Patient-specific Network Research Articles

Criticality in probabilistic models of spreading dynamics in brain networks: Epileptic seizures.

The spread of seizures across brain networks is the main impairing factor, often leading to loss-of-consciousness, in people with epilepsy. Despite advances in recording and modeling brain activity, uncovering the nature of seizure spreading dynamics remains an important challenge to understanding and treating pharmacologically resistant epilepsy. To address this challenge, we introduce a new probabilistic model that captures the spreading dynamics in patient-specific complex networks. Network connectivity and interaction time delays between brain areas were estimated from white-matter tractography. The model's computational tractability allows it to play an important complementary role to more detailed models of seizure dynamics. We illustrate model fitting and predictive performance in the context of patient-specific Epileptor networks. We derive the phase diagram of spread size (order parameter) as a function of brain excitability and global connectivity strength, for different patient-specific networks. Phase diagrams allow the prediction of whether a seizure will spread depending on excitability and connectivity strength. In addition, model simulations predict the temporal order of seizure spread across network nodes. Furthermore, we show that the order parameter can exhibit both discontinuous and continuous (critical) phase transitions as neural excitability and connectivity strength are varied. Existence of a critical point, where response functions and fluctuations in spread size show power-law divergence with respect to control parameters, is supported by mean-field approximations and finite-size scaling analyses. Notably, the critical point separates two distinct regimes of spreading dynamics characterized by unimodal and bimodal spread-size distributions. Our study sheds new light on the nature of phase transitions and fluctuations in seizure spreading dynamics. We expect it to play an important role in the development of closed-loop stimulation approaches for preventing seizure spread in pharmacologically resistant epilepsy. Our findings may also be of interest to related models of spreading dynamics in epidemiology, biology, finance, and statistical physics.

Delineating epileptogenic networks using brain imaging data and personalized modeling in drug-resistant epilepsy.

Precise estimates of epileptogenic zone networks (EZNs) are crucial for planning intervention strategies to treat drug-resistant focal epilepsy. Here, we present the virtual epileptic patient (VEP), a workflow that uses personalized brain models and machine learning methods to estimate EZNs and to aid surgical strategies. The structural scaffold of the patient-specific whole-brain network model is constructed from anatomical T1 and diffusion-weighted magnetic resonance imaging. Each network node is equipped with a mathematical dynamical model to simulate seizure activity. Bayesian inference methods sample and optimize key parameters of the personalized model using functional stereoelectroencephalography recordings of patients' seizures. These key parameters together with their personalized model determine a given patient's EZN. Personalized models were further used to predict the outcome of surgical intervention using virtual surgeries. We evaluated the VEP workflow retrospectively using 53 patients with drug-resistant focal epilepsy. VEPs reproduced the clinically defined EZNs with a precision of 0.6, where the physical distance between epileptogenic regions identified by VEP and the clinically defined EZNs was small. Compared with the resected brain regions of 25 patients who underwent surgery, VEP showed lower false discovery rates in seizure-free patients (mean, 0.028) than in non-seizure-free patients (mean, 0.407). VEP is now being evaluated in an ongoing clinical trial (EPINOV) with an expected 356 prospective patients with epilepsy.

Constructing a Cancer Patient-Specific Network Based on Second-Order Partial Correlations of Gene Expression and DNA Methylation.

Typically patient-specific gene networks are constructed with gene expression data only. Such networks cannot distinguish direct gene interactions from indirect interactions via others such as the effect of epigenetic events to gene activity. There is an increasing evidence of inter-individual variations not only in gene expression but also in epigenetic events such as DNA methylation. In this paper we propose a new method for constructing a cancer patient-specific gene correlation network using both gene expression and DNA methylation data. We derive a patient-specific network from differential second-order partial correlations of gene expression and DNA methylation between normal samples and the patient sample. The network represents direct interactions between genes by controlling the effect of DNA methylation. Using this method, we constructed 4,000 patient-specific networks for 10 types of cancer. The networks are highly effective in classifying different types of cancer and in deriving potential prognostic gene pairs. In particular, potential prognostic gene pairs derived from the networks were powerful in predicting the survival time of cancer patients. This approach will help identify patient-specific gene correlations and predict prognosis of cancer patients.

