A Mixture Point Process for Repeated Failure Times,with an Application to a Recurrent Disease

We present a model that describes the distribution of recurring times of a disease in presence of covariate effects. After a first occurrence of the disease in an individual, the time intervals between successive cases are supposed to be independent and to be a mixture of two distributions according to the issue of the previous treatment. Both sub‐distributions of the model and the mixture proportion are allowed to involve covariates. Parametric inference is considered and we illustrate the methods with data of a recurrent disease and with simulations, using piecewise constant baseline hazard functions.     

Infectious animal disease and its control

The control of infectious diseases in the main food-producing animals is considered and the main factors involved in the epizootiology of disease are presented. The properties of infectious agents and their natural history together with factors that influence the spread and development of disease are summarized. The factors in intensive animal husbandry that affect the occurrence of infectious disease and its control are considered. These include population density, population movement, management, hygiene and genetic constitution of the host. They encourage the appearance of new diseases, changes in the character of established diseases and the development of pathogenicity in infectious agents that were previously of no importance. Intensive animal husbandry has also increased the importance of multifactorial disease, which includes diseases that require more than one infectious agent or one or more infectious agents plus other factors for their cause. The methods of control of infectious disease currently available are described and the success and difficulties of their control on a global, national and local (farm or enterprise) basis are considered. Examples of diseases of global importance where national and world programmes of control and eradication have been of varying success are described. Examples of diseases that are enzootic throughout the world and the procedures used for their control are also described. The technological opportunities for the improvement of the control of infectious disease in the future are discussed. It is considered that developments in molecular biology and immunology will provide improvements in diagnostic tools and will revolutionize the development of animal resistance to disease and the production and use of vaccines.     

Semiparametric analysis of tumor incidence rates in survival/sacrifice experiments

This paper addresses the problem of comparing treatment groups with respect to the rate of tumor development for animals in a survival experiment with some serial sacrifices. The analysis specifies a parametric model for the tumor incidence function, but places no parametric restrictions on the death rates. The procedure is feasible with as few as two sacrifice times and requires no individual data on cause of death. Other diseases need not act independently of the tumor of interest, nor are any restrictions imposed on tumor lethality or the relationship between the onset and death times for tumor-bearing animals. The proposed methods are illustrated with some survival/sacrifice data.     

类器官在乳腺癌相关研究中的应用进展

乳腺癌是女性最常见的癌症,目前乳腺癌的研究主要借助体内模型和传统细胞培养方法,然而研究表明,由于人类和动物之间固有的物种差异,以及器官和细胞之间组织结构的差异,使用上述两种研究方法研制出的药物,在临床试验中失败率高达90％,因此,类器官三维培养应运而生.类器官是一种具有空间结构的三维细胞复合体,它作为一种新的肿瘤研究模...     

改良丝线结扎法建立大鼠牙周病模型的实验研究

目的:探讨改良丝线结扎法建立大鼠牙周病模型的可行性。方法:本实验创新一种新的手段,利用玻璃离子水门汀结合传统丝线结扎法建立大鼠牙周病模型,即在丝线结扎大鼠第一磨牙之后,在大鼠磨牙牙颈部丝线附近堆砌有黏着性的玻璃离子水门汀制造利于丝线固定的外形高点并同时稍微垫高咬合面,制造咬合创伤,加快牙周病的发生发展。结果:改良丝线结扎法建立牙周病模型的成功率为95%,相比传统丝线结扎发的65%,具有更高的成功率,模型建立更稳定,相比现有各种改良方法操作更简便易行。结论:改良丝线结扎法相比传统丝线结扎法建立大鼠牙周病模型具有更高的稳定性和成功率。     

Comparative Pathogenesis of Alkhumra Hemorrhagic Fever and Kyasanur Forest Disease Viruses in a Mouse Model

Kyasanur Forest disease virus (KFDV) and Alkhumra hemorrhagic fever virus (AHFV) are genetically closely-related, tick-borne flaviviruses that cause severe, often fatal disease in humans. Flaviviruses in the tick-borne encephalitis (TBE) complex typically cause neurological disease in humans whereas patients infected with KFDV and AHFV predominately present with hemorrhagic fever. A small animal model for KFDV and AHFV to study the pathogenesis and evaluate countermeasures has been lacking mostly due to the need of a high biocontainment laboratory to work with the viruses. To evaluate the utility of an existing mouse model for tick-borne flavivirus pathogenesis, we performed serial sacrifice studies in BALB/c mice infected with either KFDV strain P9605 or AHFV strain Zaki-1. Strikingly, infection with KFDV was completely lethal in mice, while AHFV caused no clinical signs of disease and no animals succumbed to infection. KFDV and high levels of pro-inflammatory cytokines were detected in the brain at later time points, but no virus was found in visceral organs; conversely, AHFV Zaki-1 and elevated levels of cytokines were found in the visceral organs at earlier time points, but were not detected in the brain. While infection with either virus caused a generalized leukopenia, only AHFV Zaki-1 induced hematologic abnormalities in infected animals. Our data suggest that KFDV P9605 may have lost its ability to cause hemorrhagic disease as the result of multiple passages in suckling mouse brains. However, likely by virtue of fewer mouse passages, AHFV Zaki-1 has retained the ability to replicate in visceral organs, cause hematologic abnormalities, and induce pro-inflammatory cytokines without causing overt disease. Given these striking differences, the use of inbred mice and the virus passage history need to be carefully considered in the interpretation of animal studies using these viruses.     

