Developing a phenotype risk score for

Background: Phenotype Risk Scores (PheRS) leverage electronic health record (EHR) data to identify individuals at risk for Mendelian disorders, but their performance remains untested for diseases with common and/or non-specific features such as variant transthyretin amyloidosis (ATTRv), often presenting with heart failure (HF), atrial fibrillation, polyneuropathy, and other prevalent diagnoses. We optimized a PheRS for the most common form of ATTRv by integrating genomic and clinical data in Mount Sinai's Bio Methods: We developed and evaluated a customized PheRS for ATTRv that incorporated 21 expert-curated phenotypic features including 292 ICD-9 and ICD-10 diagnosis codes on a biobank cohort of V142I+ cases (n=383) and controls without any pathogenic/likely pathogenic Results: The expert-curated PheRS outperformed the standard PheRS as measured by improved precision-at- Conclusion: This work demonstrates that standard PheRS methods are insufficient for common, adult-onset cardiovascular genetic diseases such as V142I-related ATTRv, but when redesigned with disease biology, ancestry, age, and clinical context in mind, PheRS become clinically actionable tools for precision cardiology.