Functional generalized canonical correlation analysis for studying multiple longitudinal variables.

In this paper, we introduce functional generalized canonical correlation analysis, a new framework for exploring associations between multiple random processes observed jointly. The framework is based on the multiblock regularized generalized canonical correlation analysis framework. It is robust to sparsely and irregularly observed data, making it applicable in many settings. We establish the monotonic property of the solving procedure and introduce a Bayesian approach for estimating canonical components. We propose an extension of the framework that allows the integration of a univariate or multivariate response into the analysis, paving the way for predictive applications. We evaluate the method's efficiency in simulation studies and present a use case on a longitudinal dataset.

Population transcriptogenomics highlights impaired metabolism and small population sizes in tree frogs living in the Chernobyl Exclusion Zone.

BACKGROUND: Individual functional modifications shape the ability of wildlife populations to cope with anthropogenic environmental changes. But instead of adaptive response, human-altered environments can generate a succession of deleterious functional changes leading to the extinction of the population. To study how persistent anthropogenic changes impacted local species' population status, we characterised population structure, genetic diversity and individual response of gene expression in the tree frog Hyla orientalis along a gradient of radioactive contamination around the Chernobyl nuclear power plant. RESULTS: We detected lower effective population size in populations most exposed to ionizing radiation in the Chernobyl Exclusion Zone that is not compensated by migrations from surrounding areas. We also highlighted a decreased body condition of frogs living in the most contaminated area, a distinctive transcriptomics signature and stop-gained mutations in genes involved in energy metabolism. While the association with dose will remain correlational until further experiments, a body of evidence suggests the direct or indirect involvement of radiation exposure in these changes. CONCLUSIONS: Despite ongoing migration and lower total dose rates absorbed than at the time of the accident, our results demonstrate that Hyla orientalis specimens living in the Chernobyl Exclusion Zone are still undergoing deleterious changes, emphasizing the long-term impacts of the nuclear disaster.

Multiway generalized canonical correlation analysis.

Regularized generalized canonical correlation analysis (RGCCA) is a general multiblock data analysis framework that encompasses several important multivariate analysis methods such as principal component analysis, partial least squares regression, and several versions of generalized canonical correlation analysis. In this article, we extend RGCCA to the case where at least one block has a tensor structure. This method is called multiway generalized canonical correlation analysis (MGCCA). Convergence properties of the MGCCA algorithm are studied, and computation of higher-level components are discussed. The usefulness of MGCCA is shown on simulation and on the analysis of a cognitive study in human infants using electroencephalography (EEG).

Multiphase Liver MRI for Identifying the Macrotrabecular-Massive Subtype of Hepatocellular Carcinoma.

Background The recently described "macrotrabecular-massive" (MTM) histologic subtype of hepatocellular carcinoma (HCC) (MTM-HCC) represents an aggressive form of HCC and is associated with poor survival. Purpose To investigate whether preoperative MRI can help identify MTM-HCCs in patients with HCC. Materials and Methods This retrospective study included patients with HCC treated with surgical resection between January 2008 and February 2018 and who underwent preoperative multiphase contrast material-enhanced MRI. Least absolute shrinkage and selection operator (LASSO)-penalized and multivariable logistic regression analyses were performed to identify clinical, biologic, and imaging features associated with the MTM-HCC subtype. Early recurrence (within 2 years) and overall recurrence were evaluated by using Kaplan-Meier analysis. Multivariable Cox regression analysis was performed to determine predictors of early and overall recurrence. Results One hundred fifty-two patients (median age, 64 years; interquartile range, 56-72 years; 126 men) with 152 HCCs were evaluated. Twenty-six of the 152 HCCs (17%) were MTM-HCCs. LASSO-penalized logistic regression analysis identified substantial necrosis, high serum α-fetoprotein (AFP) level (>100 ng/mL), and Barcelona Clinic Liver Cancer (BCLC) stage B or C as independent features associated with MTM-HCCs. At multivariable analysis, substantial necrosis (odds ratio = 32; 95% confidence interval [CI] = 8.9, 114; P < .001), high serum AFP level (odds ratio = 4.4; 95% CI = 1.3, 16; P = .02), and BCLC stage B or C (odds ratio = 4.2; 95% CI = 1.2, 15; P = .03) were independent predictors of MTM-HCC subtype. Substantial necrosis helped identify 65% (17 of 26; 95% CI: 44%, 83%) of MTM-HCCs (sensitivity) with a specificity of 93% (117 of 126; 95% CI: 87%, 97%). In adjusted models, only the presence of satellite nodules was independently associated with both early (hazard ratio = 3.7; 95% CI: 1.5, 9.4; P = .006) and overall (hazard ratio = 3.0; 95% CI: 1.3, 7.2; P = .01) tumor recurrence. Conclusion At multiphase contrast-enhanced MRI, substantial necrosis helped identify macrotrabecular-massive hepatocellular carcinoma subtype with high specificity. © RSNA, 2020.

