Modeling the Role of Brainstem Inflammation in Systemic Dysfunction during Sepsis

Investigators
Thomas E. Dick Frank J. Jacono, Kennth A. Loparo, Yoram Vodovotz, and Yaroslav Molkov
Contact info (email)
ted3@case.edu
1. Define context(s)
aid in clinical decision making
reveal new biological insights
Current Conformance Level / Target Conformance Level
adequate
Primary goal of the model/tool/database

Our project builds on iterative interaction between modeling (data-driven and mechanistic [differential equation-based]) and experiments to determine how brainstem inflammation limits variability of physiologic patterns and uncouples biologic rhythms. Specifically, we ask do increases in the predictability of ventilatory pattern variability (VPV) and/or decreases in cardio-respiratory coupling (CRC) reflect increases in proinflammatory cytokines in the ponto-medullary circuitry controlling homeostasis. Our primary goal is to determine if quantifying VPV and CVC produce biometrics that track a health and herald the onset of sepsis. The biologic domains of the model are the expression and control of the inflammatory cytokines in the nucleus tractus solitarii, nucleus Ambiguus, and Kölliker-Fuse nuclei, which are critical nuclei in brainstem control circuits of the cardiac, sympathetic and respiratory effectors. Thus, in the experimental protocol the time scales correspond to:  1) the 10-100 milliseconds involved in the time course of cytokines effecting the synaptic efficacy in the control circuits, 2) the 0.1-1 or 1-5 seconds involved in the expression of the cardiac and respiratory cycles in rats and humans, respectively, 3) 6 - 48 hours involved in tracking the development of sepsis after systemic inoculation in rats and 4) 1-7 days in tracking critically ill patients. Currently, in the mechanistic model, we are focusing on the interaction between the autonomic and respiratory effectors, i.e., drawing scalable models for investigating the neural control of respiratory-modulation of heart rate and blood pressure and the tendency for respiratory rhythm to be delayed with increases in arterial pulse pressure. In the data-driven models of central cytokine expression, the time scales are 6-48 hours.

