Assessing the Role of Patient Generation Techniques in Virtual Clinical Trial Outcomes.

Virtual clinical trials (VCTs) are growing in popularity as a tool for quantitatively predicting heterogeneous treatment responses across a population. In the context of a VCT, a plausible patient is an instance of a mathematical model with parameter (or attribute) values chosen to reflect features of the disease and response to treatment for that particular patient. A number of techniques have been introduced to determine the set of model parametrizations to include in a virtual patient cohort. These methodologies generally start with a prior distribution for each model parameter and utilize some criteria to determine whether a parameter set sampled from the priors should be included or excluded from the plausible population. No standard technique exists, however, for generating these prior distributions and choosing the inclusion/exclusion criteria. In this work, we rigorously quantify the impact that VCT design choices have on VCT predictions. Rather than use real data and a complex mathematical model, a spatial model of radiotherapy is used to generate simulated patient data and the mathematical model used to describe the patient data is a two-parameter ordinary differential equations model. This controlled setup allows us to isolate the impact of both the prior distribution and the inclusion/exclusion criteria on both the heterogeneity of plausible populations and on predicted treatment response. We find that the prior distribution, rather than the inclusion/exclusion criteria, has a larger impact on the heterogeneity of the plausible population. Yet, the percent of treatment responders in the plausible population was more sensitive to the inclusion/exclusion criteria utilized. This foundational understanding of the role of virtual clinical trial design should help inform the development of future VCTs that use more complex models and real data.

R Markdown as a dynamic interface for teaching: Modules from math and biology classrooms.

Advancing technologies, including interactive tools, are changing classroom pedagogy across academia. Here, we discuss the R Markdown interface, which allows for the creation of partial or complete interactive classroom modules for courses using the R programming language. R Markdown files mix sections of R code with formatted text, including LaTeX, which are rendered together to form complete reports and documents. These features allow instructors to create classroom modules that guide students through concepts, while providing areas for coding and text response by students. Students can also learn to create their own reports for more independent assignments. After presenting the features and uses of R Markdown to enhance teaching and learning, we present examples of materials from two courses. In a Computational Modeling course for math students, we used R Markdown to guide students through exploring mathematical models to understand the principle of herd immunity. In a Data Visualization and Communication course for biology students, we used R Markdown for teaching the fundamentals of R programming and graphing, and for students to learn to create reproducible data investigations. Through these examples, we demonstrate the benefits of R Markdown as a dynamic teaching and learning tool.

Predicting the impact of placing an overdose prevention site in Philadelphia: a mathematical modeling approach.

BACKGROUND: Fatal overdoses from opioid use and substance disorders are increasing at an alarming rate. One proposed harm reduction strategy for reducing overdose fatalities is to place overdose prevention sites-commonly known as safe injection facilities-in proximity of locations with the highest rates of overdose. As urban centers in the USA are tackling legal hurdles and community skepticism around the introduction and location of these sites, it becomes increasingly important to assess the magnitude of the effect that these services might have on public health. METHODS: We developed a mathematical model to describe the movement of people who used opioids to an overdose prevention site in order to understand the impact that the facility would have on overdoses, fatalities, and user education and treatment/recovery. The discrete-time, stochastic model is able to describe a range of user behaviors, including the effects from how far they need to travel to the site. We calibrated the model to overdose data from Philadelphia and ran simulations to describe the effect of placing a site in the Kensington neighborhood. RESULTS: In Philadelphia, which has a non-uniform racial population distribution, choice of site placement can determine which demographic groups are most helped. In our simulations, placement of the site in the Kensington neighborhood resulted in White opioid users being more likely to benefit from the site's services. Overdoses that occur onsite can be reversed. Our results predict that for every 30 stations in the overdose prevention site, 6 per year of these would have resulted in fatalities if they had occurred outside of the overdose prevention site. Additionally, we estimate that fatalities will decrease further when referrals from the OPS to treatment are considered. CONCLUSIONS: Mathematical modeling was used to predict the impact of placing an overdose prevention site in the Kensington neighborhood of Philadelphia. To fully understand the impact of site placement, both direct and indirect effects must be included in the analysis. Introducing more than one site and distributing sites equally across neighborhoods with different racial and demographic characteristics would have the broadest public health impact. Cities and locales can use mathematical modeling to help quantify the predicted impact of placing an overdose prevention site in a particular location.