A strategy for multimodal data integration: application to biomarkers identification in spinocerebellar ataxia.

The growing number of modalities (e.g. multi-omics, imaging and clinical data) characterizing a given disease provides physicians and statisticians with complementary facets reflecting the disease process but emphasizes the need for novel statistical methods of data analysis able to unify these views. Such data sets are indeed intrinsically structured in blocks, where each block represents a set of variables observed on a group of individuals. Therefore, classical statistical tools cannot be applied without altering their organization, with the risk of information loss. Regularized generalized canonical correlation analysis (RGCCA) and its sparse generalized canonical correlation analysis (SGCCA) counterpart are component-based methods for exploratory analyses of data sets structured in blocks of variables. Rather than operating sequentially on parts of the measurements, the RGCCA/SGCCA-based integrative analysis method aims at summarizing the relevant information between and within the blocks. It processes a priori information defining which blocks are supposed to be linked to one another, thus reflecting hypotheses about the biology underlying the data blocks. It also requires the setting of extra parameters that need to be carefully adjusted.Here, we provide practical guidelines for the use of RGCCA/SGCCA. We also illustrate the flexibility and usefulness of RGCCA/SGCCA on a unique cohort of patients with four genetic subtypes of spinocerebellar ataxia, in which we obtained multiple data sets from brain volumetry and magnetic resonance spectroscopy, and metabolomic and lipidomic analyses. As a first step toward the extraction of multimodal biomarkers, and through the reduction to a few meaningful components and the visualization of relevant variables, we identified possible markers of disease progression.

Hepatobiliary MR contrast agent uptake as a predictive biomarker of aggressive features on pathology and reduced recurrence-free survival in resectable hepatocellular carcinoma: comparison with dual-tracer 18F-FDG and 18F-FCH PET/CT.

