A multimodal neuroimaging classifier for alcohol dependence

With progress in magnetic resonance imaging technology and a broader dissemination of state-of-the-art imaging facilities, the acquisition of multiple neuroimaging modalities is becoming increasingly feasible. One particular hope associated with multimodal neuroimaging is the development of reliable data-driven diagnostic classifiers for psychiatric disorders, yet previous studies have often failed to find a benefit of combining multiple modalities. As a psychiatric disorder with established neurobiological effects at several levels of description, alcohol dependence is particularly well-suited for multimodal classification. To this aim, we developed a multimodal classification scheme and applied it to a rich neuroimaging battery (structural, functional task-based and functional resting-state data) collected in a matched sample of alcohol-dependent patients (N = 119) and controls (N = 97). We found that our classification scheme yielded 79.3% diagnostic accuracy, which outperformed the strongest individual modality - grey-matter density - by 2.7%. We found that this moderate benefit of multimodal classification depended on a number of critical design choices: a procedure to select optimal modality-specific classifiers, a fine-grained ensemble prediction based on cross-modal weight matrices and continuous classifier decision values. We conclude that the combination of multiple neuroimaging modalities is able to moderately improve the accuracy of machine-learning-based diagnostic classification in alcohol dependence

A multimodal neuroimaging classifier for alcohol dependence

With progress in magnetic resonance imaging technology and a broader dissemination of state-of-the-art imaging facilities, the acquisition of multiple neuroimaging modalities is becoming increasingly feasible. One particular hope associated with multimodal neuroimaging is the development of reliable data-driven diagnostic classifiers for psychiatric disorders, yet previous studies have often failed to find a benefit of combining multiple modalities. As a psychiatric disorder with established neurobiological effects at several levels of description, alcohol dependence is particularly well-suited for multimodal classification. To this aim, we developed a multimodal classification scheme and applied it to a rich neuroimaging battery (structural, functional task-based and functional resting-state data) collected in a matched sample of alcohol-dependent patients (N = 119) and controls (N = 97). We found that our classification scheme yielded 79.3% diagnostic accuracy, which outperformed the strongest individual modality - grey-matter density - by 2.7%. We found that this moderate benefit of multimodal classification depended on a number of critical design choices: a procedure to select optimal modality-specific classifiers, a fine-grained ensemble prediction based on cross-modal weight matrices and continuous classifier decision values. We conclude that the combination of multiple neuroimaging modalities is able to moderately improve the accuracy of machine-learning-based diagnostic classification in alcohol dependence

Machine Learning Based Autism Detection Using Brain Imaging

Autism Spectrum Disorder (ASD) is a group of heterogeneous developmental disabilities that manifest in early childhood. Currently, ASD is primarily diagnosed by assessing the behavioral and intellectual abilities of a child. This behavioral diagnosis can be subjective, time consuming, inconclusive, does not provide insight on the underlying etiology, and is not suitable for early detection. Diagnosis based on brain magnetic resonance imaging (MRI)—a widely used non- invasive tool—can be objective, can help understand the brain alterations in ASD, and can be suitable for early diagnosis. However, the brain morphological findings in ASD from MRI studies have been inconsistent. Moreover, there has been limited success in machine learning based ASD detection using MRI derived brain features. In this thesis, we begin by demonstrating that the low success in ASD detection and the inconsistent findings are likely attributable to the heterogeneity of brain alterations in ASD. We then show that ASD detection can be significantly improved by mitigating the heterogeneity with the help of behavioral and demographics information. Here we demonstrate that finding brain markers in well-defined sub-groups of ASD is easier and more insightful than identifying markers across the whole spectrum. Finally, our study focused on brain MRI of a pediatric cohort (3 to 4 years) and achieved a high classification success (AUC of 95%). Results of this study indicate three main alterations in early ASD brains: 1) abnormally large ventricles, 2) highly folded cortices, and 3) low image intensity in white matter regions suggesting myelination deficits indicative of decreased structural connectivity. Results of this thesis demonstrate that the meaningful brain markers of ASD can be extracted by applying machine learning techniques on brain MRI data. This data-driven technique can be a powerful tool for early detection and understanding brain anatomical underpinnings of ASD

Clinical Prediction from Structural Brain MRI Scans: A Large-Scale Empirical Study

