| Title: | EmbedGEM: a framework to evaluate the utility of embeddings for genetic discovery |
| Journal: | Bioinformatics Advances |
| Published: | 5 Jan 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39664859/ |
| DOI: | https://doi.org/10.1093/bioadv/vbae135 |
Publication 13345
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Abstract
Summary: Machine learning-derived embeddings are a compressed representation of high content data modalities. Embeddings can capture detailed information about disease states and have been qualitatively shown to be useful in genetic discovery. Despite their promise, embeddings have a major limitation: it is unclear if genetic variants associated with embeddings are relevant to the disease or trait of interest. In this work, we describe EmbedGEM (Embedding Genetic Evaluation Methods), a framework to systematically evaluate the utility of embeddings in genetic discovery. EmbedGEM focuses on comparing embeddings along two axes: heritability and disease relevance. As measures of heritability, we consider the number of genome-wide significant associations and the mean χ 2 statistic at significant loci. For disease relevance, we compute polygenic risk scores for each embedding principal component, then evaluate their association with high-confidence disease or trait labels in a held-out evaluation patient set. While our development of EmbedGEM is motivated by embeddings, the approach is generally applicable to multivariate traits and can readily be extended to accommodate additional metrics along the evaluation axes. We demonstrate EmbedGEM's utility by evaluating embeddings and multivariate traits in two separate datasets: (i) a synthetic dataset simulated to demonstrate the ability of the framework to correctly rank traits based on their heritability and disease relevance and (ii) a real data from the UK Biobank, including metabolic and liver-related traits. Importantly, we show that greater disease relevance does not automatically follow from greater heritability.</p>
Availability and implementation: https://github.com/insitro/EmbedGEM.</p>
16 Authors
- Sumit Mukherjee
- Zachary R McCaw
- Jingwen Pei
- Anna Merkoulovitch
- Tom Soare
- Raghav Tandon
- David Amar
- Hari Somineni
- Christoph Klein
- Santhosh Satapati
- David Lloyd
- Christopher Probert
- Insitro Research Team
- Daphne Koller
- Colm O'Dushlaine
- Theofanis Karaletsos
1 Application
| Application ID | Title |
|---|---|
| 51766 | Combining genetic analysis of disease related phenotypes with in vitro disease models for development of high efficacy and low toxicity therapeutics |
Enabling scientific discoveries that improve human health