William A. Pruett

Simulations of Cyclic Breathing in the Conducting Zone of the Human Lung

Computational fluid dynamics (CFD) simulations were performed to predict the air flow in the human lung during cyclic breathing. The study employed a morphologically complex computational geometry generated using a combination of patient-specific CT-scan data for the extrathoracic and upper airway regions and a representative branching geometry for the lower airways that is available in the open literature. The geometry extended throughout the entire conducting zone and includes 16 partially resolved airway generations. For each generation beyond the third, only a fraction of the airway branches were retained, resulting in truncated flow outlets (for inspiratory flow) in generations 414. The inhalation and exhalation air flow boundary conditions were prescribed based on a physiologically realistic ventilation pattern, which was obtained using a whole-body model of human physiology. The flow was driven by specifying time-varying volumetric flowrates applied at each of the distal boundaries, while the oral boundary was maintained at constant (atmospheric) pressure. The study investigated the effectiveness of three different mass flow distribution schemes to drive the air flow. It was found that prescribed mass flow distribution fractions based on the square of the airway cross-sectional area produced the best results in terms of a uniform distal pressure distribution, while all methods produced reasonable results in terms of mass flow distribution throughout the lung airway geometry.Copyright

A Population Model of Integrative Cardiovascular Physiology

We present a small integrative model of human cardiovascular physiology. The model is population-based; rather than using best fit parameter values, we used a variant of the Metropolis algorithm to produce distributions for the parameters most associated with model sensitivity. The population is built by sampling from these distributions to create the model coefficients. The resulting models were then subjected to a hemorrhage. The population was separated into those that lost less than 15 mmHg arterial pressure (compensators), and those that lost more (decompensators). The populations were parametrically analyzed to determine baseline conditions correlating with compensation and decompensation. Analysis included single variable correlation, graphical time series analysis, and support vector machine (SVM) classification. Most variables were seen to correlate with propensity for circulatory collapse, but not sufficiently to effect reasonable classification by any single variable. Time series analysis indicated a single significant measure, the stressed blood volume, as predicting collapse in situ, but measurement of this quantity is clinically impossible. SVM uncovered a collection of variables and parameters that, when taken together, provided useful rubrics for classification. Due to the probabilistic origins of the method, multiple classifications were attempted, resulting in an average of 3.5 variables necessary to construct classification. The most common variables used were systemic compliance, baseline baroreceptor signal strength and total peripheral resistance, providing predictive ability exceeding 90%. The methods presented are suitable for use in any deterministic mathematical model.

Parathyroid hormone secretion by multiple distinct cell populations, a time dynamic mathematical model

The acute response of parathyroid hormone to perturbations in serum ionized calcium ([Ca2+]) is physiologically complex, and poorly understood. The literature provides numerous observations of quantitative and qualitative descriptions of parathyroid hormone (PTH) dynamics. We present a physiologically based mathematical model of PTH secretion constructed from mechanisms suggested in the literature, and validated against complex [Ca2+] clamping protocols from human data. The model is based on two assumptions. The first is that secretion is a fraction of cellular reserves, with the fraction being determined by the kinetics of [Ca2+] with its receptor. The second is that there are multiple distinct populations of parathyroid cells, with different secretory parameters. The steady state and transient PTH secretion responses of the model are in agreement with human experimental PTH responses to different hypocalcemia and hypercalcemia stimuli. This mathematical model suggests that a population of secreting cells is responsible for the PTH secretory dynamics observed experimentally.

Hummod browser: An exploratory visualization tool for the analysis of whole-body physiology simulation data

We present HumMod Browser, a multi-scale exploratory visualization tool that allows physiologists to explore human physiology simulation data with more than 6000 attributes. We first present a tag cloud technique to reveal the significance of time-varying attributes and then study how a chain of tag clouds can form an exploratory visuailzation that assist multiple dataset comparison and query. One purpose is to reduce the high cognitive workload of understanding complex interactions within the large attribute space. The HumMod Browser produced can give physiologists flexible control over the visualization displayed for quick understanding of complicated simulation results. The visualization is constructed through the metaphorical bubble interface to allow dynamic view controls and the data relationships and context informaiton unfold as physiologists querying groups of connected bubbles within the hierarchical or causal relationships. HumMod Browser contributions to the interaction design and provides multi-scale coordinated interactive exploration for a new type of physiological modeling data. Two case studies have been reported with real datasets containing more than 6000 physiology attributes, which provide supportive evidence on the usefulness of HumMod Browser in supporting effective large-attribute-space exploration.

