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Introduction: Existing evidence suggests that exposure to phthalates is higher among younger age groups. However, limited knowledge exists on how phthalate exposure, as well as exposure to replacement plasticizers, di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHTP), change from infancy through early childhood., Methods: Urine samples were collected across the first 5 years of life from typically developing infants and young children enrolled between 2017 and 2020 in the longitudinal UNC Baby Connectome Project. From 438 urine samples among 187 participants, we quantified concentrations of monobutyl phthalate (MnBP), mono-3-carboxypropyl phthalate (MCPP), monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), and metabolites of di(2-ethylhexyl) phthalate (DEHP), diisonoyl phthalate (DiNP), DINCH and DEHTP. Specific gravity (SG) adjusted metabolite and molar sum concentrations were compared across age groups. Intraclass correlation coefficients (ICCs) were calculated among 122 participants with multiple urine specimens (373 samples)., Results: Most phthalate metabolites showed high detection frequencies (>80% of samples). Replacement plasticizers DINCH (58-60%) and DEHTP (>97%) were also commonly found. DiNP metabolites were less frequently detected (<10%). For some metabolites, SG-adjusted concentrations were inversely associated with age, with the highest concentrations found in the first year of life. ICCs revealed low to moderate reliability in metabolite measurements (ρ = 0.10-0.48) suggesting a high degree of within-individual variation in exposure among this age group. The first 6 months (compared to remaining age groups) showed an increased ratio of carboxylated metabolites of DEHP and DEHTP, compared to other common metabolites, but no clear age trends for DINCH metabolite ratios were observed., Conclusion: Metabolites of phthalates and replacements plasticizers were widely detected in infancy and early childhood, with the highest concentrations observed in the first year of life for several metabolites. Higher proportions of carboxylated metabolites of DEHP and DEHTP in younger age groups indicate potential differences in metabolism during infancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Nonlinear changes in brain function during aging are shaped by a complex interplay of factors, including sex, age, genetics, and modifiable health risk factors. However, the combined effects and underlying mechanisms of these factors on brain functional connectivity remain poorly understood., Objective: To comprehensively investigate the combined associations of sex, age, APOE genotypes, and ten common modifiable health risk factors with brain functional connectivities during aging., Design Setting and Participants: This analysis used data from 36,630 UK Biobank participants, aged 44-81, who were assessed for sex, age, APOE genotypes, 10 health risk factors, and brain functional connectivities through resting-state functional magnetic resonance imaging., Main Outcomes and Measures: Brain functional connectivities were evaluated through within- and between-network functional connectivities and connectivity strength. Associations between risk factors and brain functional connectivities, including their interaction effects, were analyzed., Results: Hypertension, BMI, and education were the top three influential factors. Sex-specific effects were also observed in interactions involving APOE4 gene, smoking, alcohol consumption, diabetes, BMI, and education. Notably, a negative sex-excessive alcohol interaction showed a stronger negative effect on functional connectivities in males, particularly between the dorsal attention network and the language network, while moderate alcohol consumption appeared to have protective effects. A significant negative interaction between sex and APOE4 revealed a greater reduction in functional connectivity between the cingulo-opercular network and the posterior multimodal network in male APOE4 carriers. Additional findings included a negative age-BMI interaction between the visual and dorsal attention networks, and a positive age-hypertension interaction between the frontoparietal and default mode networks., Conclusions and Relevance: The findings highlight significant sex disparities in the associations between age, the APOE -ε4 gene, modifiable health risk factors, and brain functional connectivity, emphasizing the necessity of jointly considering these factors to gain a deeper understanding of the complex processes underlying brain aging., Competing Interests: Conflict of Interest Disclosures: Authors have no conflicts of interest to disclose

Microbial cell factories (MCFs) have been leveraged to construct sustainable platforms for value-added compound production. To optimize metabolism and reach optimal productivity, synthetic biology has developed various genetic devices to engineer microbial systems by gene editing, high-throughput protein engineering, and dynamic regulation. However, current synthetic biology methodologies still rely heavily on manual design, laborious testing, and exhaustive analysis. The emerging interdisciplinary field of artificial intelligence (AI) and biology has become pivotal in addressing the remaining challenges. AI-aided microbial production harnesses the power of processing, learning, and predicting vast amounts of biological data within seconds, providing outputs with high probability. With well-trained AI models, the conventional Design-Build-Test (DBT) cycle has been transformed into a multidimensional Design-Build-Test-Learn-Predict (DBTLP) workflow, leading to significantly improved operational efficiency and reduced labor consumption. Here, we comprehensively review the main components and recent advances in AI-aided microbial production, focusing on genome annotation, AI-aided protein engineering, artificial functional protein design, and AI-enabled pathway prediction. Finally, we discuss the challenges of integrating novel AI techniques into biology and propose the potential of large language models (LLMs) in advancing microbial production., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Resting-state functional magnetic resonance imaging (rs-fMRI) can reflect spontaneous neural activities in the brain and is widely used for brain disorder analysis. Previous studies focus on extracting fMRI representations using machine/deep learning methods, but these features typically lack biological interpretability. The human brain exhibits a remarkable modular structure in spontaneous brain functional networks, with each module comprised of functionally interconnected brain regions-of-interest (ROIs). However, existing learning-based methods cannot adequately utilize such brain modularity prior. In this paper, we propose a brain modularity-constrained dynamic representation learning framework for interpretable fMRI analysis, consisting of dynamic graph construction, dynamic graph learning via a novel modularity-constrained graph neural network (MGNN), and prediction and biomarker detection. The designed MGNN is constrained by three core neurocognitive modules (i.e., salience network, central executive network, and default mode network), encouraging ROIs within the same module to share similar representations. To further enhance discriminative ability of learned features, we encourage the MGNN to preserve network topology of input graphs via a graph topology reconstruction constraint. Experimental results on 534 subjects with rs-fMRI scans from two datasets validate the effectiveness of the proposed method. The identified discriminative brain ROIs and functional connectivities can be regarded as potential fMRI biomarkers to aid in clinical diagnosis.

The retina, an anatomical extension of the brain, forms physiological connections with the visual cortex of the brain. Although retinal structures offer a unique opportunity to assess brain disorders, their relationship to brain structure and function is not well understood. In this study, we conducted a systematic cross-organ genetic architecture analysis of eye-brain connections using retinal and brain imaging endophenotypes. We identified novel phenotypic and genetic links between retinal imaging biomarkers and brain structure and function measures from multimodal magnetic resonance imaging (MRI), with many associations involving the primary visual cortex and visual pathways. Retinal imaging biomarkers shared genetic influences with brain diseases and complex traits in 65 genomic regions, with 18 showing genetic overlap with brain MRI traits. Mendelian randomization suggests bidirectional genetic causal links between retinal structures and neurological and neuropsychiatric disorders, such as Alzheimer's disease. Overall, our findings reveal the genetic basis for eye-brain connections, suggesting that retinal images can help uncover genetic risk factors for brain disorders and disease-related changes in intracranial structure and function., (© 2024. The Author(s).)

