Prediction of Cumulative Exposure to Atherogenic Lipids During Early Adulthood

ORIGINAL RESEARCH Prediction of Cumulative Exposure to Atherogenic Lipids During Early Adulthood John T. Wilkins, MD, MSC, a,b Hongyan Ning, MD, MS, b Norrina B. Allen, PHD, b Alexander Zheutlin, MD, MPH, a Nilay S. Shah, MD, MPH, a,b Matthew J. Feinstein, MD, a,b Amanda M. Perak, MD, a,c Sadiya S. Khan, MD, MSC, a,b Ankeet S. Bhatt, MD, MBA, SCM, d Ravi Shah, MD, e Venkatesh Murthy, MD, PHD, f Allan Sniderman, MD, g Donald M. Lloyd-Jones, MD, SCM a,b,c ABSTRACT BACKGROUND The ability of a 1-time measurement of non–high-density lipoprotein cholesterol (non–HDL-C) or low-density lipoprotein cholesterol (LDL-C) to predict the cumulative exposure to these lipids during early adulthood (age 18-40 years) and the associated atherosclerotic cardiovascular disease (ASCVD) risk after age 40 years is not clear. OBJECTIVES The objectives of this study were to evaluate whether a 1-time measurement of non-HDL-C or LDL-C in a young adult can predict cumulative exposure to these lipids during early adulthood, and to quantify the association between cumulative exposure to non-HDL-C or LDL-C during early adulthood and the risk of ASCVD after age 40 years. METHODS We included CARDIA (Coronary Artery Risk Development in Young Adults Study) participants who were free of cardiovascular disease before age 40 years, were not taking lipid-lowering medications, and had $3 measurements of LDL-C and non–HDL-C before age 40 years. First, we assessed the ability of a 1-time measurement of LDL-C or non– HDL-C obtained between age 18 and 30 years to predict the quartile of cumulative lipid exposure from ages 18 to 40 years. Second, we assessed the associations between quartiles of cumulative lipid exposure from ages 18 to 40 years with ASCVD events (fatal and nonfatal myocardial infarction and stroke) after age 40 years. RESULTS Of 4,104 CARDIA participants who had multiple lipid measurements before and after age 30 years, 3,995 participants met our inclusion criteria and were in the final analysis set. A 1-time measure of non–HDL-C and LDL-C had excellent discrimination for predicting membership in the top or bottom quartiles of cumulative exposure (AUC: 0.93 for the 4 models). The absolute values of non–HDL-C and LDL-C that predicted membership in the top quartiles with the highest simultaneous sensitivity and specificity (highest Youden’s Index) were >135 mg/dL for non–HDL-C and >118 mg/dL for LDL-C; the values that predicted membership in the bottom quartiles were <107 mg/dL for non–HDL-C and <96 mg/dL for LDL-C. Individuals in the top quartile of non–HDL-C and LDL-C exposure had demographic-adjusted HRs of 4.6 (95% CI: 2.84-7.29) and 4.0 (95% CI: 2.50-6.33) for ASCVD events after age 40 years, respectively, when compared with each bottom quartile. CONCLUSIONS Single measures of non–HDL-C and LDL-C obtained between ages 18 and 30 years are highly predictive of cumulative exposure before age 40 years, which in turn strongly predicts later-life ASCVD events. (JACC. 2024;84:961–973) © 2024 Published by Elsevier on behalf of the American College of Cardiology Foundation ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2024.05.070 From the a Department of Medicine (Cardiology), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; b Department of Preventive Medicine (Epidemiology), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; c Department of Pediatrics (Cardiology), Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; d Kaiser Permanente, Division of Research, Oakland, California, USA; e Department of Medicine (Cardiology), Vanderbilt University School Listen to this manuscript’s audio summary by Editor Emeritus Dr Valentin Fuster on www.jacc.org/journal/jacc. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL.84,NO.11,2024 ª2024 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION The cumulative exposure to atherogenic lipids (non–high-density lipoprotein cholesterol [non–HDL-C] and low-density lipoprotein cholesterol [LDL-C]) in young adulthood (ages 18-40 years) is a primary determinant of midand late-life atherosclerotic cardiovascular disease (ASCVD). 1-3 Therefore, identifying young adults likely to experience a high cumulative exposure to atherogenic lipids may enhance understanding of long-term ASCVDriskandmayinformhealthbehavior recommendations and motivate health behavior optimization in some to reduce atherogenic lipid exposure and long-term ASCVD risk. Most adult clinical practice guidelines recommend at least 1 measurement of atherogenic lipids between ages 18 to 30 years, although there is a vital need to enhance awareness of the importance of lipid measurement because only 50% of eligible young adults undergo this screening. 