A Proxy-guided Workflow for Virtual Population Development

QSP models are increasingly being applied to drug development. Calibrating virtual populations (VPops) to clinical data helps explore patient variability, study populations of interest, and predict clinical outcomes for new therapies. In previous work, we have developed the QSP Toolbox, a library of tools and workflows for developing VPops. The aim is to create a VPop that fits clinical data from a variety of sources and with a variety of data types, allowing for differences in the quality of the data. The goodness-of-fit (GOF) of the VPop is given by a scalar function <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>p</mml:mi></mml:math> whose form is inspired by the p-value of Fisher's combined hypothesis test. However, our VPop development workflow has been hampered by the need to perform repeated optimization of "prevalence weights" to maximize <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>p</mml:mi></mml:math> . In this article, we describe how we can speed up our workflow by using proxy GOF functions whose maximization can be reduced to the relatively easy problem of minimizing a convex quadratic objective function. A successful run of this "proxy-guided" workflow generates a VPop with very good <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>p</mml:mi></mml:math> -fit, but without having to continually maximize <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>p</mml:mi></mml:math> throughout the development process. We find that our proxy-guided workflow can calibrate VPops much faster than the original ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>p</mml:mi></mml:math> -guided) workflow.