Explainable Graph-theoretical Machine Learning: with Application to Alzheimer's Disease Prediction

Alzheimer's disease (AD) affects 50 million people worldwide and is projected to overwhelm 152 million by 2050. AD is characterized by cognitive decline due partly to disruptions in metabolic brain connectivity. Thus, early and accurate detection of metabolic brain network impairments is crucial for AD management. Chief to identifying such impairments is FDG-PET data. Despite advancements, most graph-based studies using FDG-PET data rely on group-level analysis or thresholding. Yet, group-level analysis can veil individual differences and thresholding may overlook weaker but biologically critical brain connections. Additionally, machine learning-based AD prediction largely focuses on univariate outcomes, such as disease status. Here, we introduce explainable graph-theoretical machine learning (XGML), a framework employing kernel density estimation and dynamic time warping to construct individual metabolic brain graphs that capture the distance between pair-wise brain regions and identify subgraphs most predictive of multivariate AD-related outcomes. Using FDG-PET data from the Alzheimer's Disease Neuroimaging Initiative, XGML builds metabolic brain graphs and uncovers subgraphs predictive of eight AD-related cognitive scores in new subjects. XGML shows robust performance, particularly for predicting scores measuring learning, memory, language, praxis, and orientation, such as CDRSB ($r = 0.74$), ADAS11 ($r = 0.73$), and ADAS13 ($r = 0.71$). Moreover, XGML unveils key edges jointly but differentially predictive of several AD-related outcomes; they may serve as potential network biomarkers for assessing overall cognitive decline. Together, we show the promise of graph-theoretical machine learning in biomarker discovery and disease prediction and its potential to improve our understanding of network neural mechanisms underlying AD.

OPTIMUS: Predicting Multivariate Outcomes in Alzheimer's Disease Using Multi-modal Data amidst Missing Values

Alzheimer's disease, a neurodegenerative disorder, is associated with neural, genetic, and proteomic factors while affecting multiple cognitive and behavioral faculties. Traditional AD prediction largely focuses on univariate disease outcomes, such as disease stages and severity. Multimodal data encode broader disease information than a single modality and may, therefore, improve disease prediction; but they often contain missing values. Recent "deeper" machine learning approaches show promise in improving prediction accuracy, yet the biological relevance of these models needs to be further charted. Integrating missing data analysis, predictive modeling, multimodal data analysis, and explainable AI, we propose OPTIMUS, a predictive, modular, and explainable machine learning framework, to unveil the many-to-many predictive pathways between multimodal input data and multivariate disease outcomes amidst missing values. OPTIMUS first applies modality-specific imputation to uncover data from each modality while optimizing overall prediction accuracy. It then maps multimodal biomarkers to multivariate outcomes using machine-learning and extracts biomarkers respectively predictive of each outcome. Finally, OPTIMUS incorporates XAI to explain the identified multimodal biomarkers. Using data from 346 cognitively normal subjects, 608 persons with mild cognitive impairment, and 251 AD patients, OPTIMUS identifies neural and transcriptomic signatures that jointly but differentially predict multivariate outcomes related to executive function, language, memory, and visuospatial function. Our work demonstrates the potential of building a predictive and biologically explainable machine-learning framework to uncover multimodal biomarkers that capture disease profiles across varying cognitive landscapes. The results improve our understanding of the complex many-to-many pathways in AD.

VisTA: Vision-Text Alignment Model with Contrastive Learning using Multimodal Data for Evidence-Driven, Reliable, and Explainable Alzheimer's Disease Diagnosis

Objective: Assessing Alzheimer's disease (AD) using high-dimensional radiology images is clinically important but challenging. Although Artificial Intelligence (AI) has advanced AD diagnosis, it remains unclear how to design AI models embracing predictability and explainability. Here, we propose VisTA, a multimodal language-vision model assisted by contrastive learning, to optimize disease prediction and evidence-based, interpretable explanations for clinical decision-making. Methods: We developed VisTA (Vision-Text Alignment Model) for AD diagnosis. Architecturally, we built VisTA from BiomedCLIP and fine-tuned it using contrastive learning to align images with verified abnormalities and their descriptions. To train VisTA, we used a constructed reference dataset containing images, abnormality types, and descriptions verified by medical experts. VisTA produces four outputs: predicted abnormality type, similarity to reference cases, evidence-driven explanation, and final AD diagnoses. To illustrate VisTA's efficacy, we reported accuracy metrics for abnormality retrieval and dementia prediction. To demonstrate VisTA's explainability, we compared its explanations with human experts' explanations. Results: Compared to 15 million images used for baseline pretraining, VisTA only used 170 samples for fine-tuning and obtained significant improvement in abnormality retrieval and dementia prediction. For abnormality retrieval, VisTA reached 74% accuracy and an AUC of 0.87 (26% and 0.74, respectively, from baseline models). For dementia prediction, VisTA achieved 88% accuracy and an AUC of 0.82 (30% and 0.57, respectively, from baseline models). The generated explanations agreed strongly with human experts' and provided insights into the diagnostic process. Taken together, VisTA optimize prediction, clinical reasoning, and explanation.