Abstract
BackgroundIn Silico Livers (ISLs) are works in progress. They are used to challenge multilevel, multi-attribute, mechanistic hypotheses about the hepatic disposition of xenobiotics coupled with hepatic responses. To enhance ISL-to-liver mappings, we added discrete time metabolism, biliary elimination, and bolus dosing features to a previously validated ISL and initiated re-validated experiments that required scaling experiments to use more simulated lobules than previously, more than could be achieved using the local cluster technology. Rather than dramatically increasing the size of our local cluster we undertook the re-validation experiments using the Amazon EC2 cloud platform. So doing required demonstrating the efficacy of scaling a simulation to use more cluster nodes and assessing the scientific equivalence of local cluster validation experiments with those executed using the cloud platform.ResultsThe local cluster technology was duplicated in the Amazon EC2 cloud platform. Synthetic modeling protocols were followed to identify a successful parameterization. Experiment sample sizes (number of simulated lobules) on both platforms were 49, 70, 84, and 152 (cloud only). Experimental indistinguishability was demonstrated for ISL outflow profiles of diltiazem using both platforms for experiments consisting of 84 or more samples. The process was analogous to demonstration of results equivalency from two different wet-labs.ConclusionsThe results provide additional evidence that disposition simulations using ISLs can cover the behavior space of liver experiments in distinct experimental contexts (there is in silico-to-wet-lab phenotype similarity). The scientific value of experimenting with multiscale biomedical models has been limited to research groups with access to computer clusters. The availability of cloud technology coupled with the evidence of scientific equivalency has lowered the barrier and will greatly facilitate model sharing as well as provide straightforward tools for scaling simulations to encompass greater detail with no extra investment in hardware.
Highlights
In Silico Livers (ISLs) are works in progress
An ISL is a biomimetic analogue designed to help formulate and challenge mechanistic hypotheses about the hepatic disposition of xenobiotics in health and disease. It is an assembly of abstracted components representing aspects of hepatic form, space, and organization interacting with compounds
The same is true with multiscale models like ISLs
Summary
In Silico Livers (ISLs) are works in progress. They are used to challenge multilevel, multi-attribute, mechanistic hypotheses about the hepatic disposition of xenobiotics coupled with hepatic responses. An ISL is a biomimetic analogue designed to help formulate and challenge mechanistic hypotheses about the hepatic disposition of xenobiotics in health and disease It is an assembly of abstracted components representing aspects of hepatic form, space, and organization interacting with compounds (a simulated compound; when referring to an ISL feature or component that has a wet-lab counterpart, we use small caps). It has its own unique phenotype, which is necessarily simpler than that of the entire set of lobule mechanisms. Because of the stochastic nature of ISL simulations, each in silico experiment-constructed from several Monte Carlo (MC) lobule samples-generates a slightly different outflow profile
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