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1. Identifying genetic markers enriched by brain imaging endophenotypes in Alzheimer’s disease

   https://doi.org/10.1186/s12920-022-01323-8  

   Kim, Mansu; Wu, Ruiming; Yao, Xiaohui; Saykin, Andrew J.; Moore, Jason H.; Shen, Li (December 2022, BMC Medical Genomics)

   Abstract Background Alzheimer’s disease (AD) is a complex neurodegenerative disorder and the most common type of dementia. AD is characterized by a decline of cognitive function and brain atrophy, and is highly heritable with estimated heritability ranging from 60 to 80 $$\%$$ % . The most straightforward and widely used strategy to identify AD genetic basis is to perform genome-wide association study (GWAS) of the case-control diagnostic status. These GWAS studies have identified over 50 AD related susceptibility loci. Recently, imaging genetics has emerged as a new field where brain imaging measures are studied as quantitative traits to detect genetic factors. Given that many imaging genetics studies did not involve the diagnostic outcome in the analysis, the identified imaging or genetic markers may not be related or specific to the disease outcome. Results We propose a novel method to identify disease-related genetic variants enriched by imaging endophenotypes, which are the imaging traits associated with both genetic factors and disease status. Our analysis consists of three steps: (1) map the effects of a genetic variant (e.g., single nucleotide polymorphism or SNP) onto imaging traits across the brain using a linear regression model, (2) map the effects of a diagnosis phenotype onto imaging traits across the brain using a linear regression model, and (3) detect SNP-diagnosis association via correlating the SNP effects with the diagnostic effects on the brain-wide imaging traits. We demonstrate the promise of our approach by applying it to the Alzheimer’s Disease Neuroimaging Initiative database. Among 54 AD related susceptibility loci reported in prior large-scale AD GWAS, our approach identifies 41 of those from a much smaller study cohort while the standard association approaches identify only two of those. Clearly, the proposed imaging endophenotype enriched approach can reveal promising AD genetic variants undetectable using the traditional method. Conclusion We have proposed a novel method to identify AD genetic variants enriched by brain-wide imaging endophenotypes. This approach can not only boost detection power, but also reveal interesting biological pathways from genetic determinants to intermediate brain traits and to phenotypic AD outcomes. 

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2. Confounder Adjustment in Shape-on-Scalar Regression Model: Corpus Callosum Shape Alterations in Alzheimer’s Disease

   https://doi.org/10.3390/stats6040061  

   Dogra, Harshita; Ding, Shengxian; Yeon, Miyeon; Liu, Rongjie; Huang, Chao (December 2023, Stats)

   Large-scale imaging studies often face challenges stemming from heterogeneity arising from differences in geographic location, instrumental setups, image acquisition protocols, study design, and latent variables that remain undisclosed. While numerous regression models have been developed to elucidate the interplay between imaging responses and relevant covariates, limited attention has been devoted to cases where the imaging responses pertain to the domain of shape. This adds complexity to the problem of imaging heterogeneity, primarily due to the unique properties inherent to shape representations, including nonlinearity, high-dimensionality, and the intricacies of quotient space geometry. To tackle this intricate issue, we propose a novel approach: a shape-on-scalar regression model that incorporates confounder adjustment. In particular, we leverage the square root velocity function to extract elastic shape representations which are embedded within the linear Hilbert space of square integrable functions. Subsequently, we introduce a shape regression model aimed at characterizing the intricate relationship between elastic shapes and covariates of interest, all while effectively managing the challenges posed by imaging heterogeneity. We develop comprehensive procedures for estimating and making inferences about the unknown model parameters. Through real-data analysis, our method demonstrates its superiority in terms of estimation accuracy when compared to existing approaches. 

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3. Dimension constraints improve hypothesis testing for large-scale, graph-associated, brain-image data

   https://doi.org/10.1093/biostatistics/kxab001  

   Vo, Tien; Mishra, Akshay; Ithapu, Vamsi; Singh, Vikas; Newton, Michael A (February 2021, Biostatistics)

   null (Ed.)

   Summary For large-scale testing with graph-associated data, we present an empirical Bayes mixture technique to score local false-discovery rates (FDRs). Compared to procedures that ignore the graph, the proposed Graph-based Mixture Model (GraphMM) method gains power in settings where non-null cases form connected subgraphs, and it does so by regularizing parameter contrasts between testing units. Simulations show that GraphMM controls the FDR in a variety of settings, though it may lose control with excessive regularization. On magnetic resonance imaging data from a study of brain changes associated with the onset of Alzheimer’s disease, GraphMM produces greater yield than conventional large-scale testing procedures. 