OBJECTIVES: To compare the performance of the quantitative analysis of the hepatobiliary phase (HBP) tumor enhancement in gadobenate dimeglumine (Gd-BOPTA)-enhanced MRI and of dual-tracer 18F-FDG and 18F-fluorocholine (FCH) PET/CT for the prediction of tumor aggressiveness and recurrence-free survival (RFS) in resectable hepatocellular carcinoma (HCC). METHODS: This retrospective, IRB approved study included 32 patients with 35 surgically proven HCCs. All patients underwent Gd-BOPTA-enhanced MRI including delayed HBP images, 18F-FDG PET/CT, and (for 29/32 patients) 18F-FCH PET/CT during the 2 months prior to surgery. For each lesion, the lesion-to-liver contrast enhancement ratio (LLCER) on MRI HBP images and the SUVmax tumor-to-liver ratio (SUVT/L) for both tracers were calculated. Their predictive value for aggressive pathological features-including the histological grade and microvascular invasion (MVI)-and RFS were analyzed and compared using area under receiver operating characteristic (AUROC) curves and Cox regression models, respectively. RESULTS: The AUROCs for the identification of aggressive HCCs on pathology with LLCER, 18F-FDG SUVT/L, and 18F-FCH SUVT/L were 0.92 (95% CI 0.78, 0.98), 0.89 (95% CI 0.74, 0.97; p = 0.70), and 0.64 (95% CI 0.45, 0.80; p = 0.035). At multivariate Cox regression analysis, LLCER was identified as an independent predictor of RFS (HR (95% CI) = 0.91 (0.84, 0.99), p = 0.022). LLCER - 4.72% or less also accurately predicted moderate-poor differentiation grade (Se = 100%, Sp = 92.9%) and MVI (Se = 93.3%, Sp = 60%) and identified patients with poor RFS after surgical resection (p = 0.030). CONCLUSIONS: HBP tumor enhancement after Gd-BOPTA injection may help identify aggressive HCC pathological features, and patients with reduced recurrence-free survival after surgical resection. KEY POINTS: • In patients with resectable HCC, the quantitative analysis of the HBP tumor enhancement in Gd-BOPTA-enhanced MRI (LLCER) accurately identifies moderately-poorly differentiated and/or MVI-positive HCCs. • After surgical resection for HCC, patients with LLCER - 4.72% or less had significantly poorer recurrence-free survival than patients with LLCER superior to - 4.72%. • Gd-BOPTA-enhanced MRI with delayed HBP images may be suggested as part of pre-surgery workup in patients with resectable HCC.

Hepatocellular carcinoma: CT texture analysis as a predictor of survival after surgical resection.

OBJECTIVES: To determine whether image texture parameters analysed on pre-operative contrast-enhanced computed tomography (CT) can predict overall survival and recurrence-free survival in patients with hepatocellular carcinoma (HCC) treated by surgical resection. METHODS: We retrospectively included all patients operated for HCC who had liver contrast-enhanced CT within 3 months prior to treatment in our centre between 2010 and 2015. The following texture parameters were evaluated on late-arterial and portal-venous phases: mean grey-level, standard deviation, kurtosis, skewness and entropy. Measurements were made before and after spatial filtration at different anatomical scales (SSF) ranging from 2 (fine texture) to 6 (coarse texture). Lasso penalised Cox regression analyses were performed to identify independent predictors of overall survival and recurrence-free survival. RESULTS: Forty-seven patients were included. Median follow-up time was 345 days (interquartile range [IQR], 176-569). Nineteen patients had a recurrence at a median time of 190 days (IQR, 141-274) and 13 died at a median time of 274 days (IQR, 96-411). At arterial CT phase, kurtosis at SSF = 4 (hazard ratio [95% confidence interval] = 3.23 [1.35-7.71] p = 0.0084) was independent predictor of overall survival. At portal-venous phase, skewness without filtration (HR [CI 95%] = 353.44 [1.31-95102.23], p = 0.039), at SSF2 scale (HR [CI 95%] = 438.73 [2.44-78968.25], p = 0.022) and SSF3 (HR [CI 95%] = 14.43 [1.38-150.51], p = 0.026) were independently associated with overall survival. No textural feature was identified as predictor of recurrence-free survival. CONCLUSIONS: In patients with resectable HCC, portal venous phase-derived CT skewness is significantly associated with overall survival and may potentially become a useful tool to select the best candidates for resection. KEY POINTS: • HCC heterogeneity as evaluated by texture analysis of contrast-enhanced CT images may predict overall survival in patients treated by surgical resection. • Among texture parameters, skewness assessed at different anatomical scales at portal-venous phase CT is an independent predictor of overall survival after resection. • In patients with HCC, CT texture analysis may have the potential to become a useful tool to select the best candidates for resection.

Can dual-energy CT replace perfusion CT for the functional evaluation of advanced hepatocellular carcinoma?

