Neda Jahanshad

Eamonn Kennedy, Shashank Vadlamani, Hannah M Lindsey et al.

An extensive library of symptom inventories has been developed over time to measure clinical symptoms, but this variety has led to several long standing issues. Most notably, results drawn from different settings and studies are not comparable, which limits reproducibility. Here, we present an artificial intelligence (AI) approach using semantic textual similarity (STS) to link symptoms and scores across previously incongruous symptom inventories. We tested the ability of four pre-trained STS models to screen thousands of symptom description pairs for related content - a challenging task typically requiring expert panels. Models were tasked to predict symptom severity across four different inventories for 6,607 participants drawn from 16 international data sources. The STS approach achieved 74.8% accuracy across five tasks, outperforming other models tested. This work suggests that incorporating contextual, semantic information can assist expert decision-making processes, yielding gains for both general and disease-specific clinical assessment.

Roberto Goya-Maldonado, Tracy Erwin-Grabner, Ling-Li Zeng et al.

Major depressive disorder (MDD) is a complex psychiatric disorder that affects the lives of hundreds of millions of individuals around the globe. Even today, researchers debate if morphological alterations in the brain are linked to MDD, likely due to the heterogeneity of this disorder. The application of deep learning tools to neuroimaging data, capable of capturing complex non-linear patterns, has the potential to provide diagnostic and predictive biomarkers for MDD. However, previous attempts to demarcate MDD patients and healthy controls (HC) based on segmented cortical features via linear machine learning approaches have reported low accuracies. Here, we used globally representative data from the ENIGMA-MDD working group containing 7,012 participants from 30 sites (N=2,772 MDD and N=4,240 HC), which allows a comprehensive analysis with generalizable results. Based on the hypothesis that integration of vertex-wise cortical features can improve classification performance, we evaluated the classification of a DenseNet and a Support Vector Machine (SVM), with the expectation that the former would outperform the latter. We found that both classifiers exhibited close to chance performance (balanced accuracy DenseNet: 51%; SVM: 53%), when estimated on unseen sites. Slightly higher classification performance (balanced accuracy DenseNet: 58%; SVM: 55%) was found when the cross-validation folds contained subjects from all sites, indicating site effect. In conclusion, the integration of vertex-wise morphometric features and the use of the non-linear classifier did not lead to the differentiability between MDD and HC. Our results support the notion that MDD classification on this combination of such features and classifiers is unfeasible. Perhaps more sophisticated integration of multimodal information may lead to a higher performance in this diagnostic task.

Myrl G. Marmarelis, Elizabeth Haddad, Andrew Jesson et al.

Inferring causal effects of continuous-valued treatments from observational data is a crucial task promising to better inform policy- and decision-makers. A critical assumption needed to identify these effects is that all confounding variables -- causal parents of both the treatment and the outcome -- are included as covariates. Unfortunately, given observational data alone, we cannot know with certainty that this criterion is satisfied. Sensitivity analyses provide principled ways to give bounds on causal estimates when confounding variables are hidden. While much attention is focused on sensitivity analyses for discrete-valued treatments, much less is paid to continuous-valued treatments. We present novel methodology to bound both average and conditional average continuous-valued treatment-effect estimates when they cannot be point identified due to hidden confounding. A semi-synthetic benchmark on multiple datasets shows our method giving tighter coverage of the true dose-response curve than a recently proposed continuous sensitivity model and baselines. Finally, we apply our method to a real-world observational case study to demonstrate the value of identifying dose-dependent causal effects.

Andre Altmann, Ana C Lawry Aguila, Neda Jahanshad et al.

A major challenge in imaging genetics and similar fields is to link high-dimensional data in one domain, e.g., genetic data, to high dimensional data in a second domain, e.g., brain imaging data. The standard approach in the area are mass univariate analyses across genetic factors and imaging phenotypes. That entails executing one genome-wide association study (GWAS) for each pre-defined imaging measure. Although this approach has been tremendously successful, one shortcoming is that phenotypes must be pre-defined. Consequently, effects that are not confined to pre-selected regions of interest or that reflect larger brain-wide patterns can easily be missed. In this work we introduce a Partial Least Squares (PLS)-based framework, which we term Cluster-Bootstrap PLS (CLUB-PLS), that can work with large input dimensions in both domains as well as with large sample sizes. One key factor of the framework is to use cluster bootstrap to provide robust statistics for single input features in both domains. We applied CLUB-PLS to investigating the genetic basis of surface area and cortical thickness in a sample of 33,000 subjects from the UK Biobank. We found 107 genome-wide significant locus-phenotype pairs that are linked to 386 different genes. We found that a vast majority of these loci could be technically validated at a high rate: using classic GWAS or Genome-Wide Inferred Statistics (GWIS) we found that 85 locus-phenotype pairs exceeded the genome-wide suggestive (P<1e-05) threshold.

