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Title: On The Applications of Coarse Network Geometry to Personalized Immuno-Oncology
Candidate: Bannon, James
Advisor(s): Bud Mishra
Abstract:
Immune checkpoint inhibitors (ICIs), also called immune checkpoint blockers, are a promising category of targeted therapy for solid tumors. Predicting which patients will respond to ICI therapy remains an open problem under active investigation. This thesis aims to improve the precision with which immune checkpoint inhibitors are prescribed. By focusing on one type of biological measurement --- whole-tumor shotgun RNA sequencing data, which we call \textit{bulk RNA-seq} --- we are able to deeply explore the potential and limits of predictors built from this kind of measurement. Two of the algorithms presented here are based on a notion of graph curvature which we believe has extensive promise in bioinformatic inquiry.
The first part of this thesis performs a rigorous permutation testing evaluation of machine learning models for the task of predicting therapy response which we cast as a binary classification problem. We show that bulk RNA-seq data contains predictive signal but that there is an upper limit to ML model efficacy that can potentially be remedied by the curation of larger data sets or augmenting RNA-seq data with other biological measurements.
The next part presents a modular pipeline for the discovery of biomarkers from bulk RNA-seq data. We contextualize gene expression measurements using a protein-protein interaction (PPI) network and then use a notion of graph curvature to find (pairs of) genes in the PPI network that could serve as potential biomarkers. Our candidate biomarkers are evaluated using an extensive literature search and transfer learning experiments. We also provide a harmonized collection of drug-specific candidate markers found through rank aggregation that we believe merit further study.
Lastly, we cluster patients in an unsupervised manner using discrete Ollivier-Ricci Flow (ORF). Our method surfaces populations with distinct survival curves which in turn allows us to find many potential biomarkers, including gene expression modules. We believe the algorithm may be of independent interest for clustering other datasets in a diverse set of research areas.
As a result of the work here we have provided novel algorithmic techniques for analyzing (biological) data and advanced the state of the art in finding biomarkers for ICI therapy.