{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/162920"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/162920","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Unveiling Phenotype–Genotype Interplay with Deep Learning Foundation Models for scRNA-seq: A Quantitative Perspective","abstract":"Foundation models have emerged as powerful tools for analyzing single-cell RNA sequencing (scRNA-seq) data, leveraging large-scale pretraining to capture complex gene expression patterns. However, a comprehensive quantitative framework for understanding the interplay between phenotypes and genotypes remains underdeveloped. Such a framework is critical not only for validating model performance but also for uncovering previously unrecognized biological relationships. In this work, we present both traditional and deep learning-based quantitative analysis pipelines for PolyGene [1], a transformer-based scRNA-seq foundation model, aimed at disentangling the complex phenotype–genotype relationship. First, we implement a top-k classification and entropy evaluation pipeline to serve as a primary validation framework. Our results demonstrate that the pretrained PolyGene [1] is robust in top-k classification metrics and provides meaningful insights into the entropy landscape of human cells across different life stages. Second, we propose a novel deep learning gradientbased gene selection method designed to address limitations in traditional feature selection approaches, such as poor scalability and sensitivity to heterogeneity in high-dimensional data. Through empirical evaluations on benchmark scRNA-seq datasets, we show that our method enhances model interpretability and improves downstream performance, offering a more scalable and biologically relevant alternative to existing techniques. Overall, this work introduces a set of quantitative analysis tools that fill a critical gap in evaluating and interpreting scRNA-seq foundation models, contributing to a deeper understanding of the genotype–phenotype interplay through modern deep learning techniques.","abstract_html":"Foundation models have emerged as powerful tools for analyzing single-cell RNA sequencing (scRNA-seq) data, leveraging large-scale pretraining to capture complex gene expression patterns. However, a comprehensive quantitative framework for understanding the interplay between phenotypes and genotypes remains underdeveloped. Such a framework is critical not only for validating model performance but also for uncovering previously unrecognized biological relationships. In this work, we present both traditional and deep learning-based quantitative analysis pipelines for PolyGene [1], a transformer-based scRNA-seq foundation model, aimed at disentangling the complex phenotype–genotype relationship. First, we implement a top-k classification and entropy evaluation pipeline to serve as a primary validation framework. Our results demonstrate that the pretrained PolyGene [1] is robust in top-k classification metrics and provides meaningful insights into the entropy landscape of human cells across different life stages. Second, we propose a novel deep learning gradientbased gene selection method designed to address limitations in traditional feature selection approaches, such as poor scalability and sensitivity to heterogeneity in high-dimensional data. Through empirical evaluations on benchmark scRNA-seq datasets, we show that our method enhances model interpretability and improves downstream performance, offering a more scalable and biologically relevant alternative to existing techniques. Overall, this work introduces a set of quantitative analysis tools that fill a critical gap in evaluating and interpreting scRNA-seq foundation models, contributing to a deeper understanding of the genotype–phenotype interplay through modern deep learning techniques.","abstract_has_math":false,"creators":["Thadawasin, Pakaphol"],"institution":"Massachusetts Institute of Technology","degree_name":"Master","degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. 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However, a comprehensive quantitative framework for understanding the interplay between phenotypes and genotypes remains underdeveloped. Such a framework is critical not only for validating model performance but also for uncovering previously unrecognized biological relationships. In this work, we present both traditional and deep learning-based quantitative analysis pipelines for PolyGene [1], a transformer-based scRNA-seq foundation model, aimed at disentangling the complex phenotype–genotype relationship. First, we implement a top-k classification and entropy evaluation pipeline to serve as a primary validation framework. Our results demonstrate that the pretrained PolyGene [1] is robust in top-k classification metrics and provides meaningful insights into the entropy landscape of human cells across different life stages. Second, we propose a novel deep learning gradientbased gene selection method designed to address limitations in traditional feature selection approaches, such as poor scalability and sensitivity to heterogeneity in high-dimensional data. Through empirical evaluations on benchmark scRNA-seq datasets, we show that our method enhances model interpretability and improves downstream performance, offering a more scalable and biologically relevant alternative to existing techniques. Overall, this work introduces a set of quantitative analysis tools that fill a critical gap in evaluating and interpreting scRNA-seq foundation models, contributing to a deeper understanding of the genotype–phenotype interplay through modern deep learning techniques."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["M.Eng."]},{"key":"dc:title","label":"Title","values":["Unveiling Phenotype–Genotype Interplay with Deep Learning Foundation Models for scRNA-seq: A Quantitative Perspective"]}]}],"canonical_facts":{"dc:contributor.advisor":["Edelman, Elazer R."],"dc:contributor.department":["Massachusetts Institute of Technology. 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First, we implement a top-k classification and entropy evaluation pipeline to serve as a primary validation framework. Our results demonstrate that the pretrained PolyGene [1] is robust in top-k classification metrics and provides meaningful insights into the entropy landscape of human cells across different life stages. Second, we propose a novel deep learning gradientbased gene selection method designed to address limitations in traditional feature selection approaches, such as poor scalability and sensitivity to heterogeneity in high-dimensional data. Through empirical evaluations on benchmark scRNA-seq datasets, we show that our method enhances model interpretability and improves downstream performance, offering a more scalable and biologically relevant alternative to existing techniques. 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