Biological domain of the model
Central nervous system
Structure(s) of interest in the model
Brainstem Neural Circuitry and Cytokine Networks within the Brainstem
Spatial scales included in the model
Synapses, Neurons, Central Nuclei, Circuits, and Behavior Expression
Time scales included in the model
Milliseconds, Seconds, Hours and Days
2. Data for building and validating the model
Data for building the model Published? Private? How is credibility checked? Current Conformance Level / Target Conformance Level
in vitro (primary cells cell, lines, etc.)
ex vivo (excised tissues) Accptd 02/20 Repeated in-house & consistent with previous publications adequate
in vivo pre-clinical (lower-level organism or small animal) In review 2 manuscripts in preparation Collecting data
in vivo pre-clinical (large animal)
Human subjects/clinical Yes Colleague shared her data Collecting data extensive
Other: ________________________
Data for validating the model Published? Private? How is credibility checked? Current Conformance Level / Target Conformance Level
in vitro (primary cells cell, lines, etc.)
ex vivo (excised tissues)
in vivo pre-clinical (lower-level organism or small animal) Will plan experiments to test hypotheses of both models adequate
in vivo pre-clinical (large animal)
Human subjects/clinical Collecting data partial
Other: ________________________
3. Validate within context(s)
Who does it? When does it happen? How is it done? Current Conformance Level / Target Conformance Level
Verification DyNA Yoram Vodovotz & Ruben Zamora; ODE Model, Yaroslav Molkov, PI; William Barnett, senior post doc; & graduate students DyNA, Yoram Vodovotz & Ruben Zamora; ODE Model, weekly DyNA, Compare models from similar but separate experimental protocols; ODE Model, Model was implemented by independent researchers in different computing environments adequate
Validation DyNA Yoram Vodovotz & Ruben Zamora; ODE Model, Yaroslav Molkov, William Barnett DyNA, Spring 2021;ODE Model, Manuscript Spring 2020 DyNA, Compare models from a distinct protocol/perturbation suggested by the model; ODE Model, We inferred mechanisms from neuro-physiologic recordings in rats & predicted human data. adequate
Uncertainty quantification DyNA Yoram Vodovotz & Ruben Zamora; ODE Model, Yaroslav Molkov, William Barnett DyNA, Spring 2021;ODE Model, Manuscript Spring 2020 DyNA, Reproducibility of DyNA networks at similar stringency level across separate verification scenarios;ODE Model, Comparison of model and human probability density functions for heartbeats relative to the onset of inspiration. adequate
Sensitivity analysis DyNA Yoram Vodovotz & Ruben Zamora; ODE Model, Yaroslav Molkov, PI; William Barnett, senior post doc; & graduate students DyNA&ODE: Current with each model DyNA, Variables are excluded and variable ranges are determined; ODE Model, adequate
Other:__________
Additional Comments
4. Limitations
Disclaimer statement (explain key limitations) Who needs to know about this disclaimer? How is this disclaimer shared with that audience? Current Conformance Level / Target Conformance Level
DyNA network models are based on correlations across time intervals. DyNA models are thus “quasi-dynamic” in that they represent linearized portions of a full time course, as opposed to being run on all of the data from a given time course at once. Consumers and Users Mi, Q.; Constantine, G.; Ziraldo, C.; Solovyev, A.; Torres, A.; Namas, R.; Bentley, T.; Billiar, T.R.; Zamora, R.; Puyana, J.C.; Vodovotz, Y. A dynamic view of trauma/hemorrhage-induced inflammation in mice: Principal drivers and networks. PLoS ONE. 2011.6:19424. extensive
ODE Model is based on correlations but the core model has extensive history and has generated testable hypotheses. Consumers and Users Stated in publications extensive
In both models, accuracy of biologic data Consumers and Users Stated in publications extensive
5. Version control
Current Conformance Level / Target Conformance Level
adequate for both DyNA ad ODE model
Naming Conventions? Repository? Code Review?
individual modeler DyNA Ruben Zamora & ODE Model William Barnett
within the lab
collaborators
6. Documentation
Current Conformance Level / Target Conformance Level
Code commented? adequate for both DyNA and ODE model
Scope and intended use described? adequate for both DyNA and ODE model
User’s guide? The details of the DyNA model framework have been published in: Mi, Q.; Constantine, G.; Ziraldo, C.; Solovyev, A.; Torres, A.; Namas, R.; Bentley, T.; Billiar, T.R.; Zamora, R.; Puyana, J.C.; Vodovotz, Y. A dynamic view of trauma/hemorrhage-induced inflammation in mice: Principal drivers and networks. PLoS ONE. 2011.6:19424. DyNA is a data-driven model; the code is in Matlab.
Developer’s guide?
7. Dissemination
Current Conformance Level / Target Conformance Level
adequate
Target Audience(s): “Inner circle” Scientific community Public
Simulations adequate Adequate (multiple publications)
Models adequate Adequate (multiple publications, Matlab code available)
Software Adequate (multiple publications, Matlab code available)
Results adequate Adequate (multiple publications)
Implications of results adequate Adequate (multiple publications)
8. Independent reviews
Current Conformance Level / Target Conformance Level
review in Spring 2021
Reviewer(s) name & affiliation:
When was review performed?
How was review performed and outcomes of the review?
9. Test competing implementations
Current Conformance Level / Target Conformance Level
review in Spring 2021
Yes or No (briefly summarize)
Were competing implementations tested?
Did this lead to model refinement or improvement?
10. Conform to standards
Current Conformance Level / Target Conformance Level
adequate
Yes or No (briefly summarize)
Are there operating procedures, guidelines, or standards for this type of multiscale modeling? Yes, this is an established modeling approach with standard operating procedures and guidelines
How do your modeling efforts conform? DyNA, Dr. Vodovotz and Dr. Zamora have adopted the standard procedures and complied with its guidelines for this investigative approach all details to using this approach were published by these investigators see: Mi, Q, G Constantine, C Ziraldo, A Solovyev, A Torres, R Namas, T Bentley, TR Billiar, R Zamora, JC Puyana, and Y Vodovotz. A dynamic view of trauma/hemorrhage-induced inflammation in mice: Principal drivers and networks. PLoS One. 2011; 6(5): e19424. doi: 10.1371/journal.pone.0019424. ODE Model, Dr. Molkov is training Dr. Barnett in this model, its standard procedures and guidelines.