Each year, the treatment decisions for more than 230, 000 breast cancer patients in the U.S. hinge on whether the cancer has metastasized away from the breast. Metastasis detection is currently performed by pathologists reviewing large expanses of biological tissues. This process is labor intensive and error-prone. We present a framework to automatically detect and localize tumors as small as 100 × 100 pixels in gigapixel microscopy images sized 100, 000×100, 000 pixels. Our method leverages a convolutional neural network (CNN) architecture and obtains state-of-the-art results on the Camelyon16 dataset in the challenging lesion-level tumor detection task. At 8 false positives per image, we detect 92.4% of the tumors, relative to 82.7% by the previous best automated approach. For comparison, a human pathologist attempting exhaustive search achieved 73.2% sensitivity. We achieve image-level AUC scores above 97% on both the Camelyon16 test set and an independent set of 110 slides. In addition, we discover that two slides in the Came-lyon16 training set were erroneously labeled normal. Our approach could considerably reduce false negative rates in metastasis detection.

These authors contributed equally to this work.The brightfield microscope is instrumental in the visual examination of both biological and physical samples at sub-millimeter scales. One key clinical application has been in cancer histopathology, where the microscopic assessment of the tissue samples is used for the diagnosis and staging of cancer and thus guides clinical therapy 1 . However, the interpretation of these samples is inherently subjective, resulting in significant diagnostic variability 2,3 . Moreover, in many regions of the world, access to pathologists is severely limited due to lack of trained personnel 4 . In this regard, Artificial Intelligence (AI) based tools promise to improve the access and quality of healthcare 5-7 . However, despite significant advances in AI research, integration of these tools into real-world cancer diagnosis workflows remains challenging because of the costs of image digitization and difficulties in deploying AI solutions 8 , 9 . Here we propose a cost-effective solution to the integration of AI: the Augmented Reality Microscope (ARM). The ARM overlays AI-based information onto the current view of the sample through the optical pathway in real-time, enabling seamless integration of AI into the regular microscopy workflow. We demonstrate the utility of ARM in the detection of lymph node metastases in breast cancer and the identification of prostate cancer with a latency that supports real-time workflows. We anticipate that ARM will remove barriers towards the use of AI in microscopic analysis and thus improve the accuracy and efficiency of cancer diagnosis. This approach is applicable to other microscopy tasks and AI algorithms in the life sciences 10 and beyond 11,12 .Microscopic examination of samples is the gold standard for the diagnosis of cancer, autoimmune diseases, infectious diseases, and more. In cancer, the microscopic examination of stained tissue sections is critical for diagnosing and staging the patient's tumor, which informs treatment decisions and prognosis. In cancer, microscopy analysis faces three major challenges. As a form of image interpretation, these examinations are inherently subjective, exhibiting considerable inter-observer and intra-observer variability 2,3 . Moreover, clinical guidelines 1 and studies 13 have begun to require quantitative assessments as part of the effort towards better patient risk stratification 1 . For example, breast cancer staging requires counting mitotic cells and quantification of the tumor burden in lymph nodes by measuring the largest tumor focus. However, despite being helpful in treatment planning, quantification is laborious and error-prone. Lastly, access to disease experts can be limited in both developed and developing countries 4 , exacerbating the problem.

Social distancing remains an important strategy to combat the COVID-19 pandemic in the United States. However, the impacts of specific state-level policies on mobility and subsequent COVID-19 case trajectories have not been completely quantified. Using anonymized and aggregated mobility data from opted-in Google users, we found that state-level emergency declarations resulted in a 9.9% reduction in time spent away from places of residence. Implementation of one or more social distancing policies resulted in an additional 24.5% reduction in mobility the following week, and subsequent shelter-in-place mandates yielded an additional 29.0% reduction. Decreases in mobility were associated with substantial reductions in case growth two to four weeks later. For example, a 10% reduction in mobility was associated with a 17.5% reduction in case growth two weeks later. Given the continued reliance on social distancing policies to limit the spread of COVID-19, these results may be helpful to public health officials trying to balance infection control with the economic and social consequences of these policies.

IMPORTANCE For prostate cancer, Gleason grading of the biopsy specimen plays a pivotal role in determining case management. However, Gleason grading is associated with substantial interobserver variability, resulting in a need for decision support tools to improve the reproducibility of Gleason grading in routine clinical practice. OBJECTIVE To evaluate the ability of a deep learning system (DLS) to grade diagnostic prostate biopsy specimens. DESIGN, SETTING, AND PARTICIPANTS The DLS was evaluated using 752 deidentified digitized images of formalin-fixed paraffin-embedded prostate needle core biopsy specimens obtained from 3 institutions in the United States, including 1 institution not used for DLS development. To obtain the Gleason grade group (GG), each specimen was first reviewed by 2 expert urologic subspecialists from a multi-institutional panel of 6 individuals (years of experience: mean, 25 years; range, 18-34 years). A third subspecialist reviewed discordant cases to arrive at a majority opinion. To reduce diagnostic uncertainty, all subspecialists had access to an immunohistochemical-stained section and 3 histologic sections for every biopsied specimen. Their review was conducted from December 2018 to June 2019. MAIN OUTCOMES AND MEASURES The frequency of the exact agreement of the DLS with the majority opinion of the subspecialists in categorizing each tumor-containing specimen as 1 of 5 categories: nontumor, GG1, GG2, GG3, or GG4-5. For comparison, the rate of agreement of 19 general pathologists' opinions with the subspecialists' majority opinions was also evaluated. RESULTS For grading tumor-containing biopsy specimens in the validation set (n = 498), the rate of agreement with subspecialists was significantly higher for the DLS (71.7%; 95% CI, 67.9%-75.3%) than for general pathologists (58.0%; 95% CI, 54.5%-61.4%) (P < .001). In subanalyses of biopsy specimens from an external validation set (n = 322), the Gleason grading performance of the DLS remained similar. For distinguishing nontumor from tumor-containing biopsy specimens (n = 752), the rate of agreement with subspecialists was 94.3% (95% CI, 92.4%-95.9%) for the DLS and similar at 94.7% (95% CI, 92.8%-96.3%) for general pathologists (P = .58). CONCLUSIONS AND RELEVANCE In this study, the DLS showed higher proficiency than general pathologists at Gleason grading prostate needle core biopsy specimens and generalized to an independent institution. Future research is necessary to evaluate the potential utility of using the DLS as a decision support tool in clinical workflows and to improve the quality of prostate cancer grading for therapy decisions.

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