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4. Inference and uncertainty quantification for noisy matrix completion

   https://doi.org/10.1073/pnas.1910053116  

   Chen, Yuxin; Fan, Jianqing; Ma, Cong; Yan, Yuling (November 2019, Proceedings of the National Academy of Sciences)

   Noisy matrix completion aims at estimating a low-rank matrix given only partial and corrupted entries. Despite remarkable progress in designing efficient estimation algorithms, it remains largely unclear how to assess the uncertainty of the obtained estimates and how to perform efficient statistical inference on the unknown matrix (e.g., constructing a valid and short confidence interval for an unseen entry). This paper takes a substantial step toward addressing such tasks. We develop a simple procedure to compensate for the bias of the widely used convex and nonconvex estimators. The resulting debiased estimators admit nearly precise nonasymptotic distributional characterizations, which in turn enable optimal construction of confidence intervals/regions for, say, the missing entries and the low-rank factors. Our inferential procedures do not require sample splitting, thus avoiding unnecessary loss of data efficiency. As a byproduct, we obtain a sharp characterization of the estimation accuracy of our debiased estimators in both rate and constant. Our debiased estimators are tractable algorithms that provably achieve full statistical efficiency. 

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5. Data-driven retrieval of population-level EEG features and their role in neurodegenerative diseases

   https://doi.org/10.1093/braincomms/fcae227  

   Li, Wentao; Varatharajah, Yogatheesan; Dicks, Ellen; Barnard, Leland; Brinkmann, Benjamin H; Crepeau, Daniel; Worrell, Gregory; Fan, Winnie; Kremers, Walter; Boeve, Bradley; et al (January 2024, Brain Communications)

   Abstract Electrophysiologic disturbances due to neurodegenerative disorders such as Alzheimer’s disease and Lewy Body disease are detectable by scalp EEG and can serve as a functional measure of disease severity. Traditional quantitative methods of EEG analysis often require an a-priori selection of clinically meaningful EEG features and are susceptible to bias, limiting the clinical utility of routine EEGs in the diagnosis and management of neurodegenerative disorders. We present a data-driven tensor decomposition approach to extract the top 6 spectral and spatial features representing commonly known sources of EEG activity during eyes-closed wakefulness. As part of their neurologic evaluation at Mayo Clinic, 11 001 patients underwent 12 176 routine, standard 10–20 scalp EEG studies. From these raw EEGs, we developed an algorithm based on posterior alpha activity and eye movement to automatically select awake-eyes-closed epochs and estimated average spectral power density (SPD) between 1 and 45 Hz for each channel. We then created a three-dimensional (3D) tensor (record × channel × frequency) and applied a canonical polyadic decomposition to extract the top six factors. We further identified an independent cohort of patients meeting consensus criteria for mild cognitive impairment (30) or dementia (39) due to Alzheimer’s disease and dementia with Lewy Bodies (31) and similarly aged cognitively normal controls (36). We evaluated the ability of the six factors in differentiating these subgroups using a Naïve Bayes classification approach and assessed for linear associations between factor loadings and Kokmen short test of mental status scores, fluorodeoxyglucose (FDG) PET uptake ratios and CSF Alzheimer’s Disease biomarker measures. Factors represented biologically meaningful brain activities including posterior alpha rhythm, anterior delta/theta rhythms and centroparietal beta, which correlated with patient age and EEG dysrhythmia grade. These factors were also able to distinguish patients from controls with a moderate to high degree of accuracy (Area Under the Curve (AUC) 0.59–0.91) and Alzheimer’s disease dementia from dementia with Lewy Bodies (AUC 0.61). Furthermore, relevant EEG features correlated with cognitive test performance, PET metabolism and CSF AB42 measures in the Alzheimer’s subgroup. This study demonstrates that data-driven approaches can extract biologically meaningful features from population-level clinical EEGs without artefact rejection or a-priori selection of channels or frequency bands. With continued development, such data-driven methods may improve the clinical utility of EEG in memory care by assisting in early identification of mild cognitive impairment and differentiating between different neurodegenerative causes of cognitive impairment. 

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