Source-sink connectivity: a novel interictal EEG marker for seizure localization.

Over 15 million epilepsy patients worldwide have drug-resistant epilepsy. Successful surgery is a standard of care treatment but can only be achieved through complete resection or disconnection of the epileptogenic zone, the brain region(s) where seizures originate. Surgical success rates vary between 20% and 80%, because no clinically validated biological markers of the epileptogenic zone exist. Localizing the epileptogenic zone is a costly and time-consuming process, which often requires days to weeks of intracranial EEG (iEEG) monitoring. Clinicians visually inspect iEEG data to identify abnormal activity on individual channels occurring immediately before seizures or spikes that occur interictally (i.e. between seizures). In the end, the clinical standard mainly relies on a small proportion of the iEEG data captured to assist in epileptogenic zone localization (minutes of seizure data versus days of recordings), missing opportunities to leverage these largely ignored interictal data to better diagnose and treat patients. IEEG offers a unique opportunity to observe epileptic cortical network dynamics but waiting for seizures increases patient risks associated with invasive monitoring. In this study, we aimed to leverage interictal iEEG data by developing a new network-based interictal iEEG marker of the epileptogenic zone. We hypothesized that when a patient is not clinically seizing, it is because the epileptogenic zone is inhibited by other regions. We developed an algorithm that identifies two groups of nodes from the interictal iEEG network: those that are continuously inhibiting a set of neighbouring nodes ('sources') and the inhibited nodes themselves ('sinks'). Specifically, patient-specific dynamical network models were estimated from minutes of iEEG and their connectivity properties revealed top sources and sinks in the network, with each node being quantified by source-sink metrics. We validated the algorithm in a retrospective analysis of 65 patients. The source-sink metrics identified epileptogenic regions with 73% accuracy and clinicians agreed with the algorithm in 93% of seizure-free patients. The algorithm was further validated by using the metrics of the annotated epileptogenic zone to predict surgical outcomes. The source-sink metrics predicted outcomes with an accuracy of 79% compared to an accuracy of 43% for clinicians' predictions (surgical success rate of this dataset). In failed outcomes, we identified brain regions with high metrics that were untreated. When compared with high frequency oscillations, the most commonly proposed interictal iEEG feature for epileptogenic zone localization, source-sink metrics outperformed in predictive power (by a factor of 1.2), suggesting they may be an interictal iEEG fingerprint of the epileptogenic zone.

Systematic Study of Patient-Specific Organs at Risk Auto-Segmentation on Daily kVCT Images for Adaptive Head and Neck Radiotherapy