4,5 Although lipid values typically rise gradually through adulthood for most people, there is considerable variability in both the patterns and rates of change among individuals, and the ability of a single measurement of atherogenic lipids to predict the cumulative lipid exposure from young adulthood to middle age has not been systematically evaluated. 6 Further, the absolute values that define clinically “high”or “low”lipid values in untreated individuals are typically derived from normative distributions from middle-aged adult participants in epidemiologic studies. Because the absolute values of atherogenic lipids are, on average, lower in young adults when compared with middle-aged adults and they tend to increase through adulthood, these clinical thresholds may not adequately reflect clinically relevant atherogenic lipid exposure for young adults. 7 To date, absolute values of atherogenic lipids in young adults that identify who is likely to have a high or low cumulative lipid exposure through age 40 years have not been defined. Likewise, it is not clear how well these absolute values predict cumulative exposure during early adult life. Consequently, current guidelines are vague in their recommendations for what lipids values should be considered “high”or “low”among young adults. To inform this gap in the current literature, we calculated individual-level cumulative exposure to atherogenic lipids (non–HDL-C and LDL-C) from ages 18 to 40 years among CARDIA (Coronary Artery Risk Development in Young Adults) study participants. We then assessed the ability of 1-time lipid measurementsbeforeage30yearstopredictthecumulative exposure to atherogenic lipids during early adulthood (through age 40 years). We report absolute values of atherogenic lipids with the highest simultaneous sensitivity and specificity to predict cumulative exposure as well as the relative ASCVD event risk observed after age 40 years for each quartile of cumulative exposure in early adult life. Our findings may inform clinical recommendations for lipid testing and provide practical absolute lipid values to guide discussion of risk factor optimization for young adults. METHODS THE CARDIA STUDY. In 1985 and 1986, the CARDIA study recruited 5,115 Black and White men and women aged 18 through 30 years from 4 sites across the United States: Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California. At inception, the cohort was balanced by race (52% Black, 48% White), sex (55% female, 45% male), education (40% with #12 years, 60% with >12 years of education), and age (45% 18-24 years, 55% 25-30 years) at each center. 8 Participants underwent in-person examinations at baseline (Y0) and at follow-up years 2, 5, 7, 10, 15, 25, 30, and 35. Ongoing contact is maintained with participants via telephone, mail, or electronically every 6 months, with annual medical history and event ascertainment between in-person examinations. Retention rates among surviving participants at each in-person follow-up examination have been high, at 91%, 86%, 81%, 79%, 74%, 72%, 72%, 71%, and 67% (during the COVID-19 pandemic), respectively. Over the last 5 years, >90% of the surviving cohort members have been directly contacted. Follow-up for vital SEE PAGE 974 ABBREVIATIONS AND ACRONYMS ASCVD =atherosclerotic cardiovascular disease BMI =body mass index CVD =cardiovascular disease LDL-C =low-density lipoprotein cholesterol MI =myocardial infarction non–HDL-C =non–highdensity lipoprotein cholesterol of Medicine, Nashville, Tennessee, USA; f Department of Medicine (Cardiology), University of Michigan Medical School, Ann Arbor, Michigan, USA; and the g Department of Medicine (Cardiology), McGill University School of Medicine, Montreal, Quebec, Canada. Review and acceptance occurred under Dr Valentin Fuster’s term as Editor-in-Chief. