- Email: [email protected]
Improving Recognition of Cardiovascular Risk in Children
Improving Recognition of Cardiovascular Risk in Children
M
90% of the apoB are LDL particles. Therefore, total plasma easurement of low density lipoprotein-cholesterol apoB is determined by LDL apoB. (LDL-C) levels has been the gold standard to meaThere is now substantial evidence that both non-HDL-C sure the atherogenic risk attributable to low density and apoB provide more accurate estimates of LDL and, therelipoprotein (LDL) particles. In 2001, the adult dyslipidemia fore, more accurate estimates of the risk of vascular disease.2 treatment panel recommended that non-high density lipoprotein-cholesterol (non-HDL-C) levels be To be sure, not all studies support this view, See related article, p 247 measured in patients with hypertriglycerithe Emerging Risk Factor Collaboration demia.1 This was based on evidence that both non-HDL-C being the most prominent exception as it reported that all markers of the concentration of LDL, including total cholesand apolipoprotein B (apoB) are better markers of cardiovasterol, were equally accurate predictors of outcome, findings cular risk than LDL-C.2 Indeed, in youth, non-HDL-C has that contradict much previous work and that are almost been associated with premature atherosclerosis in both the certainly due, at least in part, to varying qualities of the assays Bogalusa Heart Study and the Pathobiological Determinants used to measure lipids, apoB, as well as differences in the of Atherosclerosis in Youth Study.3 Non-HDL-C has a major quality of the design and execution. But the failure of logistical advantage over LDL-C in that fasting samples are Emerging Risk Factor Collaboration to discriminate amongst not required. For these reasons, non-HDL-C risk thresholds the markers is also due to the fact that the conventional sta(<120 mg/dL optimal, $145 mg/dL elevated) were included tistical analytical approach assumes LDL-C, non-HDL-C, in the 2011 Integrated Pediatric Guidelines for Cardiovascuand apoB are independent variables, whereas they are, in lar Risk Reduction.3 fact, tightly interrelated metabolically. This intercorrelation In this issue of The Journal, Dai et al use the NHANES makes it challenging to take them apart statistically.5 database to estimate age-, ethnic-, and sex-specific values for the distribution of non-HDL-C in the pediatric populaThis analytical challenge can best be met by separating out tion.4 Their findings will be helpful to clinicians evaluating the population group in whom apoB particles contain a normal mass of cholesterol from the two subgroups in cardiovascular risk in children and adolescents. Important whom apoB particles contain substantially more or less observations from this study include an overall prevalence cholesterol than normal. In the normal cholesterol content of elevated non-HDL-C (#145 mg/dl) of about 10% and group, LDL-C, non-HDL-C, and apoB are concordant and borderline values (120-144 mg/dL) in another 15%-20%. must predict risk equally well. Only in the two subgroups Non-HDL-C values vary significantly by age and sex with in which the composition of the apoB particles is discordant the highest levels in late-adolescent boys and during precould the cholesterol markers and apoB differ in predictive puberty in both sexes. In mid-adolescence, values decline, accuracy; obese individuals are more likely to have adverse and this age-related variability suggests the need for caution discordance. By including all subjects, conventional analyses in the interpretation of screening values based on a single dilute the differences in these discordant groups and can measure. Follow-up values after diet intervention should be obscure true and important differences in predictive power. performed before finalizing risk assessment. Nevertheless, Indeed, a series of studies using discordance analysis have the rapid rise of non-HDL-C in late adolescence in both now shown that apoB or LDL particle number is superior boys and girls represents a disconcerting harbinger of accelto both LDL-C and non-HDL-C to predict cardiovascular erated vascular disease. risk.6-8 Although non-HDL-C may be an improvement over LDL-C, does non-HDL-C provide the best early estimate These differences in the mass of cholesterol within apoB of cardiovascular risk? Atherosclerosis is a multifactorial, particles