DeepGAMI: deep biologically guided auxiliary learning for multimodal integration and imputation to improve genotype-phenotype prediction.

BACKGROUND: Genotypes are strongly associated with disease phenotypes, particularly in brain disorders. However, the molecular and cellular mechanisms behind this association remain elusive. With emerging multimodal data for these mechanisms, machine learning methods can be applied for phenotype prediction at different scales, but due to the black-box nature of machine learning, integrating these modalities and interpreting biological mechanisms can be challenging. Additionally, the partial availability of these multimodal data presents a challenge in developing these predictive models. METHOD: To address these challenges, we developed DeepGAMI, an interpretable neural network model to improve genotype-phenotype prediction from multimodal data. DeepGAMI leverages functional genomic information, such as eQTLs and gene regulation, to guide neural network connections. Additionally, it includes an auxiliary learning layer for cross-modal imputation allowing the imputation of latent features of missing modalities and thus predicting phenotypes from a single modality. Finally, DeepGAMI uses integrated gradient to prioritize multimodal features for various phenotypes. RESULTS: We applied DeepGAMI to several multimodal datasets including genotype and bulk and cell-type gene expression data in brain diseases, and gene expression and electrophysiology data of mouse neuronal cells. Using cross-validation and independent validation, DeepGAMI outperformed existing methods for classifying disease types, and cellular and clinical phenotypes, even using single modalities (e.g., AUC score of 0.79 for Schizophrenia and 0.73 for cognitive impairment in Alzheimer's disease). CONCLUSION: We demonstrated that DeepGAMI improves phenotype prediction and prioritizes phenotypic features and networks in multiple multimodal datasets in complex brains and brain diseases. Also, it prioritized disease-associated variants, genes, and regulatory networks linked to different phenotypes, providing novel insights into the interpretation of gene regulatory mechanisms. DeepGAMI is open-source and available for general use.

CMOT: Cross-Modality Optimal Transport for multimodal inference.

Multimodal measurements of single-cell sequencing technologies facilitate a comprehensive understanding of specific cellular and molecular mechanisms. However, simultaneous profiling of multiple modalities of single cells is challenging, and data integration remains elusive due to missing modalities and cell-cell correspondences. To address this, we developed a computational approach, Cross-Modality Optimal Transport (CMOT), which aligns cells within available multi-modal data (source) onto a common latent space and infers missing modalities for cells from another modality (target) of mapped source cells. CMOT outperforms existing methods in various applications from developing brain, cancers to immunology, and provides biological interpretations improving cell-type or cancer classifications.

Single-cell network biology characterizes cell type gene regulation for drug repurposing and phenotype prediction in Alzheimer's disease.

Dysregulation of gene expression in Alzheimer's disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, AD-induced regulatory changes across brain cell types remains uncharted. To address this, we integrated single-cell multi-omics datasets to predict the gene regulatory networks of four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes, in control and AD brains. Importantly, we analyzed and compared the structural and topological features of networks across cell types and examined changes in AD. Our analysis shows that hub TFs are largely common across cell types and AD-related changes are relatively more prominent in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed-forward loops) further uncover cell type-specific TF-TF cooperativities in gene regulation. The cell type networks are also highly modular and several network modules with cell-type-specific expression changes in AD pathology are enriched with AD-risk genes. The further disease-module-drug association analysis suggests cell-type candidate drugs and their potential target genes. Finally, our network-based machine learning analysis systematically prioritized cell type risk genes likely involved in AD. Our strategy is validated using an independent dataset which showed that top ranked genes can predict clinical phenotypes (e.g., cognitive impairment) of AD with reasonable accuracy. Overall, this single-cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals cell-type gene dysregulation in AD.