Colorectal cancer (CRC) is a global health problem and the second deadliest cancer in the United States, resulting in an estimated 900K deaths per year. While deadly, CRC can be prevented by removing small precancerous lesions in the colon, called polyps, before they become cancerous. In fact, it is estimated that a 1% increase in the adenoma detection rate (ADR, defined as the fraction of procedures in which a physician discovers at least one polyp) can lead to a 6% decrease in the rate of interval CRCs (a CRC that is diagnosed within 60 months of a negative colonoscopy).

Colonoscopy is considered the gold standard procedure for the detection and removal of polyps. Unfortunately, the literature indicates that endoscopists miss on average 22%-28% of polyps during colonoscopies; furthermore, 20% to 24% of polyps that have the potential to become cancerous (adenomas) are missed. Two major factors that may cause an endoscopist to miss a polyp are (1) the polyp appears in the field of view, but the endoscopist misses it, perhaps due to its small size or flat shape; and (2) the polyp does not appear in the field of view, as the endoscopist has not fully covered the relevant area during the procedure.

In “Detecting Deficient Coverage in Colonoscopies”, we introduce the Colonoscopy Coverage Deficiency via Depth algorithm, or C2D2, a machine learning-based approach to improving colonoscopy coverage. The C2D2 algorithm performs a local 3D reconstruction of the colon as images are captured during the procedure, and on that basis, identifies which areas of the colon were covered and which remained outside of the field of view. C2D2 can then indicate in real time whether a particular area of the colon has suffered from deficient coverage so the endoscopist can return to that area. Our work proposes a novel approach to compute coverage in real time, for which 3D reconstruction is done using a calibration-free, unsupervised learning method, and evaluate it in a large scale way.

The C2D2 Algorithm
When considering colon coverage, it is important to estimate the coverage fraction — what percentage of the relevant regions were covered by a complete procedure. While a retrospective analysis is useful for the physician and could provide general guidance for future procedures, it is more useful to have real-time estimation of coverage fraction, on a segment by segment basis, i.e. knowledge of what fraction of the current segment has been covered while traversing the colon. The helpfulness of such functionality is clear: during the procedure itself, a physician may be alerted to segments with deficient coverage, and can immediately return to review these areas. Higher coverage will result in a higher proportion of polyps being seen.

The C2D2 algorithm is designed to compute such a segment-by-segment coverage in two phases: computing depth maps for each frame of the colonoscopy video, followed by computation of coverage based on these depth maps.

C2D2 computes a depth image from a single RGB image. Then, based on the computed depth images for a video sequence, C2D2 calculates local coverage, so it can detect where the coverage has been deficient and a second look is required.

Depth map creation consists of both depth estimation as well as pose estimation — the localization of where the endoscope is in space, as well as the direction it is pointing. In addition to the detection of deficient coverage, depth and pose estimation are useful for a variety of other interesting tasks. For example, depth can be used for improved detection of flat polyps, while pose estimation can be used for relocalizing areas of the colon (including polyps) that the endoscopist wishes to revisit, and both together can be used for visualization and navigation.

Top row: RGB image, from which the depth is computed. Bottom row: Depth image as computed by C2D2. Yellow is deeper, blue is shallower. Note that the “tunnel” structure is captured, as well as the Haustral ridges.

In order to compute coverage fractions from these depth maps, we trained C2D2 on two sources of data: synthetic sequences and real sequences. We generated the synthetic videos using a graphical model of a colon. For each synthetic video, ground truth coverage is available in the form of a number between 0 (completely uncovered) and 1 (completely covered). For real sequences, we analyzed de-identified colonoscopy videos, for which ground truth coverage is unavailable.

Performance on Synthetic Videos
When using synthetic videos, the availability of ground truth coverage enables the direct measurement of C2D2’s performance. We quantify this using the mean absolute error (MAE), which indicates how much the algorithm’s prediction differs, on average, from the ground truth. We find that C2D2’s MAE = 0.075; meaning that, on average, the prediction of C2D2 is within 7.5% of the ground truth. By contrast, a group of physicians given the same task achieved MAE = 0.177, i.e., within 17.7% of the ground truth. Thus, the C2D2 attained an accuracy rate 2.4 times higher on synthetic sequences.

Performance on Real Videos
Of course, what matters most is performance on videos of real colonoscopies. The challenge in this case is the absence of ground truth labelling: we don’t know what the actual coverage is. Additionally, one cannot use labels provided by experts directly as they are not always accurate, due to the challenges described earlier. However, C2D2 can still perform inference on real colonoscopy videos. Indeed, the learning pipeline is designed to perform equally well on synthetic and real colonoscopy videos.

To verify performance on real sequences, we used a variant of a technique common in the generative modelling literature, which involves providing video sequences to human experts along with C2D2’s coverage scores for those sequences. We then ask the experts to assess whether C2D2’s score is correct. The idea is that while it is difficult for experts to assign a score directly, the task of verifying a given score is considerably easier. (This is similar to the fact that verifying a proposed solution to an algorithmic problem is generally much easier than computing that solution.) Using this methodology, experts verified C2D2’s score 93% of the time. And in a more qualitative sense, C2D2’s output seems to pass the “eyeball test”, see the figure below.

