Immunotherapy with immune checkpoint inhibitors (ICIs) is increasingly used to treat various tumor types. Determining patient responses to ICIs presents a significant clinical challenge. Although components of the tumor microenvironment (TME) are used to predict patient outcomes, comprehensive assessments of the TME are frequently overlooked. Using a top-down approach, the TME was divided into five layers-outcome, immune role, cell, cellular component, and gene. Using this structure, a neural network called TME-NET was developed to predict responses to ICIs. Model parameter weights and cell ablation studies were used to investigate the influence of TME components. The model was developed and evaluated using a pan-cancer cohort of 948 patients across four cancer types, with Area Under the Curve (AUC) and accuracy as performance metrics. Results show that TME-NET surpasses established models such as support vector machine and k-nearest neighbors in AUC and accuracy. Visualization of model parameter weights showed that at the cellular layer, Th1 cells enhance immune responses, whereas myeloid-derived suppressor cells and M2 macrophages show strong immunosuppressive effects. Cell ablation studies further confirmed the impact of these cells. At the gene layer, the transcription factors STAT4 in Th1 cells and IRF4 in M2 macrophages significantly affect TME dynamics. Additionally, the cytokine-encoding genes IFNG from Th1 cells and ARG1 from M2 macrophages are crucial for modulating immune responses within the TME. Survival data from immunotherapy cohorts confirmed the prognostic ability of these markers, with p-values <0.01. In summary, TME-NET performs well in predicting immunotherapy responses and offers interpretable insights into the immunotherapy process. It can be customized at https://immbal.shinyapps.io/TME-NET.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) contains information on tumor morphology and physiology for breast cancer diagnosis and treatment. However, this technology requires contrast agent injection with more acquisition time than other parametric images, such as T2-weighted imaging (T2WI). Current image synthesis methods attempt to map the image data from one domain to another, whereas it is challenging or even infeasible to map the images with one sequence into images with multiple sequences. Here, we propose a new approach of cross-parametric generative adversarial network (GAN)-based feature synthesis (CPGANFS) to generate discriminative DCE-MRI features from T2WI with applications in breast cancer diagnosis. The proposed approach decodes the T2W images into latent cross-parameter features to reconstruct the DCE-MRI and T2WI features by balancing the information shared between the two. A Wasserstein GAN with a gradient penalty is employed to differentiate the T2WI-generated features from ground-truth features extracted from DCE-MRI. The synthesized DCE-MRI feature-based model achieved significantly (p = 0.036) higher prediction performance (AUC = 0.866) in breast cancer diagnosis than that based on T2WI (AUC = 0.815). Visualization of the model shows that our CPGANFS method enhances the predictive power by levitating attention to the lesion and the surrounding parenchyma areas, which is driven by the interparametric information learned from T2WI and DCE-MRI. Our proposed CPGANFS provides a framework for cross-parametric MR image feature generation from a single-sequence image guided by an information-rich, time-series image with kinetic information. Extensive experimental results demonstrate its effectiveness with high interpretability and improved performance in breast cancer diagnosis.

Assessments of multiple clinical indicators based on radiomic analysis of magnetic resonance imaging (MRI) are beneficial to the diagnosis, prognosis and treatment of breast cancer patients. Many machine learning methods have been designed to jointly predict multiple indicators for more accurate assessments while using original clinical labels directly without considering the noisy and redundant information among them. To this end, we propose a multilabel learning method based on label space dimensionality reduction (LSDR), which learns common and task-specific features via graph regularized nonnegative matrix factorization (CTFGNMF) for the joint prediction of multiple indicators in breast cancer. A nonnegative matrix factorization (NMF) is adopted to map original clinical labels to a low-dimensional latent space. The latent labels are employed to exploit task correlations by using a least square loss function with [Formula: see text]-norm regularization to identify common features, which help to improve the generalization performance of correlated tasks. Furthermore, task-specific features were retained by a multitask regression formulation to increase the discrimination power for different tasks. Common and task-specific features are incorporated by dynamic graph Laplacian regularization into a unified model to learn complementary features. Then, a multilabel classification is built to predict multiple clinical indicators including human epidermal growth factor receptor 2 (HER2), Ki-67, and histological grade. Experimental results show that CTFGNMF achieves AUCs of 0.823, 0.691 and 0.776 in the three indicator predictions, outperforming other counterparts that consider only task-independent features or common features. It indicates CTFGNMF is a promising application for multiple classification tasks in breast cancer.

