Cohort profile: rationale and methods of UK Biobank repeat imaging study eye measures to study dementia

PURPOSE: The retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study. PARTICIPANTS: UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40-69 enrolled in 2006-2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs. FINDINGS TO DATE: UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes. FUTURE PLANS: The collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022-2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia

Cohort profile:rationale and methods of UK Biobank repeat imaging study eye measures to study dementia

Purpose: the retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study.Participants: UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40-69 enrolled in 2006-2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs.Findings to date: UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes.Future plans: the collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022-2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia

Deep learning for health outcome prediction

Modern medical data contains rich information that allows us to make new types of inferences to predict health outcomes. However, the complexity of modern medical data has rendered many classical analysis approaches insufficient. Machine learning with deep neural networks enables computational models to process raw data and learn useful representations with multiple levels of abstraction. In this thesis, I present novel deep learning methods for health outcome prediction from brain MRI and genomic data. I show that a deep neural network can learn a biomarker from structural brain MRI and that this biomarker provides a useful measure for investigating brain and systemic health, can augment neuroradiological research and potentially serve as a decision-support tool in clinical environments. I also develop two tensor methods for deep neural networks: the first, tensor dropout, for improving the robustness of deep neural networks, and the second, Kronecker machines, for combining multiple sources of data to improve prediction accuracy. Finally, I present a novel deep learning method for predicting polygenic risk scores from genome sequences by leveraging both local and global interactions between genetic variants. These contributions demonstrate the benefits of using deep learning for health outcome prediction in both research and clinical settings.Open Acces

Confound modelling in UK Biobank brain imaging

© 2020 Dealing with confounds is an essential step in large cohort studies to address problems such as unexplained variance and spurious correlations. UK Biobank is a powerful resource for studying associations between imaging and non-imaging measures such as lifestyle factors and health outcomes, in part because of the large subject numbers. However, the resulting high statistical power also raises the sensitivity to confound effects, which therefore have to be carefully considered. In this work we describe a set of possible confounds (including non-linear effects and interactions that researchers may wish to consider for their studies using such data). We include descriptions of how we can estimate the confounds, and study the extent to which each of these confounds affects the data, and the spurious correlations that may arise if they are not controlled. Finally, we discuss several issues that future studies should consider when dealing with confounds

The legibility of the imaged human brain

Our knowledge of the organisation of the human brain at the population-level is yet to translate into power to predict functional differences at the individual-level, limiting clinical applications, and casting doubt on the generalisability of inferred mechanisms. It remains unknown whether the difficulty arises from the absence of individuating biological patterns within the brain, or from limited power to access them with the models and compute at our disposal. Here we comprehensively investigate the resolvability of such patterns with data and compute at unprecedented scale. Across 23810 unique participants from UK Biobank, we systematically evaluate the predictability of 25 individual biological characteristics, from all available combinations of structural and functional neuroimaging data. Over 4526 GPU*hours of computation, we train, optimize, and evaluate out-of-sample 700 individual predictive models, including multilayer perceptrons of demographic, psychological, serological, chronic morbidity, and functional connectivity characteristics, and both uni- and multi-modal 3D convolutional neural network models of macro- and micro-structural brain imaging. We find a marked discrepancy between the high predictability of sex (balanced accuracy 99.7%), age (mean absolute error 2.048 years, R2 0.859), and weight (mean absolute error 2.609Kg, R2 0.625), for which we set new state-of-the-art performance, and the surprisingly low predictability of other characteristics. Neither structural nor functional imaging predicted individual psychology better than the coincidence of common chronic morbidity (p<0.05). Serology predicted common morbidity (p<0.05) and was best predicted by it (p<0.001), followed by structural neuroimaging (p<0.05). Our findings suggest either more informative imaging or more powerful models will be needed to decipher individual level characteristics from the brain.Comment: 36 pages, 6 figures, 1 table, 2 supplementary figure

The Open-Access European Prevention of Alzheimer's Dementia (EPAD) MRI dataset and processing workflow

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer's Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features - i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features - Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) - were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses

Brain connectivity mapping with diffusion MRI across individuals and species

The human brain is a highly complex organ that integrates functionally specialised subunits. Underpinning this complexity and functional specialisation is a network of structural connections, which may be probed using diffusion tractography, a unique, powerful and non-invasive MRI technique. Estimates of brain connectivity derived through diffusion tractography allow for explorations of how the brain’s functional subunits are inter-linked to subsequently produce experiences and behaviour. This thesis develops new diffusion tractography methodology for mapping brain connectivity, both across individuals and also across species; and explores frameworks for discovering associations of such brain connectivity features with behavioural traits. We build upon the hypothesis that connectional patterns can probe regions of functional equivalence across brains. To test this hypothesis we develop standardised and automated frameworks for mapping these patterns in very diverse brains, such as from human and non-human primates. We develop protocols to extract homologous fibre bundles across two species (human and macaque monkeys). We demonstrate robustness and generalisability of these protocols, but also their ability to capture individual variability. We also present investigations into how structural connectivity profiles may be used to inform us of how functionally-related features can be linked across different brains. Further, we explore how fully data-driven tractography techniques may be utilised for similar purposes, opening the door for future work on data-driven connectivity mapping. Subsequently, we explore how such individual variability in features that probe brain organisation are associated with differences in human behaviour. One approach to performing such explorations is the use of powerful multivariate statisitical techniques, such as canonical correlation analysis (CCA). After identifying issues in out-of-sample replication using multi-modal connectivity information, we perform comprehensive explorations into the robustness of such techniques and devise a generative model for forward predictions, demonstrating significant challlenges and limitations in their current applications. Specifically, we predict that the stability and generalisability of these techniques requires an order of magnitude more subjects than typically used to avoid overfitting and mis-interpretation of results. Using population-level data from the UK Biobank and confirmations from independent imaging modalities from the Human Connectome Project, we validate this prediction and demonstrate the direct link of CCA stability and generalisability with the number of subjects used per considered feature

Application of Deep Learning to Brain Connectivity Classification in Large MRI Datasets

The use of machine learning for whole-brain classification of magnetic resonance imaging (MRI) data is of clear interest, both for understanding phenotypic differences in brain structure and function and for diagnostic applications. Developments of deep learning models in the past decade have revolutionized photographic image and speech recognition, bringing promise to do the same to other fields of science. However, there are many practical and theoretical challenges in the translation of such methods to the unique context of MRIs of the brain. This thesis presents a theoretical underpinning for whole-brain classification of extremely large datasets of multi-site MRIs, including machine learning model architecture, dataset curation methods, machine learning visualization methods, encoding of MRI data, and feature extraction. To replicate large sample sizes typically applied to deep learning models, a dataset of over 50,000 functional and structural MRIs was amassed from nine different databases, and the undertaken analyses were conducted on three covariates commonly found across these collections: sex, resting state/task, and autism spectrum disorder. I find that deep learning is not only a method that has promise for clinical application in the future, but also a powerful statistical tool for analyzing complex, nonlinear relationships in brain data where conventional statistics may fail. However, results are also dependent on factors such as dataset imbalances, confounding factors such as motion and head size, selected methods of encoding MRI data, variability of machine learning models and selected methods of visualizing the machine learning results. In this thesis, I present the following methodological innovations: (1) a method of balancing datasets as a means of regressing out measurable confounding factors; (2) a means of removing spatial biases from deep learning visualization methods; (3) methods of encoding functional and structural datasets as connectivity matrices; (4) the use of ensemble models and convolutional neural network architectures to improve classification accuracy and consistency; (5) adaptation of deep learning visualization methods to study brain connections utilized in the classification process. Additionally, I discuss interpretations, limitations, and future directions of this research.Gates Cambridge Scholarshi

Pipeline-Invariant Representation Learning for Neuroimaging

Deep learning has been widely applied in neuroimaging, including predicting brain-phenotype relationships from magnetic resonance imaging (MRI) volumes. MRI data usually requires extensive preprocessing prior to modeling, but variation introduced by different MRI preprocessing pipelines may lead to different scientific findings, even when using the identical data. Motivated by the data-centric perspective, we first evaluate how preprocessing pipeline selection can impact the downstream performance of a supervised learning model. We next propose two pipeline-invariant representation learning methodologies, MPSL and PXL, to improve robustness in classification performance and to capture similar neural network representations. Using 2000 human subjects from the UK Biobank dataset, we demonstrate that proposed models present unique and shared advantages, in particular that MPSL can be used to improve out-of-sample generalization to new pipelines, while PXL can be used to improve within-sample prediction performance. Both MPSL and PXL can learn more similar between-pipeline representations. These results suggest that our proposed models can be applied to mitigate pipeline-related biases, and to improve prediction robustness in brain-phenotype modeling.Comment: Extended Abstract presented at Machine Learning for Health (ML4H) symposium 2022, November 28th, 2022, New Orleans, United States & Virtual, http://www.ml4h.cc, 17 page