Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

An improved asymmetric susceptibility tensor imaging model with frequency offset correction.

PURPOSE: To improve susceptibility tensor imaging (STI) reconstruction using the asymmetric STI model with the correction of non-bulk-magnetic-susceptibility (NBMS) effects. METHOD: A frequency offset term was introduced into the asymmetric STI model to account for the bias between measured MRI frequency signals and conventional susceptibility tensor models because of NBMS contributions. Experiments were conducted to compare the proposed model with conventional STI, conventional STI with the proposed frequency offset correction, and asymmetric STI on simulation, ex vivo mouse brain, and in vivo human brain data. RESULTS: In the simulation where NBMS contributions are head rotation-invariant, the proposed method achieves the lowest errors in mean magnetic susceptibility (MMS) and magnetic susceptibility anisotropy (MSA) and is more robust to noise in the estimation of principal eigenvector (PEV). When considering the head orientation dependency of NBMS contributions, the proposed method shows advantages in estimating MSA and PEV. On the mouse and human brain data, the proposed method produces more reliable MSA maps and more consistent white matter fiber directions when referring to those from DTI than the compared STI methods. CONCLUSION: The proposed method can reduce the effects of NBMS-related frequency shifts on the susceptibility tensors in the brain white matter. This study inspires STI reconstruction from the perspective of better modeling the sources of frequency shifts.

Investigation of EEG-Based Biometric Identification Using State-of-the-Art Neural Architectures on a Real-Time Raspberry Pi-Based System.

Despite the growing interest in the use of electroencephalogram (EEG) signals as a potential biometric for subject identification and the recent advances in the use of deep learning (DL) models to study neurological signals, such as electrocardiogram (ECG), electroencephalogram (EEG), electroretinogram (ERG), and electromyogram (EMG), there has been a lack of exploration in the use of state-of-the-art DL models for EEG-based subject identification tasks owing to the high variability in EEG features across sessions for an individual subject. In this paper, we explore the use of state-of-the-art DL models such as ResNet, Inception, and EEGNet to realize EEG-based biometrics on the BED dataset, which contains EEG recordings from 21 individuals. We obtain promising results with an accuracy of 63.21%, 70.18%, and 86.74% for Resnet, Inception, and EEGNet, respectively, while the previous best effort reported accuracy of 83.51%. We also demonstrate the capabilities of these models to perform EEG biometric tasks in real-time by developing a portable, low-cost, real-time Raspberry Pi-based system that integrates all the necessary steps of subject identification from the acquisition of the EEG signals to the prediction of identity while other existing systems incorporate only parts of the whole system.

Predicting visual memory across images and within individuals.

We only remember a fraction of what we see-including images that are highly memorable and those that we encounter during highly attentive states. However, most models of human memory disregard both an image's memorability and an individual's fluctuating attentional states. Here, we build the first model of memory synthesizing these two disparate factors to predict subsequent image recognition. We combine memorability scores of 1100 images (Experiment 1, n = 706) and attentional state indexed by response time on a continuous performance task (Experiments 2 and 3, n = 57 total). Image memorability and sustained attentional state explained significant variance in image memory, and a joint model of memory including both factors outperformed models including either factor alone. Furthermore, models including both factors successfully predicted memory in an out-of-sample group. Thus, building models based on individual- and image-specific factors allows for directed forecasting of our memories. SIGNIFICANCE STATEMENT: Although memory is a fundamental cognitive process, much of the time memory failures cannot be predicted until it is too late. However, in this study, we show that much of memory is surprisingly pre-determined ahead of time, by factors shared across the population and highly specific to each individual. Specifically, we build a new multidimensional model that predicts memory based just on the images a person sees and when they see them. This research synthesizes findings from disparate domains ranging from computer vision, attention, and memory into a predictive model. These findings have resounding implications for domains such as education, business, and marketing, where it is a top priority to predict (and even manipulate) what information people will remember.

Regularized Asymmetric Susceptibility Tensor Imaging in the Human Brain in Vivo.

