Abstract
Virtual clinical trials (VCTs) can potentially simulate clinical trials on a computer, but their application with a limited number of past clinical cases is challenging due to the biased estimation of the statistical population. In this study, we developed ExMixup, a novel training technique based on machine learning, using iteratively redistributed extrapolated data. Information obtained from 100 patients with prostate cancer and 385 patients with oropharyngeal cancer was used to predict the recurrence after radiotherapy. Model performance was evaluated by developing outcome prediction models based on three types of training methods: training with original data (baseline), interpolation data (Mixup), and interpolation + extrapolation data (ExMixup). Two types of VCTs were conducted to predict the treatment response of patients with distinct characteristics compared to the training data obtained from patient cohorts categorized under risk classification or cancer stage. The prediction models developed with ExMixup yielded concordance indices (95% confidence intervals) of 0.751 (0.719–0.818) and 0.752 (0.734–0.785) for VCTs on the prostate and oropharyngeal cancer datasets, respectively, which significantly outperformed the baseline and Mixup models (P < 0.01). The proposed approach could enhance the ability of VCTs to predict treatment results in patients excluded from past clinical trials.
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References
Cante D, et al. Moderately hypofractionated radiotherapy with simultaneous integrated boost in prostate cancer: a comparative study with conventionally fractionated radiation. J Oncol. 2020;2020:5–10. https://doi.org/10.1155/2020/3170396.
Lee BM, Chang JS, Kim SY, Keum KC, Suh CO, Kim YB. Hypofractionated radiotherapy dose scheme and application of new techniques are associated to a lower incidence of radiation pneumonitis in breast cancer patients. Front Oncol. 2020;10(February):1–9. https://doi.org/10.3389/fonc.2020.00124.
Shen J, et al. Hypofractionated volumetric- modulated arc radiotherapy for patients with non-small-cell lung cancer not suitable for surgery or conventional chemoradiotherapy or SBRT. 2021;11(June):1–8. https://doi.org/10.3389/fonc.2021.644852.
Zhang Z, et al. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther 2020;5(1). https://doi.org/10.1038/s41392-020-00213-8.
Nguyen TK, Nguyen EK, Warner A, Louie AV, Palma DA. Failed randomized clinical trials in radiation oncology: what can we learn? Int J Radiat Oncol Biol Phys. 2018;101(5):1018–24. https://doi.org/10.1016/j.ijrobp.2018.04.030.
Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20(2):273–86. https://doi.org/10.1093/biostatistics/kxx069.
Kozłowska E, Vallius T, Hynninen J, Hietanen S, Färkkilä A, Hautaniemi S. Virtual clinical trials identify effective combination therapies in ovarian cancer. Sci Rep. 2019;9(1):1–9. https://doi.org/10.1038/s41598-019-55068-z.
Pérez-García VM, et al. Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas. bioRxiv, pp. 1–17. 2019. https://doi.org/10.1101/521559.
Jones B, Dale RG. Further radiobiologic modeling of palliative radiotherapy: use of virtual trials. Int J Radiat Oncol Biol Phys. 2007;69(1):221–9. https://doi.org/10.1016/j.ijrobp.2007.04.050.
Madhukar NS, et al. A Bayesian machine learning approach for drug target identification using diverse data types. Nat Commun. 2019;10(1):1–14. https://doi.org/10.1038/s41467-019-12928-6.
Lou B, et al. An image-based deep learning framework for individualising radiotherapy dose: a retrospective analysis of outcome prediction. Lancet Digit Heal. 2019;1(3):e136–47. https://doi.org/10.1016/S2589-7500(19)30058-5.
Jiang W, Song Y, Sun Z, Qiu J, Shi L. Dosimetric factors and radiomics features within different regions of interest in planning CT images for improving the prediction of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2021;110(4):1161–70. https://doi.org/10.1016/j.ijrobp.2021.01.049.
Mizutani T, et al. Optimization of treatment strategy by using a machine learning model to predict survival time of patients with malignant glioma after radiotherapy. J Radiat Res. 2019;60(6):818–24. https://doi.org/10.1093/jrr/rrz066.
Liu H, et al. Predicting the dissolution kinetics of silicate glasses by topology-informed machine learning, NPJ Mater Degrad. 2019; 3(1). https://doi.org/10.1038/s41529-019-0094-1.
Ramprasad R, Batra R, Pilania G, Mannodi-Kanakkithodi A, Kim C. Machine learning in materials informatics: recent applications and prospects. NPJ Comput Mater. 2017; 3(1). https://doi.org/10.1038/s41524-017-0056-5.
Abdollahi H, et al. Machine learning-based radiomic models to predict intensity-modulated radiation therapy response, Gleason score and stage in prostate cancer. Radiol Medica. 2019;124(6):555–67. https://doi.org/10.1007/s11547-018-0966-4.
Zhao W, et al. Toward automatic prediction of EGFR mutation status in pulmonary adenocarcinoma with 3D deep learning. Cancer Med. 2019;8(7):3532–43. https://doi.org/10.1002/cam4.2233.
