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Pediatr Blood Cancer 2012;58:117121

Health Consequences of Obesity
Gerald S. Berenson, MD* for the Bogalusa Heart Study group

Epidemiologic studies have established that cardiovascular (CV) largely related to obesity in childhood [1]. The concept that adult
risk factors including obesity are identiable in childhood. Child- heart diseases begin in childhood is an outgrowth of extensive long-
hood risk factors are predictive of adult cardiac risk and even term epidemiologic studies in youth, that is, the Bogalusa Heart
premature death [Franks et al. (2010) N Engl J Med 362:485 Study [Berenson et al. (1986) Causation of cardiovascular risk fac-
493]. In the United States, CV diseases remains the leading causes tors in children: Perspectives on cardiovascular risk in early life,
of death. In fact, heart disease has become the major cause of death Raven Press Books Ltd].Pediatr Blood Cancer 2012;58:117121.
worldwide, surpassing undernutrition and infectious diseases, 2011 Wiley Periodicals, Inc.

Key words: obesity; coronary disease; Bogulasa Heart Study

INTRODUCTION enlargement, as shown by the thickness of the left ventricle and

concentric hypertrophy.
Although clinical events from coronary heart disease occur
later in life evidence of subclinical adult heart diseases such as
atherosclerosis, essential hypertension, and diabetes, are clearly
found in young individuals. These are complex traits and involve Secular trends of obesity among the US population have
multiple genes interacting with environmental and lifestyle factors. shown that the prevalence of obesity has increased dramatically
An adverse outcome of unhealthy lifestyles in our population [5]. Tremendous increases of obesity over the past two decades
and in early life is the onset of obesity. Obesity (this term is also reect disturbing increase of adult onset diabetes mellitus at
used as generic for adiposity to include overweight and obesity the adolescent age. Secular trends of obesity and diabetes have
according to CDC standards), so common in our population and essentially occurred worldwide [1]. As example, lifestyles and
now worldwide [1,2] interacts with other cardiovascular (CV) risk obesity have drastically changed in Japan [6]. That nation has
factors and becomes a prime determinant of hypertension, shown a marked increase of dietary intake of fat, essentially a
dyslipidemia and diabetes. Obesity in childhood is a consistent similar dietary caloric intake and an increased prevalence of
predictor of adult heart disease [3,4]. Body fatness is related to diabetes (the small increase of daily caloric intake needed for
both a genetic predisposition and a balance between energy intake weight gain over a long period is difcult to measure by diet
and energy expenditure. Adult obesity is mostly considered studies). The mode of transportation has changed with use of
intractable. It has increased in our population with the same automobiles and motorbikes leading to a more sedentary lifestyle.
genetic pool, as shown by secular trends. Its genesis generally Dietary, availability, the food and fat content and sedentary
occurs from childhood and continues into adulthood because of lifestyles are the underlying features of this national trend.
strong tracking. Therefore, it is obvious there is a need to Comparisons between BMIs determined in 1973 at the onset
address the general population identifying children at risk for of the Bogalusa Heart Study and those from 1992 to 1994 showed
adult obesity and address attendant metabolic and clinical that there was a signicant increase of approximately 12 pounds
manifestations. average per child without a signicant increase in height [3].
The extreme consequence of obesity can be illustrated by Additional data in Bogalusa 2009 have shown that this increase
death of a young individual in our Study. This is a case of obesity has continued and the average increase of overweight in children
in a 25-year-old white male who was found dead in bed failing to is about 17 pounds [7]. This represents a rather dramatic secular
arise in the morning. He had a diagnosis of sleep apnea and trend of increasing obesity occurring in a rural population repre-
noncompliance. On physical examination, he was 60 200 , weighed senting southeastern United States, without a change in genetic
280 pounds and had a BMI of 36.2 kg/m2, which is >95th per-
centile. On autopsy, the heart weighed 440 g, with left ventricle
posterior wall thickness of 2.2 cm and the right ventricle thick- The Tulane Center for Cardiovascular Health, Tulane University
ness of 0.7 cm. There was 30% narrowing of both the right Health Sciences Center, New Orleans, Louisiana
coronary artery and the left anterior descending coronary arteries. Grant sponsor: National Institute of Aging; Grant number: AG-16592;
No calcication was evident, nor was there evidence of infarction. Grant sponsor: National Institute of Child Health and Human
The toxicology studies were negative. The liver weighed 1920 g Development; Grant number: HD-061437; Grant sponsor: American
(normal 14001800 g) with evidence of acute hepatic congestion Heart Association; Grant number: 0855082E; Grant sponsor: National
Heart, Lung and Blood Institute; Grant number: HL-38844.
and mild steatosis. The kidneys weighed 210 g each (normal
125170 g). The remaining organs showed nonspecic abnormal- The authors express appreciation to the children and families that
ities. He was seen on two occasions, but years earlier at 6 and have made the Bogalusa Heart Study possible.
7 years of age, with no abnormalities. This BMI levels on those *Correspondence to: Gerald S. Berenson, MD, Department of Epide-
examinations were within normal limits. The cause of death was miology, Tulane Center for Cardiovascular Health, New Orleans,
listed as sleep apnea and noncompliance, hypertensive heart Louisiana. 1440 Canal St. Suite 1829 New Orleans, LA 70112.
disease, coronary artery disease, and morbid obesity. This is an E-mail: berenson@tulane.edu
example of the extreme effects of obesity with massive cardiac Received 6 September 2011; Accepted 6 September 2011
2011 Wiley Periodicals, Inc.
DOI 10.1002/pbc.23373
Published online in Wiley Online Library
118 Berenson