OBJECTIVES: To determine the degree of relationship between iodine concentrations derived from dual-energy CT (DECT) and perfusion CT parameters in patients with advanced HCC under treatment. METHODS: In this single-centre IRB approved study, 16 patients with advanced HCC treated with sorafenib or radioembolization who underwent concurrent dynamic perfusion CT and multiphase DECT using a single source, fast kV switching DECT scanner were included. Written informed consent was obtained for all patients. HCC late-arterial and portal iodine concentrations, blood flow (BF)-related and blood volume (BV)-related perfusion parameters maps were calculated. Mixed-effects models of the relationship between iodine concentrations and perfusion parameters were computed. An adjusted p value (Bonferroni method) < 0.05 was considered significant. RESULTS: Mean HCC late-arterial and portal iodine concentrations were 22.7±12.7 mg/mL and 18.7±8.3 mg/mL, respectively. Late-arterial iodine concentration was significantly related to BV (mixed-effects model F statistic (F)=28.52, p<0.0001), arterial BF (aBF, F=17.62, p<0.0001), hepatic perfusion index (F=28.24, p<0.0001), positive enhancement integral (PEI, F=66.75, p<0.0001) and mean slope of increase (F=32.96, p<0.0001), while portal-venous iodine concentration was mainly related to BV (F=29.68, p<0.0001) and PEI (F=66.75, p<0.0001). CONCLUSIONS: In advanced HCC lesions, DECT-derived late-arterial iodine concentration is strongly related to both aBF and BV, while portal iodine concentration mainly reflects BV, offering DECT the ability to evaluate both morphological and perfusion changes. KEY POINTS: • Late-arterial iodine concentration is highly related to arterial BF and BV. • Portal iodine concentration mainly reflects tumour blood volume. • Dual-energy CT offers significantly decreased radiation dose compared with perfusion CT.

Variable selection for generalized canonical correlation analysis.

Regularized generalized canonical correlation analysis (RGCCA) is a generalization of regularized canonical correlation analysis to 3 or more sets of variables. RGCCA is a component-based approach which aims to study the relationships between several sets of variables. The quality and interpretability of the RGCCA components are likely to be affected by the usefulness and relevance of the variables in each block. Therefore, it is an important issue to identify within each block which subsets of significant variables are active in the relationships between blocks. In this paper, RGCCA is extended to address the issue of variable selection. Specifically, sparse generalized canonical correlation analysis (SGCCA) is proposed to combine RGCCA with an [Formula: see text]-penalty in a unified framework. Within this framework, blocks are not necessarily fully connected, which makes SGCCA a flexible method for analyzing a wide variety of practical problems. Finally, the versatility and usefulness of SGCCA are illustrated on a simulated dataset and on a 3-block dataset which combine gene expression, comparative genomic hybridization, and a qualitative phenotype measured on a set of 53 children with glioma. SGCCA is available on CRAN as part of the RGCCA package.

Generative adversarial networks (GAN)-based data augmentation of rare liver cancers: The SFR 2021 Artificial Intelligence Data Challenge.

PURPOSE: The 2021 edition of the Artificial Intelligence Data Challenge was organized by the French Society of Radiology together with the Centre National d'Études Spatiales and CentraleSupélec with the aim to implement generative adversarial networks (GANs) techniques to provide 1000 magnetic resonance imaging (MRI) cases of macrotrabecular-massive (MTM) hepatocellular carcinoma (HCC), a rare and aggressive subtype of HCC, generated from a limited number of real cases from multiple French centers. MATERIALS AND METHODS: A dedicated platform was used by the seven inclusion centers to securely upload their anonymized MRI examinations including all three cross-sectional images (one late arterial and one portal-venous phase T1-weighted images and one fat-saturated T2-weighted image) in compliance with general data protection regulation. The quality of the database was checked by experts and manual delineation of the lesions was performed by the expert radiologists involved in each center. Multidisciplinary teams competed between October 11th, 2021 and February 13th, 2022. RESULTS: A total of 91 MTM-HCC datasets of three images each were collected from seven French academic centers. Six teams with a total of 28 individuals participated in this challenge. Each participating team was asked to generate one thousand 3-image cases. The qualitative evaluation was performed by three radiologists using the Likert scale on ten randomly selected cases generated by each participant. A quantitative evaluation was also performed using two metrics, the Frechet inception distance and a leave-one-out accuracy of a 1-Nearest Neighbor algorithm. CONCLUSION: This data challenge demonstrates the ability of GANs techniques to generate a large number of images from a small sample of imaging examinations of a rare malignant tumor.

