{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:38:06Z","timestamp":1789645086320,"version":"4.0.0"},"posted":{"date-parts":[[2026,1,6]]},"group-title":"Health Systems and Quality Improvement","reference-count":29,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    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\u2019s Bio\n                    <jats:italic>Me<\/jats:italic>\n                    biobank, focusing on expert-driven phenotype definitions for the\n                    <jats:italic>TTR<\/jats:italic>\n                    variant p.Val142Ile (V142I), which is prevalent in African American (AA) populations (4%).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>TTR<\/jats:italic>\n                    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 \u2265 60 with self-reported Black or AA race\/ethnicity and at least one occurrence of HF in their EHRs.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The expert-curated PheRS outperformed the standard PheRS as measured by improved precision-at-\n                    <jats:italic>k<\/jats:italic>\n                    (0.05 vs. 0.00;\n                    <jats:italic>k<\/jats:italic>\n                    =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%).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.05.26343489","type":"posted-content","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T01:15:21Z","timestamp":1767748521000},"source":"Crossref","is-referenced-by-count":1,"title":["Developing a phenotype risk score for\n                  <i>TTR<\/i>\n                  V142I to capture undiagnosed variant transthyretin amyloidosis in health systems"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0362-8162","authenticated-orcid":false,"given":"Deepa","family":"Sarkar","sequence":"first","affiliation":[{"name":"Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen D.","family":"Ferar","sequence":"additional","affiliation":[{"name":"Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad 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