Developing a Minimally Structured Mathematical Model of Cancer Treatment with Oncolytic Viruses and Dendritic Cell Injections.

Mathematical models of biological systems must strike a balance between being sufficiently complex to capture important biological features, while being simple enough that they remain tractable through analysis or simulation. In this work, we rigorously explore how to balance these competing interests when modeling murine melanoma treatment with oncolytic viruses and dendritic cell injections. Previously, we developed a system of six ordinary differential equations containing fourteen parameters that well describes experimental data on the efficacy of these treatments. Here, we explore whether this previously developed model is the minimal model needed to accurately describe the data. Using a variety of techniques, including sensitivity analyses and a parameter sloppiness analysis, we find that our model can be reduced by one variable and three parameters and still give excellent fits to the data. We also argue that our model is not too simple to capture the dynamics of the data, and that the original and minimal models make similar predictions about the efficacy and robustness of protocols not considered in experiments. Reducing the model to its minimal form allows us to increase the tractability of the system in the face of parametric uncertainty.

Distinction in EEG slow oscillations between chronic mild traumatic brain injury and PTSD.

Spectral information from resting state EEG is altered in acute mild traumatic brain injury (mTBI) and in disorders of consciousness, but there is disagreement about whether mTBI can elicit long term changes in the spectral profile. Even when identified, any long-term changes attributed to TBI can be confounded by psychiatric comorbidities such as PTSD, particularly for combat-related mTBI where postdeployment distress is commonplace. To address this question, we measured spectral power during the resting state in a large sample of service members and Veterans varying in mTBI history and active PTSD diagnosis but matched for having had combat blast exposure. We found that PTSD was associated with decreases in low frequency power, especially in the right temporoparietal region, while conversely, blast-related mTBI was associated with increases in low frequency power, especially in prefrontal and right temporal areas. Results support the idea that long-term neurophysiological effects of mTBI share some features with states of reduced arousal and cognitive dysfunction, suggesting a role for EEG in tracking the trajectory of recovery and persisting vulnerabilities to injury. Additionally, results suggest that EEG power reflects distinct pathophysiologies for current PTSD and chronic mTBI.

Evaluating Infection Prevention Strategies in Out-Patient Dialysis Units Using Agent-Based Modeling.

Patients receiving chronic hemodialysis (CHD) are among the most vulnerable to infections caused by multidrug-resistant organisms (MDRO), which are associated with high rates of morbidity and mortality. Current guidelines to reduce transmission of MDRO in the out-patient dialysis unit are targeted at patients considered to be high-risk for transmitting these organisms: those with infected skin wounds not contained by a dressing, or those with fecal incontinence or uncontrolled diarrhea. Here, we hypothesize that targeting patients receiving antimicrobial treatment would more effectively reduce transmission and acquisition of MDRO. We also hypothesize that environmental contamination plays a role in the dissemination of MDRO in the dialysis unit. To address our hypotheses, we built an agent-based model to simulate different treatment strategies in a dialysis unit. Our results suggest that reducing antimicrobial treatment, either by reducing the number of patients receiving treatment or by reducing the duration of the treatment, markedly reduces overall colonization rates and also the levels of environmental contamination in the dialysis unit. Our results also suggest that improving the environmental decontamination efficacy between patient dialysis treatments is an effective method for reducing colonization and contamination rates. These findings have important implications for the development and implementation of future infection prevention strategies.

Characterizing effects of mild traumatic brain injury and posttraumatic stress disorder on balance impairments in blast-exposed servicemembers and Veterans using computerized posturography.

