MHCSeqNet2-improved peptide-class I MHC binding prediction for alleles with low data.

MOTIVATION: The binding of a peptide antigen to a Class I major histocompatibility complex (MHC) protein is part of a key process that lets the immune system recognize an infected cell or a cancer cell. This mechanism enabled the development of peptide-based vaccines that can activate the patient's immune response to treat cancers. Hence, the ability of accurately predict peptide-MHC binding is an essential component for prioritizing the best peptides for each patient. However, peptide-MHC binding experimental data for many MHC alleles are still lacking, which limited the accuracy of existing prediction models. RESULTS: In this study, we presented an improved version of MHCSeqNet that utilized sub-word-level peptide features, a 3D structure embedding for MHC alleles, and an expanded training dataset to achieve better generalizability on MHC alleles with small amounts of data. Visualization of MHC allele embeddings confirms that the model was able to group alleles with similar binding specificity, including those with no peptide ligand in the training dataset. Furthermore, an external evaluation suggests that MHCSeqNet2 can improve the prioritization of T cell epitopes for MHC alleles with small amount of training data. AVAILABILITY AND IMPLEMENTATION: The source code and installation instruction for MHCSeqNet2 are available at https://github.com/cmb-chula/MHCSeqNet2.

Label-free tumor cells classification using deep learning and high-content imaging.

Many studies have shown that cellular morphology can be used to distinguish spiked-in tumor cells in blood sample background. However, most validation experiments included only homogeneous cell lines and inadequately captured the broad morphological heterogeneity of cancer cells. Furthermore, normal, non-blood cells could be erroneously classified as cancer because their morphology differ from blood cells. Here, we constructed a dataset of microscopic images of organoid-derived cancer and normal cell with diverse morphology and developed a proof-of-concept deep learning model that can distinguish cancer cells from normal cells within an unlabeled microscopy image. In total, more than 75,000 organoid-drived cells from 3 cholangiocarcinoma patients were collected. The model achieved an area under the receiver operating characteristics curve (AUROC) of 0.78 and can generalize to cell images from an unseen patient. These resources serve as a foundation for an automated, robust platform for circulating tumor cell detection.

ReCasNet: Improving consistency within the two-stage mitosis detection framework.

Mitotic count (MC) is an important histological parameter for cancer diagnosis and grading, but the manual process for obtaining MC from whole-slide histopathological images is very time-consuming and prone to error. Therefore, deep learning models have been proposed to facilitate this process. Existing approaches utilize a two-stage pipeline: the detection stage for identifying the locations of potential mitotic cells and the classification stage for refining prediction confidences. However, this pipeline formulation can lead to inconsistencies in the classification stage due to the poor prediction quality of the detection stage and the mismatches in training data distributions between the two stages. In this study, we propose a Refine Cascade Network (ReCasNet), an enhanced deep learning pipeline that mitigates the aforementioned problems with three improvements. First, window relocation was used to reduce the number of poor quality false positives generated during the detection stage. Second, object re-cropping was performed with another deep learning model to adjust poorly centered objects. Third, improved data selection strategies were introduced during the classification stage to reduce the mismatches in training data distributions. ReCasNet was evaluated on two large-scale mitotic figure recognition datasets, canine cutaneous mast cell tumor (CCMCT) and canine mammary carcinoma (CMC), which resulted in up to 4.8% percentage point improvements in the F1 scores for mitotic cell detection and 44.1% reductions in mean absolute percentage error (MAPE) for MC prediction. Techniques that underlie ReCasNet can be generalized to other two-stage object detection pipeline and should contribute to improving the performances of deep learning models in broad digital pathology applications.

Improved image classification explainability with high-accuracy heatmaps.

Deep learning models have become increasingly used for image-based classification. In critical applications such as medical imaging, it is important to convey the reasoning behind the models' decisions in human-understandable forms. In this work, we propose Pyramid Localization Network (PYLON), a deep learning model that delivers precise location explanation by increasing the resolution of heatmaps produced by class activation map (CAM). PYLON substantially improves the quality of CAM's heatmaps in both general image and medical image domains and excels at pinpointing the locations of small objects. Most importantly, PYLON does not require expert annotation of the object location but instead can be trained using only image-level label. This capability is especially important for domain where expert annotation is often unavailable or costly to obtain. We also demonstrate an effective transfer learning approach for applying PYLON on small datasets and summarize technical guidelines that would facilitate wider adoption of the technique.