that produce discordance are due to cholesterolmultifaceted disease but trapping of apoB particles within ester transfer protein-mediated exchanges of core lipids the arterial wall is the fundamental event that creates and between lipoprotein particles. Patients with hypertriglyceridrives all this complexity. Because each apoB lipoprotein demia have cholesterol-depleted LDL particles because particle contains 1 molecule of apoB, the plasma apoB level cholesterol ester is transferred from LDL to very low density accurately reflects the number of apoB particles in the circulipoprotein (VLDL) in exchange for triglyceride, which, in lation, of which, except in unusual circumstances, about turn, is transferred from VLDL to LDL. In these patients, the LDL particles consequently contain less cholesterol and the LDL-C level will systematically underestimate the small apoB LDL LDL-C Non-HDL-C VLDL
Apolipoprotein B Low density lipoprotein Low density lipoprotein-cholesterol Non-high density lipoprotein-cholesterol Very low density lipoprotein
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.09.050
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Vol. 164, No. 2 February 2014 dense LDL particle number. Because non-HDL-C includes the cholesterol in VLDL as well as in LDL, non-HDL-C tends to ‘compensate’ for the error in LDL-C in estimating the LDL particle number in those with high triglycerides. This explains why high triglycerides and low HDL cholesterol may be markers of cardiovascular risk but have not been good targets for pharmacologic therapy. Both are surrogates for cholesterol-depleted LDL particles, and it is the LDL particles that injure the arterial wall and it is the reduction in LDL particles that reduces cardiovascular events.6,9 However, even in patients with cholesterol-depleted LDL particles, non-HDL-C is not necessarily as good a marker of cardiovascular risk as apoB. For example, in the JUPITER Study, a clinical trial that demonstrated the efficacy of statin therapy in patients with low LDL-C and high C-reactive protein, apoB levels were moderately high despite the low LDL-C and non-HDL-C.10 Similarly, in the INTERHEART Study, when non-HDL-C and apoB were discordant, apoB correctly identified risk, whereas non-HDL-C did not. That small cholesterol-depleted LDL particles are common is well appreciated, particularly in the obese. Unfortunately, much less attention has been paid to the second discordant group—the patients with cholesterol-enriched apoB particles in whom non-HDL-C and LDL-C will both overestimate risk because both overestimate the apoB particle number. In this group, unless apoB is measured, some patients will be treated who are not at risk because of LDL and should not be treated. Therefore, in both discordant groups, LDL-C and non-HDLC are less precise measures of cardiovascular risk than apoB because they are less precise measures of particle number than apoB. These discordant relationships between calculated LDL-C and LDL particle number exist in children as well as adults. Two recent studies published in The Journal demonstrate this phenomenon. Mietus-Snyder et al looked at lipoprotein particle distribution in school children enrolled in the Healthy Study and showed the same 20% discordance rate between the LDL particle number and distribution as in adult populations. Obesity and the associated dyslipidemia with high triglycerides and low HDL cholesterol identify those most likely to be discordant.11 Burns et al have shown that triglyceride to HDL ratio is strongly associated with LDL particle number and, in related studies, with insulin resistance.12,13 Further, non-HDL-C is strongly related to the metabolic syndrome whereas LDL-C is not.14 The bottom line is that pediatric care providers should realize that non-HDL-C is a surrogate for true risk estimation, not the gold standard. As we have reviewed, nonHDL-C is an indirect measure of the LDL particle number, and we believe atherogenic lipid risk is best estimated by measuring apoB; apoB has many advantages: not only is it a more accurate measure of risk but the measurement is standardized, has a lower coefficient of variation over time compared with conventional lipid measurements, and can also be performed non-fasting.15-17 ApoB measurement also enhances the ability to make the diagnosis of all the apoB dyslipoproteinemias possible.