The clinical management and decision-making process related to breast cancer are based on multiple histological indicators. This study aims to jointly predict the Ki-67 expression level, luminal A subtype and histological grade molecular biomarkers using a new deep multitask learning method with multiparametric magnetic resonance imaging. A multitask learning network structure was proposed by introducing a common-task layer and task-specific layers to learn the high-level features that are common to all tasks and related to a specific task, respectively. A network pretrained with knowledge from the ImageNet dataset was used and fine-tuned with MRI data. Information from multiparametric MR images was fused using the strategy at the feature and decision levels. The area under the receiver operating characteristic curve (AUC) was used to measure model performance. For single-task learning using a single image series, the deep learning model generated AUCs of 0.752, 0.722, and 0.596 for the Ki-67, luminal A and histological grade prediction tasks, respectively. The performance was improved by freezing the first 5 convolutional layers, using 20% shared layers and fusing multiparametric series at the feature level, which achieved AUCs of 0.819, 0.799 and 0.747 for Ki-67, luminal A and histological grade prediction tasks, respectively. Our study showed advantages in jointly predicting correlated clinical biomarkers using a deep multitask learning framework with an appropriate number of fine-tuned convolutional layers by taking full advantage of common and complementary imaging features. Multiparametric image series-based multitask learning could be a promising approach for the multiple clinical indicator-based management of breast cancer.

OBJECTIVE: Histologic grade and Ki-67 proliferation status are important clinical indictors for breast cancer prognosis and treatment. The purpose of this study is to improve prediction accuracy of these clinical indicators based on tumor radiomic analysis. METHODS: We jointly predicted Ki-67 and tumor grade with a multitask learning framework by separately utilizing radiomics from tumor MRI series. Additionally, we showed how multitask learning models (MTLs) could be extended to combined radiomics from the MRI series for a better prediction based on the assumption that features from different sources of images share common patterns while providing complementary information. Tumor radiomic analysis was performed with morphological, statistical and textural features extracted on the DWI and dynamic contrast-enhanced MRI (DCE-MRI) series of the precontrast and subtraction images, respectively. RESULTS: Joint prediction of Ki-67 status and tumor grade on MR images using the MTL achieved performance improvements over that of single-task-based predictive models. Similarly, for the prediction tasks of Ki-67 and tumor grade, the MTL for combined precontrast and apparent diffusion coefficient (ADC) images achieved AUCs of 0.811 and 0.816, which were significantly better than that of the single-task- based model with p values of 0.005 and 0.017, respectively. CONCLUSION: Mapping MRI radiomics to two related clinical indicators improves prediction performance for both Ki-67 expression level and tumor grade. SIGNIFICANCE: Joint prediction of indicators by multitask learning that combines correlations of MRI radiomics is important for optimal tumor therapy and treatment because clinical decisions are made by integrating multiple clinical indicators.

COVID-19 has caused a global pandemic and become the most urgent threat to the entire world. Tremendous efforts and resources have been invested in developing diagnosis, prognosis and treatment strategies to combat the disease. Although nucleic acid detection has been mainly used as the gold standard to confirm this RNA virus-based disease, it has been shown that such a strategy has a high false negative rate, especially for patients in the early stage, and thus CT imaging has been applied as a major diagnostic modality in confirming positive COVID-19. Despite the various, urgent advances in developing artificial intelligence (AI)-based computer-aided systems for CT-based COVID-19 diagnosis, most of the existing methods can only perform classification, whereas the state-of-the-art segmentation method requires a high level of human intervention. In this paper, we propose a fully-automatic, rapid, accurate, and machine-agnostic method that can segment and quantify the infection regions on CT scans from different sources. Our method is founded upon two innovations: 1) the first CT scan simulator for COVID-19, by fitting the dynamic change of real patients' data measured at different time points, which greatly alleviates the data scarcity issue; and 2) a novel deep learning algorithm to solve the large-scene-small-object problem, which decomposes the 3D segmentation problem into three 2D ones, and thus reduces the model complexity by an order of magnitude and, at the same time, significantly improves the segmentation accuracy. Comprehensive experimental results over multi-country, multi-hospital, and multi-machine datasets demonstrate the superior performance of our method over the existing ones and suggest its important application value in combating the disease.

Motivation: Annotation of enzyme function has a broad range of applications, such as metagenomics, industrial biotechnology, and diagnosis of enzyme deficiency-caused diseases. However, the time and resource required make it prohibitively expensive to experimentally determine the function of every enzyme. Therefore, computational enzyme function prediction has become increasingly important. In this paper, we develop such an approach, determining the enzyme function by predicting the Enzyme Commission number. Results: We propose an end-to-end feature selection and classification model training approach, as well as an automatic and robust feature dimensionality uniformization method, DEEPre, in the field of enzyme function prediction. Instead of extracting manually crafted features from enzyme sequences, our model takes the raw sequence encoding as inputs, extracting convolutional and sequential features from the raw encoding based on the classification result to directly improve the prediction performance. The thorough cross-fold validation experiments conducted on two large-scale datasets show that DEEPre improves the prediction performance over the previous state-of-the-art methods. In addition, our server outperforms five other servers in determining the main class of enzymes on a separate low-homology dataset. Two case studies demonstrate DEEPre's ability to capture the functional difference of enzyme isoforms. Availability and implementation: The server could be accessed freely at http://www.cbrc.kaust.edu.sa/DEEPre. Contact: [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