background. Such information clearly implicates environmental to make this diagnosis, there are limitations to these various
and lifestyle changes now being reected in cardiovascular criteria when related to children [10,11]. Variations of levels
disease, morbidity and mortality [4,5] occur with age, race, and gender. Since risk factors are a continu-
um with growth and age, we suggest percentiles for judging
INTERRELATIONSHIP OF CARDIOVASCULAR overweight and obesity for children to use data and charts
provided by CDC [12]. Since risk factors vary with age, race,
and sex, we recommend the use of percentiles for three or more
Risk factors tend to cluster and aggregate in an interactive and risk factors, but to include at least one as a measure of body
additive effect on CV risk. The Framingham Risk Score shows as fatness. BMI and waist/height suggest indices of fatness and
the number of risk factors increases both CV disease and mortali- central obesity. A measure of central obesity can be obtained
ty increase. In his 1988 Banting lecture, Reaven initiated the from waist/height measurements (Fig. 2). There are a number of
concept of Syndrome X with insulin resistance related to multiple studies in childhood at a population level that are available to
risk factors [8]. This syndrome has evolved into the metabolic provide data for percentile designation, namely: the Bogalusa
syndrome and use of various terminology and criteria. Insulin Heart Study [2], the Muscatine Study [13], and the Cardiovascular
resistance is the central feature of the metabolic syndrome and Risk in Young Finns Study [14].
a constellation of metabolic, carbohydrate- insulin-, and lipid- It is of interest to consider which comes rst, the obesity or
aberrations are included. More recently inammatory, thrombotic hyperinsulinemia [15]. The incidence of risk factors clustering
and hemodynamic factors are known to contribute to the cardio- related to both BMI or insulin quartiles in childhood show strong
metabolic picture. Several different criteria for the syndrome are relationships. When the relationship to risk variables in adulthood
now proposed by national and international guidelines. According and childhood both unadjusted BMI and fasting insulin have
to NCEP ATP III guidelines about 47 million US residents have strong and positive relationships. In contrast, when insulin levels
the metabolic syndrome. Figure 1 shows how various clusters of are adjusted for BMI, the insulin signicance decreases. This
risk factors relate signicantly to subscapular skinfolds [9]. When indicates that obesity in childhood actually precedes insulin
these risk factor clusters are adjusted for the subscapular skinfold, resistance and begins to evolve into adulthood.
the risk ratios decrease, indicating that centrality of body fatness
even occurring in childhood, inuences CV risk as found in the CONCEPT OF LIPOTOXICITY
metabolic syndrome in adults.
A variety of names including insulin resistance, Syndrome X, Fascinating studies in experimental animals have been
cardiometabolic syndrome, the Deadly Quartet, and atherogenic conducted by Unger and Scherer [16] showing the damaging
dyslipidemia have been given to this common and complex effect of fat deposition within various organ tissues, such as:
clinical picture. Even though there are different criteria provided muscle, pancreas, kidney, and the heart. The administration of