Hashimoto's Thyroiditis: From Genes to the Disease

Hashimoto's thyroiditis (HT) is the most prevalent autoimmune thyroid disorder. Intrathyroidal lymphocytic infiltration is followed by a gradual destruction of the thyroid gland which may lead to subclinical or overt hypothyroidism. Biochemical markers of the disease are thyroid peroxidase and/or thyroglobulin autoantibodies in the serum which are present with a higher prevalence in females than in males and increase with age. Although exact mechanisms of aetiology and pathogenesis of the disorder are not completely understood, a strong genetic susceptibility to the disease has been confirmed predominantly by family and twin studies. Several genes were shown to be associated with the disease occurrence, progression, and severity. Genes for human leukocyte antigen, cytotoxic T lymphocyte antigen-4, protein tyrosine phosphatase nonreceptor-type 22, thyroglobulin, vitamin D receptor, and cytokines are considered to be of utmost importance. Amongst endogenous factors for the disease development, the attention is focused predominantly on female sex, pregnancy with postpartum period and fetal microchimerism. Environmental factors influencing HT development are iodine intake, drugs, infections and different chemicals. Disturbed self-tolerance accompanied by the increased antigen presentation is a prerequisite for the HT occurrence, whereas proper interaction of thyroid cells, antigen presenting cells, and T cells are necessary for the initiation of thyroid autoimmunity. Secreted cytokines lead predominantly to T-helper type 1 (Th1) response as well as to Th 17 response which has only recently been implicated. Final outcome of HT is thyroid destruction which is mostly a consequence of the apoptotic processes combined with T-cell mediated cytotoxicity.     

Biological effectiveness of ionizing radiations of various quality in Escherichia coli bacteria (a theoretical analysis). A cell inactivation model

The dependence of the radiosensitivity of bacteria (the wild type, superresistant and rec-mutants) on linear energy transfer (LET) is considered. A nonformal model of inactivation of different bacterial mutants has been developed on the basis of the experimental data available. The concept of "metastable siles" (MS) is introduced. MS are peculliar DNA lesions arising from the occurrence of large nucleolytic gaps on both strands of DNA. Different mechanisms responsible for MS formation are considered. The kinetic equations of the model are solved and the parameters determined for both sensitive and resistant mutants.     

Nilotinib and imatinib are comparably effective in reducing growth of human eosinophil leukemia cells in a newly established xenograft model

We developed a xenograft model of human Chronic Eosinophilic Leukemia (CEL) to study disease progression and remission-induction under therapy with tyrosine kinase inhibitors using imatinib and nilotinib as examples. The FIP1L1/PDGFRA+ human CEL cell lineEOL-1 was injected intravenously into scid mice, and MR imaging and FACS analysis of mouse blood samples were performed to monitor disease development and the effects of imatinib and nilotinib. Organ infiltration was analyzed in detail by immunohistochemistry after sacrifice. All animals developed CEL and within one week of therapy, complete remissions were seen with both imatinib and nilotinib, resulting in reduced total tumor volumes by MR-imaging and almost complete disappearance of EOL-1 cells in the peripheral blood and in tissues. The new model system is feasible for the evaluation of new tyrosine kinase inhibitors and our data suggest that nilotinib may be a valuable additional targeted drug active in patients with FIP1L1/PDGFRA+ CEL.     

Amyloid β peptides with an additional cysteine residue can enhance immunogenicity and reduce the amyloid β burden in an Alzheimer’s disease mouse model

For the development of a safe vaccine for Alzheimer’s disease (AD), we studied the immunogenicity of amyloid β (Aβ) peptides without adjuvant. Addition of a cysteine residue (Cys) to Aβ peptides enhanced immunogenicity in mice compared to those without Cys. Vaccination with the Aβ-Cys peptides reduced Aβ deposits in AD model mice. From these results, the Aβ-Cys peptides, administered without adjuvant, are considered candidates for vaccine therapy for AD.     

Varietal mixtures: a viable strategy for sustainable productivity in subsistence agriculture

Remarkable parallels link the development of varietal mixtures across subsistence farming systems. Mixtures are grown and persist because they prolong harvest and income flow and provide diversity of diet. From our review of research on agronomic and disease aspects of mixtures in modern agriculture, it is also clear that improved stability and decreased disease severity are common features of mixtures relative to their components in monoculture. Such advantages are of value to both modern and subsistence agriculture. However, in the majority of cases, the yield advantage of mixtures is small. Overall, we conclude that varietal mixtures are presently a viable strategy for sustainable productivity in subsistence agriculture, have potential for improvement without sacrifice of diversity, are an important resource for future global food production and may have an expanding role in modern agriculture in situations where qualitative uniformity is not the guiding priority.     

