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Evaluation of path analysis through computer simulation: effect of incorrectly assuming independent distribution of familial correlations.

Path analysis of family data has been widely applied to resolve genetic and environmental patterns of familial resemblance. A prevalent statistical approach in path analysis has been, first, to estimate the familial correlations and, second, by assuming these estimates to be independently distributed, define a likelihood function from which maximum likelihood estimates of model parameters can be obtained and likelihood ratio tests of hypotheses performed. Although it is generally known that the independence assumption does not hold when multiple familial correlations are estimated from the same family data, this statistical method has still been used in these situations owing, in part, to the lack of any viable alternatives and, in part, to the lack of any knowledge about the specific quantitative effects of not meeting the assumption of independence. Here, using computer-simulation methods, we evaluate the robustness of this statistical method to deviations from the assumption of independence. In general, we found that the failure to meet the assumption of independence leads to a conservative test of the goodness-of-fit of the path model, although likelihood ratio tests of specific null hypotheses were at times liberal, at times conservative, and at times nearly exact. Although the test statistics were found to be distorted, the parameter estimates using this method were nearly unbiased.

Biometry↗

Quantitative interpretation of corticosteroid pharmacokinetics in inner fluids using computer simulations.

The delivery of drugs to the inner ear by applying them directly onto the round window membrane is a promising way to treat human inner ear disorders. To further develop this strategy, and to design controlled clinical trials, additional preclinical studies are necessary. It is especially important to derive the time course and total dose for the various target regions within the inner ear. Since direct pharmacokinetic measurements in the human cochlea are not possible, simulations provide a valuable tool for the interpretation and planning of animal studies, for evaluating changes of application protocols and drug delivery systems, and for extrapolating the results from animal studies to the human. The present study has analyzed two previously published data sets in which concentration time courses of corticosteroids in the cochlear fluids were reported. Drug movements were simulated with a finite element computer model of the inner ear fluids. The time course of corticosteroid pharmacokinetics could be approximated for each study by consideration of the specific experimental paradigm. Although the experimental studies reported considerably different drug levels in the fluid samples taken from the cochlea, these differences were largely explained by considering the experimental design of the respective studies. After correction for experimental differences, the calculated perilymph levels of drug were within a factor of two of each other. The simulations demonstrated that an important factor controlling the drug level achieved is the time the drug solution remains in the middle ear. It can be concluded that small differences in delivery protocols may cause large variations in the drug levels achieved in the inner ear fluids.

Adrenal Cortex Hormones↗

An assessment of the physiological significance of cimetidine interactions with copper and zinc in biofluids as based on the computer-simulated distribution of the involved complexes at therapeutic levels of the drug.

The hypothesis was formerly put forward that the main therapeutic action of cimetidine (the histamine H2-receptor antagonist marketed as Tagamet) as well as some of its side effects might be mediated by its interactions with essential metal ions. The present paper reports the potentiometric study of the coordination of the drug with copper(II) and zinc(II) in NaCl 0.15 mol dm-3 at 37 degrees C. Special attention was paid to copper complexes, due to (i) the involvement of cimetidine in rheumatoid arthritis evolution which could be related to the well-established role of copper against this disease, (ii) the anti-ulcer and anti-inflammatory properties of copper. In particular, the copper-cimetidine-histamine and copper-cimetidine-histidine ternary systems were investigated. Computer simulations of the distribution of cimetidine, zinc and copper in blood plasma were performed at therapeutic levels of the drug. No influence can be expected from cimetidine on the bioavailability of these metal ions, the opposite being also true. The mediation of copper in the action of cimetidine on rheumatoid arthritis should thus be ruled out, the influence of the drug being rather interpretable in terms of reduction of histamine release. Similarly, the sexual dysfunctions due to cimetidine administration are unlikely to arise from the interactions of drug with zinc in blood plasma. The possible involvement of copper and zinc in cimetidine gastrointestinal absorption is also discussed.

Cimetidine↗

Clonal attenuation in chick embryo fibroblasts. Experimental data, a model and computer simulations.