Synthetic MR image generation of macrotrabecular-massive hepatocellular carcinoma using generative adversarial networks.

PURPOSE: The purpose of this study was to develop a method for generating synthetic MR images of macrotrabecular-massive hepatocellular carcinoma (MTM-HCC). MATERIALS AND METHODS: A set of abdominal MR images including fat-saturated T1-weighted images obtained during the arterial and portal venous phases of enhancement and T2-weighted images of 91 patients with MTM-HCC, and another set of MR abdominal images from 67 other patients were used. Synthetic images were obtained using a 3-step pipeline that consisted in: (i), generating a synthetic MTM-HCC tumor on a neutral background; (ii), randomly selecting a background among the 67 patients and a position inside the liver; and (iii), merging the generated tumor in the background at the specified location. Synthetic images were qualitatively evaluated by three radiologists and quantitatively assessed using a mix of 1-nearest neighbor classifier metric and Fréchet inception distance. RESULTS: A set of 1000 triplets of synthetic MTM-HCC images with consistent contrasts were successfully generated. Evaluation of selected synthetic images by three radiologists showed that the method gave realistic, consistent and diversified images. Qualitative and quantitative evaluation led to an overall score of 0.64. CONCLUSION: This study shows the feasibility of generating realistic synthetic MR images with very few training data, by leveraging the wide availability of liver backgrounds. Further studies are needed to assess the added value of those synthetic images for automatic diagnosis of MTM-HCC.

Significant correlation between a set of genetic polymorphisms and a functional brain network revealed by feature selection and sparse Partial Least Squares.

Brain imaging is increasingly recognised as an intermediate phenotype to understand the complex path between genetics and behavioural or clinical phenotypes. In this context, a first goal is to propose methods to identify the part of genetic variability that explains some neuroimaging variability. Classical univariate approaches often ignore the potential joint effects that may exist between genes or the potential covariations between brain regions. In this paper, we propose instead to investigate an exploratory multivariate method in order to identify a set of Single Nucleotide Polymorphisms (SNPs) covarying with a set of neuroimaging phenotypes derived from functional Magnetic Resonance Imaging (fMRI). Recently, Partial Least Squares (PLS) regression or Canonical Correlation Analysis (CCA) have been proposed to analyse DNA and transcriptomics. Here, we propose to transpose this idea to the DNA vs. imaging context. However, in very high-dimensional settings like in imaging genetics studies, such multivariate methods may encounter overfitting issues. Thus we investigate the use of different strategies of regularisation and dimension reduction techniques combined with PLS or CCA to face the very high dimensionality of imaging genetics studies. We propose a comparison study of the different strategies on a simulated dataset first and then on a real dataset composed of 94 subjects, around 600,000 SNPs and 34 functional MRI lateralisation indexes computed from reading and speech comprehension contrast maps. We estimate the generalisability of the multivariate association with a cross-validation scheme and demonstrate the significance of this link, using a permutation procedure. Univariate selection appears to be necessary to reduce the dimensionality. However, the significant association uncovered by this two-step approach combining univariate filtering and L1-regularised PLS suggests that discovering meaningful genetic associations calls for a multivariate approach.

Over-optimism in bioinformatics: an illustration.

MOTIVATION: In statistical bioinformatics research, different optimization mechanisms potentially lead to 'over-optimism' in published papers. So far, however, a systematic critical study concerning the various sources underlying this over-optimism is lacking. RESULTS: We present an empirical study on over-optimism using high-dimensional classification as example. Specifically, we consider a 'promising' new classification algorithm, namely linear discriminant analysis incorporating prior knowledge on gene functional groups through an appropriate shrinkage of the within-group covariance matrix. While this approach yields poor results in terms of error rate, we quantitatively demonstrate that it can artificially seem superior to existing approaches if we 'fish for significance'. The investigated sources of over-optimism include the optimization of datasets, of settings, of competing methods and, most importantly, of the method's characteristics. We conclude that, if the improvement of a quantitative criterion such as the error rate is the main contribution of a paper, the superiority of new algorithms should always be demonstrated on independent validation data. AVAILABILITY: The R codes and relevant data can be downloaded from http://www.ibe.med.uni-muenchen.de/organisation/mitarbeiter/020_professuren/boulesteix/overoptimism/, such that the study is completely reproducible.