The work of the panel drafting the 2011 Integrated Pediatric Guidelines for Cardiovascular Risk Reduction and supporting research such as that reported by Dai et al in this issue of The Journal represents both a model for how to proceed and a step forward in improving pediatric cardiovascular risk assessment.4 However, these improvements are insufficient. More research with state-of-the-art tools, including the characterization of the role of lipoprotein particles in relation to early atherosclerosis and the impact of healthy childhood behaviors on those lipoprotein particles, is needed. Given the current obesity epidemic and the fact that the disproportionate risk related to the increased LDL particle number resides in obese individuals, much detailed information is needed on apoB as well as non-HDL-C in younger individuals. Without the most precise risk assessment, separating the many children for whom improved health behaviors are best from the few children in whom rapid development of atherosclerosis is highly likely and more aggressive therapies required, cannot be accomplished, and meaningful and effective intervention will not occur. n Samuel S. Gidding, MD Nemours Cardiac Center A. I. DuPont Hospital for Children Wilmington, Delaware Allan Sniderman, MD Mike Rosenbloom Laboratory for Cardiovascular Research McGill University Health Center Montreal, Quebec, Canada Reprint requests: Samuel S. Gidding, MD, Nemours Cardiac Center, 1600 Rockland Road, Wilmington, DE 19803. E-mail: [email protected]
References 1. Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel iii) final report. Circulation 2002;106:3143-421. 2. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein b as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011; 4:337-45. 3. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011; 128(Suppl 5):S213-56. 4. Dai S, Yang Q, Yuan K, Loustalot F, Fang J, Daniels SR, Hong Y. Nonhigh-density lipoprotein cholesterol: distribution and prevalence of high serum level in children and adolescents: US National health and nutrition examination surveys, 2005–2010. J Pediatr 2014;164:247-53. 5. Di Angelantonio E, Gao P, Pennells L, Kaptoge S, Caslake M, Thompson A, et al. Lipid-related markers and cardiovascular disease prediction. JAMA 2012;307:2499-506. 6. Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. J Clin Lipidol 2011;5:105-13. 7. Cromwell WC, Otvos JD, Keyes MJ, Pencina MJ, Sullivan L, Vasan RS, et al. LDL particle number and risk of future cardiovascular disease in the 229
THE JOURNAL OF PEDIATRICS
8.
9.
10.
11.
12.
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www.jpeds.com
framingham offspring study—implications for LDL management. J Clin Lipidol 2007;1:583-92. Sniderman AD, Islam S, Yusuf S, McQueen MJ. Discordance analysis of apolipoprotein b and non-high density lipoprotein cholesterol as markers of cardiovascular risk in the interheart study. Atherosclerosis 2012;225:444-9. Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol 2013. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Reduction in c-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the jupiter trial. Lancet 2009;373:1175-82. Mietus-Snyder M, Drews KL, Otvos JD, Willi SM, Foster GD, Jago R, et al. Low-density lipoprotein cholesterol versus particle number in middle school children. J Pediatr 2013;163:355-62. e352. Burns SF, Lee SJ, Arslanian SA. Surrogate lipid markers for small dense lowdensity lipoprotein particles in overweight youth. J Pediatr 2012;161:991-6.
Vol. 164, No. 2 13. Burns SF, Lee S, Arslanian SA. In vivo insulin sensitivity and lipoprotein particle size and concentration in black and white children. Diabetes Care 2009;32:2087-93. 14. Li C, McBride PE, Kwiterovich PO, McCrindle BW, Gidding SS. Nonhigh-density lipoprotein cholesterol concentration is associated with the metabolic syndrome among us youth aged 12-19 years. J Pediatr 2011;158:201-7. 15. Cole TG, Contois JH, Csako G, McConnell JP, Remaley AT, Devaraj S, et al. Association of apolipoprotein b and nuclear magnetic resonance spectroscopy-derived LDL particle number with outcomes in 25 clinical studies: assessment by the aacc lipoprotein and vascular diseases division working group on best practices. Clin Chem 2013;59:752-70. 16. Sniderman A, Couture P, de Graaf J. Diagnosis and treatment of apolipoprotein b dyslipoproteinemias. Nature Rev Endocrinol 2010;6:335-46. 17. Gidding SS, Stone NJ, Bookstein LC, Laskarzewski PM, Stein EA. Month-to-month variability of lipids, lipoproteins, and apolipoproteins and the impact of acute infection in adolescents. J Pediatr 1998; 133:242-6.
