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Accounting for both random errors and systematic errors in uncertainty propagation analysis of computer models involving experimental measurements with Monte Carlo methods.

A Monte Carlo method is presented to study the effect of systematic and random errors on computer models mainly dealing with experimental data. It is a common assumption in this type of models (linear and nonlinear regression, and nonregression computer models) involving experimental measurements that the error sources are mainly random and independent with no constant background errors (systematic errors). However, from comparisons of different experimental data sources evidence is often found of significant bias or calibration errors. The uncertainty analysis approach presented in this work is based on the analysis of cumulative probability distributions for output variables of the models involved taking into account the effect of both types of errors. The probability distributions are obtained by performing Monte Carlo simulation coupled with appropriate definitions for the random and systematic errors. The main objectives are to detect the error source with stochastic dominance on the uncertainty propagation and the combined effect on output variables of the models. The results from the case studies analyzed show that the approach is able to distinguish which error type has a more significant effect on the performance of the model. Also, it was found that systematic or calibration errors, if present, cannot be neglected in uncertainty analysis of models dependent on experimental measurements such as chemical and physical properties. The approach can be used to facilitate decision making in fields related to safety factors selection, modeling, experimental data measurement, and experimental design.

Journal Article↗

Using computer modeling to help identify patient subgroups in clinical data repositories.

OBJECTIVE: The ability to accurately and efficiently identify patient cases of interest in a hospital information system has many important clinical, research, educational and administrative uses. The identification of cases of interest sometimes can be difficult. This paper describes a two-stage method for searching for cases of interest. DESIGN: First, a Boolean search is performed using coded database variables. The user classifies the retrieved cases as being of interest or not. Second, based on the user-classified cases, a computer model of the patient cases of interest is constructed. The model is then used to help locate additional cases. These cases provide an augmented training set for constructing a new computer model of the cases of interest. This cycle of modeling and user classification continues until halted by the user. MEASUREMENTS: This paper describes a pilot study in which this method is used to identify the records of patients who have venous thrombosis. RESULTS: The results indicate that computer modeling enhances the identification of patient cases of interest.

Bayes Theorem↗

Computational models of normal and abnormal action potential propagation in cardiac tissue: linking experimental and clinical cardiology.

Computational models have the potential to make a huge impact on our understanding of normal and abnormal cardiac function. The aim of this article is to review tools that have been developed to simulate the electrophysiology of cardiac cells and tissue, and to show how computational models have been used to gain insight into normal and abnormal action potential propagation. Some of the practical problems experienced in the development and application of these models are described, and examples are given.

Action Potentials↗

Parallel neural systems for classical conditioning: support from computational modeling.

Classical conditioning has been explained by two main types of theories that postulate different learning mechanisms. Rescorla and Wagner (1972) put forth a theory in which conditioning is based on the ability of the US to drive learning through error correction. Alternatively, Mackintosh (1973) put forth a theory in which the ability of the CS to be associated with the unconditioned stimulus is modulated. We have proposed a reconciliation of these two mechanisms as working in parallel within different neural systems: a cerebellar system for US modulation and a hippocampal system for CS modulation. We developed a computational model of cerebellar function in eyeblink conditioning based on the error correction mechanism of the Rescorla-Wagner rule in which learning-related activity from the cerebellum inhibits the inferior olive, which is the US input pathway to the cerebellum (Gluck et al., 1994). We developed a computational model of the hippocampal region that forms altered representations of conditioned stimuli based on their behavioral outcomes (Gluck & Myers, 1993; Myers et al., 1995). Overall, computational modeling and empirical findings support the idea that, at least in the case of eyeblink conditioning, there may be two different neural systems: the cerebellum which mediates US-based error correction and hippocampus which alters representations of CSs.

Animals↗

Computational model of an adaptive rhythm generator within the olivocerebellar system.