The high rate of blast exposures experienced by U.S. servicemembers (SMs) during the recent conflicts in Iraq and Afghanistan has resulted in frequent combat-related mild traumatic brain injuries (mTBIs). Dizziness and postural instability can persist after mTBI as a component of postconcussion syndrome, but also occur among the somatic complaints of posttraumatic stress disorder (PTSD). The goals of this study were to examine the use of computerized posturography (CPT) to objectively characterize chronic balance deficits after mTBI and to explore the utility of CPT in distinguishing between combat and blast-exposed participants with and without mTBI and PTSD. Data were analyzed from a subject pool of 166 combat-exposed SMs and Veterans who had a blast experience within the past 2 yr while deployed. Using nonparametric tests and measures of impairment, we found that balance was deficient in participants diagnosed with mTBI with posttraumatic amnesia (PTA) or PTSD versus those with neither and that deficits were amplified for participants with both diagnoses. In addition, unique deficiencies were found using CPT for individuals having isolated mTBI with PTA and isolated PTSD. Computerized balance assessment offers an objective technique to examine the physiologic effects and provide differentiation between participants with combat-associated mTBI and PTSD.

Quantitative impact of immunomodulation versus oncolysis with cytokine-expressing virus therapeutics.

The past century's description of oncolytic virotherapy as a cancer treatment involving specially-engineered viruses that exploit immune deficiencies to selectively lyse cancer cells is no longer adequate. Some of the most promising therapeutic candidates are now being engineered to produce immunostimulatory factors, such as cytokines and co-stimulatory molecules, which, in addition to viral oncolysis, initiate a cytotoxic immune attack against the tumor. This study addresses the combined effects of viral oncolysis and T-cell-mediated oncolysis. We employ a mathematical model of virotherapy that induces release of cytokine IL-12 and co-stimulatory molecule 4-1BB ligand. We found that the model closely matches previously published data, and while viral oncolysis is fundamental in reducing tumor burden, increased stimulation of cytotoxic T cells leads to a short-term reduction in tumor size, but a faster relapse. In addition, we found that combinations of specialist viruses that express either IL-12 or 4-1BBL might initially act more potently against tumors than a generalist virus that simultaneously expresses both, but the advantage is likely not large enough to replace treatment using the generalist virus. Finally, according to our model and its current assumptions, virotherapy appears to be optimizable through targeted design and treatment combinations to substantially improve therapeutic outcomes.

Differential eye movements in mild traumatic brain injury versus normal controls.

OBJECTIVES: Objective measures to diagnose and to monitor improvement of symptoms following mild traumatic brain injury (mTBI) are lacking. Computerized eye tracking has been advocated as a rapid, user friendly, and field-ready technique to meet this need. DESIGN: Eye-tracking data collected via a head-mounted, video-based binocular eye tracker was used to examine saccades, fixations, and smooth pursuit movement in military Service Members with postconcussive syndrome (PCS) and asymptomatic control subjects in an effort to determine if eye movement differences could be found and quantified. PARTICIPANTS: Sixty Military Service Members with PCS and 26 asymptomatic controls. OUTCOME MEASURES: The diagnosis of mTBI was confirmed by the study physiatrist's history, physical examination, and a review of any medical records. Various features of saccades, fixation and smooth pursuit eye movements were analyzed. RESULTS: Subjects with symptomatic mTBI had statistically larger position errors, smaller saccadic amplitudes, smaller predicted peak velocities, smaller peak accelerations, and longer durations. Subjects with symptomatic mTBI were also less likely to follow a target movement (less primary saccades). In general, symptomatic mTBI tracked the stepwise moving targets less accurately, revealing possible brain dysfunction. CONCLUSIONS: A reliable, standardized protocol that appears to differentiate mTBI from normals was developed for use in future research. This investigation represents a step toward objective identification of those with PCS. Future studies focused on increasing the specificity of eye movement differences in those with PCS are needed.

Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections.