M
90% of the apoB are LDL particles. Therefore, total plasma easurement of low density lipoprotein-cholesterol apoB is determined by LDL apoB. (LDL-C) levels has been the gold standard to meaThere is now substantial evidence that both non-HDL-C sure the atherogenic risk attributable to low density and apoB provide more accurate estimates of LDL and, therelipoprotein (LDL) particles. In 2001, the adult dyslipidemia fore, more accurate estimates of the risk of vascular disease.2 treatment panel recommended that non-high density lipoprotein-cholesterol (non-HDL-C) levels be To be sure, not all studies support this view, See related article, p 247 measured in patients with hypertriglycerithe Emerging Risk Factor Collaboration demia.1 This was based on evidence that both non-HDL-C being the most prominent exception as it reported that all markers of the concentration of LDL, including total cholesand apolipoprotein B (apoB) are better markers of cardiovasterol, were equally accurate predictors of outcome, findings cular risk than LDL-C.2 Indeed, in youth, non-HDL-C has that contradict much previous work and that are almost been associated with premature atherosclerosis in both the certainly due, at least in part, to varying qualities of the assays Bogalusa Heart Study and the Pathobiological Determinants used to measure lipids, apoB, as well as differences in the of Atherosclerosis in Youth Study.3 Non-HDL-C has a major quality of the design and execution. But the failure of logistical advantage over LDL-C in that fasting samples are Emerging Risk Factor Collaboration to discriminate amongst not required. For these reasons, non-HDL-C risk thresholds the markers is also due to the fact that the conventional sta(<120 mg/dL optimal, $145 mg/dL elevated) were included tistical analytical approach assumes LDL-C, non-HDL-C, in the 2011 Integrated Pediatric Guidelines for Cardiovascuand apoB are independent variables, whereas they are, in lar Risk Reduction.3 fact, tightly interrelated metabolically. This intercorrelation In this issue of The Journal, Dai et al use the NHANES makes it challenging to take them apart statistically.5 database to estimate age-, ethnic-, and sex-specific values for the distribution of non-HDL-C in the pediatric populaThis analytical challenge can best be met by separating out tion.4 Their findings will be helpful to clinicians evaluating the population group in whom apoB particles contain a normal mass of cholesterol from the two subgroups in cardiovascular risk in children and adolescents. Important whom apoB particles contain substantially more or less observations from this study include an overall prevalence cholesterol than normal. In the normal cholesterol content of elevated non-HDL-C (#145 mg/dl) of about 10% and group, LDL-C, non-HDL-C, and apoB are concordant and borderline values (120-144 mg/dL) in another 15%-20%. must predict risk equally well. Only in the two subgroups Non-HDL-C values vary significantly by age and sex with in which the composition of the apoB particles is discordant the highest levels in late-adolescent boys and during precould the cholesterol markers and apoB differ in predictive puberty in both sexes. In mid-adolescence, values decline, accuracy; obese individuals are more likely to have adverse and this age-related variability suggests the need for caution discordance. By including all subjects, conventional analyses in the interpretation of screening values based on a single dilute the differences in these discordant groups and can measure. Follow-up values after diet intervention should be obscure true and important differences in predictive power. performed before finalizing risk assessment. Nevertheless, Indeed, a series of studies using discordance analysis have the rapid rise of non-HDL-C in late adolescence in both now shown that apoB or LDL particle number is superior boys and girls represents a disconcerting harbinger of accelto both LDL-C and non-HDL-C to predict cardiovascular erated vascular disease. risk.6-8 Although non-HDL-C may be an improvement over LDL-C, does non-HDL-C provide the best early estimate These differences in the mass of cholesterol within apoB of cardiovascular risk? Atherosclerosis is a multifactorial, particles that produce discordance are due to