When cells from mass cultures of chick embryo fibroblasts are grown at very low density, some cells yield large clones while others produce smaller clones, and some cells fail to divide at all. The distribution of clone sizes is related to the number of population doublings which the donor mass culture has undergone: the more doublings which have occurred, the smaller the average clone size. In this report we describe a model which analyses this phenomenon, referred to as 'clonal attenuation', in detail. The model is based on the concept that a cell with hypothetically unlimited replicative potential--i.e. a 'stem' cell--can become 'committed' to a programme of limited replicative potential. This event is assumed to be stochastic and to have a fixed probability per stem cell division. The parameters of the model are: Pc, the probability of commitment; N, the number of differentiative divisions; and Tc, the cell-cycle times. By computer simulation, it is shown that Pc increases roughly exponentially at each successive stem cell division. According to the model, when the daughter of a stem cell becomes committed, its progeny proceed through N obligatory divisions before becoming terminally differentiated (post-mitotic). The best-fit value of N was found to be seven. The simulations also reveal that the absolute number of stem cells in the total population increases for most of the lifespan of the culture. When Pc becomes much greater than 0.5, the number of stem cells declines rapidly to zero, and the culture nears senescence. Sensitivity analysis shows that Pc can assume only a limited range of values at each stem-cell division.

Animals↗

Computer simulations of lymph node metastasis for optimizing the pathologic examination of sentinel lymph nodes in patients with breast carcinoma.

BACKGROUND: Many empiric protocols are used to detect metastases in sentinel lymph nodes (SLNs), but comparison of the efficacy of these methods is impractical because tissue is lost in processing, making reassessment with another policy difficult. Consequently, performance indicators of this test are largely unknown. DESIGN: The authors retrospectively examined 112 SLNs removed from 89 patients with breast carcinoma treated at the authors' institution and used the histologic data to devise a mathematic model of a SLN with Matlab modeling software. The authors simulated examination of this computer-generated (virtual) lymph node according to several macroscopic and histologic sampling protocols and for each protocol assessed the probability of detecting micrometastases of specified sizes. The authors used published costing figures to estimate the cost of the policies. RESULTS: Direct comparison of 6 sectioning strategies currently in use by pathology laboratories showed the chances of detecting a 500-microm metastasis ranged from 20% to 75%. Four of the 6 protocols had a less than 30% chance of detecting metastases of this size. The detection rate of smaller metastases was poorer. Cost was not a good discriminator because some policies were more efficient than others. CONCLUSIONS: The detection of metastases is highly dependent on the methods used to look for them. The authors' simulations suggest that commonly used methods of examining lymph nodes have high false-negative rates, particularly for small metastases. There is an urgent need for pathologists and clinicians to agree on the minimum size of SLN metastases that will be sought by histology and set standard methods for examining these lymph nodes.

Breast Neoplasms↗

Structure of star-burst dendrimers: a comparison between small angle x-ray scattering and computer simulation results.

We investigated the generation dependent shape and internal structure of star-burst dendrimers under good solvent conditions using small angle x-ray scattering and molecular modeling. Measurements have been performed on poly(amidoamine) dendrimers with generations ranging from g=0 up to g=8 at low concentrations in methanol. We described the static form factor P(q) by a model taking into account the compact, globular shape as well as the loose, polymeric character of dendrimers. Monomer distributions within dendrimers are of special interest for potential applications and have been characterized by the pair correlation function gamma(r), as well as by the monomer and end-group density profile, rho(r) and rho(e)(r), respectively. Monomer density profiles and gamma(r) can be derived from P(q) by modeling and via a model independent approach using the inverse Fourier transformation algorithm first introduced by Glatter. Experimental results are compared with computer simulations performed for single dendrimers of various generations using the cooperative motion algorithm. The simulation gives direct access to gamma(r) and rho(r), allows an independent determination of P(q), and yields in addition to the scattering experiment information about the distribution of the end groups. Excellent qualitative agreement between experiment and simulation has been found.

Journal Article↗

The proliferative response of the coagulating gland of the castrated mouse under continuous androgen stimulation: an experimental and computer simulation model.

