Chemotherapy drug administration is a complex problem that often requires expensive clinical trials to evaluate potential regimens; one way to alleviate this burden and better inform future trials is to build reliable models for drug administration. This paper presents a mixed-integer program for combination chemotherapy (utilization of multiple drugs) optimization that incorporates various important operational constraints and, besides dose and concentration limits, controls treatment toxicity based on its effect on the count of white blood cells. To address the uncertainty of tumor heterogeneity, we also propose chance constraints that guarantee reaching an operable tumor size with a high probability in a neoadjuvant setting. We present analytical results pertinent to the accuracy of the model in representing biological processes of chemotherapy and establish its potential for clinical applications through a numerical study of breast cancer. History: Accepted by Paul Brooks, Area Editor for Applications in Biology, Medicine, & Healthcare. Funding: This work was supported by the National Science Foundation [Grants CMMI-1933369 and CMMI-1933373]. Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2022.0207 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2022.0207 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .
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A Shrinkage Approach to Improve Direct Bootstrap Resampling Under Input Uncertainty
Discrete-event simulation models generate random variates from input distributions and compute outputs according to the simulation logic. The input distributions are typically fitted to finite real-world data and thus are subject to estimation errors that can propagate to the simulation outputs: an issue commonly known as input uncertainty (IU). This paper investigates quantifying IU using the output confidence intervals (CIs) computed from bootstrap quantile estimators. The standard direct bootstrap method has overcoverage due to convolution of the simulation error and IU; however, the brute-force way of washing away the former is computationally demanding. We present two new bootstrap methods to enhance direct resampling in both statistical and computational efficiencies using shrinkage strategies to down-scale the variabilities encapsulated in the CIs. Our asymptotic analysis shows how both approaches produce tight CIs accounting for IU under limited input data and simulation effort along with the simulation sample-size requirements relative to the input data size. We demonstrate performances of the shrinkage strategies with several numerical experiments and investigate the conditions under which each method performs well. We also show advantages of nonparametric approaches over parametric bootstrap when the distribution family is misspecified and over metamodel approaches when the dimension of the distribution parameters is high. History: Accepted by Bruno Tuffin, Area Editor for Simulation. Funding: This work was supported by the National Science Foundation [CAREER CMMI-1834710, CAREER CMMI-2045400, DMS-1854659, and IIS-1849280]. Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2022.0044 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2022.0044 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .
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- Award ID(s):
- 2246281
- PAR ID:
- 10525465
- Publisher / Repository:
- INFORMS
- Date Published:
- Journal Name:
- INFORMS Journal on Computing
- ISSN:
- 1091-9856
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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