Cyclic Breathing Simulations in Large-Scale Models of the Lung Airway From the Oronasal Opening to the Terminal Bronchioles

els of the human lung airway and unsteady periodic breathing conditions. The computational domain included fully coupled representations of the orotracheal region and large conducting zone up to generation four (G4) obtained from patient-specific CT data, and the small conducting zone (to the 16th generation) obtained from a stochastically generated airway tree with statistically realistic morphological characteristics. A reducedgeometry airway model was used, in which several airway branches in each generation were truncated, and only select flow paths were retained to the 16th generation. The inlet and outlet flow boundaries corresponded to the oral opening, the physical inlet/outlet boundaries at the terminal bronchioles, and the unresolved airway boundaries created from the truncation procedure. The total flow rate was specified according to the expected ventilation pattern for a healthy adult male, which was supplied by the wholebody modeling software HumMod. The unsteady mass flow distribution at the distal boundaries was prescribed based on a preliminary steady-state simulation with an applied flow rate equal to the average flow rate during the inhalation phase of the breathing cycle. In contrast to existing studies, this approach allows fully coupled simulation of the entire conducting zone, with no need to specify distal mass flow or pressure boundary conditions a priori, and without the use of impedance or one-dimensional (1D) flow models downstream of the truncated boundaries. The results show that: (1) physiologically realistic flow is obtained in the model, in terms of cyclic mass conservation and approximately uniform pressure distribution in the distal airways; (2) the predicted alveolar pressure is in good agreement with correlated experimental data; and (3) the use of reduced-order geometry modeling allows accurate and efficient simulation of large-scale breathing lung flow, provided care is taken to use a physiologically realistic geometry and to properly address the unsteady boundary conditions. [DOI: 10.1115/1.4027485]

HumMod Browser: An Exploratory Visualization Tool for Model Validation of Whole-Body Physiology Simulation

We present HumMod Browser, a multi-scale exploratory visualization tool that lets physiologists validate human physiology simulation results. Showing correlations, exploring causality relationships, analyzing important attributes, and comparing numerous set of ensemble runs are common tasks in model validation. The lack of interactive exploration often hinders efforts to employ classical graph-visualization approaches in these tasks. Our HumMod Browser contributes to the interaction design and provides powerful multi-scale coordinated uncluttered interactive exploration based on tag-cloud visualization and a metaphorical interface. Two case studies containing more than 6000 physiology attributes suggest the usefulness of HumMod Browser in physiological simulation

Role of the Heart in Blood Pressure Lowering During Chronic Baroreflex Activation: Insight from an in Silico Analysis

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity (RSNA) and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insights into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three-week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine and increases in plasma atrial natriuretic peptide (ANP), providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to a sustained depression of cardiac function and increased secretion of ANP. Increased ANP and suppression of RSNA both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of RSNA was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. NEW & NOTEWORTHY Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using HumMod, a mathematical model of integrative human physiology, indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation.

Visualization and classification of physiological failure modes in ensemble hemorrhage simulation

In an emergency situation such as hemorrhage, doctors need to predict which patients need immediate treatment and care. This task is difficult because of the diverse response to hemorrhage in human population. Ensemble physiological simulations provide a means to sample a diverse range of subjects and may have a better chance of containing the correct solution. However, to reveal the patterns and trends from the ensemble simulation is a challenging task. We have developed a visualization framework for ensemble physiological simulations. The visualization helps users identify trends among ensemble members, classify ensemble member into subpopulations for analysis, and provide prediction to future events by matching a new patient’s data to existing ensembles. We demonstrated the effectiveness of the visualization on simulated physiological data. The lessons learned here can be applied to clinically-collected physiological data in the future.

Use of Computer Simulations to Understand Female Physiology: Where's the Data?

Physiology is defined in Websters Dictionary as “a branch of biology that deals with the functions and activities of life or of living matter (as whole body, organs, tissues, or cells) and of the physical and chemical phenomena involved.” As scientists, we operate with the hope that the

Calibrating and Analyzing a Mathematical Model of Human Circulation and its Response to Hemorrhage

Complex physiological events such as hemorrhage are met with a continuum of responses in individual test subjects that range from complete compensation to circulatory failure. Predicting the circulatory outcome of an individual potentially affects treatment modalities, for example, by indicating that aggressive intervention is justified based on the likelihood of a negative result with a more passive therapy. We have previously determined an algorithm for calibrating and sampling parameter distributions that generate experimentally verified output distributions via an application of the Metropolis algorithm. This technique is advanced here by the addition of a three-pronged post hoc analysis. First is an inductive algorithm generating minimal parameter sets yielding efficient classification (MER). This algorithm is validated with PCA on the resulting parameter subsets. Finally, we provide an analysis on the response characteristics of clusters determined by a density dependent algorithm on the parameter/variable subspace indicated by the MER.Copyright