cholesterolmultifaceted disease but trapping of apoB particles within ester transfer protein-mediated exchanges of core lipids the arterial wall is the fundamental event that creates and between lipoprotein particles. Patients with hypertriglyceridrives all this complexity. Because each apoB lipoprotein demia have cholesterol-depleted LDL particles because particle contains 1 molecule of apoB, the plasma apoB level cholesterol ester is transferred from LDL to very low density accurately reflects the number of apoB particles in the circulipoprotein (VLDL) in exchange for triglyceride, which, in lation, of which, except in unusual circumstances, about turn, is transferred from VLDL to LDL. In these patients, the LDL particles consequently contain less cholesterol and the LDL-C level will systematically underestimate the small apoB LDL LDL-C Non-HDL-C VLDL
Apolipoprotein B Low density lipoprotein Low density lipoprotein-cholesterol Non-high density lipoprotein-cholesterol Very low density lipoprotein
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.09.050
228
Vol. 164, No. 2 February 2014 dense LDL particle number. Because non-HDL-C includes the cholesterol in VLDL as well as in LDL, non-HDL-C tends to ‘compensate’ for the error in LDL-C in estimating the LDL particle number in those with high triglycerides. This explains why high triglycerides and low HDL cholesterol may be markers of cardiovascular risk but have not been good targets for pharmacologic therapy. Both are surrogates for cholesterol-depleted LDL particles, and it is the LDL particles that injure the arterial wall and it is the reduction in LDL particles that reduces cardiovascular events.6,9 However, even in patients with cholesterol-depleted LDL particles, non-HDL-C is not necessarily as good a marker of cardiovascular risk as apoB. For example, in the JUPITER Study, a clinical trial that demonstrated the efficacy of statin therapy in patients with low LDL-C and high C-reactive protein, apoB levels were moderately high despite the low LDL-C and non-HDL-C.10 Similarly, in the INTERHEART Study, when non-HDL-C and apoB were discordant, apoB correctly identified risk, whereas non-HDL-C did not. That small cholesterol-depleted LDL particles are common is well appreciated, particularly in the obese. Unfortunately, much less attention has been paid to the second discordant group—the patients with cholesterol-enriched apoB particles in whom non-HDL-C and LDL-C will both overestimate risk because both overestimate the apoB particle number. In this group, unless apoB is measured, some patients will be treated who are not at risk because of LDL and should not be treated. Therefore, in both discordant groups, LDL-C and non-HDLC are less precise measures of cardiovascular risk than apoB because they are less precise measures of particle number than apoB. These discordant relationships between calculated LDL-C and LDL particle number exist in children as well as adults. Two recent studies published in The Journal demonstrate this phenomenon. Mietus-Snyder et al looked at lipoprotein particle distribution in school children enrolled in the Healthy Study and showed the same 20% discordance rate between the LDL particle number and distribution as in adult populations. Obesity and the associated dyslipidemia with high triglycerides and low HDL cholesterol identify those most likely to be discordant.11 Burns et al have shown that triglyceride to HDL ratio is strongly associated with LDL particle number and, in related studies, with insulin resistance.12,13 Further, non-HDL-C is strongly related to the metabolic syndrome whereas LDL-C is not.14 The bottom line is that pediatric care providers should realize that non-HDL-C is a surrogate for true risk estimation, not the gold standard. As we have reviewed, nonHDL-C is an indirect measure of the LDL particle number, and we believe atherogenic lipid risk is best estimated by measuring apoB; apoB has many advantages: not only is it a more accurate measure of risk but the measurement is standardized, has a lower coefficient of variation over time compared with conventional lipid measurements, and can also be performed non-fasting.15-17 ApoB measurement also enhances the ability to make the diagnosis of all the apoB dyslipoproteinemias possible.
