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Register a new userPan-Cancer Integrative Histology-Genomic Analysis via Interpretable Multimodal Deep Learning
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Richard Chen J
Publication date
2021
fields
Informatics Engineering
and research's language is
English
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The rapidly emerging field of deep learning-based computational pathology has demonstrated promise in developing objective prognostic models from histology whole slide images. However, most prognostic models are either based on histology or genomics alone and do not address how histology and genomics can be integrated to develop joint image-omic prognostic models. Additionally identifying explainable morphological and molecular descriptors from these models that govern such prognosis is of interest. We used multimodal deep learning to integrate gigapixel whole slide pathology images, RNA-seq abundance, copy number variation, and mutation data from 5,720 patients across 14 major cancer types. Our interpretable, weakly-supervised, multimodal deep learning algorithm is able to fuse these heterogeneous modalities for predicting outcomes and discover prognostic features from these modalities that corroborate with poor and favorable outcomes via multimodal interpretability. We compared our model with unimodal deep learning models trained on histology slides and molecular profiles alone, and demonstrate performance increase in risk stratification on 9 out of 14 cancers. In addition, we analyze morphologic and molecular markers responsible for prognostic predictions across all cancer types. All analyzed data, including morphological and molecular correlates of patient prognosis across the 14 cancer types at a disease and patient level are presented in an interactive open-access database (http://pancancer.mahmoodlab.org) to allow for further exploration and prognostic biomarker discovery. To validate that these model explanations are prognostic, we further analyzed high attention morphological regions in WSIs, which indicates that tumor-infiltrating lymphocyte presence corroborates with favorable cancer prognosis on 9 out of 14 cancer types studied.
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Weakly-supervised learning (WSL) has recently triggered substantial interest as it mitigates the lack of pixel-wise annotations. Given global image labels, WSL methods yield pixel-level predictions (segmentations), which enable to interpret class predictions. Despite their recent success, mostly with natural images, such methods can face important challenges when the foreground and background regions have similar visual cues, yielding high false-positive rates in segmentations, as is the case in challenging histology images. WSL training is commonly driven by standard classification losses, which implicitly maximize model confidence, and locate the discriminative regions linked to classification decisions. Therefore, they lack mechanisms for modeling explicitly non-discriminative regions and reducing false-positive rates. We propose novel regularization terms, which enable the model to seek both non-discriminative and discriminative regions, while discouraging unbalanced segmentations. We introduce high uncertainty as a criterion to localize non-discriminative regions that do not affect classifier decision, and describe it with original Kullback-Leibler (KL) divergence losses evaluating the deviation of posterior predictions from the uniform distribution. Our KL terms encourage high uncertainty of the model when the latter inputs the latent non-discriminative regions. Our loss integrates: (i) a cross-entropy seeking a foreground, where model confidence about class prediction is high; (ii) a KL regularizer seeking a background, where model uncertainty is high; and (iii) log-barrier terms discouraging unbalanced segmentations. Comprehensive experiments and ablation studies over the public GlaS colon cancer data and a Camelyon16 patch-based benchmark for breast cancer show substantial improvements over state-of-the-art WSL methods, and confirm the effect of our new regularizers.
Breast cancer is one of the leading causes of mortality in women. Early detection and treatment are imperative for improving survival rates, which have steadily increased in recent years as a result of more sophisticated computer-aided-diagnosis (CAD) systems. A critical component of breast cancer diagnosis relies on histopathology, a laborious and highly subjective process. Consequently, CAD systems are essential to reduce inter-rater variability and supplement the analyses conducted by specialists. In this paper, a transfer-learning based approach is proposed, for the task of breast histology image classification into four tissue sub-types, namely, normal, benign, textit{in situ} carcinoma and invasive carcinoma. The histology images, provided as part of the BACH 2018 grand challenge, were first normalized to correct for color variations resulting from inconsistencies during slide preparation. Subsequently, image patches were extracted and used to fine-tune Google`s Inception-V3 and ResNet50 convolutional neural networks (CNNs), both pre-trained on the ImageNet database, enabling them to learn domain-specific features, necessary to classify the histology images. The ResNet50 network (based on residual learning) achieved a test classification accuracy of 97.50% for four classes, outperforming the Inception-V3 network which achieved an accuracy of 91.25%.
Microscopic examination of tissues or histopathology is one of the diagnostic procedures for detecting colorectal cancer. The pathologist involved in such an examination usually identifies tissue type based on texture analysis, especially focusing on tumour-stroma ratio. In this work, we automate the task of tissue classification within colorectal cancer histology samples using deep transfer learning. We use discriminative fine-tuning with one-cycle-policy and apply structure-preserving colour normalization to boost our results. We also provide visual explanations of the deep neural networks decision on texture classification. With achieving state-of-the-art test accuracy of 96.2% we also embark on using deployment friendly architecture called SqueezeNet for memory-limited hardware.
How do the neural networks distinguish two images? It is of critical importance to understand the matching mechanism of deep models for developing reliable intelligent systems for many risky visual applications such as surveillance and access control. However, most existing deep metric learning methods match the images by comparing feature vectors, which ignores the spatial structure of images and thus lacks interpretability. In this paper, we present a deep interpretable metric learning (DIML) method for more transparent embedding learning. Unlike conventional metric learning methods based on feature vector comparison, we propose a structural matching strategy that explicitly aligns the spatial embeddings by computing an optimal matching flow between feature maps of the two images. Our method enables deep models to learn metrics in a more human-friendly way, where the similarity of two images can be decomposed to several part-wise similarities and their contributions to the overall similarity. Our method is model-agnostic, which can be applied to off-the-shelf backbone networks and metric learning methods. We evaluate our method on three major benchmarks of deep metric learning including CUB200-2011, Cars196, and Stanford Online Products, and achieve substantial improvements over popular metric learning methods with better interpretability. Code is available at https://github.com/wl-zhao/DIML
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 3,652 cases (27,300 slides). When evaluated on two validation datasets containing 1,239 cases (9,340 slides) and 738 cases (7,140 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 9 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 explain the majority of the variance (R2 of 73% to 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.
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