Oncolytic viruses (OVs) are used to treat cancer, as they selectively replicate inside of and lyse tumor cells. The efficacy of this process is limited and new OVs are being designed to mediate tumor cell release of cytokines and co-stimulatory molecules, which attract cytotoxic T cells to target tumor cells, thus increasing the tumor-killing effects of OVs. To further promote treatment efficacy, OVs can be combined with other treatments, such as was done by Huang et al., who showed that combining OV injections with dendritic cell (DC) injections was a more effective treatment than either treatment alone. To further investigate this combination, we built a mathematical model consisting of a system of ordinary differential equations and fit the model to the hierarchical data provided from Huang et al. We used the model to determine the effect of varying doses of OV and DC injections and to test alternative treatment strategies. We found that the DC dose given in Huang et al. was near a bifurcation point and that a slightly larger dose could cause complete eradication of the tumor. Further, the model results suggest that it is more effective to treat a tumor with immunostimulatory oncolytic viruses first and then follow-up with a sequence of DCs than to alternate OV and DC injections. This protocol, which was not considered in the experiments of Huang et al., allows the infection to initially thrive before the immune response is enhanced. Taken together, our work shows how the ordering, temporal spacing, and dosage of OV and DC can be chosen to maximize efficacy and to potentially eliminate tumors altogether.

Effects of hyperbaric oxygen on eye tracking abnormalities in males after mild traumatic brain injury.

The effects of hyperbaric oxygen (HBO2) on eye movement abnormalities in 60 military servicemembers with at least one mild traumatic brain injury (TBI) from combat were examined in a single-center, randomized, double-blind, sham-controlled, prospective study at the Naval Medicine Operational Training Center. During the 10 wk of the study, each subject was delivered a series of 40, once a day, hyperbaric chamber compressions at a pressure of 2.0 atmospheres absolute (ATA). At each session, subjects breathed one of three preassigned oxygen fractions (10.5%, 75%, or 100%) for 1 h, resulting in an oxygen exposure equivalent to breathing either surface air, 100% oxygen at 1.5 ATA, or 100% oxygen at 2.0 ATA, respectively. Using a standardized, validated, computerized eye tracking protocol, fixation, saccades, and smooth pursuit eye movements were measured just prior to intervention and immediately postintervention. Between and within groups testing of pre- and postintervention means revealed no significant differences on eye movement abnormalities and no significant main effect for HBO2 at either 1.5 ATA or 2.0 ATA equivalent compared with the sham-control. This study demonstrated that neither 1.5 nor 2.0 ATA equivalent HBO2 had an effect on postconcussive eye movement abnormalities after mild TBI when compared with a sham-control.

A mathematical model for cell cycle-specific cancer virotherapy.

Oncolytic viruses preferentially infect and replicate in cancerous cells, leading to elimination of tumour populations, while sparing most healthy cells. Here, we study the cell cycle-specific activity of viruses such as vesicular stomatitis virus (VSV). In spite of its capacity as a robust cytolytic agent, VSV cannot effectively attack certain tumour cell types during the quiescent, or resting, phase of the cell cycle. In an effort to understand the interplay between the time course of the cell cycle and the specificity of VSV, we develop a mathematical model for cycle-specific virus therapeutics. We incorporate the minimum biologically required time spent in the non-quiescent cell cycle phases using systems of differential equations with incorporated time delays. Through analysis and simulation of the model, we describe how varying the minimum cycling time and the parameters that govern viral dynamics affect the stability of the cancer-free equilibrium, which represents therapeutic success.

Efficacy of infection control interventions in reducing the spread of multidrug-resistant organisms in the hospital setting.

Multidrug-resistant organisms (MDRO) continue to spread in hospitals globally, but the population-level impact of recommended preventive strategies and the relative benefit of individual strategies targeting all MDRO in the hospital setting are unclear. To explore the dynamics of MDRO transmission in the hospital, we develop a model extending data from clinical individual-level studies to quantify the impact of hand hygiene, contact precautions, reducing antimicrobial exposure and screening surveillance cultures in decreasing the prevalence of MDRO colonization and infection. The effect of an ongoing increase in the influx of patients colonized with MDRO into the hospital setting is also quantified. We find that most recommended strategies have substantial effect in decreasing the prevalence of MDRO over time. However, screening for asymptomatic MDRO colonization among patients who are not receiving antimicrobials is of minimal value in reducing the spread of MDRO.