Paper:
Deep neural networks (DNN) have shown promising performance in computer vision. In medical imaging, encouraging results have been achieved with deep learning for applications such as segmentation, lesion detection and classification. Nearly all of the deep learning based image analysis methods work on reconstructed images, which are obtained from original acquisitions via solving inverse problems (reconstruction). The reconstruction algorithms are designed for human observers, but not necessarily optimized for DNNs which can often observe features that are incomprehensible for human eyes. Hence, it is desirable to train the DNNs directly from the original data which lie in a different domain with the images. In this paper, we proposed an end-to-end DNN for abnormality detection in medical imaging. To align the acquisition with the annotations made by radiologists in the image domain, a DNN was built as the unrolled version of iterative reconstruction algorithms to map the acquisitions to images, and followed by a 3D convolutional neural network (CNN) to detect the abnormality in the reconstructed images. The two networks were trained jointly in order to optimize the entire DNN for the detection task from the original acquisitions. The DNN was implemented for lung nodule detection in low-dose chest computed tomography (CT), where a numerical simulation was done to generate acquisitions from 1,018 chest CT images with radiologists' annotations. The proposed end-to-end DNN demonstrated better sensitivity and accuracy for the task compared to a two-step approach, in which the reconstruction and detection DNNs were trained separately. A significant reduction of false positive rate on suspicious lesions were observed, which is crucial for the known over-diagnosis in low-dose lung CT imaging. The images reconstructed by the proposed end-to-end network also presented enhanced details in the region of interest.

Review:
This paper proposes to jointly model computed tomography reconstruction and lesion detection in the lung, training the mapping from raw sinogram to detection outputs in an end-to-end manner. In practice, such a mapping is computed separately, without regard to the task for wich the data is to be used. Because such a mapping loses information, optimizing such a mapping jointly with the task should preserve more information that is relevant to the task. Thus, using raw medical image data should be useful for lesion detection in CT as well as most other medical image analysis tasks.
Style considerations:
The work is adequately motivated and the writing is generally clear. However, some phrases are awkward and unclear and there are occasional minor grammar errors. It would be useful to ask a native English speaker to polish these up, if possible. Also, there are numerous typos that could nonetheless be easily remedied with some final proofreading. Generally, the work is well articulated with sound structure but needs polish.
A few other minor style points to address:
- "g" is used throughout the paper for two different networks and also to define gradients - if would be more clear if you would choose other letters.
- S3.3, p. 7 : reusing term "iteration"; clarify
- fig 10: label the columns in the figure, not in the description
- fig 11: label the columns in the figure with iterations
- fig 8 not referenced in text
Questions:
1. Before fine-tuning, were the reconstruction and detection networks trained end-to-end (with both L2 loss and cross-entropy loss) or were they trained separately and then joined during fine-tuning?
(If it is the former and not the latter, please make that more clear in the text. I expect that it was indeed the former; in case that it was not, I would expect fully end-to-end training in the revision.)
2. Please confirm: during the fine-tuning phase of training, did you use only the cross-entropy loss and not the L2 loss?
3a. From equation 3 to equation 4 (on an iteration of reconstruction), the network g() was dropped. It appears to replace the diagonal of a Hessian (of R) which is probably a conditioning term. Have you tried training a g() network? Please discuss the ramifications of removing this term.
3b. Have you tracked the condition number of the Jacobian of f() across iterations? This should be like tracking the condition number of the Hessian of R(x).
4. Please discuss: is it better to replace operations on R() with neural networks rather than to replace R()? Why?
5. On page 5, you write "masks for lung regions were pre-calculated". Were these masks manual segmentations or created with an automated method?
6. Why was detection only targetted on "non-small nodules"? Have you tried detecting small nodules?
7. On page 11, you state: "The tissues in lung had much better contrast in the end-to-end network compared to that in the two-step network". I don't see evidence to support that claim. Could you demonstrate that?
8. On page 12, relating to figure 11, you state:
"Whereas both methods kept similar structural component, the end-to-end method had more focus on the edges and tissues inside lung compared to the two-step method. As observed in figure 11(b), the structures of the lung tissue were much more clearer in the end-to-end networks. This observation indicated that sharper edge and structures were of more importance for the detection network than the noise level in the reconstructed images, which is in accordance with human perceptions when radiologists perform the same task."
However, while these claims appear intuitive and such results may be expected, they are not backed up by figure 11. Looking at the feature map samples in this figure, I could not identify whether they came from different populations. I do not see the evidence for "more focus on the edges and tissues inside lung" for the end-to-end method in fig 11. It is also not obvious whether indeed "the structures of the lung tissue were much more clearer" for the end-to-end method, in fig 11. Can you clarify the evidence in support of these claims? 
Other points to address:
1. Please report statistical significance for your results (eg. in fig 5b, in the text, etc.). Also, please include confidence intervals in table 2.
2. Although cross-entropy values, detection metrics were not (except for the ROC curve with false positives and false negatives). Please compute: accuracy, precision, and recall to more clearly evaluate detection performance.
3a. "Abnormality detection" implies the detection of anything that is unusual in the data. The method you present targets a very specific abnormality (lesions). I would suggest changing "abnormality detection" to "lesion detection".
3b. The title should also be updated accordingly. Considering also that the presented work is on a single task (lesion detection) and a single medical imaging modality (CT), the current title appears overly broad. I would suggest changing it from "End-to-End Abnormality Detection in Medical Imaging" -- possibly to something like "End-to-End Computed Tomography for Lesion Detection".
Conclusion:
The motivation of this work is valid and deserves attention. The implementation details for modeling reconstruction are also valuable. It is interesting to see improvement in lesion detection when training end-to-end from raw sinogram data.  However, while lung lesion detection is the only task on which the utility of this method is evaluated, detection improvement appears modest. This work would benefit from additional experimental results or improved analysis and discussion.