Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Preprint |
| Published: |
2024
|
| Subjects: | |
| Online Access: | https://arxiv.org/abs/2410.14127 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Table of Contents:
- A central question in human immunology is how a patient's repertoire of T cells impacts disease. Here, we introduce a method to infer the causal effects of T cell receptor (TCR) sequences on patient outcomes using observational TCR repertoire sequencing data and clinical outcomes data. Our approach corrects for unobserved confounders, such as a patient's environment and life history, by using the patient's immature, pre-selection TCR repertoire. The pre-selection repertoire can be estimated from nonproductive TCR data, which is widely available. It is generated by a randomized mutational process, V(D)J recombination, which provides a natural experiment. We show formally how to use the pre-selection repertoire to draw causal inferences, and develop a scalable neural-network estimator for our identification formula. Our method produces an estimate of the effect of interventions that add a specific TCR sequence to patient repertoires. As a demonstration, we use it to analyze the effects of TCRs on COVID-19 severity, uncovering potentially therapeutic TCRs that are (1) observed in patients, (2) bind SARS-CoV-2 antigens in vitro and (3) have strong positive effects on clinical outcomes.