Presentation

ML based Prediction of Immunogenic Neoantigens for immunotherapy

--- From bearlyunderstanding

This project was started at the AI Genomics Hackathon on June 23-25, 2017, hosted by Silicon Valley Artificial Intelligence in San Francisco.

The goal of our project is to identify Neoantigen candidates for potential immunotherapy of Onno's NF2 condition. To do this, we use a combination of existing genomics tools and a novel protein structure-based machine learning setup to identify the most promising HLA (Human leukocyte antigen) restricted peptides.

The immune system is an incredibly complex and robust orchestra of molecules, cells, and processes that works to protect the body against both pathogenic infections and native cell dysfunction. One of the processes that the immune system uses to keep mutated cells from propagating (that is, to prevent cancers) is to identify cells with non-native (mutated) proteins and eliminate them before the mutant cells that encode them can spread. Vastly simplify this processes for the purpose of explanation, there are proteins in every cell that cut other proteins into short (8-12 amino acid long) peptide fragments. Some of these fragments are then presented by MHC (Major histocompatibility complex) molecules on the surface of the cell as antigens for inspection by cytotoxic T-cells; if a T-cell identifies an antigen as non-native, it will kill the cell.

When a tumor grows, this natural process is not working successfully. Immunotherapy comes in by attempting to enhance the natural process at some point along the signaling pathway. One focal point for immunotherapy is the binding of the cut-up protein fragments with the HLA proteins because that is the most chemically selective step along the pathway. In this project, we identify the most viable candidate epitopes for Onno's NF2 based on existing epitope-HLA binding affinity data and structural data of his HLA protein.

Identifying all epitope candidates

The project integrates diverse biological data sources include whole genome sequencing data (tumor-normal) and multiple 3rd party software include RTGtools, snpEff, netchop3.1 and netMHCpan3.0 to predict the potential MiHAs by comparing the variants between Onno's tumor and normal tissue. It simulates the antigen processing and presenting on tumor cell surface via restricted HLA molecules.

T cell targets tumor tissue by recognizing neoantigens

Side Project: Topological Features for Binding Affinity Predictions

Recent advances in computational topology have resulted in applications in sensor networks, neuroscience, archaeology, and cancer biology among numerous other fields. Such methods usually arise by considering a collection of data points as a finite sampling of some manifold whose topology is of interest. Understanding the topological structure of data can yield insights into previously difficult problems and allows for a variety of new approaches for data analysis and classification.

Given a point cloud of data in some metric space, we can construct a higher dimensional generalization of a graph called a simplicial complex. A simplicial complex is formed by k-dimensional convex polytopes called simplices. For low dimensions, we already know of points, lines, faces, and tetrahedrons. For higher dimensions, do what everyone does (but claims otherwise) and just extrapolate from 3D space.

Topological data analysis for use in characterizing cosmic filaments.

Specifically, we used a tool called persistent homology to study X-ray crystallography structures of HLA genes, using a resulting distance measure as input to a feedforward ANN for binding affinity predictions. .PDB files were read in via BioPython, alpha carbon positions extracted, and distance matrices constructed. The resulting data can be used to study the homology of the space (non-contractible k-dimensional cycles).