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Constructing a representative in-silico population for paediatric simulations: Application to HIV-positive African
Roeland E Wasmann1, Elin M Svensson2,3, A Sarah Walker4
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Insights
This study developed a flexible workflow to create virtual pediatric patient populations for pharmacokinetic-pharmacodynamic simulations. The method accurately simulates weight, height, sex, and age combinations, improving in silico population representation.
Area of Science:
- Pharmacokinetics-Pharmacodynamics
- Computational Biology
- Pediatric Research
Background:
- Simulations require representative in silico populations, especially for pediatric pharmacokinetics-pharmacodynamics.
- Standard growth charts (WHO, CDC) may not represent specific pediatric populations (e.g., malnourished, acutely unwell).
- Correlated covariates like weight, height, sex, and age complicate virtual population construction.
Purpose of the Study:
- To present a workflow for constructing virtual pediatric patient populations.
- To improve the representativeness of in silico populations for pharmacokinetic-pharmacodynamic simulations.
- To provide a flexible methodology applicable to diverse pediatric cohorts.
Main Methods:
- Developed a workflow using World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) growth charts.
- Employed piecewise linear functions to adjust growth chart medians by sex and age.
- Utilized visual diagnostics for comparison with target populations.
- Applied the workflow to a cohort of 1206 HIV-positive African children.
Main Results:
- Unadjusted WHO and CDC charts overestimated weight and height compared to observed data.
- The proposed methodology successfully adjusted growth charts to match observed data.
- Simulated weight, height, sex, and age combinations showed good agreement with the observed pediatric population.
Conclusions:
- The presented methodology offers a flexible approach for creating representative virtual pediatric populations.
- This workflow enhances the reliability of in silico simulations in pediatric pharmacokinetics-pharmacodynamics.
- R scripts and a ready-to-use pediatric population dataset are provided to facilitate research.
Aims:
Simulations are an essential tool for investigating scenarios in pharmacokinetics-pharmacodynamics. The models used during simulation often include the effect of highly correlated covariates such as weight, height and sex, and for children also age, which complicates the construction of an in silico population. For this reason, a suitable and representative patient population is crucial for the simulations to produce meaningful results. For simulation in paediatric patients, international growth charts from the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) provide a reference, but these may not always be representative for specific populations, such as malnourished children with HIV or acutely unwell children.
Methods:
We present a workflow to construct a virtual paediatric patient population using WHO and CDC growth charts, suggest piecewise linear functions to adjust the median of the growth charts by sex and age, and suggest visual diagnostics to compare with the target population. We applied this workflow in a population of 1206 HIV-positive African children, consisting of 19 742 observations with weight ranging from 3.8 to 79.7 kg, height from 55.5 to 180 cm, and an age between 0.40 and 18 years.
Results:
Before adjustment, the WHO and CDC charts produced weights and heights higher compared to the observed data. After applying our methodology, we could simulate weight, height, sex and age combinations in good agreement with the observed data.
Conclusion:
The methodology presented here is flexible and may be applied to other scenarios where WHO and CDC growth standards might not be appropriate. In addition we provide R scripts and a large ready-to-use paediatric population.