Fig. 1. Risk ratios of various clusters of risk factors related to skin folds by race and sex. Note the strong relation to subscapular skinfold,
more so in white males and the lack of relation when corrected for subscapular skinfold, indicating a stronger relation to central body fatness in
childhood: The Bogalusa Heart Study [9].
Pediatr Blood Cancer DOI 10.1002/pbc
Health Consequences of Obesity 119

from childhood are shown in Table II to associate with prediabetic

and diabetic adults [18]. The interrelationship of blood pressure to
lipid parameters and glucose occurs is through adiposity and
hyperinsulinemia. Thus, body fatness underlies anatomic, meta-
bolic, and functional characteristics that can lead to heart disease.


Perhaps more appropriate for the impact of the metabolic
syndrome is the title of The Deadly Quartet, when considering
implications of the risk factor burden on the CV system [19]. The
classic cluster of risk factors of upper body obesity or central
obesity, glucose intolerance or insulin resistance, hypertriglycer-
idemia, and hypertension is reected in autopsy studies. As shown
in Figure 3, an acceleration of collagen-capped brous plaques
Fig. 2. Waist/height ratio percentiles in children. 0.5 is an index of occurs with increasing numbers of risk factors. Obesity as de-
being overweight: The Bogalusa Heart Study [12].
scribed, is central to the occurrence of the metabolic risk factors
[20]. The importance of brous lesions found in coronary arteries
Troglitazone inhibits such changes. As well as lipid changes, tend to progress to more severe atherosclerosis. The incidence of
collagen staining in the kidney shows increased brosis in these lesions increases in adolescence to young adulthood. Obser-
glomeruli. Metabolically, carnitine is increased by nonoxidative vations of the Pathologic Determinants of Atherosclerosis in
fatty acid metabolism. The impact of obesity producing CV renal Youth (PDAY) also provide evidence of the presence of calcium
disease occurs from fat cell generation of metabolic, hormonal, in vascular tissue that becomes visible with progression [21].
and inammatory mediators. The impact of fat deposition
contributing to risk factors and CV disease becomes more under- CARDIOVASCULAR STUDIES BY
standable in our epidemic of obesity and its consequences.

PREVALENCE OF PREDIABETES, DIABETES, Although the autopsy studies are rather dramatic and extreme-
ly important, it is not possible to obtain such information on large
numbers of individuals. Fortunately, there are now instruments in
The common prevalence of silent aberrant carbohydrate- which observations by noninvasive methods can demonstrate
insulin-metabolism and diabetes mellitus status are depicted and cardiac and vascular abnormalities. Echo Doppler studies have
dened as prediabetes and diabetes. These are predictable from provided most information. The carotid intima media thickness
childhood by risk factors levels of glucose, insulin, obesity and (IMT) increases in young adults with increasing numbers of risk
family history [17]. The levels of different variables for children factors including obesity similar to that found in the autopsy
with normal glycemia compared to those who later developed studies [22]. Studies on carotid IMT indicate this is a surrogate
prediabetes and diabetes as adults are shown in Table I. Striking marker indicating coronary artery atherosclerosis. Additional
differences for anthropometric variables, systolic blood pressure, observations show increasing IMT and vascular stiffness relate
low HDL-C, glucose, and insulin parameters are evident. As to parental history of coronary artery disease as well as childhood
expected, increase of hyperinsulinemia associated with metabolic obesity [23]. The carotid artery IMT by percentiles related to age
syndrome characteristics, include greater BMI levels. The longi- (Fig. 4) can be used to develop a vascular score in contrast to
tudinal rates of change of various risk factors including obesity the chronological score of Framingham [24]. It is possible to

TABLE I. Risk Variables of Metabolic Syndrome in Childhood by Adult Diabetes Status: The Bogalusa Heart Study

Variable (mean  SE)a Normoglycemia (n 1838) Prediabetes (n 90) Diabetes (n 60)