The aim of this study is to investigate via computation whether the olivocerebellar system is capable of functioning as an adaptive rhythm generator. For this purpose, a detailed and physiologically realistic computational model of the olivocerebellar system is developed, based on the known intrinsic cell and network topological properties of this brain system. The present network, where individual cells are modelled by leaky integrate-and-fire units, converts the irregular spikes produced by the olivary cells into a precise rhythmic signal at the output. The simulation results reveal that the computational model, which normally does not exhibit any rhythmic activity, could be switched into a new mode in which it functions as a rhythm generator producing pulses within three different frequency ranges corresponding to alpha, beta, or gamma bands, respectively. In either mode of operation, the firing rates of all simulated cell types are observed to match real data. The results of this study therefore support the experimental findings of researchers who argue that a biological clock producing rhythmic pulses within different temporal ranges is located within the cerebellum.

Action Potentials↗

Computational modelling of blood flow through curved stenosed arteries.

A computational model of three-dimensional blood flow in curved arteries with elliptic stenosis was developed. Two groups of models, (a) different angles of curvature and (b) degrees of stenosis, have been studied under typical conditions for stenosed coronary artery. Useful information on the haemodynamics has been obtained. Results of pressure drop show that the presence of the curvature augments the increased flow resistance due to stenotic lesions. The study also demonstrates the significant presence of secondary flow in a curved artery. In addition, the results have shown that the secondary flow in a curved artery brings about elevated shear stress on the vessel wall. These results indicated that both curvature and stenosis should be considered together by cardiologists to assess or quantify the severity of the stenosis. This study employed a powerful computer-aided design (CAD) package to construct the model and a commercial computational fluid dynamics (CFD) code for the analysis of blood flow in stenosed arteries. The long-term application of this form of research promises to be an effective tool for gaining insights into the pathology of arterial diseases.

Arteries↗

Regularity of cochlear nucleus stellate cells: a computational modeling study.

This article reports on a computational modeling study designed to investigate the generation of the transient chopper response of cochlear nucleus stellate cells. The model is based on a simulation of the auditory periphery which feeds a generic stellate-cell model. Physiological recordings of transient chopper units in response to short, best frequency, tone bursts show a brief initial period (typically < 10 ms) of rapid rate adaptation as evidenced by a rapid rise in mean interspike interval. Associated with this rate adaptation is a significant increase in firing irregularity. The changes in rate and irregularity have recently been attributed to the activation of noisy inhibitory inputs on the cell [e.g., Banks and Sachs, J. Neurophysiol. 65, 606-629 (1991)]. However, the results show that the transient chopper response pattern can be generated without the need for inhibitory inputs. The transience of the initial chopping pattern is sensitive to the following model parameters: (a) the firing threshold of the cell, (b) the number of excitatory inputs that converge on the cell, and (c) the magnitude of the current delivered to the cell for each active input. The response was also found to be relatively insensitive to changes in the degree of dendritic filtering imposed on the auditory-nerve input. The results of each simulation can be explained by considering the pattern of depolarization the cell receives during the course of a tone burst.

Acoustic Stimulation↗

Deliberate systemic hypotension to facilitate endovascular therapy of cerebral arteriovenous malformations: a computer modeling study.

With the aid of a computer model, this investigation describes the relationship between mean arterial pressure (MAP) reduction and its effect on total arteriovenous malformation (AVM) shunt flow, feeding artery velocities, and cerebral blood flow in hypotensive, structurally normal vascular beds adjacent to the AVM nidus. Simulations were performed for two feeding artery sizes (2 and 4 mm in diameter) and two AVM shunt flows (500 and 1000 ml/minute) with and without the presence of autoregulation in normal brain. Systemic arterial hypotension was simulated in a stepwise fashion by reducing aortic pressure from 100 to 10 mm Hg in 10-mm Hg steps. The percentage of MAP that resulted in a 50% reduction of shunt flow was calculated (%MAP reduction at half-maximal shunt flow). As the MAP decreased, the shunt flow decreased in a nearly linear fashion; the cerebral blood flow remained constant in neighboring brain until the MAP dropped below 60 and 80 mm Hg for the medium and large AVMs, respectively. The %MAP reductions at half-maximal shunt flow for the medium and large AVMs were not significantly different from 50%: 44% and 47%, respectively. Results for 2 and 4 mm AVM feeding artery sizes were similar. The decrease in both total shunt flow and flow velocity in feeding artery pedicles, potentially embolized by glue injection, were nearly linear with the institution of systemic hypotension. The presence or absence of autoregulation in normal brain, or different variations in the simulated angioarchitecture of the AVMs, did not affect this relationship in the model.