Susceptibility tensor imaging (STI) is a promising tool for studying orientation-dependent tissue magnetic susceptibility and for mapping white matter fiber orientations complementary to diffusion tensor imaging (DTI). However, the limited head rotation range within modern head coils for data acquisition makes in vivo STI reconstruction ill-conditioned. Conventional STI reconstruction method is usually vulnerable to noise and requires sufficiently large head rotations to solve this ill-conditioned inverse problem. In this study, based on the recently proposed asymmetric STI (aSTI) model, a new method termed aSTI+ was proposed to improve in vivo STI reconstruction by enforcing isotropic susceptibility tensor inside cerebrospinal fluid (CSF) and applying morphology constraint in white matter. Experimental results showed superior performance of the proposed method with reduced noise, improved tissue contrast and better fiber orientation estimation over previous methods. Thus aSTI+ may promote in vivo human brain STI studies on white matter and myelin-related brain diseases.

A multiple-tissue-specific magnetic resonance imaging model for diagnosing Parkinson's disease: a brain radiomics study.

Brain radiomics can reflect the characteristics of brain pathophysiology. However, the value of T1-weighted images, quantitative susceptibility mapping, and R2* mapping in the diagnosis of Parkinson's disease (PD) was underestimated in previous studies. In this prospective study to establish a model for PD diagnosis based on brain imaging information, we collected high-resolution T1-weighted images, R2* mapping, and quantitative susceptibility imaging data from 171 patients with PD and 179 healthy controls recruited from August 2014 to August 2019. According to the inclusion time, 123 PD patients and 121 healthy controls were assigned to train the diagnostic model, while the remaining 106 subjects were assigned to the external validation dataset. We extracted 1408 radiomics features, and then used data-driven feature selection to identify informative features that were significant for discriminating patients with PD from normal controls on the training dataset. The informative features so identified were then used to construct a diagnostic model for PD. The constructed model contained 36 informative radiomics features, mainly representing abnormal subcortical iron distribution (especially in the substantia nigra), structural disorganization (e.g., in the inferior temporal, paracentral, precuneus, insula, and precentral gyri), and texture misalignment in the subcortical nuclei (e.g., caudate, globus pallidus, and thalamus). The predictive accuracy of the established model was 81.1 ± 8.0% in the training dataset. On the external validation dataset, the established model showed predictive accuracy of 78.5 ± 2.1%. In the tests of identifying early and drug-naïve PD patients from healthy controls, the accuracies of the model constructed on the same 36 informative features were 80.3 ± 7.1% and 79.1 ± 6.5%, respectively, while the accuracies were 80.4 ± 6.3% and 82.9 ± 5.8% for diagnosing middle-to-late PD and those receiving drug management, respectively. The accuracies for predicting tremor-dominant and non-tremor-dominant PD were 79.8 ± 6.9% and 79.1 ± 6.5%, respectively. In conclusion, the multiple-tissue-specific brain radiomics model constructed from magnetic resonance imaging has the ability to discriminate PD and exhibits the advantages for improving PD diagnosis.

Markers of kidney function, genetic variation related to cognitive function, and cognitive performance in the UK Biobank.

BACKGROUND: Chronic kidney disease has been linked to worse cognition. However, this association may be dependent on the marker of kidney function used, and studies assessing modification by genetics are lacking. This study examined associations between multiple measures of kidney function and assessed effect modification by a polygenic score for general cognitive function. METHODS: In this cross-sectional study of up to 341,208 European ancestry participants from the UK Biobank study, we examined associations between albuminuria and estimated glomerular filtration rate based on creatinine (eGFRcre) or cystatin C (eGFRcys) with cognitive performance on tests of verbal-numeric reasoning, reaction time and visual memory. Adjustment for confounding factors was performed using multivariate regression and propensity-score matching. Interaction between kidney function markers and a polygenic risk score for general cognitive function was also assessed. RESULTS: Albuminuria was associated with worse performance on tasks of verbal-numeric reasoning (ß(points) = -0.09, p < 0.001), reaction time (ß(milliseconds) = 7.06, p < 0.001) and visual memory (ß(log errors) = 0.013, p = 0.01). A polygenic score for cognitive function modified the association between albuminuria and verbal-numeric reasoning with significantly lower scores in those with albuminuria and a lower polygenic score (p = 0.009). Compared to participants with eGFRcre ≥ 60 ml/min, those with eGFRcre < 60 ml/min had lower verbal-numeric reasoning scores and slower mean reaction times (verbal numeric reasoning ß = -0.11, p < 0.001 and reaction time ß = 6.08, p < 0.001 for eGFRcre < 60 vs eGFRcre ≥ 60). Associations were stronger using cystatin C-based eGFR than creatinine-based eGFR (verbal numeric reasoning ß = -0.21, p < 0.001 and reaction time ß = 11.21, p < 0.001 for eGFRcys < 60 vs eGFRcys ≥ 60). CONCLUSIONS: Increased urine albumin is associated with worse cognition, but this may depend on genetic risk. Cystatin C-based eGFR may better predict cognitive performance than creatinine-based estimates.

