Abstract
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 BioMe biobank, focusing on expert-driven phenotype definitions for the TTR variant p.Val142Ile (V142I), which is prevalent in African American (AA) populations (4%). 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 TTR variants (n=30,642). We compared its performance with the standard automated PheRS approach using different metrics. To account for age-dependent penetrance and high lifelong risk of HF, we further tested the customized PheRS for V142I in a subset of individuals of age ≥ 60 with self-reported Black or AA race/ethnicity and at least one occurrence of HF in their EHRs. RESULTS: The expert-curated PheRS outperformed the standard PheRS as measured by improved precision-at-k (0.05 vs. 0.00; k=100), a demonstrably, clinically relevant metric. In the subcohort enriched for anticipated penetrance (older, Black/AA HF patients), the expert-curated PheRS identified more V142I+ individuals (6.0%) among the top 100-scoring individuals than a strategy that randomly sampled from the population (3.6%). 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.