Correlation between immunotherapy biomarker PD-L1 expression and genetic alteration in patients with non-small cell lung cancer.

Programmed death-ligand 1 (PD-L1) has been widely used in immunotherapy evaluation of patients with non-small cell lung cancer (NSCLC). However, the effect is not particularly ideal, and the association between PD-L1 and genetic alterations requires more exploration. Here, we performed targeted next-generation sequencing and PD-L1 immunohistochemistry (IHC) testing for PD-L1 expression on both tumor cells (TCs) and tumor-infiltrating immune cells (ICs) in 1549 patients. Our studies showed that surgical method of resection was positively correlated with IC+, and a low tumor mutation burden (TMB) was negatively correlated with TC+. Furthermore, we found that EGFR was mutually exclusive with both ALK and STK11. In addition, the features between PD-L1 expression status and genomic alterations were characterized. These results suggest that clinical characteristics and molecular phenotypes are associated with PD-L1 expression signatures, which may provide novel insights for improving the efficiency of immune checkpoint inhibitors (ICIs) in immunotherapy.

Artificial Intelligence-Assisted Score Analysis for Predicting the Expression of the Immunotherapy Biomarker PD-L1 in Lung Cancer.

Programmed cell death ligand 1 (PD-L1) is a critical biomarker for predicting the response to immunotherapy. However, traditional quantitative evaluation of PD-L1 expression using immunohistochemistry staining remains challenging for pathologists. Here we developed a deep learning (DL)-based artificial intelligence (AI) model to automatically analyze the immunohistochemical expression of PD-L1 in lung cancer patients. A total of 1,288 patients with lung cancer were included in the study. The diagnostic ability of three different AI models (M1, M2, and M3) was assessed in both PD-L1 (22C3) and PD-L1 (SP263) assays. M2 and M3 showed improved performance in the evaluation of PD-L1 expression in the PD-L1 (22C3) assay, especially at 1% cutoff. Highly accurate performance in the PD-L1 (SP263) was also achieved, with accuracy and specificity of 96.4 and 96.8% in both M2 and M3, respectively. Moreover, the diagnostic results of these three AI-assisted models were highly consistent with those from the pathologist. Similar performances of M1, M2, and M3 in the 22C3 dataset were also obtained in lung adenocarcinoma and lung squamous cell carcinoma in both sampling methods. In conclusion, these results suggest that AI-assisted diagnostic models in PD-L1 expression are a promising tool for improving the efficiency of clinical pathologists.

Dual-scale categorization based deep learning to evaluate programmed cell death ligand 1 expression in non-small cell lung cancer.

ABSTRACT: In precision oncology, immune check point blockade therapy has quickly emerged as novel strategy by its efficacy, where programmed death ligand 1 (PD-L1) expression is used as a clinically validated predictive biomarker of response for the therapy. Automating pathological image analysis and accelerating pathology evaluation is becoming an unmet need. Artificial Intelligence and deep learning tools in digital pathology have been studied in order to evaluate PD-L1 expression in PD-L1 immunohistochemistry image. We proposed a Dual-scale Categorization (DSC)-based deep learning method that employed 2 VGG16 neural networks, 1 network for 1 scale, to critically evaluate PD-L1 expression. The DSC-based deep learning method was tested in a cohort of 110 patients diagnosed as non-small cell lung cancer. This method showed a concordance of 88% with pathologist, which was higher than concordance of 83% of 1-scale categorization-based method. Our results show that the DSCbased method can empower the deep learning application in digital pathology and facilitate computer-aided diagnosis.

Detecting and Testing Altered Brain Connectivity Networks with K-partite Network Topology.