Intra-tumor heterogeneity is an important driver of tumor evolution and therapy response. Advances in precision cancer treatment will require understanding of mutation clonality and subclonal architecture. Currently the slow computational speed of subclonal reconstruction hinders large cohort studies. To overcome this bottleneck, we developed Clonal structure identification through Pairwise Penalization, or CliPP, which clusters subclonal mutations using a regularized likelihood model. CliPP reliably processed whole-genome and whole-exome sequencing data from over 12,000 tumor samples within 24 hours, thus enabling large-scale downstream association analyses between subclonal structures and clinical outcomes. Through a pan-cancer investigation of 7,827 tumors from 32 cancer types, we found that high subclonal mutational load (sML), a measure of latency time in tumor evolution, was significantly associated with better patient outcomes in 16 cancer types with low to moderate tumor mutation burden (TMB). In a cohort of prostate cancer patients participating in an immunotherapy clinical trial, high sML was indicative of favorable response to immune checkpoint blockade. This comprehensive study using CliPP underscores sML as a key feature of cancer. sML may be essential for linking mutation dynamics with immunotherapy response in the large population of non-high TMB cancers.

Background: Alzheimer's disease (AD), a progressive neurodegenerative disorder, continues to increase in prevalence without any effective treatments to date. In this context, knowledge graphs (KGs) have emerged as a pivotal tool in biomedical research, offering new perspectives on drug repurposing and biomarker discovery by analyzing intricate network structures. Our study seeks to build an AD-specific knowledge graph, highlighting interactions among AD, genes, variants, chemicals, drugs, and other diseases. The goal is to shed light on existing treatments, potential targets, and diagnostic methods for AD, thereby aiding in drug repurposing and the identification of biomarkers., Results: We annotated 800 PubMed abstracts and leveraged GPT-4 for text augmentation to enrich our training data for named entity recognition (NER) and relation classification. A comprehensive data mining model, integrating NER and relationship classification, was trained on the annotated corpus. This model was subsequently applied to extract relation triplets from unannotated abstracts. To enhance entity linking, we utilized a suite of reference biomedical databases and refine the linking accuracy through abbreviation resolution. As a result, we successfully identified 3,199,276 entity mentions and 633,733 triplets, elucidating connections between 5,000 unique entities. These connections were pivotal in constructing a comprehensive Alzheimer's Disease Knowledge Graph (ADKG). We also integrated the ADKG constructed after entity linking with other biomedical databases. The ADKG served as a training ground for Knowledge Graph Embedding models with the high-ranking predicted triplets supported by evidence, underscoring the utility of ADKG in generating testable scientific hypotheses. Further application of ADKG in predictive modeling using the UK Biobank data revealed models based on ADKG outperforming others, as evidenced by higher values in the areas under the receiver operating characteristic (ROC) curves., Conclusion: The ADKG is a valuable resource for generating hypotheses and enhancing predictive models, highlighting its potential to advance AD's disease research and treatment strategies., Competing Interests: Competing interests The authors declare that they have no competing interests.

Background: Estrogen-containing hormonal contraception (HC) is a well-established risk factor for venous thromboembolism (VTE). Women with sickle cell disease (SCD) also have an increased risk of VTE. However, it is unknown if exposure to HC exacerbates the risk of VTE in women with SCD., Objectives: Assess the impact of HC on VTE risk in women with SCD and explore additional risk factors contributing to VTE development., Methods: We analyzed a retrospective cohort of women of reproductive age (15-49 years) with SCD at the University of North Carolina from 2010 to 2022., Results: We identified 370 women with SCD, and 93 (25.1%) had a history of VTE. Among 219 women exposed to HC, 38 of 184 (20.6%) had a VTE while actively using HC, whereas 20 of 151 (13.2%) women never exposed to HC had a VTE. Of the patients exposed to HC, 64 of 184 (34.7%) were on estrogen-containing HC, with 120 of 184 (65.3%) using progestin-only formulations. Cox regression analysis found that progestin-only formulations increased VTE risk (hazard ratio: 2.03; 95% CI: 1.107-3.726, P  < .05). However, when accounting for disease severity, the association between progestin-only treatment and VTE risk was not significant. Indeed, a nuanced analysis revealed that both severe (odds ratio: 11.79; 95% CI: 5.14-27.06; P  < .001) and moderate (odds ratio: 4.37; 95% CI: 1.77-10.76; P  = .001) disease increased risk compared with mild disease. Neither genotype nor hydroxyurea use influenced VTE risk., Conclusion: Overall, we found that increased thrombotic risk is more likely influenced by disease status than HC exposure and should play a role in shared decision-making with patients., (© 2024 The Author(s).)

The UK Biobank (UKB) imaging project is a crucial resource for biomedical research, but is limited to 100,000 participants due to cost and accessibility barriers. Here we used genetic data to predict heritable imaging-derived phenotypes (IDPs) for a larger cohort. We developed and evaluated 4,375 IDP genetic scores (IGS) derived from UKB brain and body images. When applied to UKB participants who were not imaged, IGS revealed links to numerous phenotypes and stratified participants at increased risk for both brain and somatic diseases. For example, IGS identified individuals at higher risk for Alzheimer's disease and multiple sclerosis, offering additional insights beyond traditional polygenic risk scores of these diseases. When applied to independent external cohorts, IGS also stratified those at high disease risk in the All of Us Research Program and the Alzheimer's Disease Neuroimaging Initiative study. Our results demonstrate that, while the UKB imaging cohort is largely healthy and may not be the most enriched for disease risk management, it holds immense potential for stratifying the risk of various brain and body diseases in broader external genetic cohorts.

Genetic prediction holds immense promise for translating genetic discoveries into medical advances. As the high-dimensional covariance matrix (or the linkage disequilibrium (LD) pattern) of genetic variants often presents a block-diagonal structure, numerous methods account for the dependence among variants in predetermined local LD blocks. Moreover, due to privacy considerations and data protection concerns, genetic variant dependence in each LD block is typically estimated from external reference panels rather than the original training data set. This paper presents a unified analysis of blockwise and reference panel-based estimators in a high-dimensional prediction framework without sparsity restrictions. We find that, surprisingly, even when the covariance matrix has a block-diagonal structure with well-defined boundaries, blockwise estimation methods adjusting for local dependence can be substantially less accurate than methods controlling for the whole covariance matrix. Further, estimation methods built on the original training data set and external reference panels are likely to have varying performance in high dimensions, which may reflect the cost of having only access to summary level data from the training data set. This analysis is based on novel results in random matrix theory for block-diagonal covariance matrix. We numerically evaluate our results using extensive simulations and real data analysis in the UK Biobank.