Biomarkers of kidney function and cognitive ability: A Mendelian randomization study.

BACKGROUND: Estimated glomerular filtration rate (eGFR), albuminuria and serum uric acid (SUA) are markers of kidney function that have been associated with cognitive ability. However, whether these associations are causal is unclear. METHODS: We performed one-sample Mendelian randomization (MR) to estimate the effects of kidney function markers on cognitive performance using data from the UK Biobank. Polygenic scores for SUA, urine albumin to creatinine ratio (ACR), estimated glomerular filtration rate based on serum creatinine (eGFRcre) and serum cystatin C (eGFRcys) were used as instrumental variables, and cognitive function outcomes included tests of verbal-numeric reasoning, reaction time, visual memory, and numeric memory. RESULTS: We found no evidence of a causal effect of genetically determined SUA, eGFRcre or eGFRcys on cognitive function outcomes. There was no association between a polygenic score for ACR and verbal-numeric reasoning or numeric memory. However, there was suggestive evidence of a relationship between genetically increased ACR and slower reaction time and worse visual memory. ACR was no longer significantly associated with visual memory in analyses using an unweighted polygenic score and in analyses stratified by sex and age category. Pleiotropy adjusted estimates were directionally consistent with those of the principal analysis but overlapped with the null. CONCLUSIONS: This MR study does not support causal effects of SUA, eGFRcre or eGFRcys on cognitive performance. Genetically increased ACR was associated with slower processing speed and visual memory, but results need confirmation in independent samples.

Asymmetric susceptibility tensor imaging.

PURPOSE: To investigate the symmetry constraint in susceptibility tensor imaging. THEORY: The linear relationship between the MRI frequency shift and the magnetic susceptibility tensor is derived without constraining the tensor to be symmetric. In the asymmetric case, the system matrix is shown to be maximally rank 6. Nonetheless, relaxing the symmetry constraint may still improve tensor estimation because noise and image artifacts do not necessarily follow the constraint. METHODS: Gradient echo phase data are obtained from postmortem mouse brain and kidney samples. Both symmetric and asymmetric tensor reconstructions are applied to the data. The reconstructions are then used for susceptibility tensor imaging fiber tracking. Simulations with ground truth and at various noise levels are also performed. The reconstruction methods are compared qualitatively and quantitatively. RESULTS: Compared to regularized and unregularized symmetric reconstructions, the asymmetric reconstruction shows reduced noise and streaking artifacts, better contrast, and more complete fiber tracking. In simulation, the asymmetric reconstruction achieves better mean squared error and better angular difference in the presence of noise. Decomposing the asymmetric tensor into its symmetric and antisymmetric components confirms that the underlying susceptibility tensor is symmetric and that the main sources of asymmetry are noise and streaking artifacts. CONCLUSION: Whereas the susceptibility tensor is symmetric, asymmetric reconstruction is more effective in suppressing noise and artifacts, resulting in more accurate estimation of the susceptibility tensor.

Imaging diamagnetic susceptibility of collagen in hepatic fibrosis using susceptibility tensor imaging.

PURPOSE: To characterize the magnetic susceptibility changes of liver fibrosis using susceptibility tensor imaging. METHODS: Liver biopsy tissue samples of patients with liver fibrosis were obtained. Three-dimensional gradient-echo and diffusion-weighted images were acquired at 9.4 T. Susceptibility tensors of the samples were calculated using the gradient-echo phase signal acquired at 12 different orientations relative to the B0 field. Susceptibility anisotropy of the liver collagen fibers was quantified and compared with diffusion anisotropy, measured by DTI. For validation, a comparison was made to histology including hematoxylin and eosin staining, iron staining, and Masson's trichrome staining. RESULTS: Areas with strong diamagnetic susceptibility were observed in the tissue samples forming fibrous patterns. This diamagnetic susceptibility was highly anisotropic. Both the mean magnetic susceptibility and susceptibility anisotropy of collagen fibers exhibited a strong contrast against the surrounding nonfibrotic tissues. The same regions also showed an elevated diffusion anisotropy but with much lower tissue contrast. Masson's trichrome staining identified concentrated collagens in the fibrous regions with high susceptibility anisotropy, and a linear correlation was found between the susceptibility anisotropy and the histology-based staging. CONCLUSION: Diamagnetic susceptibility indicates the presence of collagen in the fibrotic liver tissues. Mapping magnetic susceptibility anisotropy may serve as a potential marker to quantify collagen fiber changes in patients with liver fibrosis.