Emerging brain connectivity network studies suggest that interactions between various distributed neuronal populations may be characterized by an organized complex topological structure. Many neuropsychiatric disorders are associated with altered topological patterns of brain connectivity. Therefore, a key inquiry of connectivity analysis is to detect group-level differentially expressed connectome patterns from the massive neuroimaging data. Recently, statistical methods have been developed to detect differentially expressed connectivity features at a subnetwork level, extending more commonly applied edge level analysis. However, the graph topological structures in these methods are limited to community/cliques which may not effectively uncover the underlying complex and disease-related brain circuits/subnetworks. Building on these previous subnetwork detection methods, a new statistical approach is developed to automatically identify the latent differentially expressed brain connectivity subnetworks with k-partite graph topological structures from large brain connectivity matrices. In addition, statistical inferential techniques are provided to test the detected topological structure. The new methods are evaluated via extensive simulation studies and then applied to resting state fMRI data (24 cases and 18 controls) for Parkinson's disease research. A differentially expressed connectivity network with the k-partite graph topological structure is detected which reveals underlying neural features distinguishing Parkinson's disease patients from healthy control subjects.

Bayesian modeling of dependence in brain connectivity data.

Brain connectivity studies often refer to brain areas as graph nodes and connections between nodes as edges, and aim to identify neuropsychiatric phenotype-related connectivity patterns. When performing group-level brain connectivity alternation analyses, it is critical to model the dependence structure between multivariate connectivity edges to achieve accurate and efficient estimates of model parameters. However, specifying and estimating dependencies between connectivity edges presents formidable challenges because (i) the dimensionality of parameters in the covariance matrix is high (of the order of the fourth power of the number of nodes); (ii) the covariance between a pair of edges involves four nodes with spatial location information; and (iii) the dependence structure between edges can be related to unknown network topological structures. Existing methods for large covariance/precision matrix regularization and spatial closeness-based dependence structure specification/estimation models may not fully address the complexity and challenges. We develop a new Bayesian nonparametric model that unifies information from brain network areas (nodes), connectivity (edges), and covariance between edges by constructing the function of covariance matrix based on the underlying network topological structure. We perform parameter estimation using an efficient Markov chain Monte Carlo algorithm. We apply our method to resting-state functional magnetic resonance imaging data from 60 subjects of a schizophrenia study and simulated data to demonstrate the performance of our method.

Latent and Abnormal Functional Connectivity Circuits in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is associated with disrupted brain networks. Neuroimaging techniques provide noninvasive methods of investigating abnormal connectivity patterns in ASD. In the present study, we compare functional connectivity networks in people with ASD with those in typical controls, using neuroimaging data from the Autism Brain Imaging Data Exchange (ABIDE) project. Specifically, we focus on the characteristics of intrinsic functional connectivity based on data collected by resting-state functional magnetic resonance imaging (rs-fMRI). Our aim was to identify disrupted brain connectivity patterns across all networks, instead of in individual edges, by using advanced statistical methods. Unlike many brain connectome studies, in which networks are prespecified before the edge connectivity in each network is compared between clinical groups, we detected the latent differentially expressed networks automatically. Our network-level analysis identified abnormal connectome networks that (i) included a high proportion of edges that were differentially expressed between people with ASD and typical controls; and (ii) showed highly-organized graph topology. These findings provide new insight into the study of the underlying neuropsychiatric mechanism of ASD.

A parsimonious statistical method to detect groupwise differentially expressed functional connectivity networks.

Group-level functional connectivity analyses often aim to detect the altered connectivity patterns between subgroups with different clinical or psychological experimental conditions, for example, comparing cases and healthy controls. We present a new statistical method to detect differentially expressed connectivity networks with significantly improved power and lower false-positive rates. The goal of our method was to capture most differentially expressed connections within networks of constrained numbers of brain regions (by the rule of parsimony). By virtue of parsimony, the false-positive individual connectivity edges within a network are effectively reduced, whereas the informative (differentially expressed) edges are allowed to borrow strength from each other to increase the overall power of the network. We develop a test statistic for each network in light of combinatorics graph theory, and provide p-values for the networks (in the weak sense) by using permutation test with multiple-testing adjustment. We validate and compare this new approach with existing methods, including false discovery rate and network-based statistic, via simulation studies and a resting-state functional magnetic resonance imaging case-control study. The results indicate that our method can identify differentially expressed connectivity networks, whereas existing methods are limited.