Journal Article↗

The use of selective inhibitors and computer modelling to evaluate the role of specific high affinity cyclic AMP phosphodiesterases in the hormonal regulation of hepatocyte intracellular cyclic AMP concentrations.

Using experimentally derived data for the activities and kinetic constants of hepatocyte cyclic AMP phosphodiesterase isoenzymes together with the derived changes in adenylate cyclase activity, due to stimulation and subsequent desensitization by glucagon, a computer model was established to simulate hepatocyte cyclic AMP metabolism. The established ability of glucagon to activate the 'dense-vesicle' cyclic AMP phosphodiesterase by eliciting its cyclic AMP-dependent phosphorylation was shown on the model to be capable of eliciting a profound reduction in the glucagon-stimulated increase in intracellular cyclic AMP. This was consistent with experimentally derived observations using the compound ICI 118233 which was used to inactivate the 'dense-vesicle' enzyme selectively. The non-hydrolysable adenosine agonist N6 (phenylisopropyl)-adenosine (PIA), which prevents glucagon pre-treatment of hepatocytes blocking the ability of insulin to stimulate the peripheral plasma membrane cyclic AMP phosphodiesterase, is shown here to accentuate the ability of insulin to decrease glucagon-elevated intracellular cyclic AMP concentrations. This effect was obliterated using the compound ICI 63197, a selective inhibitor of the peripheral plasma membrane phosphodiesterase. Computer modelling studies, taking into account experimentally derived actions in insulin in activating the peripheral plasma membrane phosphodiesterase, confirmed the potential of this enzyme to decrease intracellular cyclic AMP concentrations. Modelling of the putative effect of an insulin 'mediator' in activating the two cyclic GMP-stimulated cyclic AMP phosphodiesterase isoenzymes was shown to elicit a decrease in intracellular cyclic AMP concentrations which was comparable to that caused by insulin's action on intact hepatocytes. The relative contribution of each phosphodiesterase form to the metabolism of hepatocyte intracellular cyclic AMP, together with an assessment of the potential effect of inhibition and activation of specific species, was evaluated using the computer model. These experimental and stimulation studies indicate that alterations in the phosphodiesterase activity of the 'dense-vesicle' enzyme, the peripheral plasma membrane enzyme, the cyclic GMP-stimulated cyclic AMP isoforms and the IBMX-insensitive PDE-MQ-II can elicit profound effects upon hepatocyte intracellular cyclic AMP concentrations.

3',5'-Cyclic-AMP Phosphodiesterases↗

A computational model for the prediction of total knee replacement kinematics in the sagittal plane.

A computational model has been developed using a current generation computer-aided engineering (CAE) package to predict total knee replacement (TKR) kinematic in the sagittal plane. The model includes friction and soft tissue restraint varying according to the flexion angle. The model was validated by comparing the outcomes of anterior-posterior (A-P) laxity tests of two contemporary knee replacements against data obtained from a knee simulating machine. It was also validated against predictions from a computer model reported in the literature. Results show good agreement in terms of A-P displacements. Further tests were performed to determined the influence of the soft tissue restraints varying with flexion angle. This work represents the first attempt to use a sophisticated commercial CAE package to predict TKR motions and the advantages of the modelling procedure chosen are discussed.

Biomechanical Phenomena↗

A computer model of lung morphology to analyze SPECT images.

Measurement of the spatial distribution of aerosol deposition in human lungs can be performed using single photon emission computed tomography (SPECT). To relate deposition patterns to real lung structures, a computer model of the airway network has been developed. Computer simulations are presented that are compatible with the analysis of SPECT images. Computational techniques that are consistent with clinical procedures are used to analyze airways by type and number within transverse slices of the lung volume. The computer models serve as customized templates, which when analyzed alongside gamma scintigraphy images, can assist in the interpretation of human test data.

Computer Simulation↗

Coupling of spinal locomotor networks in larval lamprey revealed by receptor blockers for inhibitory amino acids: neurophysiology and computer modeling.

