Estimating the Causal Effects of T Cell Receptors

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.

Hierarchical Causal Models

Scientists often want to learn about cause and effect from hierarchical data, collected from subunits nested inside units. Consider students in schools, cells in patients, or cities in states. In such settings, unit-level variables (e.g. each school's budget) may affect subunit-level variables (e.g. the test scores of each student in each school) and vice versa. To address causal questions with hierarchical data, we propose hierarchical causal models, which extend structural causal models and causal graphical models by adding inner plates. We develop a general graphical identification technique for hierarchical causal models that extends do-calculus. We find many situations in which hierarchical data can enable causal identification even when it would be impossible with non-hierarchical data, that is, if we had only unit-level summaries of subunit-level variables (e.g. the school's average test score, rather than each student's score). We develop estimation techniques for hierarchical causal models, using methods including hierarchical Bayesian models. We illustrate our results in simulation and via a reanalysis of the classic "eight schools" study.

ProGen2: Exploring the Boundaries of Protein Language Models

Attention-based models trained on protein sequences have demonstrated incredible success at classification and generation tasks relevant for artificial intelligence-driven protein design. However, we lack a sufficient understanding of how very large-scale models and data play a role in effective protein model development. We introduce a suite of protein language models, named ProGen2, that are scaled up to 6.4B parameters and trained on different sequence datasets drawn from over a billion proteins from genomic, metagenomic, and immune repertoire databases. ProGen2 models show state-of-the-art performance in capturing the distribution of observed evolutionary sequences, generating novel viable sequences, and predicting protein fitness without additional finetuning. As large model sizes and raw numbers of protein sequences continue to become more widely accessible, our results suggest that a growing emphasis needs to be placed on the data distribution provided to a protein sequence model. We release the ProGen2 models and code at https://github.com/salesforce/progen.