Age (years) 10.8  0.1 12.4  0.4 12.3  0.5
BMI (kg/m2) 18.3  0.1 19.5  0.4 22.2  0.8
Subscapular skinfold (mm) 12.6  0.2 14.2  0.7 17.0  1.1
Systolic BP (mm Hg/year) 100.8  0.3 105.0  1.2 107.5  1.7
Diastolic BP (mm Hg) 61.8  0.2 64.5  1.2 65.0  1.3
LDL-C (mmol/L) 2.27  0.2 2.36  0.07 2.32  0.10
HDL-C (mmol/L) 1.60  0.01 1.62  0.06 1.38  0.06
TG (mmol/L) 0.73  0.01 0.78  0.04 0.90  0.05
Glucose (mmol/L) 4.7  0.01 5.0  0.1 5.1  0.1
Insulin (pmol/L) 53.6  1.6 76.7  15.9 98.1  17.4
HOMA-IR 1.8  0.1 2.8  0.6 3.8  0.8

P-values were adjusted for age, race, and sex, except age; different from normoglycemia: P < 0.05; P < 0.01; P < 0.001;

P < 0.0001.
Pediatr Blood Cancer DOI 10.1002/pbc
120 Berenson

TABLE II. Longitudinal Rates of Change in Risk Variables of Metabolic Syndrome since Childhood by Adult Diabetes Status: The
Bogalusa Heart Study

(n 1838) Prediabetes (n 90) Diabetes (n 60)
Risk variable D D P-value D P-value
BMI (kg/m2 per year) 0.39 0.51 <0.01 0.58 <0.0001
Subscapular skinfold (mm/year) 0.55 0.72 <0.01 0.86 <0.0001
Systolic BP (mm Hg/year) 0.57 0.60 0.60 0.64 0.31
Diastolic BP (mm Hg/year) 0.64 0.72 0.10 0.78 <0.05
LDL-C (mmol/L per year) 0.03 0.04 0.12 0.03 0.42
HDL-C (mmol/L per year) 0.01 0.01 0.97 0.01 0.88
TG (mmol/L per year) 0.03 0.04 <0.01 0.06 <0.001
Glucose (mm0l/L per year) 0.005 0.03 <0.0001 0.16 <0.0001
Insulin (pmol/L per year) 0.19 1.86 <0.001 1.75 <0.01
HOMA-IR (year) 0.01 0.11 <0.0001 0.24 <0.0001

Values are GEE method regression slope, related to age, years, adjusted for race and sex, and race by sex interaction; versus

obtain a chronological score and also explore a vascular score to PREVENTION STRATEGIES
determine the underlying effects of the risk factor burden on the
We have developed two types of prevention strategies based on
CV system. The combination of clinical and vascular changes can
our experiences from the Bogalusa Heart Study: A population
be rather valuable in studying actual CV risk in individuals. Other
strategy and a high-risk model.
noninvasive methodology are now available to study CV risk.
Obesity as well as hypertension in childhood predicts adult cardi-
ac enlargement and increased left ventricular end diastolic diam- A Population Strategy
eter [25]. The most consistent predictor of such changes is The most important is a public health model that focuses on
childhood obesity, while the combination of obesity and hyper- school children and individuals at a young age [29,30]. This pro-
tension enhance early cardiac dysfunction and impending heart gram is a kindergarten to sixth grade (K-6) comprehensive health
failure. Pulse wave velocity, vascular stiffness, and cardiac education program that addresses the entire school environment.
enlargement are other important measures in which obesity, as The program is strongly behavioral and begins teaching children in
part of the Metabolic Syndrome, is a major contributor to these kindergarten to have respect for their bodies, to consider taking
changes in the CV system [26,27]. These vascular changes also care of their health through good decision-making. It starts by
show an interrelation to the metabolic syndrome and multiple risk encouraging self-esteem beginning in kindergarten. The overall
factors. Overall the studies at autopsy and the noninvasive meth- curriculum has many activities that encourage teachers and parents
odology clearly show the adverse health consequences of obesity. to become involved as important role models. A physical education
In the general population, obesity is the major contributor to CV curriculum, Super Kid/Super Fit, is provided that has some 75
disease at a young age. It is suggested the epidemic of obesity noncompetitive exercises available for all children as well as
may inhibit the successful decrease of mortality from heart dis- athletes. In addition, the program has many class activities to
ease that has been noted over the past four decades [28]. encourage improved social behavior as well.
This health education program has been shown to be successful
and has noted weight reduction in schools implementing the pro-
gram aggressively. The program has also been implemented through-
out a Parish (County) and has involved all the elementary schools
throughout the Parish, addressing some 57,000 children in the area
[31]. This is a model that other Parishes or Counties can adopt.