1. Receptor blockers for inhibitory amino acids were applied to part or all of the spinal cord of larval lamprey during brain stem-initiated locomotor activity. Blocking glycinergic inhibition with strychnine applied to the entire spinal cord converted the locomotor pattern from left-right alternation to synchronous left-right bursting. The results suggest that left and right oscillators are connected by relatively strong reciprocal inhibitory (glycinergic) connections in parallel with weaker reciprocal excitatory connections. This possible organization was supported by results from a computer model consisting of left and right oscillators connected by reciprocal inhibition and excitation in parallel. In addition, the results suggest that reciprocal inhibition is not required for left-right rhythmicity but rather is involved primarily with phasing of left-right activity. 2. Locally blocking glycinergic inhibition with strychnine in the rostral spinal cord resulted in synchronous left-right burst activity in that region of the cord as well as in more caudal areas of the cord in which reciprocal inhibition should still be functional. 3. Blocking glycinergic inhibition in the caudal spinal cord converted the pattern in that region of the cord to left-right synchronous activity. The effects in the ascending direction on the burst patterns in more rostral areas of the spinal cord were less than those mentioned above in the descending direction with application of strychnine to the rostral spinal cord. 4. With glycinergic inhibition or GABAergic inhibition blocked in the entire spinal cord, stable longitudinal coupling along the spinal cord persisted. This and the neurophysiology results mentioned above suggest that the main mechanism for longitudinal coupling between locomotor networks in adjacent regions of the spinal cord is ipsilateral excitatory connections and not crossed inhibitory connections. This possible organization was supported by results from a computer model, which consisted of a pair of oscillators in the more rostral and more caudal spinal cord that could be connected by various types of coupling schemes. 5. The neurophysiological data above suggest that ipsilateral, excitatory coupling is stronger in the descending direction than in the ascending direction. In the computer model, a dominant descending coupling is a necessary requirement to produce positive longitudinal phase lags.

Animals↗

Computational model of response maps in the dorsal cochlear nucleus.

The neurons in the mammalian (gerbil, cat) dorsal cochlear nucleus (DCN) have responses to tones and noise that have been used to classify them into unit types. These types (I-V) are based on excitatory and inhibitory responses to tones organized into plots called response maps (RMs). Type I units show purely excitatory responses, while type V units are primarily inhibited. A computational model of the neural circuitry of the mammalian DCN, based on the MacGregor neuromime, was used to investigate RMs of the principal cells (P-cells) that represent the fusiform and giant cells. In gerbils, fusiform cells have been shown to have primarily type III unit response properties; however, fusiform cells in the cat DCN are thought to have type IV unit response properties. The DCN model is based on a previous computational model of the cat (Hancock and Voigt Ann Biomed Eng 27: 73-87, 1999) and gerbil (Zheng and Voigt Ann Biomed Eng 34: 697-708, 2006) DCN. The basic model for both species is architecturally the same, and to get either type III unit RMs or type IV unit RMs, connection parameters were adjusted. Interestingly, regardless of the RM type, these units in gerbils and cats show spectral notch sensitivity and are thought to play a role in sound localization in the median plane. In this study, further parameter adjustments were made to systematically explore their effect on P-cell RMs. Significantly, type I, type III, type III-i, type IV, type IV-T and type V unit RMs can be created for the modeled P-cells. Thus major RMs observed in the cat and gerbil DCN are recreated by the model. These results suggest that RMs of individual DCN projection neurons are the result of specific assortment of excitatory and inhibitory inputs to that neuron and that subtle differences in the complement of inputs can result in different RM types. Modulation of the efficacy of certain synapses suggests that RM type may change dynamically.

Animals↗

Biomorphometric analysis of human prostatic carcinoma by using three-dimensional computer models.

Advances in the detection of carcinoma of the prostate during the last 15 years have accounted for a sharp increase and then an abrupt decrease in the incidence of the disease. A more recent decline in its mortality rates has been variously interpreted as either the success of early detection and improved treatment or lead-time bias. The recently reported Prostate Cancer Prevention Trial had an overall detection rate that approached the 30%-40% prevalence rates reported in autopsy series in which men died of other causes. However, the prognostic information that can be obtained from prostate cancer found on biopsy is limited. Three-dimensional computer modeling is one technique that allows multiple studies on "immortal" prostates to test methods of biopsy sampling accuracy and to assist in the determination of the disease's severity. Computer modeling can assess detection rates and assesses tumor multifocality and heterogeneity. It can provide a more accurate representation of tumor volume, aiding in therapeutic decision making, and can assess sampling errors of various biopsy methods. It has been shown to be superior to wire-frame technique by immortalizing the original shape and dimensions of the surgically excised prostate gland. Moreover, our 3-dimensional computer modeling system improves upon other systems: It is more than a simple extension of the planimetric technique, and it is able to demarcate clearly the boundaries of Gleason grades just 1 grade apart.

