How to remove or control confounds in predictive models, with applications to brain biomarkers.

BACKGROUND: With increasing data sizes and more easily available computational methods, neurosciences rely more and more on predictive modeling with machine learning, e.g., to extract disease biomarkers. Yet, a successful prediction may capture a confounding effect correlated with the outcome instead of brain features specific to the outcome of interest. For instance, because patients tend to move more in the scanner than controls, imaging biomarkers of a disease condition may mostly reflect head motion, leading to inefficient use of resources and wrong interpretation of the biomarkers. RESULTS: Here we study how to adapt statistical methods that control for confounds to predictive modeling settings. We review how to train predictors that are not driven by such spurious effects. We also show how to measure the unbiased predictive accuracy of these biomarkers, based on a confounded dataset. For this purpose, cross-validation must be modified to account for the nuisance effect. To guide understanding and practical recommendations, we apply various strategies to assess predictive models in the presence of confounds on simulated data and population brain imaging settings. Theoretical and empirical studies show that deconfounding should not be applied to the train and test data jointly: modeling the effect of confounds, on the training data only, should instead be decoupled from removing confounds. CONCLUSIONS: Cross-validation that isolates nuisance effects gives an additional piece of information: confound-free prediction accuracy.

Benchmarking functional connectome-based predictive models for resting-state fMRI.

Functional connectomes reveal biomarkers of individual psychological or clinical traits. However, there is great variability in the analytic pipelines typically used to derive them from rest-fMRI cohorts. Here, we consider a specific type of studies, using predictive models on the edge weights of functional connectomes, for which we highlight the best modeling choices. We systematically study the prediction performances of models in 6 different cohorts and a total of 2000 individuals, encompassing neuro-degenerative (Alzheimer's, Post-traumatic stress disorder), neuro-psychiatric (Schizophrenia, Autism), drug impact (Cannabis use) clinical settings and psychological trait (fluid intelligence). The typical prediction procedure from rest-fMRI consists of three main steps: defining brain regions, representing the interactions, and supervised learning. For each step we benchmark typical choices: 8 different ways of defining regions -either pre-defined or generated from the rest-fMRI data- 3 measures to build functional connectomes from the extracted time-series, and 10 classification models to compare functional interactions across subjects. Our benchmarks summarize more than 240 different pipelines and outline modeling choices that show consistent prediction performances in spite of variations in the populations and sites. We find that regions defined from functional data work best; that it is beneficial to capture between-region interactions with tangent-based parametrization of covariances, a midway between correlations and partial correlation; and that simple linear predictors such as a logistic regression give the best predictions. Our work is a step forward to establishing reproducible imaging-based biomarkers for clinical settings.

White Matter Tract Integrity in Alzheimer's Disease vs. Late Onset Bipolar Disorder and Its Correlation with Systemic Inflammation and Oxidative Stress Biomarkers.

Background: Late Onset Bipolar Disorder (LOBD) is the development of Bipolar Disorder (BD) at an age above 50 years old. It is often difficult to differentiate from other aging dementias, such as Alzheimer's Disease (AD), because they share cognitive and behavioral impairment symptoms. Objectives: We look for WM tract voxel clusters showing significant differences when comparing of AD vs. LOBD, and its correlations with systemic blood plasma biomarkers (inflammatory, neurotrophic factors, and oxidative stress). Materials: A sample of healthy controls (HC) (n = 19), AD patients (n = 35), and LOBD patients (n = 24) was recruited at the Alava University Hospital. Blood plasma samples were obtained at recruitment time and analyzed to extract the inflammatory, oxidative stress, and neurotrophic factors. Several modalities of MRI were acquired for each subject, Methods: Fractional anisotropy (FA) coefficients are obtained from diffusion weighted imaging (DWI). Tract based spatial statistics (TBSS) finds FA skeleton clusters of WM tract voxels showing significant differences for all possible contrasts between HC, AD, and LOBD. An ANOVA F-test over all contrasts is carried out. Results of F-test are used to mask TBSS detected clusters for the AD > LOBD and LOBD > AD contrast to select the image clusters used for correlation analysis. Finally, Pearson's correlation coefficients between FA values at cluster sites and systemic blood plasma biomarker values are computed. Results: The TBSS contrasts with by ANOVA F-test has identified strongly significant clusters in the forceps minor, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and cingulum gyrus. The correlation analysis of these tract clusters found strong negative correlation of AD with the nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) blood biomarkers. Negative correlation of AD and positive correlation of LOBD with inflammation biomarker IL6 was also found. Conclusion: TBSS voxel clusters tract atlas localizations are consistent with greater behavioral impairment and mood disorders in LOBD than in AD. Correlation analysis confirms that neurotrophic factors (i.e., NGF, BDNF) play a great role in AD while are absent in LOBD pathophysiology. Also, correlation results of IL1 and IL6 suggest stronger inflammatory effects in LOBD than in AD.