Unsupervised domain adaptation (UDA) via deep learning has attracted appealing attention for tackling domain-shift problems caused by distribution discrepancy across different domains. Existing UDA approaches highly depend on the accessibility of source domain data, which is usually limited in practical scenarios due to privacy protection, data storage and transmission cost, and computation burden. To tackle this issue, many source-free unsupervised domain adaptation (SFUDA) methods have been proposed recently, which perform knowledge transfer from a pre-trained source model to the unlabeled target domain with source data inaccessible. A comprehensive review of these works on SFUDA is of great significance. In this paper, we provide a timely and systematic literature review of existing SFUDA approaches from a technical perspective. Specifically, we categorize current SFUDA studies into two groups, i.e., white-box SFUDA and black-box SFUDA, and further divide them into finer subcategories based on different learning strategies they use. We also investigate the challenges of methods in each subcategory, discuss the advantages/disadvantages of white-box and black-box SFUDA methods, conclude the commonly used benchmark datasets, and summarize the popular techniques for improved generalizability of models learned without using source data. We finally discuss several promising future directions in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Motivation: Imaging genetics integrates imaging and genetic techniques to examine how genetic variations influence the function and structure of organs like the brain or heart, providing insights into their impact on behavior and disease phenotypes. The use of organ-wide imaging endophenotypes has increasingly been used to identify potential genes associated with complex disorders. However, analyzing organ-wide imaging data alongside genetic data presents two significant challenges: high dimensionality and complex relationships. To address these challenges, we propose a novel, nonlinear inference framework designed to partially mitigate these issues., Results: We propose a functional partial least squares through distance covariance (FPLS-DC) framework for efficient genome wide analyses of imaging phenotypes. It consists of two components. The first component utilizes the FPLS-derived base functions to reduce image dimensionality while screening genetic markers. The second component maximizes the distance correlation between genetic markers and projected imaging data, which is a linear combination of the FPLS-basis functions, using simulated annealing algorithm. In addition, we proposed an iterative FPLS-DC method based on FPLS-DC framework, which effectively overcomes the influence of inter-gene correlation on inference analysis. We efficiently approximate the null distribution of test statistics using a gamma approximation. Compared to existing methods, FPLS-DC offers computational and statistical efficiency for handling large-scale imaging genetics. In real-world applications, our method successfully detected genetic variants associated with the hippocampus, demonstrating its value as a statistical toolbox for imaging genetic studies., Availability and Implementation: The FPLS-DC method we propose opens up new research avenues and offers valuable insights for analyzing functional and high-dimensional data. In addition, it serves as a useful tool for scientific analysis in practical applications within the field of imaging genetics research. The R package FPLS-DC is available in Github: https://github.com/BIG-S2/FPLSDC., (© The Author(s) 2024. Published by Oxford University Press.)

Temporomandibular joint osteoarthritis (TMJ OA) is a prevalent degenerative disease characterized by chronic pain and impaired jaw function. The complexity of TMJ OA has hindered the development of prognostic tools, posing a significant challenge in timely, patient-specific management. Addressing this gap, our research employs a comprehensive, multidimensional approach to advance TMJ OA prognostication. We conducted a prospective study with 106 subjects, 74 of whom were followed up after 2 to 3 y of conservative treatment. Central to our methodology is the development of an innovative, open-source predictive modeling framework, the Ensemble via Hierarchical Predictions through Nested cross-validation tool (EHPN). This framework synergistically integrates 18 feature selection, statistical, and machine learning methods to yield an accuracy of 0.87, with an area under the ROC curve of 0.72 and an F1 score of 0.82. Our study, beyond technical advancements, emphasizes the global impact of TMJ OA, recognizing its unique demographic occurrence. We highlight key factors influencing TMJ OA progression. Using SHAP analysis, we identified personalized prognostic predictors: lower values of headache, lower back pain, restless sleep, condyle high gray level-GL-run emphasis, articular fossa GL nonuniformity, and long-run low GL emphasis; and higher values of superior joint space, mouth opening, saliva Vascular-endothelium-growth-factor, Matrix-metalloproteinase-7, serum Epithelial-neutrophil-activating-peptide, and age indicate recovery likelihood. Our multidimensional and multimodal EHPN tool enhances clinicians' decision-making, offering a transformative translational infrastructure. The EHPN model stands as a significant contribution to precision medicine, offering a paradigm shift in the management of temporomandibular disorders and potentially influencing broader applications in personalized healthcare., Competing Interests: Competing interests statement:The authors declare no competing interest.

As an essential part of the central nervous system, white matter coordinates communications between different brain regions and is related to a wide range of neurodegenerative and neuropsychiatric disorders. Previous genome-wide association studies (GWASs) have uncovered loci associated with white matter microstructure. However, GWASs suffer from limited reproducibility and difficulties in detecting multi-single-nucleotide polymorphism (multi-SNP) and epistatic effects. In this study, we adopt the concept of supervariants, a combination of alleles in multiple loci, to account for potential multi-SNP effects. We perform supervariant identification and validation to identify loci associated with 22 white matter fractional anisotropy phenotypes derived from diffusion tensor imaging. To increase reproducibility, we use United Kingdom (UK) Biobank White British (n = 30,842) data for discovery and internal validation, and UK Biobank White but non-British (n = 1927) data, Europeans from the Adolescent Brain Cognitive Development study (n = 4399) data, and Europeans from the Human Connectome Project (n = 319) data for external validation. We identify 23 novel loci on the discovery set that have not been reported in the previous GWASs on white matter microstructure. Among them, three supervariants on genomic regions 5q35.1, 8p21.2, and 19q13.32 have P -values lower than 0.05 in the meta-analysis of the three independent validation data sets. These supervariants contain genetic variants located in genes that have been related to brain structures, cognitive functions, and neuropsychiatric diseases. Our findings provide a better understanding of the genetic architecture underlying white matter microstructure., (© 2024 Wang et al.; Published by Cold Spring Harbor Laboratory Press.)

The aim of this paper is to systematically investigate merging and ensembling methods for spatially varying coefficient mixed effects models (SVCMEM) in order to carry out integrative learning of neuroimaging data obtained from multiple biomedical studies. The "merged" approach involves training a single learning model using a comprehensive dataset that encompasses information from all the studies. Conversely, the "ensemble" approach involves creating a weighted average of distinct learning models, each developed from an individual study. We systematically investigate the prediction accuracy of the merged and ensemble learners under the presence of different degrees of interstudy heterogeneity. Additionally, we establish asymptotic guidelines for making strategic decisions about when to employ either of these models in different scenarios, along with deriving optimal weights for the ensemble learner. To validate our theoretical results, we perform extensive simulation studies. The proposed methodology is also applied to 3 large-scale neuroimaging studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Biometric Society.)