Learning-based single-step quantitative susceptibility mapping reconstruction without brain extraction.

Quantitative susceptibility mapping (QSM) estimates the underlying tissue magnetic susceptibility from MRI gradient-echo phase signal and typically requires several processing steps. These steps involve phase unwrapping, brain volume extraction, background phase removal and solving an ill-posed inverse problem relating the tissue phase to the underlying susceptibility distribution. The resulting susceptibility map is known to suffer from inaccuracy near the edges of the brain tissues, in part due to imperfect brain extraction, edge erosion of the brain tissue and the lack of phase measurement outside the brain. This inaccuracy has thus hindered the application of QSM for measuring susceptibility of tissues near the brain edges, e.g., quantifying cortical layers and generating superficial venography. To address these challenges, we propose a learning-based QSM reconstruction method that directly estimates the magnetic susceptibility from total phase images without the need for brain extraction and background phase removal, referred to as autoQSM. The neural network has a modified U-net structure and is trained using QSM maps computed by a two-step QSM method. 209 healthy subjects with ages ranging from 11 to 82 years were employed for patch-wise network training. The network was validated on data dissimilar to the training data, e.g., in vivo mouse brain data and brains with lesions, which suggests that the network generalized and learned the underlying mathematical relationship between magnetic field perturbation and magnetic susceptibility. Quantitative and qualitative comparisons were performed between autoQSM and other two-step QSM methods. AutoQSM was able to recover magnetic susceptibility of anatomical structures near the edges of the brain including the veins covering the cortical surface, spinal cord and nerve tracts near the mouse brain boundaries. The advantages of high-quality maps, no need for brain volume extraction, and high reconstruction speed demonstrate autoQSM's potential for future applications.

Quantitative susceptibility mapping of articular cartilage in patients with osteoarthritis at 3T.

BACKGROUND: Quantitative susceptibility mapping (QSM) has recently been applied in humans to quantify the magnetic susceptibility of collagen fibrils in the articular cartilage. PURPOSE: To determine the ability of QSM to detect cartilage matrix degeneration between normal and early knee osteoarthritis (OA) patients. STUDY TYPE: Prospective. POPULATION: Twenty-four patients with knee OA and 24 age- and sex-matched healthy controls. FIELD STRENGTH/SEQUENCE: 3D gradient echo, T1 turbo spin echo, and proton density-weighted (PDw) spectral attenuated inversion recovery (SPAIR) sequence at 3.0T. ASSESSMENT: Scan-rescan reproducibility of the susceptibility values in the cartilage was assessed in control subjects. Cartilage thickness, volume, mean, and standard deviation (SD) of susceptibility values of the cartilage compartments were compared between normal and OA patients. The relationship between magnetic susceptibility values and cartilage lesion grading based on MR images was studied. STATISTICAL TESTS: The Wilcoxon Rank-Sum test was used to compare cartilage thickness, volume, mean, and SD of susceptibility values between control subjects and OA patients. A Spearman rank correlation was performed to study the relationship between the mean and SD of susceptibility values and the cartilage thinning grades. RESULTS: The SD of magnetic susceptibility values in the knee cartilage was significantly lower in OA patients compared with healthy controls, and it decreased with more severe MR grades of cartilage thinning degeneration. Significant correlations between the SD of susceptibility values and cartilage thinning grades were observed with R2 = 0.64 and P = 0.000, R2 = 0.47 and P = 0.002, R2 = 0.52 and P = 0.001, R2 = 0.42 and P = 0.0006, and R2 = 0.67 and P = 0.000 for medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibia (MT), lateral tibia (LT), and patella, respectively. No significant difference was found in cartilage volume (P = 0.17, P = 0.13, P = 0.20, P = 0.25, and P = 0.18 for MFC, LFC, MT, LT, and patella, respectively) and thickness (P = 0.31, P = 0.19, P = 0.16, P = 0.09, and P = 0.22 for MFC, LFC, MT, LT, and patella, respectively) between OA patients and healthy controls. DATA CONCLUSION: The variations of susceptibility values in the knee cartilage decrease with the degree of cartilage degeneration. QSM may be a sensitive indicator for alteration of the collagen network and shows potential to detect cartilage degeneration at early stage. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.