<h3>Purpose/Objective(s)</h3> A newly developed biology-guided radiotherapy (BgRT) system has been set up in our institution, which enables high-quality kVCT imaging for each treatment fraction. This study explored deep learning-based patient-specific auto-segmentation to facilitate adaptive radiotherapy, based on data of the first head and neck patient case treated with this new system. <h3>Materials/Methods</h3> The esophagus, larynx, and pharynx were selected as the organs at risk (OAR) for auto-segmentation analysis. A population network was first learned on a population dataset, which contains 67 different patient cases from conventional intensity-modulated radiotherapy (IMRT). Then the pre-trained population network was adapted to this specific patient using a transfer learning method based on the longitudinal data from the initial treatment planning and 17 sets of daily image guidance kVCT images. The selected OARs were contoured by a radiation oncologist on 18 sets of images as the ground truth. The performance of the patient-specific network was compared with the population network as well as the clinical rigid registration method. The corresponding dosimetric impacts resulting from different segmentation and registration methods were also investigated. <h3>Results</h3> The initial Dice similarity coefficient (DSC) results of the population network on the patient-specific evaluation set were 0.821, 0.537, 0.739 for esophagus, larynx, and pharynx respectively, and they were markedly improved to 0.887, 0.889, 0.850 with the proposed patient-specific network. These results also outperformed the results of 0.670, 0.792, 0.709 with the registration-based method in current clinical practice. The contouring accuracy of the patient-specific network gradually increased with the increase of longitudinal training cases and approached saturation with more than six training cases. The qualification result also shows the population network was adapted to the specific manual contouring style after the patient-specific learning. Discrepancies of the mean doses by using the manual contour and the patient-specific auto-segmentation result were -1.29%, -1.05%, -0.13% for the three OARs respectively, better than the differences of 4.80%, -6.56%, -1.84% using the registration contour. The OAR dose underestimation in some treatment fractions based on the registration contour was markedly improved when using the patient-specific auto-segmentation result. <h3>Conclusion</h3> Auto-segmentation of daily kVCT images was studied based on patient-specific learning to facilitate future adaptive radiotherapy. Compared with the common population network and the clinical registration method, the patient-specific network could achieve a much better contouring and dosimetric accuracy and thus is promising to become a powerful tool in adaptive radiotherapy applications.

Patient-Specific Auto-Segmentation of Target and OARs via Deep Learning on Daily Fan-Beam CT for Adaptive Prostate Radiotherapy

<h3>Purpose/Objective(s)</h3> Contouring the target and organs at risk (OARs) of the treated patient in each fraction is a key step of daily adaptive radiotherapy. We designed a patient-specific deep learning study to improve the auto-segmentation performance for adaptive prostate radiotherapy, by leveraging the daily image-guidance fan-beam CT images of the specific patient available in the current IGRT workflow. <h3>Materials/Methods</h3> Our institution has set up a newly developed biology-guided radiotherapy (BgRT) system enabling high-quality fan-beam CT imaging for daily treatments. The data of the first prostate patient treated with this system including 26 daily fan-beam CT scans were utilized in this study. A population network was first trained for the auto-segmentation of the prostate and seven pelvic OARs, based on a population dataset containing 56 different patient cases treated on the regular Linac. The pre-trained population network was intentionally fine-tuned to adapt to this specific patient with a transfer learning method. The selected OARs of this patient were contoured by two radiation oncologists on the initial treatment planning and all sets of daily fan-beam CT images as the ground truth for the patient-specific learning. Three different fine-tuning methods, i.e., fine-tuning the last convolution layer, the last convolution block and the whole network were analyzed. A longitudinal study was conducted by exploring the relationship between the auto-segmentation performance and the number of the sequential prior data used for learning. The performance of the patient-specific network was compared with the population network as well as the clinical rigid registration method to highlight its efficiency in radiotherapy practice. <h3>Results</h3> The Dice similarity coefficient (DSC) results of the proposed patient-specific network were 0.882, 0.934, 0.864, 0.827, 0.952, 0.954, 0.921 and 0.904 for the prostate, bladder, rectum, seminal vesicle, left and right femoral head, bowel and lymph nodes, respectively, outperforming the population network (mean DSC of 0.627) and the clinical registration method (mean DSC of 0.716). The whole network fine-tuning method outperformed the other two fine-tuning methods, showing it is more effective in this study. The contouring accuracy of the patient-specific network gradually increased with the increment of longitudinal training cases and approached saturation with more than four training cases. <h3>Conclusion</h3> This study proposes an accurate auto-segmentation method based on the patient-specific deep learning for adaptive prostate radiotherapy. By utilizing the image and contour similarity between the treatment fractions, the patient-specific auto-segmentation could outperform the common population network and the clinical registration method by a large margin, and thus is promising to facilitate more precise radiotherapy based on the new BgRT system.

