Fig 1.
Overview of components of an ISCT (necessary components in white boxes, possible components in light blue boxes).
Left side: a virtual cohort (set of virtual patients) can be created given a baseline patient model and a cohort generation method. Coupling with a device model, and potentially other sub-models, results in the virtual cohort for the ISCT, which is run using the ISCT study protocol to obtain the ISCT results. The right-hand box shows four approaches to generating a virtual cohort (not comprehensive). Approach A): Construct subject-specific virtual patients from subject-specific data. B) Construct subject-specific virtual patients and alter to create synthetic patients. C) Generate synthetic patients by sampling from probability distributions derived from subject-specific virtual patients; D) Generate synthetic patients by sampling from prescribed probability distributions. Two parameters, p1 and p2, shown for simplicity. See text for discussion.
Table 1.
Overview and comparison of ISCTs discussed in Section 2.3.
MR: magnetic resonance, RF: radiofrequency, AUC: area under receiver operator characteristic curve, ODE: ordinary differential equation, CGM: continuous glucose monitor, FEA: finite element analysis.
Table 2.
Selection of possible validation tests that could be performed to evaluate an ISCT, identified in Section 3.2.
This is not intended to be a comprehensive list of options; many options or variants are possible.
Fig 2.
Possibilities for validation of device and patient models (not comprehensive).
Equality sign with question mark indicates "Compared as part of validation activity”. See text for discussion.
Fig 3.
Possibilities for cohort validation (not comprehensive).
Equality sign with question mark indicates "Compared as part of validation activity”. (a) N subject-specific virtual patients each individually validated against data from the corresponding real-world subjects. (b) Distribution of a model output across the virtual cohort validated against corresponding data from the real-world population. (c) Results of an ISCT directly compared to a real-world clinical trial.
Fig 4.
Overview of sub-steps in Step 4 of the workflow.
Equality sign with question mark indicates "Compared as part of validation activity”.
Table 3.
Credibility factors and gradations that could be used for population-level validation of the virtual cohort.