Nancy R. Newlin, Kurt Schilling, Serge Koudoro et al.

White matter alterations are increasingly implicated in neurological diseases and their progression. International-scale studies use diffusion-weighted magnetic resonance imaging (DW-MRI) to qualitatively identify changes in white matter microstructure and connectivity. Yet, quantitative analysis of DW-MRI data is hindered by inconsistencies stemming from varying acquisition protocols. There is a pressing need to harmonize the preprocessing of DW-MRI datasets to ensure the derivation of robust quantitative diffusion metrics across acquisitions. In the MICCAI-CDMRI 2023 QuantConn challenge, participants were provided raw data from the same individuals collected on the same scanner but with two different acquisitions and tasked with preprocessing the DW-MRI to minimize acquisition differences while retaining biological variation. Submissions are evaluated on the reproducibility and comparability of cross-acquisition bundle-wise microstructure measures, bundle shape features, and connectomics. The key innovations of the QuantConn challenge are that (1) we assess bundles and tractography in the context of harmonization for the first time, (2) we assess connectomics in the context of harmonization for the first time, and (3) we have 10x additional subjects over prior harmonization challenge, MUSHAC and 100x over SuperMUDI. We find that bundle surface area, fractional anisotropy, connectome assortativity, betweenness centrality, edge count, modularity, nodal strength, and participation coefficient measures are most biased by acquisition and that machine learning voxel-wise correction, RISH mapping, and NeSH methods effectively reduce these biases. In addition, microstructure measures AD, MD, RD, bundle length, connectome density, efficiency, and path length are least biased by these acquisition differences.

Soroosh Safari Loaliyan, Jose-Luis Ambite, Paul M. Thompson et al.

Federated Learning (FL) trains models locally at each research center or clinic and aggregates only model updates, making it a natural fit for medical imaging, where strict privacy laws forbid raw data sharing. A major obstacle is scanner-induced domain shift: non-biological variations in hardware or acquisition protocols can cause models to fail on external sites. Most harmonization methods correct this shift by directly comparing data across sites, conflicting with FL's privacy constraints. Domain Generalization (DG) offers a privacy-friendly alternative - learning site-invariant representations without sharing raw data - but standard DG pipelines still assume centralized access to multi-site data, again violating FL's guarantees. This paper meets these difficulties with a straightforward integration of a Domain-Adversarial Neural Network (DANN) within the FL process. After demonstrating that a naive federated DANN fails to converge, we propose a proximal regularization method that stabilizes adversarial training among clients. Experiments on T1-weighted 3-D brain MRIs from the OpenBHB dataset, performing brain-age prediction on participants aged 6-64 y (mean 22+/-6 y; 45 percent male) in training and 6-79 y (mean 19+/-13 y; 55 percent male) in validation, show that training on 15 sites and testing on 19 unseen sites yields superior cross-site generalization over FedAvg and ERM while preserving data privacy.

Nikita Mokrov, Maxim Panov, Boris A. Gutman et al.

This paper considers the problem of brain disease classification based on connectome data. A connectome is a network representation of a human brain. The typical connectome classification problem is very challenging because of the small sample size and high dimensionality of the data. We propose to use simultaneous approximate diagonalization of adjacency matrices in order to compute their eigenstructures in more stable way. The obtained approximate eigenvalues are further used as features for classification. The proposed approach is demonstrated to be efficient for detection of Alzheimer's disease, outperforming simple baselines and competing with state-of-the-art approaches to brain disease classification.

Dmitry Petrov, Alexander Ivanov, Joshua Faskowitz et al.

There is no consensus on how to construct structural brain networks from diffusion MRI. How variations in pre-processing steps affect network reliability and its ability to distinguish subjects remains opaque. In this work, we address this issue by comparing 35 structural connectome-building pipelines. We vary diffusion reconstruction models, tractography algorithms and parcellations. Next, we classify structural connectome pairs as either belonging to the same individual or not. Connectome weights and eight topological derivative measures form our feature set. For experiments, we use three test-retest datasets from the Consortium for Reliability and Reproducibility (CoRR) comprised of a total of 105 individuals. We also compare pairwise classification results to a commonly used parametric test-retest measure, Intraclass Correlation Coefficient (ICC).

Dajiang Zhu, Brandalyn C. Riedel, Neda Jahanshad et al.