Resting State Effective Connectivity Allows Auditory Hallucination Discrimination.

Hallucinations are elusive phenomena that have been associated with psychotic behavior, but that have a high prevalence in healthy population. Some generative mechanisms of Auditory Hallucinations (AH) have been proposed in the literature, but so far empirical evidence is scarce. The most widely accepted generative mechanism hypothesis nowadays consists in the faulty workings of a network of brain areas including the emotional control, the audio and language processing, and the inhibition and self-attribution of the signals in the auditive cortex. In this paper, we consider two methods to analyze resting state fMRI (rs-fMRI) data, in order to measure effective connections between the brain regions involved in the AH generation process. These measures are the Dynamic Causal Modeling (DCM) cross-covariance function (CCF) coefficients, and the partially directed coherence (PDC) coefficients derived from Granger Causality (GC) analysis. Effective connectivity measures are treated as input classifier features to assess their significance by means of cross-validation classification accuracy results in a wrapper feature selection approach. Experimental results using Support Vector Machine (SVM) classifiers on an rs-fMRI dataset of schizophrenia patients with and without a history of AH confirm that the main regions identified in the AH generative mechanism hypothesis have significant effective connection values, under both DCM and PDC evaluation.

Innovations in healthcare and medicine editorial.

This special issue editorial begins with a brief discussion on the current trends of innovations in healthcare and medicine driven by the evolution of sensing devices as well as the information processing techniques, and the social media revolution. This discussion aims to set the stage for the actual papers accepted for the special issue which are extensions of the papers presented at the InMed 2014 conference held in San Sebastian, Spain, in July 2014.

Eigenanatomy on Fractional Anisotropy Imaging Provides White Matter Anatomical Features Discriminating Between Alzheimer's Disease and Late Onset Bipolar Disorder.

BACKGROUND: Late Onset Bipolar Disorder (LOBD) is the arousal of Bipolar Disorder (BD) at old age (>60) without any previous history of disorders. LOBD is often difficult to distinguish from degenerative dementias, such as Alzheimer Disease (AD), due to comorbidities and common cognitive symptoms. Moreover, LOBD prevalence is increasing due to population aging. Biomarkers extracted from blood plasma are not discriminant because both pathologies share pathophysiological features related to neuroinflammation, therefore we look for anatomical features highly correlated with blood biomarkers that allow accurate diagnosis prediction. This may shed some light on the basic biological mechanisms leading to one or another disease. Moreover, accurate diagnosis is needed to select the best personalized treatment. OBJECTIVE: We look for white matter features which are correlated with blood plasma biomarkers (inflammatory and neurotrophic) discriminating LOBD from AD. MATERIALS: A sample of healthy controls (HC) (n=19), AD patients (n=35), and BD patients (n=24) has been recruited at the Alava University Hospital. Plasma biomarkers have been obtained at recruitment time. Diffusion weighted (DWI) magnetic resonance imaging (MRI) are obtained for each subject. METHODS: DWI is preprocessed to obtain diffusion tensor imaging (DTI) data, which is reduced to fractional anisotropy (FA) data. In the selection phase, eigenanatomy finds FA eigenvolumes maximally correlated with plasma biomarkers by partial sparse canonical correlation analysis (PSCCAN). In the analysis phase, we take the eigenvolume projection coefficients as the classification features, carrying out cross-validation of support vector machine (SVM) to obtain discrimination power of each biomarker effects. The John Hopkins Universtiy white matter atlas is used to provide anatomical localizations of the detected feature clusters. RESULTS: Classification results show that one specific biomarker of oxidative stress (malondialdehyde MDA) gives the best classification performance ( accuracy 85%, F-score 86%, sensitivity, and specificity 87%, ) in the discrimination of AD and LOBD. Discriminating features appear to be localized in the posterior limb of the internal capsule and superior corona radiata. CONCLUSION: It is feasible to support contrast diagnosis among LOBD and AD by means of predictive classifiers based on eigenanatomy features computed from FA imaging correlated to plasma biomarkers. In addition, white matter eigenanatomy localizations offer some new avenues to assess the differential pathophysiology of LOBD and AD.

