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Theor Biol Med Model [journal]
- Bayesian approach for the estimation of cyclosporine area under the curve using limited sampling strategies in pediatric hematopoietic stem cell transplantation. [JOURNAL ARTICLE]
- Theor Biol Med Model 2014 Sep 5; 11(1):39.
The optimal marker for cyclosporine (CsA) monitoring in transplantation patients remains controversial. However, there is a growing interest in the use of the area under the concentration-time curve (AUC), particularly for cyclosporine dose adjustment in pediatric hematopoietic stem cell transplantation. In this paper, we develop Bayesian limited sampling strategies (B-LSS) for cyclosporine AUC estimation using population pharmacokinetic (Pop-PK) models and investigate related issues, with the aim to improve B-LSS prediction performance.Twenty five pediatric hematopoietic stem cell transplantation patients receiving intravenous and oral cyclosporine were investigated. Pop-PK analyses were carried out and the predictive performance of B-LSS was evaluated using the final Pop-PK model and several related ones. The performance of B-LSS when targeting different versions of AUC was also discussed.A two-compartment structure model with a lag time and a combined additive and proportional error is retained. The final covariate model does not improve the B-LSS prediction performance. The best performing models for intravenous and oral cyclosporine are the structure ones with combined and additive error, respectively. Twelve B-LSS, consisting of 4 or less sampling points obtained within 4 hours post-dose, predict AUC with 95th percentile of the absolute values of relative prediction errors of 20% or less. Moreover, B-LSS perform better for the prediction of the 'underlying' AUC derived from the Pop-PK model estimated concentrations that exclude the residual errors, in comparison to their prediction of the observed AUC directly calculated using measured concentrations.B-LSS can adequately estimate cyclosporine AUC. However, B-LSS performance is not perfectly in line with the standard Pop-PK model selection criteria; hence the final model might not be ideal for AUC prediction purpose. Therefore, for B-LSS application, Pop-PK model diagnostic criteria should additionally account for AUC prediction errors.
- Dimensional analysis yields the general second-order differential equation underlying many natural phenomena: the mathematical properties of a phenomenon's data plot then specify a unique differential equation for it. [Journal Article]
- Theor Biol Med Model 2014.:38.
This study uses dimensional analysis to derive the general second-order differential equation that underlies numerous physical and natural phenomena described by common mathematical functions. It eschews assumptions about empirical constants and mechanisms. It relies only on the data plot's mathematical properties to provide the conditions and constraints needed to specify a second-order differential equation that is free of empirical constants for each phenomenon.A practical example of each function is analyzed using the general form of the underlying differential equation and the observable unique mathematical properties of each data plot, including boundary conditions. This yields a differential equation that describes the relationship among the physical variables governing the phenomenon's behavior. Complex phenomena such as the Standard Normal Distribution, the Logistic Growth Function, and Hill Ligand binding, which are characterized by data plots of distinctly different sigmoidal character, are readily analyzed by this approach.It provides an alternative, simple, unifying basis for analyzing each of these varied phenomena from a common perspective that ties them together and offers new insights into the appropriate empirical constants for describing each phenomenon.
- Computational identification of surrogate genes for prostate cancer phases using machine learning and molecular network analysis. [Journal Article, Research Support, Non-U.S. Gov't]
- Theor Biol Med Model 2014.:37.
Prostate cancer is one of the most common malignant diseases and is characterized by heterogeneity in the clinical course. To date, there are no efficient morphologic features or genomic biomarkers that can characterize the phenotypes of the cancer, especially with regard to metastasis--the most adverse outcome. Searching for effective surrogate genes out of large quantities of gene expression data is a key to cancer phenotyping and/or understanding molecular mechanisms underlying prostate cancer development.Using the maximum relevance minimum redundancy (mRMR) method on microarray data from normal tissues, primary tumors and metastatic tumors, we identifed four genes that can optimally classify samples of different prostate cancer phases. Moreover, we constructed a molecular interaction network with existing bioinformatic resources and co-identifed eight genes on the shortest-paths among the mRMR-identified genes, which are potential co-acting factors of prostate cancer. Functional analyses show that molecular functions involved in cell communication, hormone-receptor mediated signaling, and transcription regulation play important roles in the development of prostate cancer.We conclude that the surrogate genes we have selected compose an effective classifier of prostate cancer phases, which corresponds to a minimum characterization of cancer phenotypes on the molecular level. Along with their molecular interaction partners, it is fairly to assume that these genes may have important roles in prostate cancer development; particularly, the un-reported genes may bring new insights for the understanding of the molecular mechanisms. Thus our results may serve as a candidate gene set for further functional studies.
