Investigating Causal Genetic Effects on Overall Survival of Glioblastoma Patients using Normalizing Flow and Structural Causal Model.

Glioblastoma (GBM) is the most common and aggressive brain tumor with short overall survival (OS) of about 15 months. Understanding the causal factors affecting the patient survival is crucial for disease prognosis and treatment planning. Although previous efforts on survival prediction using multi-omics data has yielded useful predictive models, the causation of the correlated genetic risk factors has not been addressed. Recent advances in causal deep learning models enable the study of causality from complex dataset. In this paper, we leverage the recently proposed structural causal model (SCM) with normalizing flows parameterized by deep networks to perform the counterfactual query to investigate the causal relationship between gene mutation and OS with the presence of other confounders including sex, age and radiomics features. The query amounts to the question that what the survival days will be if the gene mutation status has been changed, i.e., from mutant to non-mutant and vice versa. The trained causal model will infer the counterfactual outcome given the intervention on specific gene mutation. We apply multivariate Cox-PH model to find the genes associated with survival, and investigate the causal genetic effect by comparing the original and counterfactual survival days in a bi-directional fashion. Particularly, the following two scenarios are considered: (1) intervention on a specific gene with non-mutant status to generate the counterfactual survival days as if the gene is mutant, with which the original survival days of the subjects with that mutant gene will be compared; (2) intervention on the gene with mutant status and perform the comparison with survival days of subjects with that non-mutant gene. Our experimental results show that no causation of two correlated genes (NF1, RB1) was revealed in the cohort (n=181), while their genetic effects on OS in terms of prolonging or shortening are generally in accordance with clinical findings.

CDPNet: a radiomic feature learning method with epigenetic application to estimating MGMT promoter methylation status in glioblastoma.

Radiomics has been widely recognized for its effectiveness in decoding tumor phenotypes through the extraction of quantitative imaging features. However, the robustness of radiomic methods to estimate clinically relevant biomarkers non-invasively remains largely untested. In this study, we propose Cascaded Data Processing Network (CDPNet), a radiomic feature learning method to predict tumor molecular status from medical images. We apply CDPNet to an epigenetic case, specifically targeting the estimation of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation from Magnetic Resonance Imaging (MRI) scans of glioblastoma patients. CDPNet has three components: 1) Principal Component Analysis (PCA), 2) Fisher Linear Discriminant (FLD), and 3) a combination of hashing and blockwise histograms. The outlined architectural framework capitalizes on PCA to reconstruct input image patches, followed by FLD to extract discriminative filter banks, and finally using binary hashing and blockwise histogram module for indexing, pooling, and feature generation. To validate the effectiveness of CDPNet, we conducted an exhaustive evaluation on a comprehensive retrospective cohort comprising 484 IDH-wildtype glioblastoma patients with pre-operative multi-parametric MRI scans (T1, T1-Gd, T2, and T2-FLAIR). The prediction of MGMT promoter methylation status was cast as a binary classification problem. The developed model underwent rigorous training via 10-fold cross-validation on a discovery cohort of 446 patients. Subsequently, the model's performance was evaluated on a distinct and previously unseen replication cohort of 38 patients. Our method achieved an accuracy of 70.11% and an area under the curve of 0.71 (95% CI: 0.65 - 0.74).

Integrating imaging and genomic data for the discovery of distinct glioblastoma subtypes: a joint learning approach.

Glioblastoma is a highly heterogeneous disease, with variations observed at both phenotypical and molecular levels. Personalized therapies would be facilitated by non-invasive in vivo approaches for characterizing this heterogeneity. In this study, we developed unsupervised joint machine learning between radiomic and genomic data, thereby identifying distinct glioblastoma subtypes. A retrospective cohort of 571 IDH-wildtype glioblastoma patients were included in the study, and pre-operative multi-parametric MRI scans and targeted next-generation sequencing (NGS) data were collected. L21-norm minimization was used to select a subset of 12 radiomic features from the MRI scans, and 13 key driver genes from the five main signal pathways most affected in glioblastoma were selected from the genomic data. Subtypes were identified using a joint learning approach called Anchor-based Partial Multi-modal Clustering on both radiomic and genomic modalities. Kaplan-Meier analysis identified three distinct glioblastoma subtypes: high-risk, medium-risk, and low-risk, based on overall survival outcome (p < 0.05, log-rank test; Hazard Ratio = 1.64, 95% CI 1.17-2.31, Cox proportional hazard model on high-risk and low-risk subtypes). The three subtypes displayed different phenotypical and molecular characteristics in terms of imaging histogram, co-occurrence of genes, and correlation between the two modalities. Our findings demonstrate the synergistic value of integrated radiomic signatures and molecular characteristics for glioblastoma subtyping. Joint learning on both modalities can aid in better understanding the molecular basis of phenotypical signatures of glioblastoma, and provide insights into the biological underpinnings of tumor formation and progression.

Applications of generative adversarial networks in neuroimaging and clinical neuroscience.

Generative adversarial networks (GANs) are one powerful type of deep learning models that have been successfully utilized in numerous fields. They belong to the broader family of generative methods, which learn to generate realistic data with a probabilistic model by learning distributions from real samples. In the clinical context, GANs have shown enhanced capabilities in capturing spatially complex, nonlinear, and potentially subtle disease effects compared to traditional generative methods. This review critically appraises the existing literature on the applications of GANs in imaging studies of various neurological conditions, including Alzheimer's disease, brain tumors, brain aging, and multiple sclerosis. We provide an intuitive explanation of various GAN methods for each application and further discuss the main challenges, open questions, and promising future directions of leveraging GANs in neuroimaging. We aim to bridge the gap between advanced deep learning methods and neurology research by highlighting how GANs can be leveraged to support clinical decision making and contribute to a better understanding of the structural and functional patterns of brain diseases.