Image Understanding Applications of Lattice Autoassociative Memories.

Multivariate mathematical morphology (MMM) aims to extend the mathematical morphology from gray scale images to images whose pixels are high-dimensional vectors, such as remote sensing hyperspectral images and functional magnetic resonance images (fMRIs). Defining an ordering over the multidimensional image data space is a fundamental issue MMM, to ensure that ensuing morphological operators and filters are mathematically consistent. Recent approaches use the outputs of two-class classifiers to build such reduced orderings. This paper presents the applications of MMM built on reduced supervised orderings based on lattice autoassociative memories (LAAMs) recall error measured by the Chebyshev distance. Foreground supervised orderings use one set of training data from a foreground class, whereas background/foreground supervised orderings use two training data sets, one for each relevant class. The first case study refers to the realization of the thematic segmentation of the hyperspectral images using spatial-spectral information. Spectral classification is enhanced by a spatial processing consisting in the spatial correction guided by a watershed segmentation computed by the LAAM-based morphological operators. The approach improves the state-of-the-art hyperspectral spatial-spectral thematic map building approaches. The second case study is the analysis of resting state fMRI data, working on a data set of healthy controls, schizophrenia patients with and without auditory hallucinations. We perform two experiments: 1) the localization of differences in brain functional networks on population-dependent templates and 2) the classification of subjects into each possible pair of cases. In this data set, we find that the LAAM-based morphological features improve over the conventional correlation-based graph measure features often employed in fMRI data classification.

Discrimination between Alzheimer's Disease and Late Onset Bipolar Disorder Using Multivariate Analysis.

BACKGROUND: Late onset bipolar disorder (LOBD) is often difficult to distinguish from degenerative dementias, such as Alzheimer disease (AD), due to comorbidities and common cognitive symptoms. Moreover, LOBD prevalence in the elder population is not negligible and it is increasing. Both pathologies share pathophysiological neuroinflammation features. Improvements in differential diagnosis of LOBD and AD will help to select the best personalized treatment. OBJECTIVE: The aim of this study is to assess the relative significance of clinical observations, neuropsychological tests, and specific blood plasma biomarkers (inflammatory and neurotrophic), separately and combined, in the differential diagnosis of LOBD versus AD. It was carried out evaluating the accuracy achieved by classification-based computer-aided diagnosis (CAD) systems based on these variables. MATERIALS: A sample of healthy controls (HC) (n = 26), AD patients (n = 37), and LOBD patients (n = 32) was recruited at the Alava University Hospital. Clinical observations, neuropsychological tests, and plasma biomarkers were measured at recruitment time. METHODS: We applied multivariate machine learning classification methods to discriminate subjects from HC, AD, and LOBD populations in the study. We analyzed, for each classification contrast, feature sets combining clinical observations, neuropsychological measures, and biological markers, including inflammation biomarkers. Furthermore, we analyzed reduced feature sets containing variables with significative differences determined by a Welch's t-test. Furthermore, a battery of classifier architectures were applied, encompassing linear and non-linear Support Vector Machines (SVM), Random Forests (RF), Classification and regression trees (CART), and their performance was evaluated in a leave-one-out (LOO) cross-validation scheme. Post hoc analysis of Gini index in CART classifiers provided a measure of each variable importance. RESULTS: Welch's t-test found one biomarker (Malondialdehyde) with significative differences (p < 0.001) in LOBD vs. AD contrast. Classification results with the best features are as follows: discrimination of HC vs. AD patients reaches accuracy 97.21% and AUC 98.17%. Discrimination of LOBD vs. AD patients reaches accuracy 90.26% and AUC 89.57%. Discrimination of HC vs LOBD patients achieves accuracy 95.76% and AUC 88.46%. CONCLUSION: It is feasible to build CAD systems for differential diagnosis of LOBD and AD on the basis of a reduced set of clinical variables. Clinical observations provide the greatest discrimination. Neuropsychological tests are improved by the addition of biomarkers, and both contribute significantly to improve the overall predictive performance.