The proliferative response of the coagulating gland of the castrated male mouse has been examined during continuous treatment with testosterone propionate. Fourteen days after castration, s.c. daily injections of testosterone propionate were begun. Mitotic (Im) and labelling (IL) index values were obtained at 3 h intervals for up to 100 h after the initial injection. These showed a biphasic response, in which IL reached a maximum at 30 and 70 h, and Im at approximately 45 and 75 h. Fraction-labelled mitoses (FLM) curves were begun 24, 48, and 72 h after the first androgen injection. In each curve the first wave of labelled mitoses rose to 100% and showed a square form indicating little spread in the durations of the G2 and S phases. Values of 7.5, 1.3 and 0.7 h were obtained for the durations of DNA synthesis (ts), the post-synthetic period (tG2) and of mitosis (tm) respectively. In none of the FLM curves was it possible to demonstrate a second wave of labelled mitoses and direct measurement of the cell cycle time (Tc) was not obtained. Continuous tritiated thymidine labelling indices revealed that after a latent period of 25 h, DNA synthesis began and labelling rose rapidly to 80% by 45 h and then more slowly to 95% by 97 h. Cell population changes during androgen stimulation estimated from measurements of total glandular DNA indicated that the number of cells present in the glands remained constant during the first 30 h after stimulation and thereafter increased to approximately 2-3 times the original value. The data are compared with a mathematical model which assumes that the cell population of castrated mice when stimulated passes from a GO compartment through successive waves of DNA synthesis and mitosis. After each cell division the cells may leave or remain in the proliferative cycle. This model has been subjected to computer simulation using the cell cycle parameters obtained in the kinetic experiments. There was good agreement between the stimulation and experimental results in the Im and IL curves, continuous labelling, and total cell number experiments. The simulation of FLM curves was less successful. Although the first wave of labelled mitoses was clearly seen the model predicts a distinct second wave of labelled mitoses. It is concluded that this does not appear because of variation in the duration of G1.

Animals↗

An experimental study and computer simulation of the turnover of choline in erythrocytes of patients treated with lithium carbonate.

The mechanism by which choline accumulates in erythrocytes during treatment with lithium salts has been elucidated. A component of the study was a kinetic description of erythrocyte phospholipase-D, which catalyses the release of intracellular choline from phospholipids. Apparent steady-state kinetic parameters for calcium ions were determined: Km (+/- SD) = 0.6 +/- 0.3 mmol/l aqueous cell volume and Vmax (+/- SD) = 12 +/- 4 mumol/l packed red blood cells (RBC) min-1. Competitive inhibition of the phospholipase-D by barium ions was also observed. Other information concerning choline and lithium levels and red cell life-time was obtained from the literature. Details of the kinetics were used to develop a comprehensive dynamic model of choline metabolism by erythrocytes. The scheme is as follows; phosphatidylcholine associated with high density lipoproteins exchanges with the erythrocyte membrane phospholipids, the neutral phospholipids undergo two dimensional translational and rotational motion and also flip between each layer of the bilayer thus becoming exposed to an intracellularly-located phospholipase-D, whereupon the choline is hydrolysed and released into the intracellular milieu. A choline transport protein, which is able to be inhibited by lithium, mediates the influx and efflux of choline. The differential equations that describe reactant flux in this scheme were integrated numerically and the choline accumulation profiles under various conditions of transport and enzyme inhibition are presented. Computer solution of the model, by using as input values plasma lithium levels in the upper limit of the therapeutic range, required that the red cell life-time be reduced in order to explain the previously observed negative association between choline and increasing lithium levels. The results of the computer simulations under varying initial conditions of plasma and erythrocyte lithium and choline concentrations permit, for the first time, a comprehensive description of those factors affecting erythrocyte choline levels.

Barium↗

[Computer simulation of the activity of selected functional systems in the body during maintenance of homeostasis].

