## 4 Discussion  
In this study, we aimed to quantitatively describe the spatial presentation of excess fluid in CF. MR lung density images that identify excess fluid indicative of lung abnormalities were obtained for 13 CF subjects across mild-to-severe disease severity and age- and sex-matched healthy control subjects. We implemented a thresholding-based image processing technique that segments excess fluid in the lungs using healthy controls as a baseline and developed novel metrics to quantify the spatial presentations of the excess lung fluid. We characterized the spatial presentations of excess fluid in each CF subject and healthy control subject based on the location, size, and density of excess fluid present in different regions of their lungs. The percent area of excess fluid, referred to as the spatial distribution, was computed for the total lung and different regions of interest. We found that the spatial distribution was a key factor in identifying the differences in spatial presentation between CF and control subjects. We developed metrics based on spatial distribution to capture differences in excess fluid regionally and globally. These metrics were used to define the spatial presentation of each lung in one of three groups: (i) generalized if the fluid was sparse, (ii) localized diffuse if at least one locality of fluid was present with a dense distribution of fluid elsewhere, and (iii) localized if at least one locality of fluid was present with a sparse distribution. With our metrics, we found that 96% of our healthy control subjects exhibited a generalized spatial pattern. Conversely, CF subjects made up 93% of the localized and localized diffuse spatial patterns (Figure 11). A key contribution from this study is the ability to characterize CF subjects into groupings based on the anatomical features of their disease using an automated methodology, eliminating the potential for variability due to manual annotation. This study is the first of its kind, to our knowledge, to identify and characterize the spatial presentation of CF disease in this way. An interesting finding is the spatial presentation of a subject was not always identical in both lungs. Two CF subjects had varying spatial presentations in either lung, CF 3 and CF 7, along with one control subject (Table 3, Figure 12A,B). This response suggests the heterogeneity of lung fluid density even within one subject. The amount of excess fluid present in the lung plays a large role in the spatial presentation ultimately used to categorize the subject. As an example, we can see that in Figure 12B, CF 7 has a strong localization of fluid in the bottom anterior ROI 16 with a large amount of fluid elsewhere. The spread of the excess fluid is otherwise low, as the percent coverage across all ROIs are similar. CF 3 also had differing spatial presentations in the right and left lung (Figure 12A). In this case, the left lung is on the outer boundary of a localized distribution where a small increase in total coverage (\(SD_{W}\)) would lead to a localized diffuse category (Table 3). The metrics defined in this study can identify these subtle characteristics that distinguish one lung from the next with sensitivity to category boundaries. Figure 12: Subjects with differing spatial presentations in the right and left lung where red boxes mark locality region, if applicable. (**A**) CF subject 3 has a localized diffuse spatial presentation in the right lung and a localized spatial presentation in the left lung. (**B**) CF subject 7 has a localized diffuse spatial presentation in the right lung and a localized spatial presentation in the left lung. (**C**) CTL subject 12 has a localized spatial presentation in the right lung and a generalized spatial presentation in the left lung. Additionally, we grouped the spatial presentation of a control subject (CTL 12) as generalized in the left lung and localized in the right (Figure 12C). In this particular case, we hypothesize the localization was due to the hilar vessels being present in the image.