Computer aided diagnosis of schizophrenia on resting state fMRI data by ensembles of ELM.

Resting state functional Magnetic Resonance Imaging (rs-fMRI) is increasingly used for the identification of image biomarkers of brain diseases or psychiatric conditions such as schizophrenia. This paper deals with the application of ensembles of Extreme Learning Machines (ELM) to build Computer Aided Diagnosis systems on the basis of features extracted from the activity measures computed over rs-fMRI data. The power of ELM to provide quick but near optimal solutions to the training of Single Layer Feedforward Networks (SLFN) allows extensive exploration of discriminative power of feature spaces in affordable time with off-the-shelf computational resources. Exploration is performed in this paper by an evolutionary search approach that has found functional activity map features allowing to achieve quite successful classification experiments, providing biologically plausible voxel-site localizations.

Discrimination of schizophrenia auditory hallucinators by machine learning of resting-state functional MRI.

Auditory hallucinations (AH) are a symptom that is most often associated with schizophrenia, but patients with other neuropsychiatric conditions, and even a small percentage of healthy individuals, may also experience AH. Elucidating the neural mechanisms underlying AH in schizophrenia may offer insight into the pathophysiology associated with AH more broadly across multiple neuropsychiatric disease conditions. In this paper, we address the problem of classifying schizophrenia patients with and without a history of AH, and healthy control (HC) subjects. To this end, we performed feature extraction from resting state functional magnetic resonance imaging (rsfMRI) data and applied machine learning classifiers, testing two kinds of neuroimaging features: (a) functional connectivity (FC) measures computed by lattice auto-associative memories (LAAM), and (b) local activity (LA) measures, including regional homogeneity (ReHo) and fractional amplitude of low frequency fluctuations (fALFF). We show that it is possible to perform classification within each pair of subject groups with high accuracy. Discrimination between patients with and without lifetime AH was highest, while discrimination between schizophrenia patients and HC participants was worst, suggesting that classification according to the symptom dimension of AH may be more valid than discrimination on the basis of traditional diagnostic categories. FC measures seeded in right Heschl's gyrus (RHG) consistently showed stronger discriminative power than those seeded in left Heschl's gyrus (LHG), a finding that appears to support AH models focusing on right hemisphere abnormalities. The cortical brain localizations derived from the features with strong classification performance are consistent with proposed AH models, and include left inferior frontal gyrus (IFG), parahippocampal gyri, the cingulate cortex, as well as several temporal and prefrontal cortical brain regions. Overall, the observed findings suggest that computational intelligence approaches can provide robust tools for uncovering subtleties in complex neuroimaging data, and have the potential to advance the search for more neuroscience-based criteria for classifying mental illness in psychiatry research.

Findings in resting-state fMRI by differences from K-means clustering.

Resting state fMRI has growing number of studies with diverse aims, always centered on some kind of functional connectivity biomarker obtained from correlation regarding seed regions, or by analytical decomposition of the signal towards the localization of the spatial distribution of functional connectivity patterns. In general, studies are computationally costly and very sensitive to noise and preprocessing of data. In this paper we consider clustering by K-means as a exploratory procedure which can provide some results with little computational effort, due to efficient implementations that are readily available. We demonstrate the approach on a dataset of schizophrenia patients, finding differences between patients with and without auditory hallucinations.