The work of the panel drafting the 2011 Integrated Pediatric Guidelines for Cardiovascular Risk Reduction and supporting research such as that reported by Dai et al in this issue of The Journal represents both a model for how to proceed and a step forward in improving pediatric cardiovascular risk assessment.4 However, these improvements are insufficient. More research with state-of-the-art tools, including the characterization of the role of lipoprotein particles in relation to early atherosclerosis and the impact of healthy childhood behaviors on those lipoprotein particles, is needed. Given the current obesity epidemic and the fact that the disproportionate risk related to the increased LDL particle number resides in obese individuals, much detailed information is needed on apoB as well as non-HDL-C in younger individuals. Without the most precise risk assessment, separating the many children for whom improved health behaviors are best from the few children in whom rapid development of atherosclerosis is highly likely and more aggressive therapies required, cannot be accomplished, and meaningful and effective intervention will not occur. n Samuel S. Gidding, MD Nemours Cardiac Center A. I. DuPont Hospital for Children Wilmington, Delaware Allan Sniderman, MD Mike Rosenbloom Laboratory for Cardiovascular Research McGill University Health Center Montreal, Quebec, Canada Reprint requests: Samuel S. Gidding, MD, Nemours Cardiac Center, 1600 Rockland Road, Wilmington, DE 19803. E-mail: [email protected]
References 1. Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel iii) final report. Circulation 2002;106:3143-421. 2. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein b as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011; 4:337-45. 3. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011; 128(Suppl 5):S213-56. 4. Dai S, Yang Q, Yuan K, Loustalot F, Fang J, Daniels SR, Hong Y. Nonhigh-density lipoprotein cholesterol: distribution and prevalence of high serum level in children and adolescents: US National health and nutrition examination surveys, 2005–2010. J Pediatr 2014;164:247-53. 5. Di Angelantonio E, Gao P, Pennells L, Kaptoge S, Caslake M, Thompson A, et al. Lipid-related markers and cardiovascular disease prediction. JAMA 2012;307:2499-506. 6. Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. J Clin Lipidol 2011;5:105-13. 7. Cromwell WC, Otvos JD, Keyes MJ, Pencina MJ, Sullivan L, Vasan RS, et al. LDL particle number and risk of future cardiovascular disease in the 229
THE JOURNAL OF PEDIATRICS
8.
9.
10.
11.
12.
230
www.jpeds.com
framingham offspring study—implications for LDL management. J Clin Lipidol 2007;1:583-92. Sniderman AD, Islam S, Yusuf S, McQueen MJ. Discordance analysis of apolipoprotein b and non-high density lipoprotein cholesterol as markers of cardiovascular risk in the interheart study. Atherosclerosis 2012;225:444-9. Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol 2013. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Reduction in c-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the jupiter trial. Lancet 2009;373:1175-82. Mietus-Snyder M, Drews KL, Otvos JD, Willi SM, Foster GD, Jago R, et al. Low-density lipoprotein cholesterol versus particle number in middle school children. J Pediatr 2013;163:355-62. e352. Burns SF, Lee SJ, Arslanian SA. Surrogate lipid markers for small dense lowdensity lipoprotein particles in overweight youth. J Pediatr 2012;161:991-6.
Vol. 164, No. 2 13. Burns SF, Lee S, Arslanian SA. In vivo insulin sensitivity and lipoprotein particle size and concentration in black and white children. Diabetes Care 2009;32:2087-93. 14. Li C, McBride PE, Kwiterovich PO, McCrindle BW, Gidding SS. Nonhigh-density lipoprotein cholesterol concentration is associated with the metabolic syndrome among us youth aged 12-19 years. J Pediatr 2011;158:201-7. 15. Cole TG, Contois JH, Csako G, McConnell JP, Remaley AT, Devaraj S, et al. Association of apolipoprotein b and nuclear magnetic resonance spectroscopy-derived LDL particle number with outcomes in 25 clinical studies: assessment by the aacc lipoprotein and vascular diseases division working group on best practices. Clin Chem 2013;59:752-70. 16. Sniderman A, Couture P, de Graaf J. Diagnosis and treatment of apolipoprotein b dyslipoproteinemias. Nature Rev Endocrinol 2010;6:335-46. 17. Gidding SS, Stone NJ, Bookstein LC, Laskarzewski PM, Stein EA. Month-to-month variability of lipids, lipoproteins, and apolipoproteins and the impact of acute infection in adolescents. J Pediatr 1998; 133:242-6.