Multivariate pattern analysis (MVPA) methods have become an important tool in neuroimaging, revealing complex associations and yielding powerful prediction models. Despite methodological developments and novel application domains, there has been little effort to compile benchmark results that researchers can reference and compare against. This study takes a significant step in this direction. We employed three classes of state-of-the-art MVPA algorithms and common types of structural measurements from brain Magnetic Resonance Imaging (MRI) scans to predict an array of clinically relevant variables (diagnosis of Alzheimer’s, schizophrenia, autism, and attention deficit and hyperactivity disorder; age, cerebrospinal fluid derived amyloid-β levels and mini-mental state exam score). We analyzed data from over 2,800 subjects, compiled from six publicly available datasets. The employed data and computational tools are freely distributed (https://www.nmr.mgh.harvard.edu/lab/mripredict), making this the largest, most comprehensive, reproducible benchmark image-based prediction experiment to date in structural neuroimaging. Finally, we make several observations regarding the factors that influence prediction performance and point to future research directions. Unsurprisingly, our results suggest that the biological footprint (effect size) has a dramatic influence on prediction performance. Though the choice of image measurement and MVPA algorithm can impact the result, there was no universally optimal selection. Intriguingly, the choice of algorithm seemed to be less critical than the choice of measurement type. Finally, our results showed that cross-validation estimates of performance, while generally optimistic, correlate well with generalization accuracy on a new dataset.BrightFocus Foundation (Alzheimer’s Disease pilot grant (AHAF A2012333))National Institutes of Health (U.S.) (K25 grant (NIBIB 1K25EB013649-01))National Center for Research Resources (U.S.) (U24 RR021382)National Institutes of Health. National Institute for Biomedical Imaging and Bioengineering (R01EB006758)National Institute of Neurological Disorders and Stroke (U.S.) (R01 NS052585-01, 1R21NS072652-01, 1R01NS070963, R01NS083534)National Institutes of Health (U.S.) (Blueprint for Neuroscience Research (5U01-MH093765)

Advancing Statistical Inference For Population Studies In Neuroimaging Using Machine Learning

Modern neuroimaging techniques allow us to investigate the brain in vivo and in high resolution, providing us with high dimensional information regarding the structure and the function of the brain in health and disease. Statistical analysis techniques transform this rich imaging information into accessible and interpretable knowledge that can be used for investigative as well as diagnostic and prognostic purposes. A prevalent area of research in neuroimaging is group comparison, i.e., the comparison of the imaging data of two groups (e.g. patients vs. healthy controls or people who respond to treatment vs. people who don\u27t) to identify discriminative imaging patterns that characterize different conditions. In recent years, the neuroimaging community has adopted techniques from mathematics, statistics, and machine learning to introduce novel methodologies targeting the improvement of our understanding of various neuropsychiatric and neurodegenerative disorders. However, existing statistical methods are limited by their reliance on ad-hoc assumptions regarding the homogeneity of disease effect, spatial properties of the underlying signal and the covariate structure of data, which imposes certain constraints about the sampling of datasets. 1. First, the overarching assumption behind most analytical tools, which are commonly used in neuroimaging studies, is that there is a single disease effect that differentiates the patients from controls. In reality, however, the disease effect may be heterogeneously expressed across the patient population. As a consequence, when searching for a single imaging pattern that characterizes the difference between healthy controls and patients, we may only get a partial or incomplete picture of the disease effect. 2. Second, and importantly, most analyses assume a uniform shape and size of disease effect. As a consequence, a common step in most neuroimaging analyses it to apply uniform smoothing of the data to aggregate regional information to each voxel to improve the signal to noise ratio. However, the shape and size of the disease patterns may not be uniformly represented across the brain. 3. Lastly, in practical scenarios, imaging datasets commonly include variations due to multiple covariates, which often have effects that overlap with the searched disease effects. To minimize the covariate effects, studies are carefully designed by appropriately matching the populations under observation. The difficulty of this task is further exacerbated by the advent of big data analyses that often entail the aggregation of large datasets collected across many clinical sites. The goal of this thesis is to address each of the aforementioned assumptions and limitations by introducing robust mathematical formulations, which are founded on multivariate machine learning techniques that integrate discriminative and generative approaches. Specifically, 1. First, we introduce an algorithm termed HYDRA which stands for heterogeneity through discriminative analysis. This method parses the heterogeneity in neuroimaging studies by simultaneously performing clustering and classification by use of piecewise linear decision boundaries. 2. Second, we propose to perform regionally linear multivariate discriminative statistical mapping (MIDAS) toward finding the optimal level of variable smoothing across the brain anatomy and tease out group differences in neuroimaging datasets. This method makes use of overlapping regional discriminative filters to approximate a matched filter that best delineates the underlying disease effect. 3. Lastly, we develop a method termed generative discriminative machines (GDM) toward reducing the effect of confounds in biased samples. The proposed method solves for a discriminative model that can also optimally generate the data when taking into account the covariate structure. We extensively validated the performance of the developed frameworks in the presence of diverse types of simulated scenarios. Furthermore, we applied our methods on a large number of clinical datasets that included structural and functional neuroimaging data as well as genetic data. Specifically, HYDRA was used for identifying distinct subtypes of Alzheimer\u27s Disease. MIDAS was applied for identifying the optimally discriminative patterns that differentiated between truth-telling and lying functional tasks. GDM was applied on a multi-site prediction setting with severely confounded samples. Our promising results demonstrate the potential of our methods to advance neuroimaging analysis beyond the set of assumptions that limit its capacity and improve statistical power