Adenocarcinoma↗

A computational model of selection by consequences.

Darwinian selection by consequences was instantiated in a computational model that consisted of a repertoire of behaviors undergoing selection, reproduction, and mutation over many generations. The model in effect created a digital organism that emitted behavior continuously. The behavior of this digital organism was studied in three series of computational experiments that arranged reinforcement according to random-interval (RI) schedules. The quantitative features of the model were varied over wide ranges in these experiments, and many of the qualitative features of the model also were varied. The digital organism consistently showed a hyperbolic relation between response and reinforcement rates, and this hyperbolic description of the data was consistently better than the description provided by other, similar, function forms. In addition, the parameters of the hyperbola varied systematically with the quantitative, and some of the qualitative, properties of the model in ways that were consistent with findings from biological organisms. These results suggest that the material events responsible for an organism's responding on RI schedules are computationally equivalent to Darwinian selection by consequences. They also suggest that the computational model developed here is worth pursuing further as a possible dynamic account of behavior.

Algorithms↗

Validation of a head-neck computer model for whiplash simulation.

A head-neck computer model was comprehensively validated over a range of rear-impact velocities using experiments conducted by the same group of authors in the same laboratory. Validations were based on mean +/- 1 standard deviation response curves, i.e. corridors. Global head-neck angle, segmental angle and local facet joint regional kinematic responses from the model fell within experimental corridors. This was true for all impact velocities (1.3, 1.8 and 2.6 m s(-1)). The non-physiological S-curvature lasted approximately 100 ms. The present, comprehensively validated model can be used to conduct parametric studies and investigate the effects of factors such as active sequential and parallel muscle contractions, thoracic ramping and local tissue strain responses, as a function of cervical level, joint region and impact velocity in whiplash injury assessment.

Biomechanical Phenomena↗

Subsite mapping of enzymes. Application of the depolymerase computer model to two alpha-amylases.

In the preceding paper (Allen and Thoma, 1976) we developed a depolymerase computer model, which uses a minimization routine to establish a subsite map for a depolymerase. In the present paper we show how the model is applied to experimental data for two alpha-amylases. Michaelis parameters and bond-cleavage frequencies for substrates of chain lengths up to twelve glucosyl units have been reported for Bacillus amyloliquefaciens, and a subsite map has been proposed for this enzyme [Thoma et al. (1971) J. Biol. Chem. 246, 5621-5635]. By applying the computer model to the experimental data, we have arrived at a ten-subsite map. We find that a significant improvement in this map is achieved by allowing the hydrolytic rate coefficient to vary as a function of the number of occupied subsites comprising the enzyme-binding region. The bond-cleavage frequencies, the enzyme is found to have eight subsites. A partial subsite map is arrived at, but the entire binding region cannot be mapped because Michaelis parameters are complicated by transglycosylation reactions. The hydrolytic rate coefficients for this enzyme are not constant.

Amino Acid Sequence↗

[Computer models of the electrophysiological properties of the heart].

Computer models of the heart can improve the understanding of the electrophysiological processes in healthy and diseased heart. They become more and more important for detailed diagnosis of arrhythmias and for optimization of therapy. Models of myocardium cells known today are described--they are based on the properties of all relevant ion channels in the cell membrane. Then it is demonstrated, how many cells can be joined to form a cell patch and how finally the complete heart can be modelled. A simpler approach is using a so called cellular automation that allows for a significant reduction of calculation time while sacrificing some accordance to reality. Adaptive cellular automations allow for a fast simulation with acceptable accuracy. Using them some results were gained for the simulation of typical arrhythmias, in the field of validation using an animal model and for therapy planning with RF-ablation.

Arrhythmias, Cardiac↗