On the limits of graph neural networks for the early diagnosis of Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative disease whose molecular mechanisms are activated several years before cognitive symptoms appear. Genotype-based prediction of the phenotype is thus a key challenge for the early diagnosis of AD. Machine learning techniques that have been proposed to address this challenge do not consider known biological interactions between the genes used as input features, thus neglecting important information about the disease mechanisms at play. To mitigate this, we first extracted AD subnetworks from several protein–protein interaction (PPI) databases and labeled these with genotype information (number of missense variants) to make them patient-specific. Next, we trained Graph Neural Networks (GNNs) on the patient-specific networks for phenotype prediction. We tested different PPI databases and compared the performance of the GNN models to baseline models using classical machine learning techniques, as well as randomized networks and input datasets. The overall results showed that GNNs could not outperform a baseline predictor only using the APOE gene, suggesting that missense variants are not sufficient to explain disease risk beyond the APOE status. Nevertheless, our results show that GNNs outperformed other machine learning techniques and that protein–protein interactions lead to superior results compared to randomized networks. These findings highlight that gene interactions are a valuable source of information in predicting disease status.

Predicting respiratory motion using a novel patient specific dual deep recurrent neural networks

Real-time tracking of a target volume is a promising solution for reducing the planning margins and both dosimetric and geometric uncertainties in the treatment of thoracic and upper-abdomen cancers. Respiratory motion prediction is an integral part of real-time tracking to compensate for the latency of tracking systems. The purpose of this work was to develop a novel method for accurate respiratory motion prediction using dual deep recurrent neural networks (RNNs). The respiratory motion data of 111 patients were used to train and evaluate the method. For each patient, two models (Network1 and Network2) were trained on 80% of the respiratory wave, and the remaining 20% was used for evaluation. The first network (Network 1) is a ‘coarse resolution’ prediction of future points and second network (Network 2) provides a ‘fine resolution’ prediction to interpolate between the future predictions. The performance of the method was tested using two types of RNN algorithms : Long Short-Term Memory (LSTM) and Gated Recurrent Unit (GRU). The accuracy of each model was evaluated using the root mean square error (RMSE) and mean absolute error (MAE). Overall, the RNN model with GRU- function had better accuracy than the RNN model with LSTM-function (RMSE (mm): 0.4 ± 0.2 versus 0.6 ± 0.3; MAE (mm): 0.4 ± 0.2 versus 0.6 ± 0.2). The GRU was able to predict the respiratory motion accurately (<1 mm) up to the latency period of 440 ms, and LSTM’s accuracy was acceptable only up to 240 ms. The proposed method using GRU function can be used for respiratory-motion prediction up to a latency period of 440 ms.

New trends in network modeling of psychopathology.

New trends in network modeling of psychopathology.

Critical dynamics in the spread of focal epileptic seizures: Network connectivity, neural excitability and phase transitions.

Focal epileptic seizures can remain localized or, alternatively, spread across brain areas, often resulting in impairment of cognitive function and loss of consciousness. Understanding the factors that promote spread is important for developing better therapeutic approaches. Here, we show that: (1) seizure spread undergoes “critical” phase transitions in models (epileptor-networks) that capture the neural dynamics of spontaneous seizures while incorporating patient-specific brain network connectivity, axonal delays and identified epileptogenic zones (EZs). We define a collective variable for the spreading dynamics as the spread size, i.e. the number of areas or nodes in the network to which a seizure has spread. Global connectivity strength and excitability in the surrounding non-epileptic areas work as phase-transition control parameters for this collective variable. (2) Phase diagrams are predicted by stability analysis of the network dynamics. (3) In addition, the components of the Jacobian’s leading eigenvector, which tend to reflect the connectivity strength and path lengths from the EZ to surrounding areas, predict the temporal order of network-node recruitment into seizure. (4) However, stochastic fluctuations in spread size in a near-criticality region make predictability more challenging. Overall, our findings support the view that within-patient seizure-spread variability can be characterized by phase-transition dynamics under transient variations in network connectivity strength and excitability across brain areas. Furthermore, they point to the potential use and limitations of model-based prediction of seizure spread in closed-loop interventions for seizure control.

