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oai:dspace.mit.edu:1721.1/1648252026-02-13T03:49:10Zcom_1721.1_7582com_1721.1_7581col_1721.1_131023

Kellis, Manolis Guo, Sophie J. Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science 2026-02-12T17:12:48Z 2026-02-12T17:12:48Z 2025-09 2025-09-15T14:56:27.937Z https://hdl.handle.net/1721.1/164825 Advances in artificial intelligence (AI) and generative AI for representation learning have transformed our ability to model complex biological systems. Single-cell RNA sequencing (scRNA-seq) provides unprecedented resolution into cellular heterogeneity, offering a powerful substrate for modeling disease circuitry. However, predicting patient-level phenotypes from scRNA-seq remains challenging due to limited sample sizes, variable cell counts, and the computational burden of modeling long-context dependencies. We present scPhen, a flexible, parametric deep-learning framework for phenotype prediction from single-cell transcriptomic data, applied here to Alzheimer’s disease (AD) as a paradigm of complex, heterogeneous pathology. scPhen consists of a cell embedding module and a patient embedding module, designed to capture both fine-grained molecular patterns and higher-order cell–cell relationships. The framework supports multiple architectural backbones, including Transformers, Graph Neural Networks (GNNs), and state-space models such as Mamba, Mamba2, and BiMamba2, allowing exploration of tunable components for optimized performance. Across classification and regression tasks, state-space models, and in particular BiMamba2, demonstrated superior predictive accuracy and computational efficiency compared to Transformer-based and hybrid approaches. We further integrated attention-based multiple instance learning to enable variable cell counts per patient and to prioritize phenotype-informative cellular subsets. Interpretability analyses using Integrated Gradients and cell-level attention scores revealed gene programs and cell populations associated with AD progression, highlighting known neuroinflammatory signatures and suggesting novel molecular targets. By unifying cutting-edge sequence modeling architectures with scalable single-cell analysis, scPhen provides a generalizable, high-resolution approach to phenotype prediction. While demonstrated here in AD, this framework is readily extensible to other complex diseases and multi-modal cellular datasets, bridging computational innovation and biological discovery. M.Eng. Massachusetts Institute of Technology In Copyright - Educational Use Permitted Copyright retained by author(s) https://rightsstatements.org/page/InC-EDU/1.0/ scPhen: Single-Cell Phenotype Predictor for Alzheimer’s Disease Thesis application/pdf Master Master of Engineering in Electrical Engineering and Computer Science Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="92130183-5951-4f2b-891b-9a1081d4a70b"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Title>scPhen: Single-Cell Phenotype Predictor for Alzheimer’s Disease</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2025-09</PublicationDate> <Authors> <Author> <DisplayName>Guo, Sophie J.</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>https://rightsstatements.org/page/InC-EDU/1.0/</License> <Abstract>Advances in artificial intelligence (AI) and generative AI for representation learning have transformed our ability to model complex biological systems. Single-cell RNA sequencing (scRNA-seq) provides unprecedented resolution into cellular heterogeneity, offering a powerful substrate for modeling disease circuitry. However, predicting patient-level phenotypes from scRNA-seq remains challenging due to limited sample sizes, variable cell counts, and the computational burden of modeling long-context dependencies. We present scPhen, a flexible, parametric deep-learning framework for phenotype prediction from single-cell transcriptomic data, applied here to Alzheimer’s disease (AD) as a paradigm of complex, heterogeneous pathology. scPhen consists of a cell embedding module and a patient embedding module, designed to capture both fine-grained molecular patterns and higher-order cell–cell relationships. The framework supports multiple architectural backbones, including Transformers, Graph Neural Networks (GNNs), and state-space models such as Mamba, Mamba2, and BiMamba2, allowing exploration of tunable components for optimized performance. Across classification and regression tasks, state-space models, and in particular BiMamba2, demonstrated superior predictive accuracy and computational efficiency compared to Transformer-based and hybrid approaches. We further integrated attention-based multiple instance learning to enable variable cell counts per patient and to prioritize phenotype-informative cellular subsets. Interpretability analyses using Integrated Gradients and cell-level attention scores revealed gene programs and cell populations associated with AD progression, highlighting known neuroinflammatory signatures and suggesting novel molecular targets. By unifying cutting-edge sequence modeling architectures with scalable single-cell analysis, scPhen provides a generalizable, high-resolution approach to phenotype prediction. While demonstrated here in AD, this framework is readily extensible to other complex diseases and multi-modal cellular datasets, bridging computational innovation and biological discovery.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>