Mounting evidence suggests considerable diversity in brain aging trajectories, primarily arising from the complex interplay between age, genetic, and environmental risk factors, leading to distinct patterns of micro- and macro-cerebral aging. The underlying mechanisms of such effects still remain unclear. We conducted a comprehensive association analysis between cerebral structural measures and prevalent risk factors, using data from 36,969 UK Biobank subjects aged 44-81. Participants were assessed for brain volume, white matter diffusivity, Apolipoprotein E (APOE) genotypes, polygenic risk scores, lifestyles, and socioeconomic status. We examined genetic and environmental effects and their interactions with age and sex, and identified 726 signals, with education, alcohol, and smoking affecting most brain regions. Our analysis revealed negative age-APOE-ε4 and positive age-APOE-ε2 interaction effects, respectively, especially in females on the volume of amygdala, positive age-sex-APOE-ε4 interaction on the cerebellar volume, positive age-excessive-alcohol interaction effect on the mean diffusivity of the splenium of the corpus callosum, positive age-healthy-diet interaction effect on the paracentral volume, and negative APOE-ε4-moderate-alcohol interaction effects on the axial diffusivity of the superior fronto-occipital fasciculus. These findings highlight the need of considering age, sex, genetic, and environmental joint effects in elucidating normal or abnormal brain aging., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The aim of this paper is to propose a novel method for estimating trans-ancestry genetic correlations in genome-wide association studies (GWAS) using genetically-predicted observations. These correlations describe how genetic architecture of complex traits varies among populations. Our new estimator corrects for biases arising from prediction errors in high-dimensional weak GWAS signals, while addressing the ethnic diversity inherent in GWAS data, such as linkage disequilibrium (LD) differences. A distinguishing feature of our approach is its flexibility regarding sample sizes: it necessitates a large GWAS sample only from one population, while the secondary population may have a much smaller cohort, even in the hundreds. This design directly addresses the existing imbalance in GWAS data resources, where datasets for European populations typically outnumber those of non-European ancestries. Through extensive simulations and real data analysis from the UK Biobank study encompassing 26 complex traits, we validate the reliability of our method. Our results illuminate the broader implications of transferring genetic findings across diverse populations., Competing Interests: Disclosure statement: The authors report there are no competing interests to declare.

Purpose: Falls are associated with ocular trauma in the elderly. However, it is unlikely for a fall to cause ocular injury unless there is a disruption in the protective maneuvers that shield the face. We suspect ocular injury may be an early indicator of systemic or neurologic degeneration. This study investigates the 5-year incidence of cardiovascular and neurodegenerative diseases in older patients who sustained ocular or periorbital injuries., Patients and Methods: This was a retrospective cohort study. The study population included 141 patients over the age of 65 who sustained trauma to the eye, orbit, or eyelid between April 2011 and June 2016. The control population included 141 patients with a similar range of comorbidities who received cataract surgery during the same period. The study measured new diagnoses of various disorders during the 5-year period following presentation., Results: There were a total of 180 females and 102 males in the study. The mean ages of the control and subject group were 76 and 81.8, respectively. Of our twelve tested comorbidity types, patients that suffered a periocular trauma were more likely to develop heart failure (p=0.00244), dementia (p=0.00002), Alzheimer's disease (p=0.00087), and vascular disease (p=0.00037)., Conclusion: Geriatric patients who sustained ocular and periocular injuries had a greater incidence of heart failure, dementia, Alzheimer's disease, and atherosclerosis diagnoses in the 5-year period following injury. The findings of this study suggest that periocular trauma may be an early indicator of underlying degenerative or systemic disease. Ophthalmologists should ensure proper primary care follow-up in conjunction with recovery from injury., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Pham et al.)

Multi-site brain magnetic resonance imaging (MRI) has been widely used in clinical and research domains, but usually is sensitive to non-biological variations caused by site effects ( e.g. , field strengths and scanning protocols). Several retrospective data harmonization methods have shown promising results in removing these non-biological variations at feature or whole-image level. Most existing image-level harmonization methods are implemented through generative adversarial networks, which are generally computationally expensive and generalize poorly on independent data. To this end, this paper proposes a disentangled latent energy-based style translation (DLEST) framework for image-level structural MRI harmonization. Specifically, DLEST disentangles site-invariant image generation and site-specific style translation via a latent autoencoder and an energy-based model. The autoencoder learns to encode images into low-dimensional latent space, and generates faithful images from latent codes. The energy-based model is placed in between the encoding and generation steps, facilitating style translation from a source domain to a target domain implicitly. This allows highly generalizable image generation and efficient style translation through the latent space. We train our model on 4,092 T1-weighted MRIs in 3 tasks: histogram comparison, acquisition site classification, and brain tissue segmentation. Qualitative and quantitative results demonstrate the superiority of our approach, which generally outperforms several state-of-the-art methods.

Disease heterogeneity is ubiquitous in biomedical and clinical studies. In genetic studies, researchers are increasingly interested in understanding the distinct genetic underpinning of subtypes of diseases. However, existing set-based analysis methods for genome-wide association studies are either inadequate or inefficient to handle such multicategorical outcomes. In this paper, we proposed a novel set-based association analysis method, sequence kernel association test (SKAT)-MC, the sequence kernel association test for multicategorical outcomes (nominal or ordinal), which jointly evaluates the relationship between a set of variants (common and rare) and disease subtypes. Through comprehensive simulation studies, we showed that SKAT-MC effectively preserves the nominal type I error rate while substantially increases the statistical power compared to existing methods under various scenarios. We applied SKAT-MC to the Polish breast cancer study (PBCS), and identified gene FGFR2 was significantly associated with estrogen receptor (ER)+ and ER- breast cancer subtypes. We also investigated educational attainment using UK Biobank data ( N = 127 , 127 $N=127,127$ ) with SKAT-MC, and identified 21 significant genes in the genome. Consequently, SKAT-MC is a powerful and efficient analysis tool for genetic association studies with multicategorical outcomes. A freely distributed R package SKAT-MC can be accessed at https://github.com/Zhiwen-Owen-Jiang/SKATMC., (© 2023 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC.)

Motivated by the analysis of longitudinal neuroimaging studies, we study the longitudinal functional linear regression model under asynchronous data setting for modeling the association between clinical outcomes and functional (or imaging) covariates. In the asynchronous data setting, both covariates and responses may be measured at irregular and mismatched time points, posing methodological challenges to existing statistical methods. We develop a kernel weighted loss function with roughness penalty to obtain the functional estimator and derive its representer theorem. The rate of convergence, a Bahadur representation, and the asymptotic pointwise distribution of the functional estimator are obtained under the reproducing kernel Hilbert space framework. We propose a penalized likelihood ratio test to test the nullity of the functional coefficient, derive its asymptotic distribution under the null hypothesis, and investigate the separation rate under the alternative hypotheses. Simulation studies are conducted to examine the finite-sample performance of the proposed procedure. We apply the proposed methods to the analysis of multitype data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, which reveals significant association between 21 regional brain volume density curves and the cognitive function. Data used in preparation of this paper were obtained from the ADNI database (adni.loni.usc.edu)., (© 2022 The International Biometric Society.)

Mild cognitive impairment (MCI) is a clinical syndrome characterized by the onset and evolution of cognitive impairments, often considered a transitional stage to Alzheimer's disease (AD). The genetic traits of MCI patients who experience a rapid progression to AD can enhance early diagnosis capabilities and facilitate drug discovery for AD. While a genome-wide association study (GWAS) is a standard tool for identifying single nucleotide polymorphisms (SNPs) related to a disease, it fails to detect SNPs with small effect sizes due to stringent control for multiple testing. Additionally, the method does not consider the group structures of SNPs, such as genes or linkage disequilibrium blocks, which can provide valuable insights into the genetic architecture. To address the limitations, we propose a Bayesian bi-level variable selection method that detects SNPs associated with time of conversion from MCI to AD. Our approach integrates group inclusion indicators into an accelerated failure time model to identify important SNP groups. Additionally, we employ data augmentation techniques to impute censored time values using a predictive posterior. We adapt Dirichlet-Laplace shrinkage priors to incorporate the group structure for SNP-level variable selection. In the simulation study, our method outperformed other competing methods regarding variable selection. The analysis of Alzheimer's Disease Neuroimaging Initiative (ADNI) data revealed several genes directly or indirectly related to AD, whereas a classical GWAS did not identify any significant SNPs.

