Michael Levin
@MGLevin
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🫀Cardiologist @PennCardiology and @VAPhiladelphia 🧬Interested in human genetics of cardiovascular disease | #rstats enthusiast
Joined February 2008
🚨 Our work exploring polygenic risk scores for Coronary Heart Disease is now out in @JAMA_current and presented at #AHA24 by all-star @SarnoffCardio fellow @sabramowitz_: .
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RT @pnatarajanmd: Very excited to share our preprint led by @MGLevin @skoyamamd @jakob_woerner & with @damrauer assessing genome-wide pleio….
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RT @KSusztak: Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum | @NatureGenet….
nature.com
Nature Genetics - Common-variant and rare-variant association analyses combining datasets from multiple populations yield insights into the genetic architecture of all-cause heart failure across...
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RT @PennCVFellows: Check out this editorial just published in @JAMACardio by our very own💫@PennCardiology fellow Anthony Anguiera & @sabram….
jamanetwork.com
Transthyretin (TTR) is a hepatically derived tetrameric protein that is secreted into the circulation, where it is responsible for transporting hormones. In some individuals, due to a combination of...
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RT @PennMedicine: New research by @damrauer & @MGLevin suggests that polygenic risk scores may provide conflicting results for detecting he….
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RT @sabramowitz_: Now out in @JAMA_current: How well do individual risk estimates from different CHD polygenic scores agree? Grateful to wo….
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14/ To learn more,.- Check out this editorial: - Listen to this AI-generated podcast summary:
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13/ It was fun working with the team:.@sabramowitz_, @damrauer, @BoulierKristin, @karlkeat, @MarylynRitchie, @bvoight28, @bpasaniuc and everyone else. More exciting work to come!.
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12/ Overall, we need better frameworks for evaluating PRS at both the individual and population level, and approaches for dealing with the variability/uncertainty if PRS are going to become clinically useful.
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11/ These results don't address other uses of PRS where individual-level performance may be less critical (eg. population-health, enriching the average risk of a clinical trial cohort, etc.).
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10/ Our findings raise important practical questions about the implementation of PRS: .- When PRS from two different sources disagree, which should we believe?.- How should we counsel patients about uncertainty?.- Can CAD PRS be individually useful given these limitations?.
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8/ Concerningly, ~20% of participants had at least one score in both the top 5% and bottom 5%, and ~80% had at least one score in the top/bottom 20%.
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7/ Quantifying this agreement at the individual-level using metrics like intraclass correlation and Light's kappa, we found generally poor agreement. The standard deviation (22%) and coefficient of variation (50%) were also high.
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6/ Next, we sought to understand individual-level agreement/precision of these scores. Despite similar population-level performance, risk estimates from these scores were only modestly correlated at the individual-level.
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5/ Using a "Region of Practical Equivalence" framework considering important measures of predictive performance (calibration and discrimination), we found that most scores are "practically equivalent" in their ability to identify CAD at the population-level.
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4/ To start, we identified published CAD PRS from the.@PGSCatalog, and evaluated population-level performance in 3 large/diverse biobanks: @AllofUsResearch, @PennMedicine, and @UCLA.
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3/ Despite these applications, the individual-level agreement of PRS risk estimates has been poorly characterized. Because there's no gold-standard to benchmark the accuracy of individual-level scores, this problem is challenging.
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2/ Historically, polygenic risk scores have been evaluated at the population level. However, many applications of PRS are targeted at individuals (eg. in the clinic, direct-to-consumer testing).
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