High-Risk Model
Another model is for individuals who have already developed
risk factors or clinical CV disease [32,33]. This program is con-
ducted with a multidisciplinary team training groups of families.
It is ideal for cardiologists or physicians interested in CV preven-
tion and it is conducted by a nutritionist, an exercise person and a
psychologist as a multidisciplinary team that teaches families,
Fig. 3. Percent of atherosclerotic surface involvement in the aorta including children, on a weekly basis. It is conducted on multiple
and coronary arteries of young individuals. The relation with increas- families at the same time on how to improve their CV risk with
ing numbers of risk factors show an acceleration of lesions, especially improved lifestyles. A CV risk factor prole is obtained on all
of brotic lesions in coronary vessels: The Bogalusa Heart Study [20]. family members, including children. The program is implemented
Pediatr Blood Cancer DOI 10.1002/pbc
Health Consequences of Obesity 121

Fig. 4. The percentiles of carotid IMT increasing with age, indicating the degree of vascular involvement. Such data can be used to estimate a
vascular score: The Bogalusa Heart Study (24).

11. Chen W, Bao W, Begum S. et al. Age-related patterns of the clustering of cardiovascular risk variables
by the multidisciplinary team over 1012 weeks in an effort to of Syndrome X from childhood to young adulthood in a population made up of black and white
change lifestyles and improve their health behaviors. subjects: The Bogalusa Heart Study. Diabetes 2000;49:10421048.
12. Mokha JS, DasMahapatra P, Chen W, et al. Utility of Waist-to-Height ratio in assessing Cardiometa-
Prevention has been a major concern of cardiologists who have bolic Risk Prole among Normal Weight and Overweight/Obese Black and White Children: The
conducted many clinical trials. But, current clinical trials are Bogalusa Heart Study. 2010 (Submitted).
13. Lauer RM, Burns TL, Daniels SR. Pediatric prevention of atherosclerotic cardiovascular disease. New
largely directed toward adults and for primary and secondary York: Oxford University Press; 2006.
14. Jokela M, Kivimaki M, Elovainio M, et al. Body mass index in adolescence and number of children in
prevention often after CV events have occurred. Primary preven- adulthood. Epidemiology 2007;18:599606.
tion where CV risk factors have already developed but even 15. Srinivasan SR, Myers L, Berenson GS. Predictability of childhood adiposity and insulin for developing
insulin resistance syndrome (Syndrome X) in young adulthood: The Bogalusa Heart Study. Diabetes
without overt disease is an important area to involve children. 2002;51:204209.
Primordial prevention should begin in childhood in an effort to 16. Unger RH, Scherer PE. Gluttony, sloth and the metabolic syndrome: A roadmap to lipotoxicity. Trends
Endocrinol Metab 2010;21:345352.
address the problem of preventing the development of risk factors 17. Nguyen QM, Srinivasan SR, Xu JH, et al. Inuence of childhood parental history of type 2 diabetes on
at a young age [34]. the pre-diabetic and diabetic status in adulthood: The Bogalusa Heart Study. Eur J Epidemiol
18. Nguyen QM, Srinivasan SR, Xu JH, et al. Fasting plasma glucose levels within the normoglycemic
CONCLUSION range in childhood as a predictor of prediabetes and type 2 diabetes in adulthood: The Bogalusa Heart
Study. Arch Pediatr Adolesc Med 2010;164:124128.
19. Kaplan NM. The deadly quartet and the insulin resistance syndrome: An historical overview. Hyper-
The message of the Bogalusa Heart Study and the problem of tens Res 1996;19:S911.
20. Berenson GS, Wattigney WA, Tracy RE. et al. Atherosclerosis of the aorta and coronary arteries and
obesity is that heart diseases begin in childhood. Obesity has cardiovascular risk factors in persons aged 630 years and studied at necropsy: (The Bogalusa Heart
become a major target for prevention since its consequences are Study). Am J Cardiol 1992;70:851858.
