Terminal ductal lobular unit (TDLU) involution is the regression of milk-producing structures in the breast. Women with less TDLU involution are more likely to develop breast cancer. A major bottleneck in studying TDLU involution in large cohort studies is the need for labor-intensive manual assessment of TDLUs. We developed a computational pathology solution to automatically capture TDLU involution measures. Whole slide images (WSIs) of benign breast biopsies were obtained from the Nurses Health Study (NHS). A first set of 92 WSIs was annotated for TDLUs, acini and adipose tissue to train deep convolutional neural network (CNN) models for detection of acini, and segmentation of TDLUs and adipose tissue. These networks were integrated into a single computational method to capture TDLU involution measures including number of TDLUs per tissue area, median TDLU span and median number of acini per TDLU. We validated our method on 40 additional WSIs by comparing with manually acquired measures. Our CNN models detected acini with an F1 score of 0.73$pm$0.09, and segmented TDLUs and adipose tissue with Dice scores of 0.86$pm$0.11 and 0.86$pm$0.04, respectively. The inter-observer ICC scores for manual assessments on 40 WSIs of number of TDLUs per tissue area, median TDLU span, and median acini count per TDLU were 0.71, 95% CI [0.51, 0.83], 0.81, 95% CI [0.67, 0.90], and 0.73, 95% CI [0.54, 0.85], respectively. Intra-observer reliability was evaluated on 10/40 WSIs with ICC scores of >0.8. Inter-observer ICC scores between automated results and the mean of the two observers were: 0.80, 95% CI [0.63, 0.90] for number of TDLUs per tissue area, 0.57, 95% CI [0.19, 0.77] for median TDLU span, and 0.80, 95% CI [0.62, 0.89] for median acini count per TDLU. TDLU involution measures evaluated by manual and automated assessment were inversely associated with age and menopausal status.
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