Central arterial pressure and patient-specific model parameter estimation based on radial pressure measurements

One-dimensional arterial flow simulations are suitable to estimate the aortic pressure from peripheral measurements in a patient-specific arterial network. This study introduces a reduction of the system parameters, and a novel calculation method to estimate the patient-specific set and the aortic curve based on radial applanation tonometry. Peripheral and aortic pressure curves were measured in patients, optimization were carried out. The aortic pressure curves were reproduced well, with an overestimation of the measured Systolic and Mean Blood Pressures on average by 0.6 and 0.5 mmHg respectively, and the Root Mean Square Difference of the curves was 3 mmHg on average.

Identifying network biomarkers of cancer by sample-specific differential network

Abundant datasets generated from various big science projects on diseases have presented great challenges and opportunities, which contributed to unfolding the complexity of diseases. The discovery of disease-associated molecular networks for each individual plays an important role in personalized therapy and precision treatment of cancer-based on the reference networks. However, there are no effective ways to distinguish the consistency of different reference networks. In this study, we developed a statistical method, i.e. a sample-specific differential network (SSDN), to construct and analyze such networks based on gene expression of a single sample against a reference dataset. We proved that the SSDN is structurally consistent even with different reference datasets if the reference dataset can follow certain conditions. The SSDN also can be used to identify patient-specific disease modules or network biomarkers as well as predict the potential driver genes of a tumor sample.

Patient specific deep learning based segmentation for magnetic resonance guided prostate radiotherapy.

Background and PurposeTreatments on combined Magnetic Resonance (MR) scanners and Linear Accelerators (Linacs) for radiotherapy, called MR-Linacs, often require daily contouring. Currently, deformable image registration (DIR) algorithms propagate contours from reference scans, however large shape and size changes can be troublesome. Artificial neural network (ANN) based contouring may alleviate this issue, however generally requires large datasets for training. Mitigating the problem of scarcity of data, we propose patient specific networks trained on a single dataset for each patient, for contouring onto the following datasets in an adaptive MR-Linacworkflow.Materials and MethodsMR-scans from 17 prostate patients treated on an MR-Linac with contours of Clinical Target Volume (CTV), bladder and rectum were utilized. U-net shaped models were trained based on the image from the first fraction of each patient, and subsequently applied onto the following treatment images. Results were compared with manual contours in terms of the Dice coefficient and Added Path Length (APL). As benchmark, contours propagated through the clinical DIR algorithm were similarly evaluated.ResultsIn Dice coefficient the ANN output was 0.92 ± 0.03, 0.93 ± 0.07 and 0.84 ± 0.10 while for DIR 0.95 ± 0.03, 0.93 ± 0.08, 0.88 ± 0.06 for CTV, bladder and rectum respectively. Similarly, APL where 3109 ± 1642, 7250 ± 4234 and 5041 ± 2666 for ANN and 1835 ± 1621, 7236 ± 4287 and 4170 ± 2920 voxels for DIR.ConclusionsPatient specific ANN models trained on images from the first fraction of a prostate MR-Linac treatment showed similar accuracy when applied to the subsequent fraction images as a clinically implemented DIR method.

A1D–0D–3Dcoupled model for simulating blood flow and transport processes in breast tissue