21. Wissler RW, Strong JP. the PDAY Research Group. Risk factors and progression of atherosclerosis in
clearly the development of cardiac diseases and diabetes. The youth. Am J Pathol 1998;153:10231033.
consequences of obesity should encourage cardiologists and 22. Freedman DS, Patel DA, Srinivasan SR, et al. The Contribution of Childhood Obesity to Adult Carotid
Intima-media Thickness: The Bogalusa Heart Study. Intl J Obesity 2008;121:924929.
primary care physicians to provide leadership for the problem 23. Urbina EM, Srinivasan SR, Kieltyka RL. et al. Correlates of carotid artery stiffness in young adults:
of controlling risk factors and obesity as they begin in early life. The Bogalusa Heart Study. Atherosclerosis 2004;176:157164.
24. Tzou WS, Douglas PS, Srinivasan SR, et al. Distribution of predictors of carotid intima-media
thickness in young adults. Prev Cardiol 2007;10:181189.
25. Haji SA, Ulsoy RE, Patel DA. et al. Predictors of left ventricular dilatation in young adults (from the
REFERENCES Bogalusa Heart Study). Am J Cardiol 2006;98:12341237.
26. Li S, Chen W, Srinivasan SR. et al. Inuence of metabolic syndrome on arterial stiffness and its
age-related change in young adults: The Bogalusa Heart Study. Atherosclerosis 2005;180:349354.
1. Wang Y, Lobstein T. Worldwide trends in childhood overweight and obesity. Int J Pediatr Obes
27. Toprak A, Wang H, Chen W, et al. Relation of childhood risk factors to left ventricular hypertrophy
(eccentric or concentric) in relatively young adulthood (from the Boglusa Heart Study). Am J Cardiol
2. Berenson GS, editor, Causation of cardiovascular risk factors in children: Perspectives on cardiovas-
cular risk in early life. New York: Raven Press Books Ltd; 1986.
28. Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United
3. Baker JL, Olsen LW, Sorensen TI. Childhood body-mass index and the risk of coronary heart disease in
States in the 21st century. N Engl J Med 2005;352:11381145.
adulthood. N Engl J Med 2007;357:23292337.
29. Downey AM, Frank GC, Webber LS, et al. Implementation of Heart Smart: A cardiovascular school
4. Must A, Jacques PF, Dallal GE, et al. Long-term morbidity and mortality of overweight adolescents.
health promotion program. J Sch Health 1987;57:98104.
A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med 1992;327:13501355.
5. Centers for Disease Control and Prevention. US Obesity Trends 10012003. CDC Online reference. 30. Berenson GS, Editor, Introduction of comprehensive health promotion for elementary schools: The
Accessed at: www.cdc.gov/obesity/data/trends.html. Health Ahead/Heart Smart Program. New York, NY: Vintage Press Inc; 1998.
6. Matsushita Y, Nobuo Y, Kaneda F, et al. Trends in Childhood Obesity in Japan over the Last 25 years 31. Berenson GS. Cardiovascular health promotion for children: A model for a Parish (County)-wide
from the National Nutrition Survey. Obs Res 2004;12:205214. program (implementation and preliminary results). Prev Cardiol 2010;13:2328.
7. Broyles S, Katzmarzyk PT, Srinivasan SR, et al. The pediatric obesity epidemic continues unabated in 32. Berenson GS, Harsha DW, Johson CC. et al. Teach families to be heart smart. Patient Care 1993;
Bogalusa, Louisiana. Pediatrics 2010;125:900905. 6:134135.
8. Reaven GM. Banting lecture. Role of insulin resistance in human disease. Diabetes 1988;37:15951607. 33. Johnson CC, Nicklas TA. Health ahead-heart smart family approach to prevention of cardiovascular
9. Smoak CG, Burke GL, Harsha DW, et al. Relation of obesity to clustering of cardiovascular disease risk disease. Am J Med Sci 1995;310:S127S132.
factors in children and young adults: The Bogalusa Heart Study. Am J Epidemiol 1987;125:364372. 34. Berenson GS. Bogalusa Heart Study Group. Primordial preventionA perspective from the Bogalusa
10. Chen W, Berenson GS. Metabolic Syndrome: Denition and prevalence in children. J Pediatr (RijoJ) Heart Study. The University of Pittsburgh Online Supercourse. 2009; Accessed at www.pitt.edu/
2007;83:12. super1/lecture/lec36561/index.htm.

Pediatr Blood Cancer DOI 10.1002/pbc