Dose–response modeling in high-throughput cancer drug screenings: an end-to-end approach
| Autor: | David M. Blei, Scott W. Linderman, Chris H. Wiggins, Wesley Tansey, Haoran Zhang, Raul Rabadan, Kathy Li |
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| Rok vydání: | 2021 |
| Předmět: |
Statistics and Probability
Computer science High-throughput screening Drug Evaluation Preclinical Antineoplastic Agents Computational biology Bayesian inference 01 natural sciences 010104 statistics & probability 03 medical and health sciences End-to-end principle Neoplasms medicine Humans 0101 mathematics Throughput (business) Early Detection of Cancer 030304 developmental biology Profiling (computer programming) 0303 health sciences Drug discovery business.industry Cancer Bayes Theorem Articles General Medicine medicine.disease High-Throughput Screening Assays Personalized medicine Statistics Probability and Uncertainty business |
| Zdroj: | Biostatistics |
| ISSN: | 1468-4357 1465-4644 |
| DOI: | 10.1093/biostatistics/kxaa047 |
| Popis: | Summary Personalized cancer treatments based on the molecular profile of a patient’s tumor are an emerging and exciting class of treatments in oncology. As genomic tumor profiling is becoming more common, targeted treatments for specific molecular alterations are gaining traction. To discover new potential therapeutics that may apply to broad classes of tumors matching some molecular pattern, experimentalists and pharmacologists rely on high-throughput, in vitro screens of many compounds against many different cell lines. We propose a hierarchical Bayesian model of how cancer cell lines respond to drugs in these experiments and develop a method for fitting the model to real-world high-throughput screening data. Through a case study, the model is shown to capture nontrivial associations between molecular features and drug response, such as requiring both wild type TP53 and overexpression of MDM2 to be sensitive to Nutlin-3(a). In quantitative benchmarks, the model outperforms a standard approach in biology, with $\approx20\%$ lower predictive error on held out data. When combined with a conditional randomization testing procedure, the model discovers markers of therapeutic response that recapitulate known biology and suggest new avenues for investigation. All code for the article is publicly available at https://github.com/tansey/deep-dose-response. |
| Databáze: | OpenAIRE |
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