Patient centered prediction of clinically important outcomes arising from pathogenic variants

PROJECT SUMMARY / ABSTRACT
As genetic testing becomes more common in medical care, an increasing number of individuals will discover
that they carry a pathogenic variant. For some, this result will explain current symptoms and aid in diagnosis.
For others, the future health impacts of a pathogenic variant may be less clear, causing uncertainty but also
presenting an opportunity to prevent or mitigate serious health outcomes in the future. This uncertainty arises
from incomplete penetrance and variable expressivity. Whether a symptom manifests in a carrier depends on
numerous individual factors (only some of which are known), creating a dilemma for practitioners regarding
whether and how to intervene.
Using what we can learn from past clinical experience in variant carrying individuals captured in a growing
number of resources like biobanks, we can address this clinical dilemma by creating a machine learning /
artificial intelligence (ML/AI) tool that predicts the likelihood a pathogenic variant carrier will develop disease.
Building on our extensive experience in creating computable and portable phenotypes from data in the
electronic health record (EHR) that accurately represent clinical trajectories in pathogenic variant carriers, we
propose to refine our understanding of disease prediction by modeling factors affecting variant expressivity and
using longitudinal patient trajectories to identify early, often subtle, phenotypic indicators of disease
progression. Finally, we will use a Bayesian transfer learning approach to synthesize multimodal data for
generating individualized predictions of risk of key clinical outcomes in the context of a given pathogenic
variant.
To develop a viable model for clinical translation that addresses the significant risks and challenges associated
with developing ML/AI tools, we will employ a knowledge-guided framework that incorporates input from
Ethical, Legal and Social Implications (ELSI) experts, clinicians, statisticians, geneticists, and informaticians at
every stage of the design process, from defining key clinical outcomes, selecting and engineering model
inputs, and developing approaches to communicate predictions to patients and providers. Our framework will
allow us to synthesize current knowledge of pathogenic variants with the patterns mined from real-world data
while addressing the significant ELSI concerns inherent in ML/AI tool development.
Our proposal brings together a transdisciplinary team of experts in informatics, ethics, machine learning, cloud
computing, genomics, and clinical medicine, and leverages exceptional local data resources to bring the
potential of ML/AI genomic medicine. With this innovative proposal, we aim to create resources that will enable
the development and validation of valuable genomic medicine tools for the future.

Grant Number: 1UG3HG014376-01
NIH Institute/Center: NIH
Principal Investigator: Lisa Bastarache