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. Manuscript received December 4, 2023; revised manuscript received May 2, 2024, accepted May 16, 2024. Wilkins et al JACC VOL. 84, NO. 11, 2024 Prediction of Lipid Exposure in Young Adults SEPTEMBER 10, 2024:961–973 962 status is virtually complete through related contacts and intermittent National Death Index searches. The CARDIA study was approved by the Northwestern Institutional Review Board. STUDY SAMPLE AND EXCLUSION CRITERIA. For the primary analysis, eligible adults were 4,104 CARDIA participants who had $1measurementoffasting lipids between ages 18 to 30 years, and at least 1 measurement between age 35 to 45 years. Individuals who used lipid-lowering pharmacotherapy between ages 18 and 40 years were excluded from this analysis (n ¼88). Individuals who experienced an ASCVD event before age 40 years (n ¼21) were excluded as well. A total of 3,995 participants were included in the final analysis set. We performed a secondary analysis to assess the ability of 2 measurements of atherogenic lipids before age 30 years to predict the cumulative exposure through age 40 years. Of the 3,995 CARDIA participants in the primary analysis, 1,806 participants had $2measurementsofnon–HDL-C or LDL-C prior to age 30 years. These participants with $2measurements were included in the secondary analysis. TRADITIONAL RISK FACTOR ASSESSMENT. Age, race, and sex were determined by self-report. Height, weight, and waist circumference were measured with the participants in light clothing using a standardized stadiometer, tape measure, and calibrated scale; body mass index (BMI) (kg/m 2 ) was calculated. At each CARDIA examination, participants were given the interviewer-administered Physical Activity History Questionnaire. 9,10 The physical activity score summed frequency times intensity over the 13 activities to get total activity (in exercise units). Smoking habits and educational attainment were determined with the use of standardized and validated questionnaires. Blood pressure–and cholesterol-lowering medication use was determined by self-report. Blood pressure was measured after 5 minutes of rest in the seated position using a random zero mercury sphygmomanometer, replaced from Y20 forward with an Omron oscillometer (calibrated to the random zero). The means of the second and third systolic and diastolic measurements were used. LABORATORY AND LIPID MEASUREMENTS. After a 12-hour fast, blood was drawn from a vein in the antecubital fossa into a Vacutainer, coated with EDTA for plasma. Serum and plasma samples were obtained and stored at –80 C for future analysis. Samples were shipped on dry ice to the Northwest Lipid Research Center in Seattle, Washington. Plasma concentrations of total cholesterol and triglycerides were measured using a standard enzymatic assay. High-density lipoprotein cholesterol was quantified after precipitation with dextral sulfate-magnesium chloride on an ABA 200 Biochromatic instrument (Abbott Laboratories). 8 To reduce error in LDL-C estimation at high or low LDL-C values and in individuals with elevated triglyceride levels, we used LDL-C estimation as published by Sampson et al. 11 Non–HDL-C was calculated as the difference between total cholesterol and high-density lipoprotein cholesterol for each participant. CALCULATION OF CUMULATIVE EXPOSURE. The mean number of lipid measurements between ages 18 and 40 years was 5.1 (Q1-Q3: 5.0-6.0). Cumulative non–HDL-C and LDL-C were defined based on the predicted value in each year during ages 18 to 40 years. We chose an age-based analysis instead of examination-time-based analysis and we present the visit time at each examination by participants’ ages. We applied a nonparametric quartic splinedbased mixed model to estimate the subject-specific non–HDL-C and LDL-C trajectory from ages 18 to 40 years for all participants. 12 This approach allows aflexible shape for the individual trajectories and estimates the lipid levels for participants with insufficient data by borrowing strength from other individuals. The area under the curve of lipid exposure from age 18 to 40 (AUC [18-40 years]) was then calculated as the overall cumulative exposure and expressed in the unit of mg/dL years. This method was selected due to its ability to tailor a nonlinear lipid curve over the exposure period. Cumulative atherogenic lipid values were then divided into quartiles. For ease of interpretation, we divided the cumulative values by 22 years (the fixed follow-up interval) to represent usual yearly non– HDL-C or LDL-C. 13 ASSESSMENT OF ASCVD ENDPOINTS. We defined ASCVD events as fatal or nonfatal myocardial infarction (MI) or stroke as adjudicated by the CARDIA Endpoints Committee. We included all ASCVD events that occurred after participant age 40 years and 2022. Participants were followed by yearly telephone interviews with either the participants or a designated proxy to assess interim ASCVD events, hospitalizations, outpatient procedures, or death. Medical records were requested for participants who had been hospitalized or received an outpatient revascularization procedure (eg, percutaneous coronary intervention). Medical records were reviewed and adjudicated independently by 2 physician members of the endpoints