Multi-source multi-modal markers for Bayesian Networks: Application to the extremely preterm born brain.

The preterm phenotype results from the interplay of multiple disorders affecting the brain and cognitive outcomes. Accurately characterising these interactions can reveal prematurity markers. Bayesian Networks (BNs) are powerful tools to disentangle these relationships, as they inherently measure associations between variables while mitigating confounding factors. We present Modified PC-HC (MPC-HC), a Bayesian Network (BN) structural learning algorithm. MPC-HC employs statistical testing and search-and-score techniques to explore equivalent classes. We employ MPC-HC to estimate BNs for extremely preterm (EP) young adults and full-term controls. Using MRI measurements and cognitive performance markers, we investigate predictive relationships and mutual influences through predictions and sensitivity analysis. We assess the confidence in the estimated BN structures using bootstrapping. Furthermore, MPC-HC's validation involves assessing its ability to recover benchmark BN structures. MPC-HC achieves an average prediction accuracy of 72.5% compared to 62.5% of PC, 64.5% of MMHC, and 71.5% of HC, while it outperforms PC, MMHC, and HC algorithms in reconstructing the true structure of benchmark BNs. The sensitivity analysis shows that MRI measurements mainly affect EP cognitive scores. Our work has two key contributions: first, the introduction and validation of a new BN structure learning method. Second, demonstrating the potential of BNs in modelling variable relationships, predicting variables of interest, modelling uncertainty, and evaluating how variables impact each other. Finally, we demonstrate this by characterising complex phenotypes, such as preterm birth, and discovering results consistent with literature findings.

White matter analysis of the extremely preterm born adult brain.

The preterm brain has been analysed after birth by a large body of neuroimaging studies; however, few studies have focused on white matter alterations in preterm subjects beyond infancy, especially in individuals born at extremely low gestation age - before 28 completed weeks. Neuroimaging data of extremely preterm young adults are now available to investigate the long-term structural alterations of disrupted neurodevelopment. We examined white matter hierarchical organisation and microstructure in extremely preterm young adults. Specifically, we first identified the putative hubs and peripheral regions in 85 extremely preterm young adults and compared them with 53 socio-economically matched and full-term born peers. Moreover, we analysed Fractional Anisotropy (FA), Mean Diffusivity (MD), Neurite Density Index (NDI), and Orientation Dispersion Index (ODI) of white matter in hubs, peripheral regions, and over the whole brain. Our results suggest that the hierarchical organisation of the extremely preterm adult brain remains intact. However, there is evidence of significant alteration of white matter connectivity at both the macro- and microstructural level, with overall diminished connectivity, reduced FA and NDI, increased MD, and comparable ODI; suggesting that, although the spatial configuration of WM fibres is comparable, there are less WM fibres per voxel. These alterations are found throughout the brain and are more prevalent along the pathways between deep grey matter regions, frontal regions and cerebellum. This work provides evidence that white matter abnormalities associated with the premature exposure to the extrauterine environment not only are present at term equivalent age but persist into early adulthood.

Neuropsychiatric disease classification using functional connectomics - results of the connectomics in neuroimaging transfer learning challenge.

Large, open-source datasets, such as the Human Connectome Project and the Autism Brain Imaging Data Exchange, have spurred the development of new and increasingly powerful machine learning approaches for brain connectomics. However, one key question remains: are we capturing biologically relevant and generalizable information about the brain, or are we simply overfitting to the data? To answer this, we organized a scientific challenge, the Connectomics in NeuroImaging Transfer Learning Challenge (CNI-TLC), held in conjunction with MICCAI 2019. CNI-TLC included two classification tasks: (1) diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) within a pre-adolescent cohort; and (2) transference of the ADHD model to a related cohort of Autism Spectrum Disorder (ASD) patients with an ADHD comorbidity. In total, 240 resting-state fMRI (rsfMRI) time series averaged according to three standard parcellation atlases, along with clinical diagnosis, were released for training and validation (120 neurotypical controls and 120 ADHD). We also provided Challenge participants with demographic information of age, sex, IQ, and handedness. The second set of 100 subjects (50 neurotypical controls, 25 ADHD, and 25 ASD with ADHD comorbidity) was used for testing. Classification methodologies were submitted in a standardized format as containerized Docker images through ChRIS, an open-source image analysis platform. Utilizing an inclusive approach, we ranked the methods based on 16 metrics: accuracy, area under the curve, F1-score, false discovery rate, false negative rate, false omission rate, false positive rate, geometric mean, informedness, markedness, Matthew's correlation coefficient, negative predictive value, optimized precision, precision, sensitivity, and specificity. The final rank was calculated using the rank product for each participant across all measures. Furthermore, we assessed the calibration curves of each methodology. Five participants submitted their method for evaluation, with one outperforming all other methods in both ADHD and ASD classification. However, further improvements are still needed to reach the clinical translation of functional connectomics. We have kept the CNI-TLC open as a publicly available resource for developing and validating new classification methodologies in the field of connectomics.

Hemodynamic matrix factorization for functional magnetic resonance imaging.

The General Linear Model (GLM) used in task-fMRI relates activated brain areas to extrinsic task conditions. The translation of resulting neural activation into a hemodynamic response is commonly approximated with a linear convolution model using a hemodynamic response function (HRF). There are two major limitations in GLM analysis. Firstly, the GLM assumes that neural activation is either on or off and matches the exact stimulus duration in the corresponding task timings. Secondly, brain networks observed in resting-state fMRI experiments present also during task experiments, but the GLM approach models these task-unrelated brain activity as noise. A novel kernel matrix factorization approach, called hemodynamic matrix factorization (HMF), is therefore proposed that addresses both limitations by assuming that task-related and task-unrelated brain activity can be modeled with the same convolution model as in GLM analysis. By contrast to the GLM, the proposed HMF is a blind source separation (BSS) technique, which decomposes fMRI data into modes. Each mode comprises of a neural activation time course and a spatial mapping. Two versions of HMF are proposed in which the neural activation time course of each mode is convolved with either the canonical HRF or predetermined subject-specific HRFs. Firstly, HMF with the canonical HRF is applied to two open-source cohorts. These cohorts comprise of several task experiments including motor, incidental memory, spatial coherence discrimination, verbal discrimination task and a very short localization task, engaging multiple parts of the eloquent cortex. HMF modes were obtained whose neural activation time course followed original task timings and whose corresponding spatial map matched cortical areas known to be involved in the respective task processing. Secondly, the alignment of these neural activation time courses to task timings were further improved by replacing the canonical HRF with subject-specific HRFs during HMF mode computation. In addition to task-related modes, HMF also produced seemingly task-unrelated modes whose spatial maps matched known resting-state networks. The validity of a fMRI task experiment relies on the assumption that the exposure to a stimulus for a given time causes an imminent increase in neural activation of equal duration. The proposed HMF is an attempt to falsify this assumption and allows to identify subject task participation that does not comply with the experiment instructions.

Study protocol: Insight 46 - a neuroscience sub-study of the MRC National Survey of Health and Development.

BACKGROUND: Increasing age is the biggest risk factor for dementia, of which Alzheimer's disease is the commonest cause. The pathological changes underpinning Alzheimer's disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment - including ß-amyloid depostion, vascular disease, network breakdown and atrophy - to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms. METHODS/DESIGN: This paper outlines the clinical, cognitive and imaging protocol of "Insight 46", a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer's disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60-64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, ß-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73). DISCUSSION: Through the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer's disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.