Comparative analysis of machine learning approaches to classify tumor mutation burden in lung adenocarcinoma using histopathology images.

Both histologic subtypes and tumor mutation burden (TMB) represent important biomarkers in lung cancer, with implications for patient prognosis and treatment decisions. Typically, TMB is evaluated by comprehensive genomic profiling but this requires use of finite tissue specimens and costly, time-consuming laboratory processes. Histologic subtype classification represents an established component of lung adenocarcinoma histopathology, but can be challenging and is associated with substantial inter-pathologist variability. Here we developed a deep learning system to both classify histologic patterns in lung adenocarcinoma and predict TMB status using de-identified Hematoxylin and Eosin (H&E) stained whole slide images. We first trained a convolutional neural network to map histologic features across whole slide images of lung cancer resection specimens. On evaluation using an external data source, this model achieved patch-level area under the receiver operating characteristic curve (AUC) of 0.78-0.98 across nine histologic features. We then integrated the output of this model with clinico-demographic data to develop an interpretable model for TMB classification. The resulting end-to-end system was evaluated on 172 held out cases from TCGA, achieving an AUC of 0.71 (95% CI 0.63-0.80). The benefit of using histologic features in predicting TMB is highlighted by the significant improvement this approach offers over using the clinical features alone (AUC of 0.63 [95% CI 0.53-0.72], p = 0.002). Furthermore, we found that our histologic subtype-based approach achieved performance similar to that of a weakly supervised approach (AUC of 0.72 [95% CI 0.64-0.80]). Together these results underscore that incorporating histologic patterns in biomarker prediction for lung cancer provides informative signals, and that interpretable approaches utilizing these patterns perform comparably with less interpretable, weakly supervised approaches.

Interpretable survival prediction for colorectal cancer using deep learning.

Deriving interpretable prognostic features from deep-learning-based prognostic histopathology models remains a challenge. In this study, we developed a deep learning system (DLS) for predicting disease-specific survival for stage II and III colorectal cancer using 3652 cases (27,300 slides). When evaluated on two validation datasets containing 1239 cases (9340 slides) and 738 cases (7140 slides), respectively, the DLS achieved a 5-year disease-specific survival AUC of 0.70 (95% CI: 0.66-0.73) and 0.69 (95% CI: 0.64-0.72), and added significant predictive value to a set of nine clinicopathologic features. To interpret the DLS, we explored the ability of different human-interpretable features to explain the variance in DLS scores. We observed that clinicopathologic features such as T-category, N-category, and grade explained a small fraction of the variance in DLS scores (R2 = 18% in both validation sets). Next, we generated human-interpretable histologic features by clustering embeddings from a deep-learning-based image-similarity model and showed that they explained the majority of the variance (R2 of 73-80%). Furthermore, the clustering-derived feature most strongly associated with high DLS scores was also highly prognostic in isolation. With a distinct visual appearance (poorly differentiated tumor cell clusters adjacent to adipose tissue), this feature was identified by annotators with 87.0-95.5% accuracy. Our approach can be used to explain predictions from a prognostic deep learning model and uncover potentially-novel prognostic features that can be reliably identified by people for future validation studies.

Deep learning-based survival prediction for multiple cancer types using histopathology images.

Providing prognostic information at the time of cancer diagnosis has important implications for treatment and monitoring. Although cancer staging, histopathological assessment, molecular features, and clinical variables can provide useful prognostic insights, improving risk stratification remains an active research area. We developed a deep learning system (DLS) to predict disease specific survival across 10 cancer types from The Cancer Genome Atlas (TCGA). We used a weakly-supervised approach without pixel-level annotations, and tested three different survival loss functions. The DLS was developed using 9,086 slides from 3,664 cases and evaluated using 3,009 slides from 1,216 cases. In multivariable Cox regression analysis of the combined cohort including all 10 cancers, the DLS was significantly associated with disease specific survival (hazard ratio of 1.58, 95% CI 1.28-1.70, p<0.0001) after adjusting for cancer type, stage, age, and sex. In a per-cancer adjusted subanalysis, the DLS remained a significant predictor of survival in 5 of 10 cancer types. Compared to a baseline model including stage, age, and sex, the c-index of the model demonstrated an absolute 3.7% improvement (95% CI 1.0-6.5) in the combined cohort. Additionally, our models stratified patients within individual cancer stages, particularly stage II (p = 0.025) and stage III (p<0.001). By developing and evaluating prognostic models across multiple cancer types, this work represents one of the most comprehensive studies exploring the direct prediction of clinical outcomes using deep learning and histopathology images. Our analysis demonstrates the potential for this approach to provide significant prognostic information in multiple cancer types, and even within specific pathologic stages. However, given the relatively small number of cases and observed clinical events for a deep learning task of this type, we observed wide confidence intervals for model performance, thus highlighting that future work will benefit from larger datasets assembled for the purposes for survival modeling.

Analyzing personalized policies for online biometric verification.

Motivated by India's nationwide biometric program for social inclusion, we analyze verification (i.e., one-to-one matching) in the case where we possess similarity scores for 10 fingerprints and two irises between a resident's biometric images at enrollment and his biometric images during his first verification. At subsequent verifications, we allow individualized strategies based on these 12 scores: we acquire a subset of the 12 images, get new scores for this subset that quantify the similarity to the corresponding enrollment images, and use the likelihood ratio (i.e., the likelihood of observing these scores if the resident is genuine divided by the corresponding likelihood if the resident is an imposter) to decide whether a resident is genuine or an imposter. We also consider two-stage policies, where additional images are acquired in a second stage if the first-stage results are inconclusive. Using performance data from India's program, we develop a new probabilistic model for the joint distribution of the 12 similarity scores and find near-optimal individualized strategies that minimize the false reject rate (FRR) subject to constraints on the false accept rate (FAR) and mean verification delay for each resident. Our individualized policies achieve the same FRR as a policy that acquires (and optimally fuses) 12 biometrics for each resident, which represents a five (four, respectively) log reduction in FRR relative to fingerprint (iris, respectively) policies previously proposed for India's biometric program. The mean delay is [Formula: see text] sec for our proposed policy, compared to 30 sec for a policy that acquires one fingerprint and 107 sec for a policy that acquires all 12 biometrics. This policy acquires iris scans from 32-41% of residents (depending on the FAR) and acquires an average of 1.3 fingerprints per resident.