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Quantifying uncertainty in brain-predicted age using scalar-on-image quantile regression
Abstract
Prediction of subject age from brain anatomical MRI has the potential to provide a sensitive summary of brain changes, indicative of different neurodegenerative diseases. However, existing studies typically neglect the uncertainty of these predictions. In this work we take into account this uncertainty by applying methods of functional data analysis. We propose a penalised functional quantile regression model of age on brain structure with cognitively normal (CN) subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and use it to predict brain age in Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) subjects. Unlike the machine learning approaches available in the literature of brain age prediction, which provide only point predictions, the outcome of our model is a prediction interval for each subject.
... Therefore, the establishment of new therapy for AD is important. [1][2][3][4] Alzheimer disease is considered pathologically through the age-related amyloid-beta (Ab) admission, neurofibrillary masses, synapses, and neuronal damage. Aberrant accumulation of Ab, especially its 42 amino acid isoforms (Ab42), is the essential pathogenic mechanism of AD. ...
Last few years, struggles have been reported to develop the nanovesicles for drug delivery via the brain–blood barrier (BBB). Novel drugs, for instance, iAβ 5 , are efficient to inhibit the aggregates connected to the treatment of Alzheimer disease and are being evaluated, but most of the reports reflect some drawbacks of the drugs to reach the brain in preferred concentrations owing to the less BBB penetrability of the surface dimensions. In this report, we designed and developed a new approach to enhance the transport of drug via BBB, constructed with lactoferrin (Lf)-coated polyethylene glycol-polylactide nanoparticles (Lf-PPN) with superficial monoclonal antibody-functionalized antitransferrin receptor and anti-Aβ to deliver the iAβ 5 hooked on the brain. The porcine brain capillary endothelial cells were utilized as BBB typically to examine the framework efficacy and toxicity. The cellular uptake of the immuno-nanoparticles with measured conveyance of the iAβ 5 peptide was significantly enhanced and associated with Lf-PPN without monoclonal antibody functionalizations.
With the aging population, prevalence of neurodegenerative diseases is increasing, thus placing a growing burden on individuals and the whole society. However, individual rates of aging are shaped by a great variety of and the interactions between environmental, genetic, and epigenetic factors. Establishing biomarkers of the neuroanatomical aging processes exemplifies a new trend in neuroscience in order to provide risk-assessments and predictions for age-associated neurodegenerative and neuropsychiatric diseases at a single-subject level. The “Brain Age Gap Estimation (BrainAGE)” method constitutes the first and actually most widely applied concept for predicting and evaluating individual brain age based on structural MRI. This review summarizes all studies published within the last 10 years that have established and utilized the BrainAGE method to evaluate the effects of interaction of genes, environment, life burden, diseases, or life time on individual neuroanatomical aging. In future, BrainAGE and other brain age prediction approaches based on structural or functional markers may improve the assessment of individual risks for neurological, neuropsychiatric and neurodegenerative diseases as well as aid in developing personalized neuroprotective treatments and interventions.
It is of increasing interest to study "brain age" - the apparent age of a subject, as inferred from brain imaging data. The difference between brain age and actual age (the "delta") is typically computed, reflecting deviation from the population norm. This therefore may reflect accelerated aging (positive delta) or resilience (negative delta) and has been found to be a useful correlate with factors such as disease and cognitive decline. However, although there has been a range of methods proposed for estimating brain age, there has been little study of the optimal ways of computing the delta. In this technical note we describe problems with the most common current approach, and present potential improvements. We evaluate different estimation methods on simulated and real data. We also find the strongest correlations of corrected brain age delta with 5,792 non-imaging variables (non-brain physical measures, life-factor measures, cognitive test scores, etc.), and also with 2,641 multimodal brain imaging-derived phenotypes, with data from 19,000 participants in UK Biobank.
Epilepsy is a diverse brain disorder, and the pathophysiology of its various forms and comorbidities is largely unknown. A recent machine learning method enables us to estimate an individual’s “brain-age” from MRI; this brain-age prediction is expected as a novel individual biomarker of neuropsychiatric disorders. The aims of this study were to estimate the brain-age for various categories of epilepsy and to evaluate clinical discrimination by brain-age for (1) the effect of psychosis on temporal lobe epilepsy (TLE), (2) psychogenic nonepileptic seizures (PNESs) from MRI-negative epilepsies, and (3) progressive myoclonic epilepsy (PME) from juvenile myoclonic epilepsy (JME). In total, 1196 T1-weighted MRI scans from healthy controls (HCs) were used to build a brain-age prediction model with support vector regression. Using the model, we calculated the brain-predicted age difference (brain-PAD: predicted age—chronological age) of the HCs and 318 patients with epilepsy. We compared the brain-PAD values based on the research questions. As a result, all categories of patients except for extra-temporal lobe focal epilepsy showed a significant increase in brain-PAD. TLE with hippocampal sclerosis presented a significantly higher brain-PAD than several other categories. The mean brain-PAD in TLE with inter-ictal psychosis was 10.9 years, which was significantly higher than TLE without psychosis (5.3 years). PNES showed a comparable mean brain-PAD (10.6 years) to that of epilepsy patients. PME had a higher brain-PAD than JME (22.0 vs. 9.3 years). In conclusion, neuroimaging-based brain-age prediction can provide novel insight into or clinical usefulness for the diverse symptoms of epilepsy.
As populations age, prevalence of Alzheimer's disease (AD) is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.