MetaSleepLearner: A Pilot Study on Fast Adaptation of Bio-Signals-Based Sleep Stage Classifier to New Individual Subject Using Meta-Learning.

Identifying bio-signals based-sleep stages requires time-consuming and tedious labor of skilled clinicians. Deep learning approaches have been introduced in order to challenge the automatic sleep stage classification conundrum. However, the difficulties can be posed in replacing the clinicians with the automatic system due to the differences in many aspects found in individual bio-signals, causing the inconsistency in the performance of the model on every incoming individual. Thus, we aim to explore the feasibility of using a novel approach, capable of assisting the clinicians and lessening the workload. We propose the transfer learning framework, entitled MetaSleepLearner, based on Model Agnostic Meta-Learning (MAML), in order to transfer the acquired sleep staging knowledge from a large dataset to new individual subjects (source code is available at https://github.com/IoBT-VISTEC/MetaSleepLearner). The framework was demonstrated to require the labelling of only a few sleep epochs by the clinicians and allow the remainder to be handled by the system. Layer-wise Relevance Propagation (LRP) was also applied to understand the learning course of our approach. In all acquired datasets, in comparison to the conventional approach, MetaSleepLearner achieved a range of 5.4% to 17.7% improvement with statistical difference in the mean of both approaches. The illustration of the model interpretation after the adaptation to each subject also confirmed that the performance was directed towards reasonable learning. MetaSleepLearner outperformed the conventional approaches as a result from the fine-tuning using the recordings of both healthy subjects and patients. This is the first work that investigated a non-conventional pre-training method, MAML, resulting in a possibility for human-machine collaboration in sleep stage classification and easing the burden of the clinicians in labelling the sleep stages through only several epochs rather than an entire recording.

Uncovering Thousands of New Peptides with Sequence-Mask-Search Hybrid De Novo Peptide Sequencing Framework.

Typical analyses of mass spectrometry data only identify amino acid sequences that exist in reference databases. This restricts the possibility of discovering new peptides such as those that contain uncharacterized mutations or originate from unexpected processing of RNAs and proteins. De novo peptide sequencing approaches address this limitation but often suffer from low accuracy and require extensive validation by experts. Here, we develop SMSNet, a deep learning-based de novo peptide sequencing framework that achieves >95% amino acid accuracy while retaining good identification coverage. Applications of SMSNet on landmark proteomics and peptidomics studies reveal over 10,000 previously uncharacterized HLA antigens and phosphopeptides, and in conjunction with database-search methods, expand the coverage of peptide identification by almost 30%. The power to accurately identify new peptides of SMSNet would make it an invaluable tool for any future proteomics and peptidomics studies, including tumor neoantigen discovery, antibody sequencing, and proteome characterization of non-model organisms.

MHCSeqNet: a deep neural network model for universal MHC binding prediction.

BACKGROUND: Immunotherapy is an emerging approach in cancer treatment that activates the host immune system to destroy cancer cells expressing unique peptide signatures (neoepitopes). Administrations of cancer-specific neoepitopes in the form of synthetic peptide vaccine have been proven effective in both mouse models and human patients. Because only a tiny fraction of cancer-specific neoepitopes actually elicits immune response, selection of potent, immunogenic neoepitopes remains a challenging step in cancer vaccine development. A basic approach for immunogenicity prediction is based on the premise that effective neoepitope should bind with the Major Histocompatibility Complex (MHC) with high affinity. RESULTS: In this study, we developed MHCSeqNet, an open-source deep learning model, which not only outperforms state-of-the-art predictors on both MHC binding affinity and MHC ligand peptidome datasets but also exhibits promising generalization to unseen MHC class I alleles. MHCSeqNet employed neural network architectures developed for natural language processing to model amino acid sequence representations of MHC allele and epitope peptide as sentences with amino acids as individual words. This consideration allows MHCSeqNet to accept new MHC alleles as well as peptides of any length. CONCLUSIONS: The improved performance and the flexibility offered by MHCSeqNet should make it a valuable tool for screening effective neoepitopes in cancer vaccine development.