committee. If disagreement occurred, cases JACCVOL.84,NO.11,2024 Wilkins et al SEPTEMBER 10, 2024:961–973 Prediction of Lipid Exposure in Young Adults 963 were reviewed by the entire endpoints committee to obtain consensus. Criteria for fatal or nonfatal MI, and fatal and nonfatal stroke are outlined in the CARDIA manual of operations. Briefly, MI was defined as symptoms consistent with cardiac ischemia, with elevations in biomarkers (troponin, creatinine kinase), with or without the presence of consistent electrocardiographic changes. Stroke was defined as a neurologic deficitthatlasts>24 hours and is consistent with acute disruption of blood flow to a vascular territory with or without supportive imaging findings on computed tomography scan or magnetic resonance imaging. A fatal MI or cerebrovascular accident event was defined as death within 30 days of either acute diagnosis. STATISTICAL ANALYSIS. We created quartiles of cumulative exposure to non–HDL-C or LDL-C separately and compared participant characteristics, including demographics, anthropometrics, lifestyle behaviors, and traditional risk factors across quartiles using analysis of variance for continuous variables and chi-square test for categorical variables as appropriate. We assessed the ability of the first measurement of atherogenic lipids between ages 18 and 30 years to predict elevated (top quartile: 75th-100th percentile) or low (0th-25th percentile) cumulative exposure, respectively, by age 40 years using receiver-operating characteristic (ROC) curves. Model 1 was a univariate logistic regression model that included a 1-time measurement of non–HDL-C or LDL-C; Model 2 included Model 1 þage, sex, race; Model 3 included Model 2 þBMI and SBP. The comparison of areas under the ROC curves generated by these models was performed according to DeLong et al. 14 We ran the analyses for non–HDL-C and LDL-C separately. We calculated cross-tables of the percentages of participants by the quartile of their first atherogenic lipid level and the first measurement made after age 40 years. We also calculated cross-tables of the percentages of participants by the quartile of their first atherogenic lipid level and the quartile of cumulative exposure through age 40 years. The agreement between the quartile ranking of these 2 measurements was assessed using the Cohen k statistic. To define thresholds with optimal performance to discriminatethosewhoarelikelytohaveahighvs low cumulative exposure, we used Youden’sindexto determine the non–HDL-C and LDL-C absolute values that were associated with the highest simultaneous sensitivity and specificity to predict membership in the highest or lowest quartile (separately) of cumulative exposure. The ability of 2 measurements of atherogenic lipids between age 18 and 30 years to predict membership in the top quartile or bottom quartile of cumulative exposure through age 40 years was assessed using separate models that included 2 LDL-C or non–HDL-C measurements that were made before age 30 years. Weranasecondsetofmodelsthatincludedage,sex, and race covariates. To quantify associations between cumulative exposure quartiles with long-term risk for ASCVD events, we used Cox proportional hazards models for each quartile of non–HDL-C or LDL-C at first measurement (between ages 18 and 30 years) and for each quartile of cumulative exposure to non–HDL-C or LDL-C (separately) from age 18 to 40 years with risk forASCVDeventsafterage40years.Modelswererun as follows: Model 1: age-, sex-, and race-adjusted; and Model 2: Model 1 þeducational attainment, BMI, systolic blood pressure, blood pressure treatment, diabetes, diabetes treatment, and current tobacco use. For quartiles of cumulative exposure, we included a third model that included all covariates from Model 2 plus the value of the first non–HDL-C or LDL-C that was made between ages 18 and 30 years. We used covariates in Model 2 from the examination that was closest to when the participant was age 40 years. RESULTS BASELINE CHARACTERISTICS BY QUARTILES OF NON–HDL-C CUMULATIVE EXPOSURE. Characteristics of CARDIA participants at time of the first lipid measurement, stratified by quartile of cumulative non–HDL-C and LDL-C exposure from age 18 to 40 years, are shown in Tables 1 and 2, respectively. The mean age was 25 years at the time of first non– HDL-C measurement. The mean non–HDL-C was approximately 10 mg/dL higher than LDL-C in young adults. The mean non–HDL-C at age 25 years in the highest non–HDL-C quartile was 161.9 mg/dL, and the mean LDL-C at age 25 years in the highest LDL-C quartile was 146.1 mg/dL. Participants in the higher quartiles