Adult twin neuroimaging studies have revealed that cortical thickness (CT) and surface area (SA) are differentially influenced by genetic information, leading to their spatially distinct genetic patterning and topography. However, the postnatal origins of the genetic topography of CT and SA remain unclear, given the dramatic cortical development from neonates to adults. To fill this critical gap, this study unprecedentedly explored how genetic information differentially regulates the spatial topography of CT and SA in the neonatal brain by leveraging brain magnetic resonance (MR) images from 202 twin neonates with minimal influence by the complicated postnatal environmental factors. We capitalized on infant-dedicated computational tools and a data-driven spectral clustering method to parcellate the cerebral cortex into a set of distinct regions purely according to the genetic correlation of cortical vertices in terms of CT and SA, respectively, and accordingly created the first genetically informed cortical parcellation maps of neonatal brains. Both genetic parcellation maps exhibit bilaterally symmetric and hierarchical patterns, but distinct spatial layouts. For CT, regions with closer genetic relationships demonstrate an anterior-posterior (A-P) division, while for SA, regions with greater genetic proximity are typically within the same lobe. Certain genetically informed regions exhibit strong similarities between neonates and adults, with the most striking similarities in the medial surface in terms of SA, despite their overall substantial differences in genetic parcellation maps. These results greatly advance our understanding of the development of genetic influences on the spatial patterning of cortical morphology. SIGNIFICANCE STATEMENT Genetic influences on cortical thickness (CT) and surface area (SA) are complex and could evolve throughout the lifespan. However, studies revealing distinct genetic topography of CT and SA have been limited to adults. Using brain structural magnetic resonance (MR) images of twins, we unprecedentedly discovered the distinct genetically-informed parcellation maps of CT and SA in neonatal brains, respectively. Each genetic parcellation map comprises a distinct spatial layout of cortical regions, where vertices within the same region share high genetic correlation. These genetic parcellation maps of CT and SA of neonates largely differ from those of adults, despite their highly remarkable similarities in the medial cortex of SA. These discoveries provide important insights into the genetic organization of the early cerebral cortex development., (Copyright © 2023 the authors.)

The aim of this review is to provide a comprehensive survey of statistical challenges in neuroimaging data analysis, from neuroimaging techniques to large-scale neuroimaging studies and statistical learning methods. We briefly review eight popular neuroimaging techniques and their potential applications in neuroscience research and clinical translation. We delineate four themes of neuroimaging data and review major image processing analysis methods for processing neuroimaging data at the individual level. We briefly review four large-scale neuroimaging-related studies and a consortium on imaging genomics and discuss four themes of neuroimaging data analysis at the population level. We review nine major population-based statistical analysis methods and their associated statistical challenges and present recent progress in statistical methodology to address these challenges.

Several studies employ multi-site rs-fMRI data for major depressive disorder (MDD) identification, with a specific site as the to-be-analyzed target domain and other site(s) as the source domain. But they usually suffer from significant inter-site heterogeneity caused by the use of different scanners and/or scanning protocols and fail to build generalizable models that can well adapt to multiple target domains. In this article, we propose a dual-expert fMRI harmonization (DFH) framework for automated MDD diagnosis. Our DFH is designed to simultaneously exploit data from a single labeled source domain/site and two unlabeled target domains for mitigating data distribution differences across domains. Specifically, the DFH consists of a domain-generic student model and two domain-specific teacher/expert models that are jointly trained to perform knowledge distillation through a deep collaborative learning module. A student model with strong generalizability is finally derived, which can be well adapted to unseen target domains and analysis of other brain diseases. To the best of our knowledge, this is among the first attempts to investigate multi-target fMRI harmonization for MDD diagnosis. Comprehensive experiments on 836 subjects with rs-fMRI data from 3 different sites show the superiority of our method. The discriminative brain functional connectivities identified by our method could be regarded as potential biomarkers for fMRI-related MDD diagnosis., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

While ample research on independent associations between infant cognition and gut microbiota composition and human milk (HM) oligosaccharides (HMOs) has been reported, studies on how the interactions between gut microbiota and HMOs may yield associations with cognitive development in infancy are lacking. We aimed to determine how HMOs and species of Bacteroides and Bifidobacterium genera interact with each other and their associations with cognitive development in typically developing infants. A total of 105 mother-infant dyads were included in this study. The enrolled infants [2.9-12 months old (8.09 ± 2.48)] were at least predominantly breastfed at 4 months old. A total of 170 HM samples from the mothers and fecal samples of the children were collected longitudinally. Using the Mullen Scales of Early Learning to assess cognition and the scores as the outcomes, linear mixed effects models including both the levels of eight HMOs and relative abundance of Bacteroides and Bifidobacterium species as main associations and their interactions were employed with adjusting covariates; infant sex, delivery mode, maternal education, site, and batch effects of HMOs. Additionally, regression models stratifying infants based on the A-tetrasaccharide (A-tetra) status of the HM they received were also employed to determine if the associations depend on the A-tetra status. With Bacteroides species, we observed significant associations with motor functions, while Bif. catenulatum showed a negative association with visual reception in the detectable A-tetra group both as main effect (value of p  = 0.012) and in interaction with LNFP-I (value of p  = 0.007). Additionally, 3-FL showed a positive association with gross motor ( p  = 0.027) and visual reception ( p  = 0.041). Furthermore, significant associations were observed with the interaction terms mainly in the undetectable A-tetra group. Specifically, we observed negative associations for Bifidobacterium species and LNT [ breve ( p  = 0.011) and longum ( p  = 0.022)], and positive associations for expressive language with 3'-SL and Bif. bifidum ( p  = 0.01), 6'-SL and B. fragilis ( p  = 0.019), and LNFP-I and Bif. kashiwanohense ( p  = 0.048), respectively. Our findings suggest that gut microbiota and HMOs are both independently and interactively associated with early cognitive development. In particular, the diverse interactions between HMOs and Bacteroides and Bifidobacterium species reveal different candidate pathways through which HMOs, Bifidobacterium and Bacteroides species potentially interact to impact cognitive development in infancy., Competing Interests: TS, JH, and NS are employees of Société des Produits Nestlé, SA, Switzerland. This study was supported in part by a grant from Nestlé Product Technology Center-Nutrition, Société des Produits Nestlé S.A., Switzerland. WL was a consultant of and received travel support from Nestlé SA, Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cho, Samuel, Li, Howell, Baluyot, Hazlett, Elison, Zhu, Hauser, Sprenger and Lin.)