Multi-omics analysis to decipher the molecular link between chronic exposure to pollution and human skin dysfunction.

Environmental pollution is composed of several factors, namely particulate matter (PM2.5, PM10), ozone and Ultra Violet (UV) rays among others and first and the most exposed tissue to these substances is the skin epidermis. It has been established that several skin disorders such as eczema, acne, lentigines and wrinkles are aggravated by exposure to atmospheric pollution. While pollutants can interact with skin surface, contamination of deep skin by ultrafine particles or Polycyclic aromatic hydrocarbons (PAH) might be explained by their presence in blood and hair cortex. Molecular mechanisms leading to skin dysfunction due to pollution exposure have been poorly explored in humans. In addition to various host skin components, cutaneous microbiome is another target of these environment aggressors and can actively contribute to visible clinical manifestation such as wrinkles and aging. The present study aimed to investigate the association between pollution exposure, skin microbiota, metabolites and skin clinical signs in women from two cities with different pollution levels. Untargeted metabolomics and targeted proteins were analyzed from D-Squame samples from healthy women (n = 67 per city), aged 25-45 years and living for at least 15 years in the Chinese cities of Baoding (used as a model of polluted area) and Dalian (control area with lower level of pollution). Additional samples by swabs were collected from the cheeks from the same population and microbiome was analysed using bacterial 16S rRNA as well as fungal ITS1 amplicon sequencing and metagenomics analysis. The level of exposure to pollution was assessed individually by the analysis of polycyclic aromatic hydrocarbons (PAH) and their metabolites in hair samples collected from each participant. All the participants of the study were assessed for the skin clinical parameters (acne, wrinkles, pigmented spots etc.). Women from the two cities (polluted and less polluted) showed distinct metabolic profiles and alterations in skin microbiome. Profiling data from 350 identified metabolites, 143 microbes and 39 PAH served to characterize biochemical events that correlate with pollution exposure. Finally, using multiblock data analysis methods, we obtained a potential molecular map consisting of multi-omics signatures that correlated with the presence of skin pigmentation dysfunction in individuals living in a polluted environment. Overall, these signatures point towards macromolecular alterations by pollution that could manifest as clinical sign of early skin pigmentation and/or other imperfections.

Detection of melanoma from dermoscopic images of naevi acquired under uncontrolled conditions.

BACKGROUND AND OBJECTIVE: Several systems for the diagnosis of melanoma from images of naevi obtained under controlled conditions have demonstrated comparable efficiency with dermatologists. However, their robustness to analyze daily routine images was sometimes questionable. The purpose of this work is to investigate to what extent the automatic melanoma diagnosis may be achieved from the analysis of uncontrolled images of pigmented skin lesions. MATERIALS AND METHODS: Images were acquired during regular practice by two dermatologists using Reflex 24 x 36 cameras combined with Heine Delta 10 dermascopes. The images were then digitalized using a scanner. In addition, five senior dermatologists were asked to give the diagnosis and therapeutic decision (exeresis) for 227 images of naevi, together with an opinion about the existence of malignancy-predictive features. Meanwhile, a learning by sample classifier for the diagnosis of melanoma was constructed, which combines image-processing with machine-learning techniques. After an automatic segmentation, geometric and colorimetric parameters were extracted from images and selected according to their efficiency in predicting malignancy features. A diagnosis was subsequently provided based on selected parameters. An extensive comparison of dermatologists' and computer results was subsequently performed. RESULTS AND CONCLUSION: The KL-PLS-based classifier shows comparable performances with respect to dermatologists (sensitivity: 95% and specificity: 60%). The algorithm provides an original insight into the clinical knowledge of pigmented skin lesions.

