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Context: Insulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming. Objective: Develop estimation models for measures of insulin resistance, including insulin sensitivity index (SI) and homeostatic model assessment of insulin resistance (HOMA-IR) from metabolomics data. Design: Insulin Resistance Atherosclerosis Family Study (IRASFS). Setting: Community based. Participants: Mexican Americans (MA) and African Americans (AA). Main outcome: Estimation models for measures of insulin resistance, i.e. SI and HOMA-IR. Results: Least Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net regression were used to build insulin resistance estimation models from 1274 metabolites combined with clinical data, e.g. age, sex, body mass index (BMI). Metabolite data were transformed using three approaches, i.e. inverse normal transformation, standardization, and Box Cox transformation. The analysis was performed in one MA recruitment site (San Luis Valley, Colorado (SLV); N = 450) and tested in another MA recruitment site (San Antonio, Texas (SA); N = 473). In addition, the two MA recruitment sites were combined and estimation models tested in the AA recruitment sample (Los Angeles, California; N = 495). Estimated and empiric SI were correlated in the SA (r2 = 0.77) and AA (r2 = 0.74) testing datasets. Further, estimated and empiric SI were consistently associated with BMI, low-density lipoprotein cholesterol (LDL), and triglycerides. We applied similar approaches to estimate HOMA-IR with similar results. Conclusions: We have developed a method for estimating insulin resistance with metabolomics data that has the potential for application to a wide range of biomedical studies and conditions. [ABSTRACT FROM AUTHOR]