- Beneficial effects of inhaled NO on apoptotic pneumocytes in pulmonary thromboembolism model. [Journal Article, Research Support, Non-U.S. Gov't]
- Theor Biol Med Model 2014.:36.
Lung ischemia-reperfusion injury (LIRI) may occur in the region of the affected lung after reperfusion therapy. Inhaled NO may be useful in treating acute and chronic pulmonary thromboembolism (PTE) due to the biological effect property of NO.A PTE canine model was established through selectively embolizing blood clots to an intended right lower lobar pulmonary artery. PaO2/FiO2, the mPAP and PVR were investigated at the time points of 2, 4, 6 hours after inhaled NO. Masson's trichrome stain, apoptotic pneumocytes and lung sample ultrastructure were also investigated among different groups.The PaO2/FiO2 in the Inhaled NO group increased significantly when compared with the Reperfusion group at time points of 4 and 6 hours after reperfusion, mPAP decreased significantly at point of 2 hours and the PVR decreased significantly at point of 6 hours after reperfusion. The amounts of apoptotic type II pneumocytes in the lower lobar lung have negative correlation trend with the arterial blood PaO2/FiO2 in Reperfusion group and Inhaled NO group. Inhaled nitric oxide given at 20 ppm for 6 hours can significantly alleviate the LIRI in the model.Dramatic physiological improvements are seen during the therapeutic use of inhaled NO in pulmonary thromboembolism canine model. Inhaled NO may be useful in treating LIRI in acute or chronic PTE by alleviating apoptotic type II pneumocytes. This potential application warrants further investigation.
- The homeostatic set point of the hypothalamus-pituitary-thyroid axis - maximum curvature theory for personalized euthyroid targets. [JOURNAL ARTICLE]
- Theor Biol Med Model 2014 Aug 8; 11(1):35.
Despite rendering serum free thyroxine (FT4) and thyrotropin (TSH) within the normal population ranges broadly defined as euthyroidism, many patients being treated for hyperthyroidism and hypothyroidism persistently experience subnormal well-being discordant from their pre-disease healthy euthyroid state. This suggests that intra-individual physiological optimal ranges are narrower than laboratory-quoted normal ranges and implies the existence of a homeostatic set point encoded in the hypothalamic-pituitary-thyroid (HPT) axis that is unique to every individual.We have previously shown that the dose-response characteristic of the hypothalamic-pituitary (HP) unit to circulating thyroid hormone levels follows a negative exponential curve. This led to the discovery that the normal reference intervals of TSH and FT4 fall within the 'knee' region of this curve where the maximum curvature of the exponential HP characteristic occurs. Based on this observation, we develop the theoretical framework localizing the position of euthyroid homeostasis over the point of maximum curvature of the HP characteristic.The euthyroid set points of patients with primary hypothyroidism and hyperthyroidism can be readily derived from their calculated HP curve parameters using the parsimonious mathematical model above. It can be shown that every individual has a euthyroid set point that is unique and often different from other individuals.In this treatise, we provide evidence supporting a set point-based approach in tailoring euthyroid targets. Rendering FT4 and TSH within the laboratory normal ranges can be clinically suboptimal if these hormone levels are distant from the individualized euthyroid homeostatic set point. This mathematical technique permits the euthyroid set point to be realistically computed using an algorithm readily implementable for computer-aided calculations to facilitate precise targeted dosing of patients in this modern era of personalized medicine.