Changes of the human skin microbiota upon chronic exposure to polycyclic aromatic hydrocarbon pollutants.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are of environmental and public health concerns and contribute to adverse skin attributes such as premature skin aging and pigmentary disorder. However, little information is available on the potential roles of chronic urban PAH pollutant exposure on the cutaneous microbiota. Given the roles of the skin microbiota have on healthy and undesirable skin phenotypes and the relationships between PAHs and skin properties, we hypothesize that exposure of PAHs may be associated with changes in the cutaneous microbiota. In this study, the skin microbiota of over two hundred Chinese individuals from two cities in China with varying exposure levels of PAHs were characterized by bacterial and fungal amplicon and shotgun metagenomics sequencing. RESULTS: Skin site and city were strong parameters in changing microbial communities and their assembly processes. Reductions of bacterial-fungal microbial network structural integrity and stability were associated with skin conditions (acne and dandruff). Multivariate analysis revealed associations between abundances of Propionibacterium and Malassezia with host properties and pollutant exposure levels. Shannon diversity increase was correlated to exposure levels of PAHs in a dose-dependent manner. Shotgun metagenomics analysis of samples (n = 32) from individuals of the lowest and highest exposure levels of PAHs further highlighted associations between the PAHs quantified and decrease in abundances of skin commensals and increase in oral bacteria. Functional analysis identified associations between levels of PAHs and abundance of microbial genes of metabolic and other pathways with potential importance in host-microbe interactions as well as degradation of aromatic compounds. CONCLUSIONS: The results in this study demonstrated the changes in composition and functional capacities of the cutaneous microbiota associated with chronic exposure levels of PAHs. Findings from this study will aid the development of strategies to harness the microbiota in protecting the skin against pollutants. Video Abstract.

A constrained singular value decomposition method that integrates sparsity and orthogonality.

We propose a new sparsification method for the singular value decomposition-called the constrained singular value decomposition (CSVD)-that can incorporate multiple constraints such as sparsification and orthogonality for the left and right singular vectors. The CSVD can combine different constraints because it implements each constraint as a projection onto a convex set, and because it integrates these constraints as projections onto the intersection of multiple convex sets. We show that, with appropriate sparsification constants, the algorithm is guaranteed to converge to a stable point. We also propose and analyze the convergence of an efficient algorithm for the specific case of the projection onto the balls defined by the norms L1 and L2. We illustrate the CSVD and compare it to the standard singular value decomposition and to a non-orthogonal related sparsification method with: 1) a simulated example, 2) a small set of face images (corresponding to a configuration with a number of variables much larger than the number of observations), and 3) a psychometric application with a large number of observations and a small number of variables. The companion R-package, csvd, that implements the algorithms described in this paper, along with reproducible examples, are available for download from https://github.com/vguillemot/csvd.

Multi-omics signature of brain amyloid deposition in asymptomatic individuals at-risk for Alzheimer's disease: The INSIGHT-preAD study.

