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Purpose/Objective(s) The precise radiomics analysis on thoracic 4DCT data is easily compromised by the respiratory motion and CT scan parameter setting, thus leading to the risk of overfitting and/or misinterpretation of data in AI-enabled therapeutic model building. In this study, we investigated the impact of respiratory amplitudes, frequencies and CT scan pitch settings within the thoracic 4DCT scan on robust radiomics feature selection. Materials/Methods A Three-dimensional QUSARTM lung tumor phantom was used to simulate different respiratory amplitudes and frequencies along with different CT scan pitch settings. A total of 43 tumor respiratory patterns extracted from 43 patients with non-small cell lung cancer were used to drive the QUSARTM lung tumor phantom to mimic the human tumor motion. The 4DCT images of the QUSARTM lung tumor phantom with different respiratory patterns and different CT scan pitch setups were acquired for radiomics feature extraction. A static high-quality CT images of the phantom acquired were also used as a reference for radiomics feature extraction. The range of respiratory amplitudes was mimicked at 3mm at left and right (LR) and anterior and posterior (AP) directions and 3mm - 15 mm at the superior and inferior (SI) direction with an interval of 2 mm. The respiratory frequencies were set at 10, 11, 12, 13, 14, 15 and 20 beats per minute (BPMs), respectively. The CT scan pitches were set at 0.025, 0.048, 0.071, 0.93, 0.108, 0.14, 0.16, 0.18, 0.21, 0.23, and 0.25, respectively, which was based on a procedure described in Med. Phys. 30(1):88-97. The pairwise Concordance Correlation Coefficient (CCC) was used to determine the robustness of radiomics feature extraction via comparing the agreement in feature values between 1766 radiomics features extracted from each image acquired under different combinations of respiratory amplitudes and frequencies and CT scan pitches of 4DCT and those extracted from the static CT images. Results (1) When the respiratory amplitudes were at 3, 5, 7, 9, 12 and 15mm in the SI direction, the maximum CCC index could be achieved at the reconstructed 4DCT phase images of 60%, 70%, 30%, 20%, 60%~70% and 10%, respectively. Under these six amplitudes, the maximum intensity projection (MIP) and average intensity projection (AIP) images reconstructed show mean CCC values of 0.778 and 0.609, respectively, in pairwise radiomics feature extraction comparison between 4DCT and static CT. (2) When the respiratory amplitude was set at 12 mm in the SI direction, the maximum CCC index could be consistently achieved at the reconstructed 4DCT phase of 90% for the seven respiratory frequencies of 10, 11, 12, 13, 14, 15 and 20 BPMs, respectively. Under these respiratory states, the MIP and AIP images reconstructed show mean CCC values of 0.702 and 0.562, respectively. (3) When the respiratory amplitude was set at 12 mm and the respiratory frequency was set at 13 BPM, the maximum CCC index could be obtained at the reconstructed 4DCT phase of 90% for all scan pitches used except the 0% phase which was obtained at the pitch setting of 0.048. Under these CT scan pitch settings, the MIP and AIP images reconstructed show mean CCC values of 0.558 and 0.782, respectively. (4) The total number of robust features were 50, 34 and 35 with different respiratory amplitudes and phases and CT scanning pitch used (CCC values ≥ 0.99). Conclusion In 4DCT, the respiratory amplitude, frequency and CT scan pitch are three limiting factors that greatly affect the robustness of radiomics feature extraction. The reconstructed 4DCT phases with better robustness along with suitable respiratory amplitude, frequency and CT scan pitch determined could be used to guide the breathing training for patients with lung cancer for radiation therapy to improve the robust radiomics feature extraction process.