Impact of Measurement Imprecision on Genetic Association Studies of Cardiac Function

Abstract

AbstractBackgroundRecent studies have leveraged quantitative traits from imaging to amplify the power of genome-wide association studies (GWAS) to gain further insights into the biology of diseases and traits. However, measurement imprecision is intrinsic to phenotyping and can impact downstream genetic analyses.MethodsLeft ventricular ejection fraction (LVEF), an important but imprecise quantitative imaging measurement, was examined to assess the impact of precision of phenotype measurement on genetic studies. Multiple approaches to obtain LVEF, as well as simulated measurement noise, were evaluated with their impact on downstream genetic analyses.ResultsEven within the same population, small changes in the measurement of LVEF drastically impacted downstream genetic analyses. Introducing measurement noise as little as 7.9% can eliminate all significant genetic associations in an GWAS with almost forty thousand individuals. An increase of 1% in mean absolute error (MAE) in LVEF had an equivalent impact on GWAS power as a decrease of 10% in the cohort sample size, suggesting optimizing phenotyping precision is a cost-effective way to improve power of genetic studies.ConclusionsImproving the precision of phenotyping is important for maximizing the yield of genome-wide association studies.Clinical perspectiveWhat Is New?Measurement imprecision in cardiac imaging phenotypes can substantially impact downstream genetic association studies, explaining much of the difference in identified genetic variants between echocardiography and cardiac magnetic resonance imaging.Using the example of left ventricular ejection fraction as an important but imprecise clinical measurement, the analysis suggests that the measurement variation within the range of clinician interpretation reduced genome-wide association studies’ power to detect genetic risk factors as much as decreasing the study population size by 20%.What Are the Clinical Implications?More precise measurements can result in a better understanding of the genetics of cardiac phenotypes and accelerate the development of precision medicine.Rather than simply increasing population size, improving measurement precision allows for cost-effective discovery of genetic associations.