BACKGROUND: One of the biggest challenge in Alzheimer's disease (AD) is to identify pathways and markers of disease prediction easily accessible, for prevention and treatment. Here we analysed blood samples from the INveStIGation of AlzHeimer's predicTors (INSIGHT-preAD) cohort of elderly asymptomatic individuals with and without brain amyloid load. METHODS: We performed blood RNAseq, and plasma metabolomics and lipidomics using liquid chromatography-mass spectrometry on 48 individuals amyloid positive and 48 amyloid negative (SUVr cut-off of 0·7918). The three data sets were analysed separately using differential gene expression based on negative binomial distribution, non-parametric (Wilcoxon) and parametric (correlation-adjusted Student't) tests. Data integration was conducted using sparse partial least squares-discriminant and principal component analyses. Bootstrap-selected top-ten features from the three data sets were tested for their discriminant power using Receiver Operating Characteristic curve. Longitudinal metabolomic analysis was carried out on a subset of 22 subjects. FINDINGS: Univariate analyses identified three medium chain fatty acids, 4-nitrophenol and a set of 64 transcripts enriched for inflammation and fatty acid metabolism differentially quantified in amyloid positive and negative subjects. Importantly, the amounts of the three medium chain fatty acids were correlated over time in a subset of 22 subjects (p < 0·05). Multi-omics integrative analyses showed that metabolites efficiently discriminated between subjects according to their amyloid status while lipids did not and transcripts showed trends. Finally, the ten top metabolites and transcripts represented the most discriminant omics features with 99·4% chance prediction for amyloid positivity. INTERPRETATION: This study suggests a potential blood omics signature for prediction of amyloid positivity in asymptomatic at-risk subjects, allowing for a less invasive, more accessible, and less expensive risk assessment of AD as compared to PET studies or lumbar puncture. FUND: Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epiniere (IHU-A-ICM), French Ministry of Research, Fondation Alzheimer, Pfizer, and Avid.

Regularized Generalized Canonical Correlation Analysis: A Framework for Sequential Multiblock Component Methods.

A new framework for sequential multiblock component methods is presented. This framework relies on a new version of regularized generalized canonical correlation analysis (RGCCA) where various scheme functions and shrinkage constants are considered. Two types of between block connections are considered: blocks are either fully connected or connected to the superblock (concatenation of all blocks). The proposed iterative algorithm is monotone convergent and guarantees obtaining at convergence a stationary point of RGCCA. In some cases, the solution of RGCCA is the first eigenvalue/eigenvector of a certain matrix. For the scheme functions x, [Formula: see text], [Formula: see text] or [Formula: see text] and shrinkage constants 0 or 1, many multiblock component methods are recovered.

Modeling a linkage between blood transcriptional expression and activity in brain regions to infer the phenotype of schizophrenia patients.

Hundreds of genetic loci participate to schizophrenia liability. It is also known that impaired cerebral connectivity is directly related to the cognitive and affective disturbances in schizophrenia. How genetic susceptibility and brain neural networks interact to specify a pathological phenotype in schizophrenia remains elusive. Imaging genetics, highlighting brain variations, has proven effective to establish links between vulnerability loci and associated clinical traits. As previous imaging genetics works in schizophrenia have essentially focused on structural DNA variants, these findings could be blurred by epigenetic mechanisms taking place during gene expression. We explored the meaningful links between genetic data from peripheral blood tissues on one hand, and regional brain reactivity to emotion task assayed by blood oxygen level-dependent functional magnetic resonance imaging on the other hand, in schizophrenia patients and matched healthy volunteers. We applied Sparse Generalized Canonical Correlation Analysis to identify joint signals between two blocks of variables: (i) the transcriptional expression of 33 candidate genes, and (ii) the blood oxygen level-dependent activity in 16 region of interest. Results suggested that peripheral transcriptional expression is related to brain imaging variations through a sequential pathway, ending with the schizophrenia phenotype. Generalization of such an approach to larger data sets should thus help in outlining the pathways involved in psychiatric illnesses such as schizophrenia. IMAGING: SEARCHING FOR LINKS TO AID DIAGNOSIS: Researchers explore links between the expression of genes associated with schizophrenia in blood cells and variations in brain activity during emotion processing. El Chérif Ibrahim and Eric Fakra at Aix-Marseille Université, France, and colleagues have developed a method to relate the expression levels of 33 schizophrenia susceptibility genes in blood cells and functional magnetic resonance imaging (fMRI) data obtained as individuals carry out a task that triggers emotional responses. Although they found no significant differences in the expression of genes between the 26 patients with schizophrenia and 26 healthy controls they examined, variations in activity in the superior temporal gyrus were strongly linked to schizophrenia-associated gene expression and presence of disease. Similar analyses of larger data sets will shed further light on the relationship between peripheral molecular changes and disease-related behaviors and ultimately, aid the diagnosis of neuropsychiatric disease.