## 2 Materials and Methods  
We used a Fujifilm Amulet Innovality (Fujifilm Corp, Tokyo, Japan) DBT system, which has 2 imaging modalities, i.e., a \"standard\" (ST) modality wherein the X-ray tube angular range continuously spans a range of 15\({}^{\circ}\), and a \"high-resolution\" (HR) modality wherein the angular range is 40\({}^{\circ}\). The number of acquired projections was 15 for both modalities. The in-plane pixel size of DBT reconstructed images was 0.1 mm in the HR modality and 0.15 mm in the ST modality. The slice thickness was 1 mm for both modalities. The automatic exposure control (AEC) of the HR modality was routinely tuned to deliver a higher dose to the breast than that of the ST modality. In order to eliminate this bias, we set up a scanning protocol to equalize the dose for both ST and HR modalities. This was carried out by applying the exposure parameters (i.e., anode/filter, kVp, mAs) for the HR modality, determined by the AEC during the ST acquisition. This study was conducted as part of a clinical trial called \"Digital Breast Tomosynthesis in a screening population--Investigation on angular range and dose level acquisition\" currently ongoing at our institute (Protocol Code: IRST174.13). The trial was approved by the IRST Ethics Committee and was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All patients gave written informed consent before being scanned. The trial inclusion criteria were: age between 45 years and 74 years and BI-RADS \(\geq\) 3 evaluated with DM from the regional screening program. Exclusion criteria were: pregnancy, participation in another clinical trial, or a clinical diagnosis of breast cancer. Patients satisfying the study criteria were scheduled to undergo a dual DBT scan in accordance with the above-mentioned scanning protocol. Each DBT scan was accompanied by an ultrasound (US) scan. The present study was conducted on a subset of the enrolled patients. In particular, we selected 34 patients (for a total of 36 image sets) whose DBT and US imaging results were scored as negative by 2 independent radiologists (i.e., BI-RADS = 1 after DBT and US re-evaluation). A follow-up of least two years was available for the selected patients. We considered the craniocaudal (CC) view for each DBT image set, focusing the analysis on 7 slices at the center of the imaging study (Figure 1). Our choice was guided by [PERSON] et al., who suggested insulating the fibro-glandular tissue for feature extraction as superficial layers (skin and subcutaneous fat) only act as anatomical noise and are not correlated with breast cancer risk [11]. This choice is particularly relevant for small-sized breasts, as the number of slices in a DBT set is a function of breast thickness. Furthermore, preliminary analysis showed that mean feature values were not influenced by increasing the number of considered slices in large-sized breasts (data not shown). In order to apply a coherent texture analysis and insulate the effect of the acquisition angle, an in-house program developed in MATLAB (MathWorks, Inc., Natick, MA, USA) was used to downsample the in-plane resolution of HR images to the in-plane resolution of ST images, i.e., from 0.1 to 0.15 mm/pixel. The downsampling was performed using nearest-neighbor interpolation to maintain the integrity of original data and avoiding generating fictitious pixel values [18; 19; 20]. A region of interest (ROI) of \(256\times 256\) pixels was placed behind the nipple (Figure 1). This combination of ROI size and position was previously reported to have the highest discrimination power with regard to texture performance in DM [8; 21] and in DBT [12]. Furthermore, the ROI size is a trade-off between different needs. In fact, the ROI size used in the present work is defined to include the limited parenchymal area of small breasts and is assumed standard for all breasts to avoid potential biases in the features' calculation. Feature computation was performed for each ROI in the 2D mode with MaZda software package [22].