A computer with an appropriate software may greatly contribute to the understanding of relationships and interactions among physiological processes in the body and thus to influence the speed and effectiveness of learning. Presented computer model "The Internal Environment", briefly described in this paper, illustrates this fact. This model allows to simulate behavior of some functional systems in various experimental situations. The subsequent evaluation of the activity changes in these systems can help students to understand and interpret principles of the activity of the homeostatic mechanisms. That is why the computer simulation is an appropriate starting point at seminars where problems of the internal environment stability maintenance are to be discussed.

Computer Simulation↗

Computer simulation of the generation of the electroencephalogram.

We have used a computer program for modeling some features of the scalp electroencephalogram (EEG) in terms of the time- and space-dependent interactions of populations of neurons in different hypothetical brain configurations of increasing levels of complexity. The input of the model consists of: (1) geometric and anatomic data characterizing the brain configuration, including interconnecting fiber pathways between neuronal groups; (2) physiologic characteristics of neurons, such as thresholds, driving potentials and conductances of excitatory and inhibitory synapses, synaptic delay times, and rise and fall times of postsynaptic potentials; and (3) functions describing the time-dependent afferent impulses to the brain configuration under study. The output of the model consists of plots of selected intracellular and extracellular potentials, including electrical potentials measured by an array of electrodes on the surface of the head, as a function of time. The objective was to assess how the characteristic frequencies seen in scalp EEG recordings might be determined by characteristics of local neuronal circuits (such as thalamic 'pacemakers') and by global circuit characteristics (such as cortico-cortical and thalamo-cortical interactions). We find that in our model the basic requirement for rhythmic behavior is the existence of local feedback circuits containing inhibitory neurons and that, when parameters of the model are chosen so that sustained rhythmic oscillations in the alpha frequency range are generated, the characteristic frequencies of these oscillations are primarily determined by the local circuit parameters, especially the duration of the inhibitory postsynaptic potentials, and are relatively independent of global circuit parameters such as the ranges of the long interconnecting axons and the propagation velocity of action potentials in these axons.

Animals↗

Computer simulation of auditory stream segregation in alternating-tone sequences.

A computer model is described that takes a novel approach to the problem of accounting for perceptual coherence in alternating pure-tone sequences by using simple physiological principles that operate at a low level. Using the same set of parameter values, the model is able to reproduce a number of phenomena associated with auditory stream segregation. These are (1) the buildup of stream segregation over time, (2) the temporal coherence and fission boundaries obtained from human listeners, and (3) the trill threshold. Whereas these phenomena are generally accounted for in terms of an auditory scene-analysis process that works on the basis of Gestalt perceptual principles, the operation of the model suggests that some Gestalt auditory grouping may be the product of low-level processes.

Acoustic Stimulation↗

Analysis of Ter-Ter enzyme kinetic mechanisms by computer simulation of isotope exchange at chemical equilibrium: development and application of ISOTER, a personal-computer-based program.

A convenient, personal-computer-based program has been developed that allows simulation of isotopic exchange kinetics at chemical equilibrium catalyzed by a three reactant-three product (TerTer) enzyme system: A + B + C integral of P + Q + R. This program, ISOTER, utilizes a rapid algebraic method to calculate the exchange rate between any reactant-product pair as a function of the substrate concentration and avoids altogether the necessity of deriving an explicit (but cumbersome and impractical) equation for exchange rate. ISOTER was used to generate model saturation patterns for 16 different TerTer kinetic mechanisms, varying different combinations of reactant-product pairs in constant ratio at equilibrium: [all substrates], [A, P], [B, Q], and [C, R], while holding the nonvaried components constant. These model studies indicate that virtually every one of these mechanisms can be distinguished from the others. In addition, ISOTER has been used to fit multiple sets of experimental data for Escherichia coli glutamine synthetase, which produced a set of rate constants consistent with the previously proposed "preferred order random" kinetic mechanism.

Computer Simulation↗

A computer simulation of cardiac emergencies.