of non–HDL-Cexposureweremorelikelyto be men and identify as White. Mean baseline BMI, systolic and diastolic blood pressures, and fasting glucosewereslightlyhigherinhighercomparedwith lower quartiles of non–HDL-C cumulative exposure. Notably, in this young adult sample, all the mean values for these measures, except for BMI, were within ranges considered clinically “normal”for middle-aged adults. Similar distributions of baseline characteristics were observed across quartiles of LDL-C as for non–HDL-C (Table 2). Wilkins et al JACC VOL. 84, NO. 11, 2024 Prediction of Lipid Exposure in Young Adults SEPTEMBER 10, 2024:961–973 964 Characteristics of CARDIA participants at the examination closest to age 40 years by quartile of cumulative non–HDL-C and LDL-C exposure (from ages 18 to 40 years) are shown in Supplemental Tables 1A and 1B, respectively. The mean non–HDL-C was about 20 mg/dL higher than the LDL-C at age 40 years. Distributions of other characteristics across quartiles were similar to those observed at baseline, although absolute values of all continuous risk factors were qualitatively higher than at baseline. DISTRIBUTION OF FIRST NON-HDL-C OR LDL-C MEASUREMENTS BY CUMULATIVE EXPOSURE QUARTILE. The distributions of first measurement of non–HDL-C and LDL-C, by quartile of cumulative exposure between ages 18 and 40 years, are shown in Figure 1A for non–HDL-C and Figure 1B for LDL-C. Notably, the mean first non–HDL-C measured at mean age 25 years differed across cumulative non– HDL-C exposure quartiles, yet overlap in the values of the first measurement is present for all 4 quartiles, demonstrating reclassification in quartile of initial measurement before age 30 years and quartile of cumulative exposure by age 40 years. Yet, there is limited overlap in baseline measurements between the highest and lowest quartiles of cumulative exposure, demonstrating that a modest percentage of individuals who were in the middle of the distribution at their initial measurement had increases or decreases in lipid levels that put them in the highest or lowest quartile of cumulative exposure by age 40 years. QUARTILE OF FIRST NON–HDL-C MEASUREMENT BY QUARTILE OF FIRST MEASUREMENT MADE AFTER AGE 40 YEARS. Cross-tables displaying the quartile of the first non–HDL-C measurement taken prior to age 30 years and the first measurement after age 40 years are presented in Supplemental Table 2A.Ofthe participants initially in the top and bottom quartiles based on their first measurement, 57.7% remained in thesamequartileafterage40years.Conversely,3.9% of those initially in the top quartile shifted to the bottom quartile after age 40 years, whereas 3.1% of those initially in the bottom quartile moved to the top quartile after age 40 years. Similar results were observed for LDL-C. QUARTILE OF FIRST NON–HDL-C AND LDL-C AND QUARTILE OF CUMULATIVE EXPOSURE. Acrosstable displaying the quartile of the first non–HDL-C takenbeforeage30yearsandthequartileofcumulative exposure is shown in Supplemental Table 2B. Approximately 75% of participants who started in the top or bottom quartile of non–HDL-C was in the same TABLE 1 Characteristics of CARDIA Participants at the Age of First Non–HDL-C Measurement Quartile of Cumulative Non–HDL-C Exposure (Range of Cumulative Exposure, mg/dL y) 0%-25% (n ¼998) (622-2,415) 25%-50% (n ¼999) (2,416-2,817) 50%-75% (n ¼999) (2,819-3,243) 75%-100% (n ¼999) (3,244-6,117) Usual a yearly non–HDL-C from age 18-40 y, mg/dL/y 98 (28-110) 119 (111-128) 137 (129-147) 162 (148-278) Non–HDL-C, mg/dL 88.9 17.1 113.2 17.2 129.3 17.5 161.9 27.1 Age, y 24.9 3.6 24.9 3.6 25.3 3.5 25.4 3.5 Black 503 (50.4) 495 (49.5) 477 (47.7) 461 (46.1) Male 358 (35.9) 372 (37.2) 458 (45.8) 569 (57.0) Education, y 15.8 2.7 15.8 4.5 15.6 2.5 15.5 3.7 Total cholesterol, mg/dL 147.2 20.7 167.7 21.3 181.5 20.9 210.4 28.5 HDL-C, mg/dL 58.2 13.3 54.6 12.3 52.3 12.7 48.6 11.6 LDL-C, mg/dL 78.1 17.0 100.4 16.8 114.6 17.7 143.2 25.8 Body mass index, kg/m 2 23.2 4.4 24.3 5.0 24.8 5.1 25.7 5.1 Systolic blood pressure, mm Hg 105.7 11.0 107.0 10.8 107.9 11.7 109.8 12.0 Diastolic blood pressure, mm Hg 67.3 9.9 68.5 9.7 69.6 9.8 71.1 10.5 Fasting glucose, mg/dL 80.8 8.9 81.4 8.6 82.2 11.3 83.2 10.4 Current smoker 282 (28.3) 265 (26.6) 275 (27.7) 299 (30.2) Physical activity intensity score 433.2 293.1 421.4 307.3 403.3 292.3 417.3 302.7 Antihypertensive medication use 16 (1.6) 18 (1.8) 20 (2.0) 30 (3.0) Hypoglycemic medication use 3 (0.3) 3 (0.3) 8 (0.8) 4 (0.4) Diabetes 3 (0.3) 3 (0.3) 2 (0.2) 2 (0.2) ASCVD events after age 40 y 21 (2.1) 57 (5.7) 59 (5.9) 106 (10.6) Values are median (range), mean SD, or n (%). a Usual non–high-density lipoprotein cholesterol (non–HDL-C) ¼cumulative non–HDL-C/22 years. ASCVD ¼atherosclerotic cardiovascular disease; HDL-C ¼high-density lipoprotein cholesterol; LDL-C ¼low-density lipoprotein cholesterol. JACCVOL.84,NO.11,2024 Wilkins et al SEPTEMBER 10, 2024:961–973 Prediction of Lipid Exposure in Young Adults 965 quartile of cumulative exposure though age 40 years. The agreement between the quartile rankings of these 2 measurements were 62.8% (kappa ¼0.66) for non– HDL-C. Similar results were observed for LDL-C. UNIVARIABLE AND MULTIVARIABLE MODELS TO PREDICT CUMULATIVE NON–HDL-C AND LDL-C. The ROC curves for models to predict cumulative non– HDL-C exposure are shown in Figures 2A and 2B.For predicting membership in the highest quartile of cumulative exposure, the C-statistics for 1-time baseline measures of non–HDL-C and LDL-C were both 0.93. Additional adjustment for age, sex, race, BMI, and systolic blood pressure (measures commonly obtained during clinical visits) did not significantly change the c-statistic. The ROC curves for models to predict membership inthelowestquartileofcumulativeexposuretonon– HDL-C and LDL-C are shown in Figures 2A and 2B.The c-statistics for a 1-time measure before age 30 years to predict membership in the lowest quartile of cumulative exposure were also 0.93 for non–HDL-C and LDL-C,respectively.Additionofage,sex,race,BMI, and systolic blood pressure did not significantly change the C-statistics. In secondary analysis, 2 measurements of non– HDL-C or LDL-C before age 30 years predicted membershipinthetoporbottomquartileofcumulative exposure, with a c-statistic of 0.97 and 0.97, respectively. COMPARISONS OF ABSOLUTE LIPID VALUES THAT PREDICT MEMBERSHIP IN THE HIGHEST AND LOWEST QUARTILES OF CUMULATIVE EXPOSURE. The performance of the absolute lipid values with the highest simultaneous sensitivity and specificity (highest Youden’s index) from our model to predict membership in the highest quartile of cumulative exposure are shown in Table 3.Fornon–HDL-C, a 1-time value >135 mg/dL between ages 18 and 30 years had 85% sensitivity and 86% specificity to predict membership in the top quartile of cumulative non–HDL-C exposure by age 40 years. In comparison, anon–HDL-C value of >160 mg/dL between ages 18 and 30 years, which is commonly used in clinical practice, had sensitivity of 48%, but higher specificity of 98% to predict membership in the top quartile of cumulative exposure to non–HDL-C by age 40 years. For LDL-C, a value >118 mg/dL between ages 18 and 30 years had sensitivity of 89% and specificity of 82% TABLE 2 Characteristics of CARDIA Participants at the Age of First LDL-C Measurement Quartile of Cumulative LDL-C Exposure (Range of Cumulative Exposure, mg/dL y) 0%-25% (n ¼998) (327-2,106) 25%-50% (n ¼999) (2,107-2,485) 50%-75% (n ¼999) (2,486-2,885) 75%-100% (n ¼999) (2,886-5,905) Usual a yearly non–HDL-C from age 18-40 y, mg/dL/y 85 (15-96) 105 (97-113) 122 (114-131) 144 (132-268) LDL-C, mg/dL 76.8 17.0 99.5 15.3 116.3 16.8 146.1 25.0 Age, y 24.9 3.6 24.9 3.6 25.2 3.6 25.6 3.4 Black 497 (49.8) 468 (46.8) 480 (48.0) 491 (49.1) Male 383 (38.4) 398 (39.8) 441 (44.1) 535 (53.6) Education, y 15.7 2.7 15.8 4.5 15.7 2.6 15.5 3.7 Total cholesterol, mg/dL 146.3 20.5 166.5 19.4 182.6 20.4 211.4 27.6 HDL-C, mg/dL 57.2 13.8 53.9 12.4 52.4 12.7 50.1 11.8 LDL-C, mg/dL 89.1 17.8 112.6 16.5 130.2 18.6 161.3 27.0 Body mass index, kg/m 2 23.4 4.5 24.4 5.0 24.5 5.0 25.6 5.1 Systolic blood pressure, mm Hg 106.3 11.4 106.8 10.6 108.0 11.5 109.2 12.1 Diastolic blood pressure, mm Hg 67.7 10.1 68.5 9.7 69.7 9.8 70.5 10.5 Fasting glucose, mg/dL 81.0 8.9 81.5 8.8 82.2 11.3 82.8 10.3 Current smoker 304 (30.5) 264 (26.5) 263 (26.4) 290 (29.3) Physical activity intensity score 435.9 290.0 427.9 316.8 395.8 285.0 415.7 302.1 Antihypertensive medication use 17 (1.7) 17 (1.7) 24 (2.4) 26 (2.6) Hypoglycemic medication use 3 (0.3) 3 (0.3) 3 (0.3) 1 (0.1) Diabetes 3 (0.3) 3 (0.3) 8 (0.8) 4 (0.4) ASCVD events after age 40 y 22 (2.2) 61 (6.1) 62 (6.2) 98 (9.8) Values are median (range), mean SD, or n (%). a Usual non–HDL-C ¼cumulative non–HDL-C/22 years. Abbreviations as in Table 1. Wilkins et al JACC VOL. 84, NO. 11, 2024 Prediction of Lipid Exposure in Young Adults SEPTEMBER 10, 2024:961–973 966 to predict membership in the top quartile of cumulative LDL-C exposure by age 40 years. A commonly used LDL-C threshold >130 mg/dL between ages 18 and30yearshadsensitivityof72%andspecificity of 93% for membership in the top quartile of cumulative LDL-C exposure by age 40 years. The performance of the absolute lipid values with the highest