- Prospects for developing an accurate diagnostic biomarker panel for low prevalence cancers. [Journal Article]
- Theor Biol Med Model 2014.:34.
Early detection screening of asymptomatic populations for low prevalence cancers requires a highly specific test in order to limit the cost and anxiety produced by falsely positive identifications. Most solid cancers are a heterogeneous collection of diseases as they develop from various combinations of genetic lesions and epigenetic modifications. Therefore, it is unlikely that a single test will discriminate all cases of any particular cancer type. We propose a novel, intuitive biomarker panel design that accommodates disease heterogeneity by allowing for diverse biomarker selection that increases diagnostic accuracy.Using characteristics of nine pancreatic ductal adenocarcinoma (PDAC) biomarkers measured in human sera, we modeled the behavior of biomarker panels consisting of a sum of indicator variables representing a subset of biomarkers within a larger biomarker data set. We then chose a cutoff for the sum to force specificity to be high and delineated the number of biomarkers required for adequate sensitivity of PDAC in our panel design.The model shows that a panel consisting of 40 non-correlated biomarkers characterized individually by 32% sensitivity at 95% specificity would require any 7 biomarkers to be above their respective thresholds and would result in a panel specificity and sensitivity of 99% each.A highly accurate blood-based diagnostic panel can be developed from a reasonable number of individual serum biomarkers that are relatively weak classifiers when used singly. A panel constructed as described is advantageous in that a high level of specificity can be forced, accomplishing a prerequisite for screening asymptomatic populations for low-prevalence cancers.
- An extended gene protein/products boolean network model including post-transcriptional regulation. [Journal Article, Research Support, Non-U.S. Gov't]
- Theor Biol Med Model 2014 May 7.:S5.
Networks Biology allows the study of complex interactions between biological systems using formal, well structured, and computationally friendly models. Several different network models can be created, depending on the type of interactions that need to be investigated. Gene Regulatory Networks (GRN) are an effective model commonly used to study the complex regulatory mechanisms of a cell. Unfortunately, given their intrinsic complexity and non discrete nature, the computational study of realistic-sized complex GRNs requires some abstractions. Boolean Networks (BNs), for example, are a reliable model that can be used to represent networks where the possible state of a node is a boolean value (0 or 1). Despite this strong simplification, BNs have been used to study both structural and dynamic properties of real as well as randomly generated GRNs.In this paper we show how it is possible to include the post-transcriptional regulation mechanism (a key process mediated by small non-coding RNA molecules like the miRNAs) into the BN model of a GRN. The enhanced BN model is implemented in a software toolkit (EBNT) that allows to analyze boolean GRNs from both a structural and a dynamic point of view. The open-source toolkit is compatible with available visualization tools like Cytoscape and allows to run detailed analysis of the network topology as well as of its attractors, trajectories, and state-space. In the paper, a small GRN built around the mTOR gene is used to demonstrate the main capabilities of the toolkit.The extended model proposed in this paper opens new opportunities in the study of gene regulation. Several of the successful researches done with the support of BN to understand high-level characteristics of regulatory networks, can now be improved to better understand the role of post-transcriptional regulation for example as a network-wide noise-reduction or stabilization mechanisms.
- Improvement of design of a surgical interface using an eye tracking device. [Journal Article]
- Theor Biol Med Model 2014 May 7.:S4.