SubCMap: subject and condition specific effect maps

Current methods for statistical analysis of neuroimaging data identify condition related structural alterations in the human brain by detecting group differences. They construct detailed maps showing population-wide changes due to a condition of interest. Although extremely useful, methods do not provide information on the subject-specific structural alterations and they have limited diagnostic value because group assignments for each subject are required for the analysis. In this article, we propose SubCMap, a novel method to detect subject and condition specific structural alterations. SubCMap is designed to work without the group assignment information in order to provide diagnostic value. Unlike outlier detection methods, SubCMap detections are condition-specific and can be used to study the effects of various conditions or for diagnosing diseases. The method combines techniques from classification, generalization error estimation and image restoration to the identify the condition-related alterations. Experimental evaluation is performed on synthetically generated data as well as data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Results on synthetic data demonstrate the advantages of SubCMap compared to population-wide techniques and higher detection accuracy compared to outlier detection. Analysis with the ADNI dataset show that SubCMap detections on cortical thickness data well correlate with non-imaging markers of Alzheimer's Disease (AD), the Mini Mental State Examination Score and Cerebrospinal Fluid amyloid-β levels, suggesting the proposed method well captures the inter-subject variation of AD effects

Converting Neuroimaging Big Data to information: Statistical Frameworks for interpretation of Image Driven Biomarkers and Image Driven Disease Subtyping

Large scale clinical trials and population based research studies collect huge amounts of neuroimaging data. Machine learning classifiers can potentially use these data to train models that diagnose brain related diseases from individual brain scans. In this dissertation we address two distinct challenges that beset a wider adoption of these tools for diagnostic purposes. The first challenge that besets the neuroimaging based disease classification is the lack of a statistical inference machinery for highlighting brain regions that contribute significantly to the classifier decisions. In this dissertation, we address this challenge by developing an analytic framework for interpreting support vector machine (SVM) models used for neuroimaging based diagnosis of psychiatric disease. To do this we first note that permutation testing using SVM model components provides a reliable inference mechanism for model interpretation. Then we derive our analysis framework by showing that under certain assumptions, the permutation based null distributions associated with SVM model components can be approximated analytically using the data themselves. Inference based on these analytic null distributions is validated on real and simulated data. p-Values computed from our analysis can accurately identify anatomical features that differentiate groups used for classifier training. Since the majority of clinical and research communities are trained in understanding statistical p-values rather than machine learning techniques like the SVM, we hope that this work will lead to a better understanding SVM classifiers and motivate a wider adoption of SVM models for image based diagnosis of psychiatric disease. A second deficiency of learning based neuroimaging diagnostics is that they implicitly assume that, `a single homogeneous pattern of brain changes drives population wide phenotypic differences\u27. In reality it is more likely that multiple patterns of brain deficits drive the complexities observed in the clinical presentation of most diseases. Understanding this heterogeneity may allow us to build better classifiers for identifying such diseases from individual brain scans. However, analytic tools to explore this heterogeneity are missing. With this in view, we present in this dissertation, a framework for exploring disease heterogeneity using population neuroimaging data. The approach we present first computes difference images by comparing matched cases and controls and then clusters these differences. The cluster centers define a set of deficit patterns that differentiates the two groups. By allowing for more than one pattern of difference between two populations, our framework makes a radical departure from traditional tools used for neuroimaging group analyses. We hope that this leads to a better understanding of the processes that lead to disease and also that it ultimately leads to improved image based disease classifiers

Cross-cohort generalizability of deep and conventional machine learning for MRI-based diagnosis and prediction of Alzheimer's disease

This work validates the generalizability of MRI-based classification of Alzheimer’s disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI).We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the Alzheimer’s Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia.AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924–0.955) and CNN (0.933; 95%CI: 0.918–0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p<0.01 for McNemar’s test). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896; 95%CI: 0.855–0.932) and CNN (0.876; 95%CI: 0.836–0.913). For prediction in MCI, performances decreased for both SVM (AUC = 0.665; 95%CI: 0.576-0.760) and CNN (AUC = 0.702; 95%CI: 0.624-0.786). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images (p=0.01).Deep and conventional classifiers performed equally well for AD classification and their performance decreased only slightly when applied to the external cohort. We expect that this work on external validation contributes towards translation of machine learning to clinical practice