simultaneous specificity and sensitivity to predict membership in the lowest quartile of cumulative exposure, compared with values commonly used in clinical practice, are shown in Table 4.Anon– HDL-C value of <107 mg/dL between ages 18 and 30 years had a specificity of 86% and a sensitivity of 87% for membership in the lowest quartile of cumulative non–HDL-C exposure by age 40 years, whereas the commonly used value of <130 mg/dL between ages 18 and30yearshadaspecificity of 51% and a sensitivity of 99%. An LDL-C value of <96 mg/dL between ages 18and30yearshadaspecificity of 84% and a sensitivity of 89% for membership in the bottom quartile of cumulative exposure by age 40 years. These values were similar to those obtained when the commonly used LDL-C value of <100mg/dLwasusedforyoung adults. The highest specificity for membership in the top or bottom quartiles can be determined from visual inspection of Figure 1 and confirmed in Figures 2A and 2B. All individuals with non–HDL-C values below 60 mg/dL were in the bottom quartile of cumulative exposure, whereas all participants with an initial measurement of 180 mg/dL or greater were in the top quartile of cumulative exposure. ASCVD RISKS BY QUARTILE OF NON–HDL-C AND LDL-C. After age 40 years, the 3,995 CARDIA participants contributed to a total of 77,141 person-years of follow-up, with a mean follow-up time of 19.2 5.4 years.TherateofASCVDeventsaftertheageof40 years was 3.15 per 1,000 person-years. The Kaplan Meier survival curves of the survival probability free from ASCVD after age 40 years by quartiles of cumulative non-HDL-C and LDL-C exposure are presented in Supplemental Figures 1A and 1B,respectively. The HRs for ASCVD events after age 40 years by quartile of non–HDL-C and LDL-C exposure from ages 18 to 40 years are shown in Table 5.One-time measurements of non–HDL-C and LDL-C obtained between ages 18 and 30 years were positively associated with ASCVD risk after age 40 years, with a riskFIGURE 1 Density Plot: First Non–HDL-C or LDL-C by Exposure Quartiles 0.000 0.005 0.010 0.015 0.020 0 50 100 First Non-HDL-C (mg/dL) AB Density 150 200 250 Cumulative Non-HDL-C Quartile 0%-25% 25%-50% 50%-75% 75%-100% 0.000 0.005 0.010 0.015 0.025 0.020 050 100 First LDL-C (mg/dL) Density 150 200 250 Cumulative LDL-C Quartile 0%-25% 25%-50% 50%-75% 75%-100% Density plot of the first non–high-density lipoprotein cholesterol (non–HDL-C) (A) or low-density lipoprotein cholesterol (LDL-C) (B) measurement made between ages 18 and 30 years in the CARDIA (Coronary Artery Risk Development in Young Adults Study) cohort and the quartile of cumulative exposure from age 18 through 40 years. The blue curve represents the lowest quartile, red and gray are sequentially higher quartiles, and purple is the highest quartile of cumulative exposure. Of note, overlap in the values of the first measurements are present for all 4 quartiles. Thus, substantial reclassification between quartile of first measurement and cumulative exposure in early adult life occurs. However, there is modest overlap between the top and bottom quartiles, demonstrating that a modest percentage of individuals who were in the middle of the distribution at their initial measurement had increases or decreases in lipid levels that put them in the highest or lowest quartile of cumulative exposure by age 40 years. JACCVOL.84,NO.11,2024 Wilkins et al SEPTEMBER 10, 2024:961–973 Prediction of Lipid Exposure in Young Adults 967 FIGURE 2 ROC Curves for the Cumulative Exposure Prediction Models ROC Curves for Comparisons ROC Curves for Comparisons A B 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 1Specificity Non-HDL-C Top Quartile ROC Curves for Comparisons Sensitivity 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 1Specificity LDL-C Top Quartile Sensitivity 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 1Specificity Non-HDL-C Bottom Quartile ROC Curves for Comparisons Sensitivity 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 1Specificity LDL-C Bottom Quartile Sensitivity ROC Curve (Area) Unadjusted (0.9304) Age/sex/race (0.9368) Age/sex/race/BMI + SBP (0.9369) ROC Curve (Area) Unadjusted (0.9325) Age/sex/race (0.9355) Age/sex/race/BMI + SBP (0.9355) ROC Curve (Area) Unadjusted (0.9332) Age/sex/race (0.9352) Age/sex/race/BMI + SBP (0.9353) ROC Curve (Area) Unadjusted (0.9338) Age/sex/race (0.9372) Age/sex/race/BMI + SBP (0.9375) ROC curves for the prediction of membership in the top or bottom quartile of cumulative exposure to (A) non–HDL-C and (B) LDL-C from age 18 to 40 years by a 1-time measurement made between ages 18 and 30 years. Overall discriminatory