Surgical interfaces are used for helping surgeons in interpretation and quantification of the patient information, and for the presentation of an integrated workflow where all available data are combined to enable optimal treatments. Human factors research provides a systematic approach to design user interfaces with safety, accuracy, satisfaction and comfort. One of the human factors research called user-centered design approach is used to develop a surgical interface for kidney tumor cryoablation. An eye tracking device is used to obtain the best configuration of the developed surgical interface.Surgical interface for kidney tumor cryoablation has been developed considering the four phases of user-centered design approach, which are analysis, design, implementation and deployment. Possible configurations of the surgical interface, which comprise various combinations of menu-based command controls, visual display of multi-modal medical images, 2D and 3D models of the surgical environment, graphical or tabulated information, visual alerts, etc., has been developed. Experiments of a simulated cryoablation of a tumor task have been performed with surgeons to evaluate the proposed surgical interface. Fixation durations and number of fixations at informative regions of the surgical interface have been analyzed, and these data are used to modify the surgical interface.Eye movement data has shown that participants concentrated their attention on informative regions more when the number of displayed Computer Tomography (CT) images has been reduced. Additionally, the time required to complete the kidney tumor cryoablation task by the participants had been decreased with the reduced number of CT images. Furthermore, the fixation durations obtained after the revision of the surgical interface are very close to what is observed in visual search and natural scene perception studies suggesting more efficient and comfortable interaction with the surgical interface. The National Aeronautics and Space Administration Task Load Index (NASA-TLX) and Short Post-Assessment Situational Awareness (SPASA) questionnaire results have shown that overall mental workload of surgeons related with surgical interface has been low as it has been aimed, and overall situational awareness scores of surgeons have been considerably high.This preliminary study highlights the improvement of a developed surgical interface using eye tracking technology to obtain the best SI configuration. The results presented here reveal that visual surgical interface design prepared according to eye movement characteristics may lead to improved usability.
- A flowgraph model for bladder carcinoma. [Journal Article, Research Support, Non-U.S. Gov't]
- Theor Biol Med Model 2014 May 7.:S3.
Superficial bladder cancer has been the subject of numerous studies for many years, but the evolution of the disease still remains not well understood. After the tumor has been surgically removed, it may reappear at a similar level of malignancy or progress to a higher level. The process may be reasonably modeled by means of a Markov process. However, in order to more completely model the evolution of the disease, this approach is insufficient. The semi-Markov framework allows a more realistic approach, but calculations become frequently intractable. In this context, flowgraph models provide an efficient approach to successfully manage the evolution of superficial bladder carcinoma. Our aim is to test this methodology in this particular case.We have built a successful model for a simple but representative case.The flowgraph approach is suitable for modeling of superficial bladder cancer.
- Seeking genetic signature of radiosensitivity--a novel method for data analysis in case of small sample sizes. [Journal Article, Research Support, Non-U.S. Gov't]
- Theor Biol Med Model 2014 May 7.:S2.
The identification of polymorphisms and/or genes responsible for an organism's radiosensitivity increases the knowledge about the cell cycle and the mechanism of the phenomena themselves, possibly providing the researchers with a better understanding of the process of carcinogenesis.The aim of the study was to develop a data analysis strategy capable of discovering the genetic background of radiosensitivity in the case of small sample size studies.Among many indirect measures of radiosensitivity known, the level of radiation-induced chromosomal aberrations was used in the study. Mathematical modelling allowed the transformation of the yield-time curve of radiation-induced chromosomal aberrations into the exponential curve with limited number of parameters, while Gaussian mixture models applied to the distributions of these parameters provided the criteria for mouse strain classification. A detailed comparative analysis of genotypes between the obtained subpopulations of mice followed by functional validation provided a set of candidate polymorphisms that might be related to radiosensitivity. Among 1857 candidate relevant SNPs, that cluster in 28 genes, eight SNPs were detected nonsynonymous (nsSNP) on protein function. Two of them, rs48840878 (gene Msh3) and rs5144199 (gene Cc2d2a), were predicted as having increased probability of a deleterious effect. Additionally, rs48840878 is capable of disordering phosphorylation with 14 PKs. In silico analysis of candidate relevant SNP similarity score distribution among 60 CGD mouse strains allowed for the identification of SEA/GnJ and ZALENDE/EiJ mouse strains (95.26% and 86.53% genetic consistency respectively) as the most similar to radiosensitive subpopulationA complete step-by-step strategy for seeking the genetic signature of radiosensitivity in the case of small sample size studies conducted on mouse models was proposed. It is shown that the strategy, which is a combination of mathematical modelling, statistical analysis and data mining methodology, allows for the discovery of candidate polymorphisms which might be responsible for radiosensitivity phenomena.