Large-scale collaborative analysis of brain imaging data, in psychiatry and neu-rology, offers a new source of statistical power to discover features that boost ac-curacy in disease classification, differential diagnosis, and outcome prediction. However, due to data privacy regulations or limited accessibility to large datasets across the world, it is challenging to efficiently integrate distributed information. Here we propose a novel classification framework through multi-site weighted LASSO: each site performs an iterative weighted LASSO for feature selection separately. Within each iteration, the classification result and the selected features are collected to update the weighting parameters for each feature. This new weight is used to guide the LASSO process at the next iteration. Only the fea-tures that help to improve the classification accuracy are preserved. In tests on da-ta from five sites (299 patients with major depressive disorder (MDD) and 258 normal controls), our method boosted classification accuracy for MDD by 4.9% on average. This result shows the potential of the proposed new strategy as an ef-fective and practical collaborative platform for machine learning on large scale distributed imaging and biobank data.

Qingyang Li, Dajiang Zhu, Jie Zhang et al.

Genome-wide association studies (GWAS) have achieved great success in the genetic study of Alzheimer's disease (AD). Collaborative imaging genetics studies across different research institutions show the effectiveness of detecting genetic risk factors. However, the high dimensionality of GWAS data poses significant challenges in detecting risk SNPs for AD. Selecting relevant features is crucial in predicting the response variable. In this study, we propose a novel Distributed Feature Selection Framework (DFSF) to conduct the large-scale imaging genetics studies across multiple institutions. To speed up the learning process, we propose a family of distributed group Lasso screening rules to identify irrelevant features and remove them from the optimization. Then we select the relevant group features by performing the group Lasso feature selection process in a sequence of parameters. Finally, we employ the stability selection to rank the top risk SNPs that might help detect the early stage of AD. To the best of our knowledge, this is the first distributed feature selection model integrated with group Lasso feature selection as well as detecting the risk genetic factors across multiple research institutions system. Empirical studies are conducted on 809 subjects with 5.9 million SNPs which are distributed across several individual institutions, demonstrating the efficiency and effectiveness of the proposed method.

Daniel Moyer, Boris A Gutman, Neda Jahanshad et al.

One of the primary objectives of human brain mapping is the division of the cortical surface into functionally distinct regions, i.e. parcellation. While it is generally agreed that at macro-scale different regions of the cortex have different functions, the exact number and configuration of these regions is not known. Methods for the discovery of these regions are thus important, particularly as the volume of available information grows. Towards this end, we present a parcellation method based on a Bayesian non-parametric mixture model of cortical connectivity.

Dmitry Petrov, Boris Gutman, Alexander Ivanov et al.

In this work, we study the extent to which structural connectomes and topological derivative measures are unique to individual changes within human brains. To do so, we classify structural connectome pairs from two large longitudinal datasets as either belonging to the same individual or not. Our data is comprised of 227 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 226 from the Parkinson's Progression Markers Initiative (PPMI). We achieve 0.99 area under the ROC curve score for features which represent either weights or network structure of the connectomes (node degrees, PageRank and local efficiency). Our approach may be useful for eliminating noisy features as a preprocessing step in brain aging studies and early diagnosis classification problems.

Daniel Moyer, Boris A. Gutman, Joshua Faskowitz et al.

In the present work we demonstrate the use of a parcellation free connectivity model based on Poisson point processes. This model produces for each subject a continuous bivariate intensity function that represents for every possible pair of points the relative rate at which we observe tracts terminating at those points. We fit this model to explore degree sequence equivalents for spatial continuum graphs, and to investigate the local differences between estimated intensity functions for two different tractography methods. This is a companion paper to Moyer et al. (2016), where the model was originally defined.

Qingyang Li, Tao Yang, Liang Zhan et al.

Genome-wide association studies (GWAS) offer new opportunities to identify genetic risk factors for Alzheimer's disease (AD). Recently, collaborative efforts across different institutions emerged that enhance the power of many existing techniques on individual institution data. However, a major barrier to collaborative studies of GWAS is that many institutions need to preserve individual data privacy. To address this challenge, we propose a novel distributed framework, termed Local Query Model (LQM) to detect risk SNPs for AD across multiple research institutions. To accelerate the learning process, we propose a Distributed Enhanced Dual Polytope Projection (D-EDPP) screening rule to identify irrelevant features and remove them from the optimization. To the best of our knowledge, this is the first successful run of the computationally intensive model selection procedure to learn a consistent model across different institutions without compromising their privacy while ranking the SNPs that may collectively affect AD. Empirical studies are conducted on 809 subjects with 5.9 million SNP features which are distributed across three individual institutions. D-EDPP achieved a 66-fold speed-up by effectively identifying irrelevant features.