Ten Simple Rules Example
Spaceflight Induced Bone Remodeling
Background: A finite element model was developed to understand bone remodeling and demineralization mechanisms in microgravity in order to: 1) appropriately quantify long term bone health risks (osteoporosis & bone fracture), and 2) establish appropriate countermeasures.
Disclaimer: This example does not necessarily demonstrate the level of detail required to fully satisfy the Committee’s credibility guidelines [1]. The granularity of how each rule is applied is solely dependent on the needs of each modeling and simulation project.
Rule 1: Define context clearly
- Domain of Use: Translational research - The bone model is being developed primarily as a spaceflight research tool, and not as a clinical tool.
- Use Capacity: The model is intended to provide additional data to gain insight on (1) mechanisms of bone demineralization in microgravity, and (2) the volumetric changes in response to in-flight and post-flight exercise countermeasures.
- Strength of Influence: This version of the model only targets the femoral neck to illustrate the capacity to make effective predictions. The model is not being developed to predict bone fracture.
Rule 2: Use appropriate data
- Model development data: Since bone parameter values are still under active research by the scientific community, we used average values from the scientific literature – see [2] for details. Parameters that were utilized in the model include: resorption depth (depth of modeling unit) for trabecular hemi-osteo; resorption depth for cortical bone; activation frequency; TG-beta 1.
Validation data came from a regression "sub-model," which was developed using total femur DEXA aBMD and QCT vBMD [BMD = bone mineral density] data from the flight study reported in Lang et al. (2004) – raw data was provided by NASA’s Life Science Data Archives. This regression “sub model” helped expand the data set to draw on to validate the computational model, as well as run investigative simulations.
Rule 3: Evaluate within context
- Validated model's ability to reproduce the observed behavior under consideration (e.g., bone mineral density (BMD) or bone volume fraction (BVF) changes) in comparison to an appropriate referent, specifically:
Bone Volume Fraction (BVF) compared against 3 other model predictions and against experimental data from Tsangari et al (2007).
- Volumetric BMD (vBMD) predicted by model compared against that from quantitative computed tomography (QCT) for both trabecular and cortical bone for 4 subjects after 70 days of bed rest (spaceflight analog).
Time course of Areal BMD (aBMD) predicted by model versus that from dual-energy X-Ray absorptiometry (DEXA) for 18 subjects during 17 weeks of bed rest (spaceflight analog) (LeBlanc et al.,1990). Raw data was provided by NASA’s Life Science Data Archives and NASA's Bone Research Lab.
- Rigorous verification, sensitivity and uncertainty analysis of the system of equations, parameters and variables identified as future work.
Rule 4: List limitations explicitly
- Limitations in the modeling approach include:
- Remodeling formulation is limited to porosity, thus restricting it to density changes within the trabecular region and to intracortical density changes. It does not cover periosteal apposition or endocortical change. Geometry changes in the bone site are not modeled.
- The model does not include the effects of sclerostin, calcitonin, osteopontin , or interleukins, some of which may play a role bone loss in microgravity and with disuse in 1g.
- Preliminary validation analysis of the computational predictions for deconditioning has only been done for up to 4 months in duration.
- The validation data used is from bed rest control subjects as an analog to gravitational unloading due to exposure to microgravity.
- The computational model is best suited for the mature adult between 25 and 55 years of age (typical age of an astronaut). Capability to make subject specific predictions is limited. Age and gender differences are not yet factored in when initializing model variables.
- Limitations imposed by the state of knowledge in bone science:
- There is a degree of uncertainty and variation in remodeling unit geometry and dimensions reported in the literature.
- It is difficult to guarantee that the remodeling unit values used in the model agree for the particular skeletal site of interest.
- There is uncertainty in the way ash fraction is modeled, and the full potential range of values estimated from experimental studies is not completely understood.
- Activation frequency and activation density are inherently difficult to appropriately model due to the lack of human values at skeletal sites other than the iliac crest or rib.
- There are several potential algebraic schemes for mapping initial data values to model state variables. They depend on several possible definitions of ash fraction and how the steady state version of their respective equations are used.
Rule 5: Use version control
- Regular commits are made to a Subversion repository. Stable version releases are created with appropriate documentation.
Rule 6: Document adequately
- Code was documented sufficiently for modelers and scientists.
- Graphical user interface was developed for intuitive use by end users.
- Every model delivery to stakeholders was accompanied with a report summarizing model features and credibility. See
J. Pennline and L. Mulugeta, “The Digital Astronaut Project Computational Bone Remodeling Model (Beta Version) Bone Summit Summary Report”, Bone Summit II Research and Clinical Advisory Panel Meeting, 1-5 Nov. 2013, Houston, TX.
- Presentations and briefings provided to stakeholder community at quarterly meetings, annual agency reports, and annual HRP Investigators’ Workshop
Peer-reviewed articles, conference presentations and technical memos were produced regularly (search Pennline and Mulugeta at the NASA Technical Report Server)
Rule 7: Disseminate broadly
- The code was developed and made available for use by NASA researchers. It was not intended for release to the general public.
Peer-reviewed articles and conference presentations are available for public consumption (search Pennline and Mulugeta at the NASA Technical Report Server).
Rule 8: Get independent reviews
In accordance to NASA STD 7009, technical reviews were conducted to ensure critique from key stakeholders (see an online example).
- In addition to obtaining feedback from the key stakeholders, NASA’s Research and Clinical Advisory Panel (external subject matter experts) were provided a summary report. The Panel used this report to provide feedback to the NASA Bone Discipline Lead regarding the potential utility and weakness of this model with respect to its context of use.
Rule 9: Test competing implementations
- This is an ongoing process. The foundational model was formed by comparing, contrasting, combining and modifying previously developed set of biochemical, cellular dynamics, and mechanical stimulus equations in the literature.
Rule 10: Conform to standards
The model and simulations were developed and applied in accordance to NASA’s Standard for Models and Simulations (NASA STD 7009).
- All human subject data were used in accordance to HIPAA.
Review Details
Information Sources
Analysis History
- Original analysis report by Lealem Mulugeta (study co-author) on May 16, 2018. Additional insight was provided based on knowledge of modeling and simulation activities beyond those reported as part of the study publication.
- Updated by Lealem Mulugeta (study co-author) on May 10, 2020
- Updated by Joy Ku on October 20, 2020 to match Ahmet Erdermir's edits for supplementary material for related publication [1].