In this work, we present mixed dimensional models for simulating blood flow and transport processes in breast tissue and the vascular tree supplying it. These processes are considered, to start from the aortic inlet to the capillaries and tissue of the breast. Large variations in biophysical properties and flow conditions exist in this system necessitating the use of different flow models for different geometries and flow regimes. In total, we consider four different model types. First, a system of 1D nonlinear hyperbolic partial differential equations (PDEs) is considered to simulate blood flow in larger arteries with highly elastic vessel walls. Second, we assign 1D linearized hyperbolic PDEs to model the smaller arteries with stiffer vessel walls. The third model type consists of ODE systems (0D models). It is used to model the arterioles and peripheral circulation. Finally, homogenized 3D porous media models are considered to simulate flow and transport in capillaries and tissue within the breast volume. Sink terms are used to account for the influence of the venous and lymphatic systems. Combining the four model types, we obtain two different 1D-0D-3D coupled models for simulating blood flow and transport processes: The first model results in a fully coupled 1D-0D-3D model covering the complete path from the aorta to the breast combining a generic arterial network with a patient specific breast network and geometry. The second model is a reduced one based on the separation of the generic and patient specific parts. The information from a calibrated fully coupled model is used as inflow condition for the patient specific sub-model allowing a significant computational cost reduction. Several numerical experiments are conducted to calibrate the generic model parameters and to demonstrate realistic flow simulations compared to existing data on blood flow in the human breast and vascular system. Moreover, we use two different breast vasculature and tissue data sets to illustrate the robustness of our reduced sub-model approach.

A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis

We describe a precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 378 UC patients we map the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. With unsupervised clustering algorithms we group these patient-specific networks into four distinct clusters driven by PRKCB, HLA, SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH hubs. The pathway analysis identifies calcium homeostasis, wound healing and cell motility as key processes in UC pathogenesis. Using transcriptomic data from an independent patient cohort, with three complementary validation approaches focusing on the SNP-affected genes, the patient specific modules and affected functions, we confirm the regulatory impact of non-coding SNPs. iSNP identified regulatory effects for disease-associated non-coding SNPs, and by predicting the patient-specific pathogenic processes, we propose a systems-level way to stratify patients.

Predicting lymph node metastasis and prognosis of individual cancer patients based on miRNA-mediated RNA interactions

BackgroundLymph node metastasis is usually detected based on the images obtained from clinical examinations. Detecting lymph node metastasis from clinical examinations is a direct way of diagnosing metastasis, but the diagnosis is done after lymph node metastasis occurs.ResultsWe developed a new method for predicting lymph node metastasis based on differential correlations of miRNA-mediated RNA interactions in cancer. The types of RNAs considered in this study include mRNAs, lncRNAs, miRNAs, and pseudogenes. We constructed cancer patient-specific networks of miRNA mediated RNA interactions and identified key miRNA–RNA pairs from the network. A prediction model using differential correlations of the miRNA–RNA pairs of a patient as features showed a much higher performance than other methods which use gene expression data. The key miRNA–RNA pairs were also powerful in predicting prognosis of an individual patient in several types of cancer.ConclusionsDifferential correlations of miRNA–RNA pairs identified from patient-specific networks of miRNA mediated RNA interactions are powerful in predicting lymph node metastasis in cancer patients. The key miRNA–RNA pairs were also powerful in predicting prognosis of an individual patient of solid cancer.

Direct simulation of blood flow with heterogeneous cell suspensions in a patient-specific capillary network

Three-dimensional (3D) simulations on blood flow in a complex patient-specific retina vascular network were performed considering deformable red blood cells, white blood cells (WBCs), and obstructed vessels. First, the impact of blockage on flow rate distribution (without cells) was investigated. It showed that the blockage might change the flow rate significantly on distant vessels that were not directly connected with the blocked vessel. The flow rate in some vessels could increase up to 1200% due to an obstruction. However, with cells, it showed a fluctuating flow pattern, and the cells showed complicated transport behavior at bifurcations. Cell accumulation might occur in some bifurcations such as a T-shaped junction that eventually led to a physical blockage. The addition of WBCs impacted the local flow rate when they were squeezed through a capillary vessel, and the flow rate could be decreased up to 32% due to the larger size of WBCs. The simulation of flow under stenosis with cells showed that cells could oscillate and become trapped in a vessel due to the fluctuating flow. Finally, a reduced order model (ROM) with multiple non-Newtonian viscosity models was used to simulate the blood flow in the network. Compared with the 3D model, all ROMs reproduced accurate predictions on hematocrit and flow rate distribution in the vascular network. Among them, the Fåhræus–Lindqvist model was found to be the most accurate one. The work can be used to build a multiscale model for blood flow through integration of ROMs and 3D multiphysics models.