Brain subcortical structures are paramount in many cognitive functions and their aberrations during infancy are predisposed to various neurodevelopmental and neuropsychiatric disorders, making it highly essential to characterize the early subcortical normative growth patterns. This study investigates the volumetric development and surface area expansion of six subcortical structures and their associations with Mullen scales of early learning by leveraging 513 high-resolution longitudinal MRI scans within the first two postnatal years. Results show that (1) each subcortical structure (except for the amygdala with an approximately linear increase) undergoes rapid nonlinear volumetric growth after birth, which slows down at a structure-specific age with bilaterally similar developmental patterns; (2) Subcortical local area expansion reveals structure-specific and spatiotemporally heterogeneous patterns; (3) Positive associations between thalamus and both receptive and expressive languages and between caudate and putamen and fine motor are revealed. This study advances our understanding of the dynamic early subcortical developmental patterns., (© 2023. The Author(s).)

Cardiovascular health interacts with cognitive and mental health in complex ways, yet little is known about the phenotypic and genetic links of heart-brain systems. We quantified heart-brain connections using multiorgan magnetic resonance imaging (MRI) data from more than 40,000 subjects. Heart MRI traits displayed numerous association patterns with brain gray matter morphometry, white matter microstructure, and functional networks. We identified 80 associated genomic loci ( P < 6.09 × 10 -10 ) for heart MRI traits, which shared genetic influences with cardiovascular and brain diseases. Genetic correlations were observed between heart MRI traits and brain-related traits and disorders. Mendelian randomization suggests that heart conditions may causally contribute to brain disorders. Our results advance a multiorgan perspective on human health by revealing heart-brain connections and shared genetic influences.

In the era of big data, univariate models have widely been used as a workhorse tool for quickly producing marginal estimators; and this is true even when in a high-dimensional dense setting, in which many features are "true," but weak signals. Genome-wide association studies (GWAS) epitomize this type of setting. Although the GWAS marginal estimator is popular, it has long been criticized for ignoring the correlation structure of genetic variants (i.e., the linkage disequilibrium [LD] pattern). In this paper, we study the effects of LD pattern on the GWAS marginal estimator and investigate whether or not additionally accounting for the LD can improve the prediction accuracy of complex traits. We consider a general high-dimensional dense setting for GWAS and study a class of ridge-type estimators, including the popular marginal estimator and the best linear unbiased prediction (BLUP) estimator as two special cases. We show that the performance of GWAS marginal estimator depends on the LD pattern through the first three moments of its eigenvalue distribution. Furthermore, we uncover that the relative performance of GWAS marginal and BLUP estimators highly depends on the ratio of GWAS sample size over the number of genetic variants. Particularly, our finding reveals that the marginal estimator can easily become near-optimal within this class when the sample size is relatively small, even though it ignores the LD pattern. On the other hand, BLUP estimator has substantially better performance than the marginal estimator as the sample size increases toward the number of genetic variants, which is typically in millions. Therefore, adjusting for the LD (such as in the BLUP) is most needed when GWAS sample size is large. We illustrate the importance of our results by using the simulated data and real GWAS., (© 2022 The International Biometric Society.)

Revealing early dynamic development of the normative cerebellar structures contributes to exploring cerebellum-related neurodevelopmental disorders. Here, leveraging infant-tailored cerebellar image processing techniques, we studied the dynamic volumetric developmental trajectories of cerebellum and 27 cerebellar sub-regions and their relationships with behavioral scores based on 511 high-resolution structural MRI scans during the first 800 postnatal days. The ratio of the entire cerebellum to the intracranial volume increases rapidly at first and then peaks at 13 months after birth. Both the absolute and relative volumes of most cerebellar sub-structures exhibit rapid increase at first, then the relative volumes decrease slightly after arriving at peaks (except for X lobules). Each lobule depicts larger absolute volume in males than in females. The within-subject variation of the cerebellar volumetric percentile score is generally stable. The volumetric development of several lobules (e.g., V, Crus I, and Crus II) has a significantly positive correlation with fine motor skills during the age range examined., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite interest in the joint modeling of multiple functional responses such as diffusion properties in neuroimaging, robust statistical methods appropriate for this task are lacking. To address this need, we propose a varying coefficient quantile regression model able to handle bivariate functional responses. Our work supports innovative insights into biomedical data by modeling the joint distribution of functional variables over their domains and across clinical covariates. We propose an estimation procedure based on the alternating direction method of multipliers and propagation separation algorithms to estimate varying coefficients using a B-spline basis and an $L&#95;2$ smoothness penalty that encourages interpretability. A simulation study and an application to a real-world neurodevelopmental data set demonstrates the performance of our model and the insights provided by modeling functional fractional anisotropy and mean diffusivity jointly and their association with gestational age and sex., (© The Author 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The objective of this study was to determine the prevalence of pyridoxine deficiency, measured by pyridoxal phosphate (PLP) levels, in patients admitted to the hospital with established (benzodiazepine-resistant) status epilepticus (SE) (eSE) and to compare to three control groups: intensive care unit (ICU) patients without SE (ICU-noSE), non-ICU inpatients without SE (non-ICU), and outpatients with or without a history of epilepsy (outpatient)., Methods: This retrospective cohort study was conducted at the University of North Carolina Hospitals and Yale New Haven Hospital. Participants included inpatients and outpatients who had serum PLP levels measured during clinical care between January 2018 and March 2021. The first PLP level obtained was categorized as normal (> 30 nmol/L), marginal (≤ 30 nmol/L), deficient (≤ 20 nmol/L), and severely deficient (≤ 5 nmol/L)., Results: A total of 293 patients were included (52 eSE, 40 ICU-noSE, 44 non-ICU, and 157 outpatient). The median age was 55 (range 19-99) years. The median PLP level of the eSE group (12 nmol/L) was lower than that of the ICU-noSE (22 nmol/L, p = 0.003), non-ICU (16 nmol/L, p = 0.05), and outpatient groups (36 nmol/L, p < 0.001). Patients with eSE had a significantly higher prevalence of marginal and deficient PLP levels (90 and 80%, respectively) than patients in each of the other three groups (ICU-noSE: 70, 50%; non-ICU: 63, 54%; outpatient: 38, 21%). This significantly higher prevalence persisted after correcting for critical illness severity and timing of PLP level collection., Conclusions: Our study confirms previous findings indicating a high prevalence of pyridoxine deficiency (as measured by serum PLP levels) in patients with eSE, including when using a more restricted definition of pyridoxine deficiency. Prevalence is higher in patients with eSE than in patients in all three control groups (ICU-noSE, non-ICU, and outpatient). Considering the role of pyridoxine, thus PLP, in the synthesis of γ-aminobutyric acid and its easy and safe administration, prospective studies on pyridoxine supplementation in patients with eSE are needed., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Functional magnetic resonance imaging (fMRI) has been widely used to identify brain regions linked to critical functions, such as language and vision, and to detect tumors, strokes, brain injuries, and diseases. It is now known that large sample sizes are necessary for fMRI studies to detect small effect sizes and produce reproducible results. Here we report a systematic association analysis of 647 traits with imaging features extracted from resting-state and task-evoked fMRI data of more than 40,000 UK Biobank participants. We used a parcellation-based approach to generate 64,620 functional connectivity measures to reveal fine-grained details about cerebral cortex functional organizations. The difference between functional organizations at rest and during task was examined, and we have prioritized important brain regions and networks associated with a variety of human traits and clinical outcomes. For example, depression was most strongly associated with decreased connectivity in the somatomotor network. We have made our results publicly available and developed a browser framework to facilitate the exploration of brain function-trait association results (http://fmriatlas.org/)., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests.

