Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling
Abstract Pharmacometric modeling can capture tumor growth inhibition (TGI) dynamics and variability. These approaches do not usually consider covariates in high‐dimensional settings, whereas high‐dimensional molecular profiling technologies (“omics”) are being increasingly considered for prediction...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-04-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12603 |
| _version_ | 1818430125910261760 |
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| author | Laura B. Zwep Kevin L. W. Duisters Martijn Jansen Tingjie Guo Jacqueline J. Meulman Parth J. Upadhyay J. G. Coen vanHasselt |
| author_facet | Laura B. Zwep Kevin L. W. Duisters Martijn Jansen Tingjie Guo Jacqueline J. Meulman Parth J. Upadhyay J. G. Coen vanHasselt |
| author_sort | Laura B. Zwep |
| collection | DOAJ |
| description | Abstract Pharmacometric modeling can capture tumor growth inhibition (TGI) dynamics and variability. These approaches do not usually consider covariates in high‐dimensional settings, whereas high‐dimensional molecular profiling technologies (“omics”) are being increasingly considered for prediction of anticancer drug treatment response. Machine learning (ML) approaches have been applied to identify high‐dimensional omics predictors for treatment outcome. Here, we aimed to combine TGI modeling and ML approaches for two distinct aims: omics‐based prediction of tumor growth profiles and identification of pathways associated with treatment response and resistance. We propose a two‐step approach combining ML using least absolute shrinkage and selection operator (LASSO) regression with pharmacometric modeling. We demonstrate our workflow using a previously published dataset consisting of 4706 tumor growth profiles of patient‐derived xenograft (PDX) models treated with a variety of mono‐ and combination regimens. Pharmacometric TGI models were fit to the tumor growth profiles. The obtained empirical Bayes estimates‐derived TGI parameter values were regressed using the LASSO on high‐dimensional genomic copy number variation data, which contained over 20,000 variables. The predictive model was able to decrease median prediction error by 4% as compared with a model without any genomic information. A total of 74 pathways were identified as related to treatment response or resistance development by LASSO, of which part was verified by literature. In conclusion, we demonstrate how the combined use of ML and pharmacometric modeling can be used to gain pharmacological understanding in genomic factors driving variation in treatment response. |
| first_indexed | 2024-12-14T15:28:27Z |
| format | Article |
| id | doaj.art-b569bda0fd6a4dffa8e75e560977a350 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-12-14T15:28:27Z |
| publishDate | 2021-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-b569bda0fd6a4dffa8e75e560977a3502022-12-21T22:55:59ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062021-04-0110435036110.1002/psp4.12603Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modelingLaura B. Zwep0Kevin L. W. Duisters1Martijn Jansen2Tingjie Guo3Jacqueline J. Meulman4Parth J. Upadhyay5J. G. Coen vanHasselt6Leiden Academic Centre for Drug Research Leiden University Leiden The NetherlandsMathematical Institute Leiden University Leiden The NetherlandsLeiden Academic Centre for Drug Research Leiden University Leiden The NetherlandsLeiden Academic Centre for Drug Research Leiden University Leiden The NetherlandsMathematical Institute Leiden University Leiden The NetherlandsLeiden Academic Centre for Drug Research Leiden University Leiden The NetherlandsLeiden Academic Centre for Drug Research Leiden University Leiden The NetherlandsAbstract Pharmacometric modeling can capture tumor growth inhibition (TGI) dynamics and variability. These approaches do not usually consider covariates in high‐dimensional settings, whereas high‐dimensional molecular profiling technologies (“omics”) are being increasingly considered for prediction of anticancer drug treatment response. Machine learning (ML) approaches have been applied to identify high‐dimensional omics predictors for treatment outcome. Here, we aimed to combine TGI modeling and ML approaches for two distinct aims: omics‐based prediction of tumor growth profiles and identification of pathways associated with treatment response and resistance. We propose a two‐step approach combining ML using least absolute shrinkage and selection operator (LASSO) regression with pharmacometric modeling. We demonstrate our workflow using a previously published dataset consisting of 4706 tumor growth profiles of patient‐derived xenograft (PDX) models treated with a variety of mono‐ and combination regimens. Pharmacometric TGI models were fit to the tumor growth profiles. The obtained empirical Bayes estimates‐derived TGI parameter values were regressed using the LASSO on high‐dimensional genomic copy number variation data, which contained over 20,000 variables. The predictive model was able to decrease median prediction error by 4% as compared with a model without any genomic information. A total of 74 pathways were identified as related to treatment response or resistance development by LASSO, of which part was verified by literature. In conclusion, we demonstrate how the combined use of ML and pharmacometric modeling can be used to gain pharmacological understanding in genomic factors driving variation in treatment response.https://doi.org/10.1002/psp4.12603 |
| spellingShingle | Laura B. Zwep Kevin L. W. Duisters Martijn Jansen Tingjie Guo Jacqueline J. Meulman Parth J. Upadhyay J. G. Coen vanHasselt Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling CPT: Pharmacometrics & Systems Pharmacology |
| title | Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling |
| title_full | Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling |
| title_fullStr | Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling |
| title_full_unstemmed | Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling |
| title_short | Identification of high‐dimensional omics‐derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling |
| title_sort | identification of high dimensional omics derived predictors for tumor growth dynamics using machine learning and pharmacometric modeling |
| url | https://doi.org/10.1002/psp4.12603 |
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