Coverage on real colonoscopy sequences. Top row: Frames from a well covered sequence — the entire “tunnel” down the lumen may be seen; C2D2 coverage = 0.931. Middle row: A partially covered sequence — the bottom may be seen, but the top is not as visible; C2D2 coverage = 0.427. Bottom row: A poorly covered sequence, much of what is seen is the wall; C2D2 coverage = 0.227.

Next steps
By alerting physicians to missed regions of the colon wall, C2D2 promises to lead to the discovery of more adenomas, thereby increasing the ADR and concomitantly decreasing the rate of interval CRC. This would be of tremendous benefit to patients.

In addition to this work that addresses colonoscopy coverage, we are concurrently conducting research to improve polyp detection by combining C2D2 with an automatic, real-time polyp detection algorithm. This study adds to the mounting evidence that physicians may use machine learning methods to augment their efforts, especially during procedures, to improve the quality of care for patients.

Acknowledgements
This research was conducted by Daniel Freedman, Yochai Blau, Liran Katzir, Amit Aides, Ilan Shimshoni, Danny Veikherman, Tomer Golany, Ariel Gordon, Greg Corrado, Yossi Matias, and Ehud Rivlin, with support from Verily. We would like to thank all of our team members and collaborators who worked on this project with us, including: Nadav Rabani, Chen Barshai, Nia Stoykova, David Ben-Shimol, Jesse Lachter, and Ori Segol, 3D-Systems and many others. We'd also like to thank Yossi Matias for support and guidance. The research was conducted by teams from Google Health and Google Research, Israel.

Left: Sixteen individual tests are required to screen 16 people — only one person’s test is positive, while 15 return negative. Right: Following Dorfman’s procedure, samples are pooled into four groups of four individuals, and tests are executed on the pooled samples. Because only the second group tests positive, 12 individuals are cleared and only those four belonging to the positive group need to be retested. This approach requires only eight tests, instead of the 16 needed for an exhaustive testing campaign.

1. Given a population of n people, an infection state is a binary vector of length n that describes who is infected (marked with a 1), and who is not (marked with a 0). At a certain time, a population is in a given state (most likely a few 1’s and mostly 0’s). The goal of group testing is to identify that state using as few tests as possible. Given a prior belief on the infection rate (the disease is rare) and test results observed so far (if any), we expect that only a small share of those infection states will be plausible. Rather than evaluating the plausibility of all 2ⁿ possible states (an extremely large number even for small n), we resort to a more efficient method to sample plausible hypotheses using a sequential Monte Carlo (SMC) sampler. Although quite costly by common standards (a few minutes using a GPU in our experimental setup), we show in this work that SMC samplers remain tractable even for large n, opening new possibilities for group testing. In short, in return for a few minutes of computations, our detectives get an extensive list of thousands of relevant hypotheses that may explain tests observed so far.
   
   
2. Equipped with a relevant list of hypotheses, our strategy proceeds, as detectives would, by selectively gathering additional evidence. If k tests can be carried out at the next iteration, our strategy will propose to test k new groups, which are computed using the framework of Bayesian optimal experimental design. Intuitively, if k=1 and one can only propose a single new group to test, there would be clear advantage in building that group such that its test outcome is as uncertain as possible, i.e., with a probability that it returns positive as close to 50% as possible, given the current set of hypotheses. Indeed, to progress in an investigation, it is best to maximize the surprise factor (or information gain) provided by new test results, as opposed to using them to confirm further what we already hold to be very likely. To generalize that idea to a set of k>1 new groups, we score this surprise factor by computing the mutual information of these “virtual” group tests vs. the distribution of hypotheses. We also consider a more involved approach that computes the expected area under the ROC curve (AUC) one would obtain from testing these new groups using the distribution of hypotheses. The maximization of these two criteria is carried out using a greedy approach, resulting in two group selectors, GMIMAX and GAUCMAX (greedy maximization of mutual information or AUC, respectively).
   

Our group testing framework describes an interaction between a testing environment, the wet_lab, whose pooled test results are used by the sampler to draw thousands of plausible hypotheses on the infection status of all individuals. These hypotheses are then used by an optimization procedure, group_selector, that figures out what groups may be the most relevant to test in order to narrow down on the true infection status. Once formed, these new groups are then tested again, closing the loop. At any point in the procedure, the hypotheses formed by the sampler can be averaged to obtain the average probability of infection for each patient. From these probabilities, a decision on whether a patient is infected or not can be done by thresholding these probabilities at a certain confidence level.

We executed 5000 simulations on a sample population of 70 individuals with an infection rate of 2%. We have assumed sensitivity/specificity values of 85% / 97% for tests with groups of maximal size 10, which are representative of current PCR machines. This figure demonstrates that our approach outperforms the other baselines with as few as 24 tests (up to 8 tests used in 3 cycles), including both adaptive and non-adaptive varieties, and performs significantly better than individual tests (plotted in the sensitivity/specificity plane as a hexagon, requiring 70 tests), highlighting the savings potential offered by group testing. See preprint for other setups.