The effect of delayed death in HIV/AIDS models

HIV-infected patients who receive treatment survive for some years after they have acquired the disease. The received treatment causes sustained reduction of viral reproduction by improving the immune function, leading to prolonged progression period to AIDS development. This prolonged progression period has created variability in survival times that affects estimates produced using mathematical models that do not include delay in disease related mortality. This paper investigates the effect of including delay in AIDS death occurrence in HIV/AIDS transmission models. A simple mathematical model with two stages of HIV progression is developed and extended to include time delay in the occurrence of AIDS deaths. Numerical simulations indicate that time delay changes the mortality curves considerably but has less effect on the proportion of infectives. The study highlights the importance of incorporating delay in models of HIV/AIDS for the production of accurate HIV/AIDS estimates.     

Log-linear models in the analysis of disease prevalence data from survival/sacrifice experiments.

This paper considers the problem of analyzing disease prevalence data from survival experiments in which there may also be some serial sacrifice. The assumptions needed for "standard" analyses are reviewed in the context of a general model recently proposed by the authors. This model is then reparametrized in log-linear form, and a generalized EM algorithm is utilized to obtain maximum likelihood estimates of the parameters for a broad class of unsaturated models. Tests based on the relative likelihood are proposed to investigate the effects of treatment, time, and the presence of other diseases on the prevalences and lethalities of specific diseases of interest. An example is given, using data from a large experiment to investigate the effects of low-level radiation on laboratory mice. Finally, some possible directions for future research are indicated.     

A variable risk clinical prognostic compartmental model

A model for predicting the occurrence of disease endpoints from a knowledge of baseline variables and intermediate events is described and illustrated with numerical examples. Maximum likelihood equations are developed and maximum likelihood estimates of coefficients in risk functions of variables included in a stepwise upward procedure are applied to a small set of data for illustrative purposes.     

Association rule mining based study for identification of clinical parameters akin to occurrence of brain tumor

Healthcare sector is generating a large amount of information corresponding to diagnosis, disease identification and treatment of an individual. Mining knowledge and providing scientific decision-making for the diagnosis & treatment of disease from the clinical dataset is therefore increasingly becoming necessary. Aim of this study was to assess the applicability of knowledge discovery in brain tumor data warehouse, applying data mining techniques for investigation of clinical parameters that can be associated with occurrence of brain tumor. In this study, a brain tumor warehouse was developed comprising of clinical data for 550 patients. Apriori association rule algorithm was applied to discover associative rules among the clinical parameters. The rules discovered in the study suggests - high values of Creatinine, Blood Urea Nitrogen (BUN), SGOT & SGPT to be directly associated with tumor occurrence for patients in the primary stage with atleast 85% confidence and more than 50% support. A normalized regression model is proposed based on these parameters along with Haemoglobin content, Alkaline Phosphatase and Serum Bilirubin for prediction of occurrence of STATE (brain tumor) as 0 (absent) or 1 (present). The results indicate that the methodology followed will be of good value for the diagnostic procedure of brain tumor, especially when large data volumes are involved and screening based on discovered parameters would allow clinicians to detect tumors at an early stage of development.     

A Bootstrap-Based Covariate Selection Method for Modeling the Risk of Lightning-Induced Fires at a Local Scale: A Case Study in Northwest Spain

In lightning-induced fire risk prediction models, the number of potential predictors is usually high, with some redundancy among them. It is therefore important to select the best subset of predictors that obtain models with the greatest discrimination capacity. With this aim in mind, the logistic generalized linear model was used to estimate lightning-induced fire occurrence using a case study of the province of León (northwest Spain). A bootstrap-based test was used to obtain the optimal number of predictors and to model this optimal number of predictors displaying the largest area under the receiver operating characteristics curve. The results show that of the 16 variables initially considered, only three were necessary to obtain the model with the best discriminatory capacity for estimating lightning-induced fire occurrence. Moreover, this model can be considered equivalent to another nine alternative models with three covariates. Both the optimal and the equivalent models are useful in the spatially explicit assessment of fire risk, the planning and coordination of regional efforts to identify areas at greatest risk, and the design of long-term wildfire management strategies. The methodology used for this case study can be applied to other wildfire risk assessment situations where multiple and interconnected covariates are available.     

Multiple Stable States of Disease Occurrence: A Note on the Implications for the Anthropological Study of Human Disease

Ecologists model human disease using predator-prey models, with humans as the prey and the pathogen as the predator. Use of these models permits the identification of stable equilibria and stable states of disease prevalence for human host-parasite systems. May (1977) has described the possibility of the presence of multiple stable states of disease prevalence for human disease systems. The model of multiple stable states implies that historical circumstances are important in determining the occurrence of disease. This model offers a theoretical framework in which to examine the occurrence of epidemics in human populations and to develop a more complete understanding of disease processes.