Over the past 30 years, magnetic resonance imaging has become a ubiquitous tool for accurately visualizing the change and development of the brain's subcortical structures (e.g., hippocampus). Although subcortical structures act as information hubs of the nervous system, their quantification is still in its infancy due to many challenges in shape extraction, representation, and modeling. Here, we develop a simple and efficient framework of longitudinal elastic shape analysis (LESA) for subcortical structures. Integrating ideas from elastic shape analysis of static surfaces and statistical modeling of sparse longitudinal data, LESA provides a set of tools for systematically quantifying changes of longitudinal subcortical surface shapes from raw structure MRI data. The key novelties of LESA include: (i) it can efficiently represent complex subcortical structures using a small number of basis functions and (ii) it can accurately delineate the spatiotemporal shape changes of the human subcortical structures. We applied LESA to analyze three longitudinal neuroimaging data sets and showcase its wide applications in estimating continuous shape trajectories, building life-span growth patterns, and comparing shape differences among different groups. In particular, with the Alzheimer's Disease Neuroimaging Initiative (ADNI) data, we found that the Alzheimer's Disease (AD) can significantly speed the shape change of ventricle and hippocampus from 60 to 75 years old compared with normal aging.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood, and is often characterized by altered executive functioning. Executive function has been found to be supported by flexibility in dynamic brain reconfiguration. Thus, we applied multilayer community detection to resting-state fMRI data in 180 children with ADHD and 180 typically developing children (TDC) to identify alterations in dynamic brain reconfiguration in children with ADHD. We specifically evaluated MR derived neural flexibility, which is thought to underlie cognitive flexibility, or the ability to selectively switch between mental processes. Significantly decreased neural flexibility was observed in the ADHD group at both the whole brain (raw p = 0.0005) and sub-network levels (p < 0.05, FDR corrected), particularly for the default mode network, attention-related networks, executive function-related networks, and primary networks. Furthermore, the subjects with ADHD who received medication exhibited significantly increased neural flexibility (p = 0.025, FDR corrected) when compared to subjects with ADHD who were medication naïve, and their neural flexibility was not statistically different from the TDC group (p = 0.74, FDR corrected). Finally, regional neural flexibility was capable of differentiating ADHD from TDC (Accuracy: 77% for tenfold cross-validation, 74.46% for independent test) and of predicting ADHD severity using clinical measures of symptom severity (R 2 : 0.2794 for tenfold cross-validation, 0.156 for independent test). In conclusion, the present study found that neural flexibility is altered in children with ADHD and demonstrated the potential clinical utility of neural flexibility to identify children with ADHD, as well as to monitor treatment responses and disease severity., (© 2022. The Author(s).)

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes., (© 2022. The Author(s).)

Early dietary exposure via human milk nutrients offers a window of opportunity to support cognitive and temperament development. While several studies have focused on associations of few pre-selected human milk nutrients with cognition and temperament, it is highly plausible that human milk nutrients synergistically and jointly support cognitive and behavioral development in early life. We aimed to discern the combined associations of three major classes of human milk nutrients with cognition and temperament during the first 6 months of life when human milk is the primary source of an infant's nutrition and explore whether there were persistent effects up to 18 months old. The Mullen Scales of Early Learning and Infant Behavior Questionnaires-Revised were used to assess cognition and temperament, respectively, of 54 exclusively/predominantly breastfed infants in the first 6 months of life, whose follow-ups were conducted at 6-9, 9-12, and 12-18 months old. Human milk samples were obtained from the mothers of the participants at less than 6 months of age and analyzed for fatty acids [total monounsaturated fatty acids, polyunsaturated fatty acid, total saturated fatty acid (TSFA), arachidonic acid (ARA), docosahexaenoic acid (DHA), ARA/DHA, omega-6/omega-3 polyunsaturated fatty acids ratio (n-6/n-3)], phospholipids [phosphatidylcholine, phosphatidylethanolamine (PE), phosphatidylinositol (PI), sphingomyelin], and choline [free choline, phosphocholine (PCho), glycerophosphocholine]. Feature selection was performed to select nutrients associated with cognition and temperament. The combined effects of selected nutrients were analyzed using multiple regression. A positive association between the arachidonic acid (ARA) and surgency was observed ( p = 0.024). A significant effect of DHA, n-6/n-3, PE, and TSFA concentrations on receptive language ( R 2 = 0.39, p = 0.025) and the elevated ARA, PCho, and PI with increased surgency ( R 2 = 0.43, p = 0.003) was identified, suggesting that DHA and ARA may have distinct roles for temperament and language functions. Furthermore, the exploratory association analyses suggest that the effects of human milk nutrients on R.L. and surgency may persist beyond the first 6 months of life, particularly surgency at 12-18 months ( p = 0.002). Our study highlighted that various human milk nutrients work together to support the development of cognition and temperament traits during early infancy., Competing Interests: TS, JH, and NS were the employees of Société des Produits Nestlé SA, Switzerland. WL was a consultant of and received travel support from Nestlé SA, Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Samuel, Zhu, Howell, Cho, Baluyot, Hazlett, Elison, Wu, Hauser, Sprenger, Zhu and Lin.)

Spatial transcriptomics (ST) technologies allow researchers to examine transcriptional profiles along with maintained positional information. Such spatially resolved transcriptional characterization of intact tissue samples provides an integrated view of gene expression in its natural spatial and functional context. However, high-throughput sequencing-based ST technologies cannot yet reach single cell resolution. Thus, similar to bulk RNA-seq data, gene expression data at ST spot-level reflect transcriptional profiles of multiple cells and entail the inference of cell-type composition within each ST spot for valid and powerful subsequent analyses. Realizing the critical importance of cell-type decomposition, multiple groups have developed ST deconvolution methods. The aim of this work is to review state-of-the-art methods for ST deconvolution, comparing their strengths and weaknesses. In particular, we construct ST spots from single-cell level ST data to assess the performance of 10 methods, with either ideal reference or non-ideal reference. Furthermore, we examine the performance of these methods on spot- and bead-level ST data by comparing estimated cell-type proportions to carefully matched single-cell ST data. In comparing the performance on various tissues and technological platforms, we concluded that RCTD and stereoscope achieve more robust and accurate inferences., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Fiber photometry is an emerging technique for recording fluorescent sensor activity in the brain. However, significant hemoglobin absorption artifacts in fiber photometry data may be misinterpreted as sensor activity changes. Because hemoglobin exists widely in the brain, and its concentration varies temporally, such artifacts could impede the accuracy of photometry recordings. Here we present use of spectral photometry and computational methods to quantify photon absorption effects by using activity-independent fluorescence signals, which can be used to derive oxy- and deoxy-hemoglobin concentration changes. Although these changes are often temporally delayed compared with the fast-responding fluorescence spikes, we found that erroneous interpretation may occur when examining pharmacology-induced sustained changes and that sometimes hemoglobin absorption could flip the GCaMP signal polarity. We provide hemoglobin-based correction methods to restore fluorescence signals and compare our results with other commonly used approaches. We also demonstrated the utility of spectral fiber photometry for delineating regional differences in hemodynamic response functions., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

The brain connectome maps the structural and functional connectivity that forms an important neurobiological basis for the analysis of human cognitive traits while the genetic predisposition and our cognition ability are frequently found in close association. The issue of how genetic architecture and brain connectome causally affect human behaviors remains unknown. To seek for the potential causal relationship, in this paper, we carried out the causal pathway analysis from single nucleotide polymorphism (SNP) data to four common human cognitive traits, mediated by the brain connectome. Specifically, we selected 942 SNPs that are significantly associated with the brain connectome, and then estimated the direct and indirect effect on the human traits for each SNP. We found out that a majority of the selected SNPs have significant direct effects on human traits and discussed the trait-related brain regions and their implications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Mandal, Zhu and Liu.)