capacity is high (c-statistics of 0.93 for all models). The addition of demographic variables, body mass index (BMI), and systolic blood pressure (SBP) yielded very modest effects on the C-statistics. ROC ¼receiver-operating characteristic; other abbreviations as in Figure 1. Wilkins et al JACC VOL. 84, NO. 11, 2024 Prediction of Lipid Exposure in Young Adults SEPTEMBER 10, 2024:961–973 968 factor adjusted HR for ASCVD events of 3.7 (95% CI: 2.3-6.1) and 2.5 (95% CI: 1.6-3.8) for the highest quartiles of first non–HDL-C and LDL-C measurement, respectively,whencomparedwiththelowestquartiles. When compared with the lowest quartile, those in the highest quartile of cumulative non–HDL-C and LDL-C had adjusted HRs of 4.6 (95% CI: 2.8-7.3) and 4.0 (95% CI: 2.5-6.3) respectively, for ASCVD events after age 40 years. The strength of association was modestly reduced by multivariable adjustment for other traditional risk factors (Model 2) including adjustment for the first lipid measurement made between ages 18-30 years (Model 3). DISCUSSION In this longitudinal cohort of young adults with repeated lipid measures, we observed that 1-time measurement of non–HDL-C or LDL-C obtained between ages 18 and 30 years can predict membership in the top and bottom quartiles of cumulative exposure of atherogenic lipids from age 18 to 40 years with a very high degree of discrimination. The age period between 18 to 40 years is a critical time of exposure to CVD risk determinants including atherogenic lipids. 2 Thus, identifying individuals likely to have the highest (or lowest) cumulative exposures with a 1-time measurement may be of significant clinical value for risk communication and preventive decision-making in young adults. Absolute values of non–HDL-C >135 mg/dL or LDL-C >118 mg/dL between ages 18 and 30 years were highly sensitive and specific for identifying young adults who were likely to have a high cumulative exposure to those respective atherogenic lipid fractions (Central Illustration). Notably, these thresholds are considerably lower than values commonly used in clinical practice (ie, non–HDL-C >160 mg/dL and LDL-C >130 mg/dL) to indicate “elevation.” Conversely, non–HDL-C values <107 mg/dL had substantially higher specificity than the currently used value of <130 mg/dL to predict membership in the bottom quartile of exposure. Absolute values of LDL-C of <96 mg/dL, very close to the commonly used threshold of <100 mg/dL, predicted membership in the bottom quartile with a specificity of 84% and a high sensitivity. As expected, membership in the highest quartile of 1-time measurement on non–HDL-C and LDL-C obtained between ages 18 and 30 years and the cumulative exposure from age 18 to 40 years was strongly associated with ASCVD event risk after age 40 years when compared with the lowest quartile of cumulative exposure. The associations between quartile of cumulative exposure and ASCVD events after age 40 years were robust to adjustment for the first TABLE 3 Test Characteristics of Thresholds to Predict Membership in the Highest Quartile of CumulativeExposurebyAge40Years Threshold, mg/dL Sensitivity %(95%CI) Specificity %(95%CI) NPV %(95%CI) PPV %(95%CI) Accuracy %(95%CI) Non–HDL-C >135 a 84.5 (82.3-86.8) 86.2 (84.9-87.5) 94.3 (93.5-95.2) 67.2 (64.6-69.8) 85.8 (84.7-86.9) >160 48.4 (44.9-51.5) 98.2 (97.7-98.7) 85.0 (83.8-86.2) 90.1 (87.5-92.6) 85.7 (84.6-86.7) LDL-C >118 a 88.8 (86.8-90.8) 82.0 (80.6-83.4) 95.6 (94.8-96.4) 62.2 (60.0-64.7) 83.7 (82.5-84.8) >130 71.7 (68.9-74.5) 93.3 (92.4-94.2) 90.8 (89.7-91.8) 78.1 (75.4-80.8) 87.7 (86.8-88.9) a Value derived from receiver-operating characteristic curve analysis (highest Youden’s Index). NPV ¼negative predictive value; PPV ¼positive predictive value; other abbreviations as in Table 1. TABLE 4 Test Characteristics of Thresholds to Predict Membership in the Lowest Quartile of Cumulative Exposure by Age 40 Years Threshold, mg/dL Sensitivity %(95%CI) Specificity %(95%CI) NPV %(95%CI) PPV %(95%CI) Accuracy %(95%CI) Non–HDL-C <107 a 86.8 (84.7-88.8) 85.7 (84.5-87.0) 95.1 (94.3-95.9) 67.0 (64.4-69.5) 86.0 (84.9-87.1) <130 99.1 (98.5-99.7) 50.9 (49.1-52.7) 99.4 (99.0-99.8) 40.2 (38.3-42.1) 62.9 (61.5-64.5) LDL-C <96 a 88.6 (86.6-90.6) 83.5 (82.1-84.8) 95.6 (94.8-96.4) 64.1 (61.5-66.6) 84.7 (83.6-85.8) <100 93.2 (91.6-94.7) 78.2 (76.7-79.7) 97.2 (96.6-97.8) 58.7 (56.3-61.6) 81.9 (80.8-83.1) a Value derived from receiver-operating characteristic curve analysis (highest Youden’s Index). Abbreviations as in Tables 1 and 3. JACCVOL.84,NO.11,2024 Wilkins et al SEPTEMBER 10, 2024:961–973 Prediction of Lipid Exposure in Young Adults 969