Novel cancer subtyping method based on patient-specific gene regulatory network

The identification of cancer subtypes is important for the understanding of tumor heterogeneity. In recent years, numerous computational methods have been proposed for this problem based on the multi-omics data of patients. It is widely accepted that different cancer subtypes are induced by different molecular regulatory networks. However, only a few incorporate the differences between their molecular systems into the identification processes. In this study, we present a novel method to identify cancer subtypes based on patient-specific molecular systems. Our method realizes this by quantifying patient-specific gene networks, which are estimated from their transcriptome data, and by clustering their quantified networks. Comprehensive analyses of The Cancer Genome Atlas (TCGA) datasets applied to our method confirmed that they were able to identify more clinically meaningful cancer subtypes than the existing subtypes and found that the identified subtypes comprised different molecular features. Our findings also show that the proposed method can identify the novel cancer subtypes even with single omics data, which cannot otherwise be captured by existing methods using multi-omics data.

LncACTdb 3.0: an updated database of experimentally supported ceRNA interactions and personalized networks contributing to precision medicine.

LncACTdb 3.0 is a comprehensive database of experimentally supported interactions among competing endogenous RNA (ceRNA) and the corresponding personalized networks contributing to precision medicine. LncACTdb 3.0 is freely available at http://bio-bigdata.hrbmu.edu.cn/LncACTdb or http://www.bio-bigdata.net/LncACTdb. We have updated the LncACTdb 3.0 database with several new features, including (i) 5669 experimentally validated ceRNA interactions across 25 species and 537 diseases/phenotypes through manual curation of published literature, (ii) personalized ceRNA interactions and networks for 16 228 patients from 62 datasets in TCGA and GEO, (iii) sub-cellular and extracellular vesicle locations of ceRNA manually curated from literature and data sources, (iv) more than 10 000 experimentally supported long noncoding RNA (lncRNA) biomarkers associated with tumor diagnosis and therapy, and (v) lncRNA/mRNA/miRNA expression profiles with clinical and pathological information of thousands of cancer patients. A panel of improved tools has been developed to explore the effects of ceRNA on individuals with specific pathological backgrounds. For example, a network tool provides a comprehensive view of lncRNA-related, patient-specific, and custom-designed ceRNA networks. LncACTdb 3.0 will provide novel insights for further studies of complex diseases at the individual level and will facilitate the development of precision medicine to treat such diseases.

Geometric network analysis provides prognostic information in patients with high grade serous carcinoma of the ovary treated with immune checkpoint inhibitors

Network analysis methods can potentially quantify cancer aberrations in gene networks without introducing fitted parameters or variable selection. A new network curvature-based method is introduced to provide an integrated measure of variability within cancer gene networks. The method is applied to high-grade serous ovarian cancers (HGSOCs) to predict response to immune checkpoint inhibitors (ICIs) and to rank key genes associated with prognosis. Copy number alterations (CNAs) from targeted and whole-exome sequencing data were extracted for HGSOC patients (n = 45) treated with ICIs. CNAs at a gene level were represented on a protein–protein interaction network to define patient-specific networks with a fixed topology. A version of Ollivier–Ricci curvature was used to identify genes that play a potentially key role in response to immunotherapy and further to stratify patients at high risk of mortality. Overall survival (OS) was defined as the time from the start of ICI treatment to either death or last follow-up. Kaplan–Meier analysis with log-rank test was performed to assess OS between the high and low curvature classified groups. The network curvature analysis stratified patients at high risk of mortality with p = 0.00047 in Kaplan–Meier analysis in HGSOC patients receiving ICI. Genes with high curvature were in accordance with CNAs relevant to ovarian cancer. Network curvature using CNAs has the potential to be a novel predictor for OS in HGSOC patients treated with immunotherapy.