Heritability analysis plays a central role in quantitative genetics to describe genetic contribution to human complex traits and prioritize downstream analyses under large-scale phenotypes. Existing works largely focus on modeling single phenotype and currently available multivariate phenotypic methods often suffer from scaling and interpretation. In this article, motivated by understanding how genetic underpinning impacts human brain variation, we develop an integrative Bayesian heritability analysis to jointly estimate heritabilities for high-dimensional neuroimaging traits. To induce sparsity and incorporate brain anatomical configuration, we impose hierarchical selection among both regional and local measurements based on brain structural network and voxel dependence. We also use a nonparametric Dirichlet process mixture model to realize grouping among single nucleotide polymorphism-associated phenotypic variations, providing biological plausibility. Through extensive simulations, we show the proposed method outperforms existing ones in heritability estimation and heritable traits selection under various scenarios. We finally apply the method to two large-scale imaging genetics datasets: the Alzheimer's Disease Neuroimaging Initiative and United Kingdom Biobank and show biologically meaningful results., (© The Author 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The human brain forms functional networks of correlated activity, which have been linked with both cognitive and clinical outcomes. However, the genetic variants affecting brain function are largely unknown. Here, we used resting-state functional magnetic resonance images from 47,276 individuals to discover and validate common genetic variants influencing intrinsic brain activity. We identified 45 new genetic regions associated with brain functional signatures (P < 2.8 × 10 -11 ), including associations to the central executive, default mode, and salience networks involved in the triple-network model of psychopathology. A number of brain activity-associated loci colocalized with brain disorders (e.g., the APOE ε4 locus with Alzheimer's disease). Variation in brain function was genetically correlated with brain disorders, such as major depressive disorder and schizophrenia. Together, our study provides a step forward in understanding the genetic architecture of brain functional networks and their genetic links to brain-related complex traits and disorders., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Osteoarthritis (OA) is the most common disabling joint disease. Magnetic resonance (MR) imaging has been commonly used to assess knee joint degeneration due to its distinct advantage in detecting morphologic cartilage changes. Although several statistical methods over conventional radiography have been developed to perform quantitative cartilage analyses, little work has been done capturing the development and progression of cartilage lesions (or abnormal regions) and how they naturally progress. There are two major challenges, including (i) the lack of building spatial-temporal correspondences and correlations in cartilage thickness and (ii) the spatio-temporal heterogeneity in abnormal regions. The goal of this work is to propose a dynamic abnormality detection and progression (DADP) framework for quantitative cartilage analysis, while addressing the two challenges. First, spatial correspondences are established on flattened 2D cartilage thickness maps extracted from 3D knee MR images both across time within each subject and across all subjects. Second, a dynamic functional mixed effects model (DFMEM) is proposed to quantify abnormality progression across time points and subjects, while accounting for the spatio-temporal heterogeneity. We systematically evaluate our DADP using simulations and real data from the Osteoarthritis Initiative (OAI). Our results show that DADP not only effectively detects subject-specific dynamic abnormal regions, but also provides population-level statistical disease mapping and subgroup analysis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Cross-trait polygenic risk score (PRS) method has gained popularity for assessing genetic correlation of complex traits using summary statistics from biobank-scale genome-wide association studies (GWAS). However, empirical evidence has shown a common bias phenomenon that highly significant cross-trait PRS can only account for a very small amount of genetic variance ( R 2 can be < 1%) in independent testing GWAS. The aim of this paper is to investigate and address the bias phenomenon of cross-trait PRS in numerous GWAS applications. We show that the estimated genetic correlation can be asymptotically biased toward zero. A consistent cross-trait PRS estimator is then proposed to correct such asymptotic bias. In addition, we investigate whether or not SNP screening by GWAS p -values can lead to improved estimation and show the effect of overlapping samples among GWAS. We analyze GWAS summary statistics of reaction time and brain structural magnetic resonance imaging-based features measured in the Pediatric Imaging, Neurocognition, and Genetics study. We find that the raw cross-trait PRS estimators heavily underestimate the genetic similarity between cognitive function and human brain structures (mean R 2 = 1.32%), whereas the bias-corrected estimators uncover the moderate degree of genetic overlap between these closely related heritable traits (mean R 2 = 22.42%). Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

Modern biomedical studies often collect multi-view data, that is, multiple types of data measured on the same set of objects. A popular model in high-dimensional multi-view data analysis is to decompose each view's data matrix into a low-rank common-source matrix generated by latent factors common across all data views, a low-rank distinctive-source matrix corresponding to each view, and an additive noise matrix. We propose a novel decomposition method for this model, called decomposition-based generalized canonical correlation analysis (D-GCCA). The D-GCCA rigorously defines the decomposition on the L 2 space of random variables in contrast to the Euclidean dot product space used by most existing methods, thereby being able to provide the estimation consistency for the low-rank matrix recovery. Moreover, to well calibrate common latent factors, we impose a desirable orthogonality constraint on distinctive latent factors. Existing methods, however, inadequately consider such orthogonality and may thus suffer from substantial loss of undetected common-source variation. Our D-GCCA takes one step further than generalized canonical correlation analysis by separating common and distinctive components among canonical variables, while enjoying an appealing interpretation from the perspective of principal component analysis. Furthermore, we propose to use the variable-level proportion of signal variance explained by common or distinctive latent factors for selecting the variables most influenced. Consistent estimators of our D-GCCA method are established with good finite-sample numerical performance, and have closed-form expressions leading to efficient computation especially for large-scale data. The superiority of D-GCCA over state-of-the-art methods is also corroborated in simulations and real-world data examples.

This article develops a novel spatial quantile function-on-scalar regression model, which studies the conditional spatial distribution of a high-dimensional functional response given scalar predictors. With the strength of both quantile regression and copula modeling, we are able to explicitly characterize the conditional distribution of the functional or image response on the whole spatial domain. Our method provides a comprehensive understanding of the effect of scalar covariates on functional responses across different quantile levels and also gives a practical way to generate new images for given covariate values. Theoretically, we establish the minimax rates of convergence for estimating coefficient functions under both fixed and random designs. We further develop an efficient primal-dual algorithm to handle high-dimensional image data. Simulations and real data analysis are conducted to examine the finite-sample performance.