Code Red! software simulates typical cardiac emergencies with a full color interactive educational simulation. The trainee can master the basic skills of recognizing cardiac rhythms and appropriately treating abnormalities through interaction with a variety of scenarios (e.g. ventricular fibrillation, bradycardia, asystole). Older character-based computer programs are limited in their ability to assist in the training of proper cardiac arrest resuscitation. Medical Directors, residents, medical students, critical care nurses, ER staff, paramedics and many other health care professionals can benefit from the software. The software, running within the Windows 3.0 graphical environment on a 386/486 PC, demonstrates the capability of today's computers to simulate a complex task and provide a powerful training tool.

Computer Graphics↗

Computer simulations of stress-related bone remodeling around noncemented acetabular components.

The authors have used computer modeling techniques to examine stress-related bone changes in the acetabular region. Using a previously developed theory for bone development and adaptation, the authors simulated the distribution of bone density in the natural pelvis as well as changes in bone density following total hip arthroplasty. The geometry of the finite element model was based on a two-dimensional slice through the pelvis. Starting from a solid, homogeneous structure, the computer simulations predicted the distribution of bone density throughout the natural pelvis. The predicted bone density distribution in this first simulation agreed well with the actual bone density distribution only when loads representing multiple activities were incorporated. Using the predicted density distribution as a starting point the authors modified the finite element models to study two designs of noncemented, metal-backed acetabular cups. The simulations with fully fixed bone-implant interfaces predicted extensive loss of bone density medial and inferior to the prosthetic components. The simulations with loose interfaces led to more moderate losses of bone density, indicating a load transfer more similar to that which occurs in the natural joint. The differences in simulated bone remodeling between the two component designs were quite minimal. These results indicate that acetabular components with full bony ingrowth may induce significant stress-related bone remodeling due to a nonphysiologic transfer of load.

Bone Density↗

Computer simulations of lung morphologies within planar gamma camera images.

A mathematical model and computer code have been developed to unambiguously interpret planar gamma camera images. Specifically, the algorithm permits airway composition of the central, intermediate and peripheral partitions of scans to be determined quantitatively. The algorithm unambigously identifies the spatial coordinates of each of the millions of airways within the adult human lung, and assigns every individual airway to a precise location within the gamma camera image format prescribed by the clinician. This is done on a patient-by-patient basis. The algorithm has evolved from clinical applications of the previous work of Martonen et al. [1]. The objective of the current work was to advance the original protocol and derive an algorithm that was: (1) from a medical perspective, more physiologically realistic; and (2) from a technical perspective, easier to apply in the medical arena. Regarding (1), the major elements of the algorithm are that the outer boundary of the lung is formulated directly from lung perfusion imaging data and that the lung is divided into distinct left and right components. Regarding (2), the algorithm has been written for use with common workstations. It is our hope that the improvements will facilitate applications of the new model-code into aerosol therapy regimens.

Adult↗

Comparative distribution of two antidepressant drugs (imipramine and indalpine) in the rat as determined by analog computer simulation.

A ten-compartment analog computer model is presented to determine the precise distribution and excretion of two antidepressant drugs, LM 5008 AND Imipramine. Eight patterns were simulated using experimental data and drug distribution in the two undetermined compartments were obtained by the analog model. Close agreement with existing experimental data lends confidence in the model as a valuable tool for predictions in a variety of therapeutic situations.

Animals↗

Computer-simulated conversion from intravenous to sustained-release oral theophylline.

A computer equipped with a pharmacokinetic program was used to theoretically determine the proper time to administer the first dose of a commonly prescribed, sustained-release oral theophylline product (Theo-Dur) in patients maintained on a continuous intravenous aminophylline infusion. Four conversion methods were tested. They included giving the first oral dose (1) immediately upon discontinuation of the iv infusion, (2) two hours after discontinuing the iv infusion, (3) four hours after discontinuing the iv infusion, and (4) two hours before discontinuing the iv infusion. Each of the four methods was simulated in three groups of patients: smokers, nonsmokers, and patients with cirrhosis. Results showed that, in most situations, given the first oral dose immediately upon discontinuation of the intravenous infusion provided minimal deviation from eventual steady-state levels. In addition, this computer simulation suggests that the initial 12-hour maintenance dose recommended by the FDA may result in toxicity in certain patient groups.

Administration, Oral↗