Hasegawa T, et al. Ku70-Expression prognostiziert Ergebnisse der Strahlentherapie beim Prostatakarzinom. Strahlentherapie und Onkol. 2017;193(1):29–37. https://doi.org/10.1007/s00066-016-1023-7.
Hasegawa T, et al. Prediction of results of radiotherapy with ku70 expression and an artificial neural network. In Vivo (Brooklyn). 2020;34(5):2865–72. https://doi.org/10.21873/invivo.12114.
Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys. 1999;43(5):1095–101. https://doi.org/10.1016/S0360-3016(98)00438-6.
Abramowitz MC, et al. The phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer. Cancer. 2008;112(1):55–60. https://doi.org/10.1002/cncr.23139.
Anderson MMD, Quantitative N, Working I. Matched computed tomography segmentation and demographic data for oropharyngeal cancer radiomics challenges. Sci data. 2017;4:170077. https://doi.org/10.1038/sdata.2017.77.
Grossberg AJ, et al. Data descriptor: imaging and clinical data archive for head and neck squamous cell carcinoma patients treated with radiotherapy. Sci Data. 2018;5:1–10. https://doi.org/10.1038/sdata.2018.173.
Clark K, et al. The cancer imaging archive (TCIA): maintaining and operating a public information repository. J Digit Imaging. 2013;26(6):1045–57. https://doi.org/10.1007/s10278-013-9622-7.
Blažek T, et al. Dose escalation in advanced floor of the mouth cancer: a pilot study using a combination of IMRT and stereotactic boost. Radiat Oncol. 2021;16(1):1–9. https://doi.org/10.1186/s13014-021-01842-1.
Van Griethuysen JJM, et al. Computational radiomics system to decode the radiographic phenotype. Cancer Res. 2017;77(21):e104–7. https://doi.org/10.1158/0008-5472.CAN-17-0339.
Zhang H, Cisse M, Dauphin YN, Lopez-Paz D. MixUp: Beyond empirical risk minimization. In: 6th Int. Conf. Learn. Represent. ICLR 2018 - Conf. Track Proc., pp. 1–13. 2018.
Yoo JE. TIMSS 2011 student and teacher predictors for mathematics achievement explored and identified via elastic net. Front Psychol. 2018; 9(MAR):1–10. https://doi.org/10.3389/fpsyg.2018.00317.
Chawla NV, Bowyer KW, Hall LO, Kegelmeyer WP. SMOTE: synthetic minority over-sampling technique. J Artif Int Res. 2002;16:321–57. https://doi.org/10.1613/jair.953.
Collins GS, Reitsma JB, Altman DG, Moons KGM. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. BMC Med. 2015;13(1):1–10. https://doi.org/10.1186/s12916-014-0241-z.
Cui S, Ten Haken RK, El Naqa I. Integrating multiomics information in deep learning architectures for joint actuarial outcome prediction in non-small cell lung cancer patients after radiation therapy. Int J Radiat Oncol Biol Phys. 2021;00533949. https://doi.org/10.1016/j.ijrobp.2021.01.042.
Uno H, Cai T, Pencina MJ, D’Agostino RB, Wei LJ. On the C-statistics for evaluating overall adequacy of risk prediction procedures with censored survival data. Stat Med. 2011;30:1105–17. https://doi.org/10.1002/sim.4154.
Stone M. Cross-validatory choice and assessment of statistical predictions. J R Stat Soc Ser B. 1974;36(2):111–33. https://doi.org/10.1111/j.2517-6161.1974.tb00994.x.
D’Amico AV, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. J Am Med Assoc. 1998;280(11):969–74. https://doi.org/10.1001/jama.280.11.969.
Edge SB, Compton CC. The american joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–1474. https://doi.org/10.1245/s10434-010-0985-4.
Catucci F, et al. Predicting radiotherapy impact on late bladder toxicity in prostate cancer patients: an observational study. Cancers (Basel). 2021;13(2):1–12. https://doi.org/10.3390/cancers13020175.
Wei S, Xu K, Wang D, Liao F, Wang H, Kong Q. Sample mixed-based data augmentation for domestic audio tagging, no. November, 2018, [Online]. Available: http://arxiv.org/abs/1808.03883.
DeVries T, Taylor GW. Dataset augmentation in feature space. In: 5th Int. Conf. Learn. Represent. ICLR 2017 - Work. Track Proc., pp. 1–12. 2019.
Luo Y, Tseng H-H, Cui S, Wei L, Ten Haken RK, El Naqa I. Balancing accuracy and interpretability of machine learning approaches for radiation treatment outcomes modeling. BJR Open. 2019;1(1):20190021. https://doi.org/10.1259/bjro.20190021.
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This work was supported by JSPS KAKENHI (Grant Number 18K15604).
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This retrospective study was approved by the Institutional Review Board of Komazawa University (No. 18–7).
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Oguma, K., Magome, T., Someya, M. et al. Virtual clinical trial based on outcome modeling with iteratively redistributed extrapolation data. Radiol Phys Technol 16, 262–271 (2023). https://doi.org/10.1007/s12194-023-00715-4
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DOI: https://doi.org/10.1007/s12194-023-00715-4