Motivation: Super-resolution fluorescence microscopy with a resolution beyond the diffraction limit of light, has become an indispensable tool to directly visualize biological structures in living cells at a nanometer-scale resolution. Despite advances in high-density super-resolution fluorescent techniques, existing methods still have bottlenecks, including extremely long execution time, artificial thinning and thickening of structures, and lack of ability to capture latent structures. Results: Here, we propose a novel deep learning guided Bayesian inference (DLBI) approach, for the time-series analysis of high-density fluorescent images. Our method combines the strength of deep learning and statistical inference, where deep learning captures the underlying distribution of the fluorophores that are consistent with the observed time-series fluorescent images by exploring local features and correlation along time-axis, and statistical inference further refines the ultrastructure extracted by deep learning and endues physical meaning to the final image. In particular, our method contains three main components. The first one is a simulator that takes a high-resolution image as the input, and simulates time-series low-resolution fluorescent images based on experimentally calibrated parameters, which provides supervised training data to the deep learning model. The second one is a multi-scale deep learning module to capture both spatial information in each input low-resolution image as well as temporal information among the time-series images. And the third one is a Bayesian inference module that takes the image from the deep learning module as the initial localization of fluorophores and removes artifacts by statistical inference. Comprehensive experimental results on both real and simulated datasets demonstrate that our method provides more accurate and realistic local patch and large-field reconstruction than the state-of-the-art method, the 3B analysis, while our method is more than two orders of magnitude faster. Availability and implementation: The main program is available at https://github.com/lykaust15/DLBI. Supplementary information: Supplementary data are available at Bioinformatics online.

Nuclear magnetic resonance (NMR) spectroscopy is attracting more attention in the field of computational structural biology. Till recently,$^1$H-detected experiments are the dominant NMR technique used due to the high sensitivity of$^1$H nuclei. However, the current availability of high magnetic fields and cryogenically cooled probe heads allow researchers to overcome the low sensitivity of$^{13}$C nuclei. Consequently,$^{13}$C-detected experiments have become a popular technique in different NMR applications especially resonance assignment and structure determination of large proteins. In this paper, we propose the first spin system forming method for$^{13}$C-detected NMR spectra. Our method is able to accurately form spin systems based on as few as two$^{13}$C-detected spectra, CBCACON, and CBCANCO. Our method picks slices from the more trusted spectrum and uses them as feedback to direct the slice picking in the less trusted one. This feedback leads to picking the accurate slices that consequently helps to form better spin systems. We tested our method on a real dataset of ‘Ubiquitin’ and a benchmark simulated dataset consisting of 12 proteins. We fed our spin systems as inputs to a genetic algorithm to generate the chemical shift assignment, and obtained 92 percent correct chemical shift assignment for Ubiquitin. For the simulated dataset, we obtained an average recall of 86 percent and an average precision of 88 percent. Finally, our chemical shift assignment of Ubiquitin was given as an input to CS-ROSETTA server that generated structures close to the experimentally determined structure.

Parameter estimation is a challenging computational problem in the reverse engineering of biological systems. Because advances in biotechnology have facilitated wide availability of time-series gene expression data, systematic parameter estimation of gene circuit models from such time-series mRNA data has become an important method for quantitatively dissecting the regulation of gene expression. By focusing on the modeling of gene circuits, we examine here the performance of three types of state-of-the-art parameter estimation methods: population-based methods, online methods and model-decomposition-based methods. Our results show that certain population-based methods are able to generate high-quality parameter solutions. The performance of these methods, however, is heavily dependent on the size of the parameter search space, and their computational requirements substantially increase as the size of the search space increases. In comparison, online methods and model decomposition-based methods are computationally faster alternatives and are less dependent on the size of the search space. Among other things, our results show that a hybrid approach that augments computationally fast methods with local search as a subsequent refinement procedure can substantially increase the quality of their parameter estimates to the level on par with the best solution obtained from the population-based methods while maintaining high computational speed. These suggest that such hybrid methods can be a promising alternative to the more commonly used population-based methods for parameter estimation of gene circuit models when limited prior knowledge about the underlying regulatory mechanisms makes the size of the parameter search space vastly large.

MOTIVATION: Systematic and scalable parameter estimation is a key to construct complex gene regulatory models and to ultimately facilitate an integrative systems biology approach to quantitatively understand the molecular mechanisms underpinning gene regulation. RESULTS: Here, we report a novel framework for efficient and scalable parameter estimation that focuses specifically on modeling of gene circuits. Exploiting the structure commonly found in gene circuit models, this framework decomposes a system of coupled rate equations into individual ones and efficiently integrates them separately to reconstruct the mean time evolution of the gene products. The accuracy of the parameter estimates is refined by iteratively increasing the accuracy of numerical integration using the model structure. As a case study, we applied our framework to four gene circuit models with complex dynamics based on three synthetic datasets and one time series microarray data set. We compared our framework to three state-of-the-art parameter estimation methods and found that our approach consistently generated higher quality parameter solutions efficiently. Although many general-purpose parameter estimation methods have been applied for modeling of gene circuits, our results suggest that the use of more tailored approaches to use domain-specific information may be a key to reverse engineering of complex biological systems. AVAILABILITY: http://sfb.kaust.edu.sa/Pages/Software.aspx. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.