Fully convolutional deep neural networks have been asserted to be fast and precise frameworks with great potential in image segmentation. One of the major challenges in training such networks raises when data is unbalanced, which is common in many medical imaging applications such as lesion segmentation where lesion class voxels are often much lower in numbers than non-lesion voxels. A trained network with unbalanced data may make predictions with high precision and low recall, being severely biased towards the non-lesion class which is particularly undesired in most medical applications where false negatives are actually more important than false positives. Various methods have been proposed to address this problem including two step training, sample re-weighting, balanced sampling, and more recently similarity loss functions, and focal loss. In this work we trained fully convolutional deep neural networks using an asymmetric similarity loss function to mitigate the issue of data imbalance and achieve much better trade-off between precision and recall. To this end, we developed a 3D fully convolutional densely connected network (FC-DenseNet) with large overlapping image patches as input and an asymmetric similarity loss layer based on Tversky index (using F _β scores). We used large overlapping image patches as inputs for intrinsic and extrinsic data augmentation, a patch selection algorithm, and a patch prediction fusion strategy using B-spline weighted soft voting to account for the uncertainty of prediction in patch borders. We applied this method to multiple sclerosis (MS) lesion segmentation based on two different datasets of MSSEG 2016 and ISBI longitudinal MS lesion segmentation challenge, where we achieved average Dice similarity coefficients of 69.9% and 65.74%, respectively, achieving top performance in both challenges. We compared the performance of our network trained with F _β loss, focal loss, and generalized Dice loss (GDL) functions. Through September 2018 our network trained with focal loss ranked first according to the ISBI challenge overall score and resulted in the lowest reported lesion false positive rate among all submitted methods. Our network trained with the asymmetric similarity loss led to the lowest surface distance and the best lesion true positive rate that is arguably the most important performance metric in a clinical decision support system for lesion detection. The asymmetric similarity loss function based on F _β scores allows training networks that make a better balance between precision and recall in highly unbalanced image segmentation. We achieved superior performance in MS lesion segmentation using a patchwise 3D FC-DenseNet with a patch prediction fusion strategy, trained with asymmetric similarity loss functions.

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