HetaProject – a Single Open Source Platform for Modeling, Simulation and Parameters Estimation in QSP
Ivan Borisov, Evgeny Metelkin
InSysBio, Moscow, Russia
Objectives: Pharmacological modeling is evolving towards large-scale dynamical models . A typical QSP project may include thousands of molecular components and several drugs. Such project is usually carried out by a group of researchers with different fields of expertise. Models’ complexity increases the requirements for computational procedures including solving large-scale differential equations systems, Monte-Carlo simulations, parameter estimation, uncertainty quantification etc. Software, which could establish the linkage between emerging QSP frameworks and fast computational methods, is of utmost importance for the field.
Methods: Heta language is a Domain Specific Language (DSL) for development and annotation of dynamical models in QSP projects. HetaCompiler  allows the users to convert Heta-based models to one of the formats: DBSolve, SimBiology, mrgsolve, SBML, Julia. Models converted to Julia can be simulated and fitted to experimental data with HetaSimulator – Julia-based simulation and parameters estimation platform. Julia allows code precompilation and simple framework for parallel simulations. The package utilizes features of SciML ecosystem, like access to 300+ ODE solvers, automatic differentiation, symbolic Jacobian derivation, etc. HetaSimulator can be integrated with the LikelihoodProfiler package  to perform identifiability and predictability analysis.
Results: HetaProject includes a DSL, HetaCompiler and HetaSimulator, which form a full-cycle modeling and simulation environment. It is intensively used in both research and commercial QSP projects at InSysBio: Alzheimer-consortium platform, Immune Response Template, PK/RO simulator for anti-PD-1 mAbs. Heta DSL and Heta Compiler allow the user to write complex QSP models and convert them to popular modeling formats, while HetaSimulator proposes an interface to define a simulation or a parameter estimation problem, which supports multi-conditional regimes, different experimental data inputs and distribution types. Both modeling and simulation operations can be performed in a single interface of VSCode.
Conclusions: HetaProject is a single platform for models development and validation in the QSP field. It was released as an ecosystem of open-source software packages (https://github.com/hetalang/) and it can be can be used as the modeling and simulation environment in QSP project of any size and complexity. A number of use-case models illustrate the stages of models development and validation, which can be performed in a single framework.
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