Statistical models support medical research by facilitating individualized outcome prognostication conditional on independent variables or by estimating effects of risk factors adjusted for covariates. Theory of statistical models is well-established if the set of independent variables to consider is fixed and small. Hence, we can assume that effect estimates are unbiased and the usual methods for confidence interval estimation are valid. In routine work, however, it is not known a priori which covariates should be included in a model, and often we are confronted with the number of candidate variables in the range 10–30. This number is often too large to be considered in a statistical model. We provide an overview of various available variable selection methods that are based on significance or information criteria, penalized likelihood, the change-in-estimate criterion, background knowledge, or combinations thereof. These methods were usually developed in the context of a linear regression model and then transferred to more generalized linear models or models for censored survival data. Variable selection, in particular if used in explanatory modeling where effect estimates are of central interest, can compromise stability of a final model, unbiasedness of regression coefficients, and validity of p-values or confidence intervals. Therefore, we give pragmatic recommendations for the practicing statistician on application of variable selection methods in general (low-dimensional) modeling problems and on performing stability investigations and inference. We also propose some quantities based on resampling the entire variable selection process to be routinely reported by software packages offering automated variable selection algorithms.
Establishing brain-behavior associations that map brain organization to phenotypic measures and generalize to novel individuals remains a challenge in neuroimaging. Predictive modeling approaches that define and validate models with independent datasets offer a solution to this problem. While these methods can detect novel and generalizable brain-behavior associations, they can be daunting, which has limited their use by the wider connectivity community. Here, we offer practical advice and examples based on functional magnetic resonance imaging (fMRI) functional connectivity data for implementing these approaches. We hope these ten rules will increase the use of predictive models with neuroimaging data.
Understanding how people make decisions from risky choices has attracted increasing attention of researchers in economics, psychology and neuroscience. While economists try to evaluate individual’s risk preference through mathematical modeling, neuroscientists answer the question by exploring the neural activities of the brain. We propose a model-free method, 3-dimensional image functional principal component analysis (3DIF), to provide a connection between active risk related brain region detection and individual’s risk preference. The 3DIF methodology is directly applicable to 3-dimensional image data without artificial vectorization or mapping and simultaneously guarantees the contiguity of risk related brain regions rather than discrete voxels. Simulation study evidences an accurate and reasonable region detection using the 3DIF method. In real data analysis, five important risk related brain regions are detected, including parietal cortex (PC), ventrolateral prefrontal cortex (VLPFC), lateral orbifrontal cortex (lOFC), anterior insula (aINS) and dorsolateral prefrontal cortex (DLPFC), while the alternative methods only identify limited risk related regions. Moreover, the 3DIF method is useful for extraction of subjective specific signature scores that carry explanatory power for individual’s risk attitude. In particular, the 3DIF method perfectly classifies both strongly and weakly risk averse subjects for in-sample analysis. In out-of-sample experiment, it achieves 73 -88 overall accuracy, among which 90 -100 strongly risk averse subjects and 49 -71 weakly risk averse subjects are correctly classified with leave- k -out cross validations.
Quantile regression has emerged as an essential statistical tool of contemporary empirical economics and biostatistics. Complementing classical least squares regression methods which are designed to estimate conditional mean models, quantile regression provides an ensemble of techniques for estimating families of conditional quantile models, thus offering a more complete view of the stochastic relationship among variables. This volume collects 12 outstanding empirical contributions in economics and offers an indispensable introduction to interpretation, implementation, and inference aspects of quantile regression.
Connectome-based predictive modeling (CPM; Finn et al., 2015; Shen et al., 2017) was recently developed to predict individual differences in traits and behaviors, including fluid intelligence (Finn et al., 2015) and sustained attention (Rosenberg et al., 2016a), from functional brain connectivity (FC) measured with fMRI. Here, using the CPM framework, we compared the predictive power of three different measures of FC (Pearson's correlation, accordance, and discordance) and two different prediction algorithms (linear and partial least square [PLS] regression) for attention function. Accordance and discordance are recently proposed FC measures that respectively track in-phase synchronization and out-of-phase anti-correlation (Meskaldji et al., 2016). We defined connectome-based models using task-based or resting-state FC data, and tested the effects of (1) functional connectivity measure and (2) feature-selection/prediction algorithm on individualized attention predictions. Models were internally validated in a training dataset using leave-one-subject-out cross-validation, and externally validated with three independent datasets. The training dataset included fMRI data collected while participants performed a sustained attention task and rested (N = 25; Rosenberg et al., 2016a). The validation datasets included: 1) data collected during performance of a stop-signal task and at rest (N = 83, including 19 participants who were administered methylphenidate prior to scanning; Rosenberg et al., 2016b; f al., 2014a), 2) data collected during Attention Network Task performance and rest (N = 41, Rosenberg et al., in press), and 3) resting-state data and ADHD symptom severity from the ADHD-200 Consortium (N = 113; Rosenberg et al., 2016a). Models defined using all combinations of functional connectivity measure (Pearson's correlation, accordance, and discordance) and prediction algorithm (linear and PLS regression) predicted attentional abilities, with correlations between predicted and observed measures of attention as high as 0.9 for internal validation, and 0.6 for external validation (all p's < 0.05). Models trained on task data outperformed models trained on rest data. Pearson's correlation and accordance features generally showed a small numerical advantage over discordance features, while PLS regression models were usually better than linear regression models. Overall, in addition to correlation features combined with linear models (Rosenberg et al., 2016a), it is useful to consider accordance features and PLS regression for CPM.