Childhood Age and Associa ions Be ween Childhood Me abolic
Synd ome and Adul Risk o Me abolic Synd ome, Type 2 Diabe es
Melli us and Ca o id In ima Media Thickness: The In e na ional
Childhood Ca dio ascula Coho Conso ium
Juha Koskinen, MD, PhD; Cos an G. Magnussen, PhD; Alan Sinaiko, MD; Jessica Woo, MHSA, PhD; Elaine U bina, MD, MS; Da id R. Jacobs,
J , PhD; Julia S einbe ge , MD, MS; Ronald P ineas, MB, BS, PhD; Ma hew A. Sabin, MD, PhD; T udy Bu ns, MPH, PhD; Ge ald Be enson,
MD; Lydia Bazzano, MD, PhD; Alison Venn, PhD; Jo ma S.A. Viika i, MD, PhD; Nina Hu i-K€
ah€
onen, MD, PhD; Olli Rai aka i, MD, PhD;
Te ence Dwye , MD, MPH; Ma kus Juonala, MD, PhD
Backg ound-—The e is pauci y o knowledge conce ning he specific age in you h when he associa ions o me abolic synd ome
(Me S) begin o be ope a i e. Thus, we in es iga ed he ela ion o age o he associa ions o childhood Me S wi h adul Me S, ype
2 diabe es melli us and high ca o id in ima-media hickness.
Me hods and Resul s-—Fi e housand eigh -hund ed h ee pa icipan s we e analyzed in 4 coho s udies (Ca dio ascula Risk in
Young Finns, Bogalusa Hea S udy, P ince on Lipid Resea ch S udy, Insulin S udy). In e na ional cu o s and p e iously used
75 h pe cen ile cu o s we e used o child en o define Me S and i s componen s. Mean ollow-up pe iod was 22.3 yea s.
Logis ic eg ession was used o calcula e isk a ios and 95% confidence in e als. Childhood Me S and o e weigh we e
associa ed wi h o e 2.4- old isk o adul Me S om he age o 5 yea s onwa d. Risk o ype 2 diabe es melli us was
inc eased om he age o 8 ( isk a io, 2.6–4.1; 95% confidence in e al, 1.35–6.76 and 1.12–7.24, espec i ely) onwa d o he
2 childhood Me S c i e ia based on in e na ional cu -o alues and o childhood o e weigh . Risk o high ca o id in ima-media
hickness was significan a ages 11 o 18 yea s in ela ion o childhood Me S o o e weigh ( isk a io, 2.44–4.22; 95%
confidence in e al, 1.55–3.55 and 2.55–5.66, espec i ely). Con inuous childhood Me S sco e was associa ed wi h adul Me S
om he age o 5, wi h ype 2 diabe es melli us om he age o 14 and wi h high ca o id in ima-media hickness om he age
o 11 yea s onwa d.
Conclusions-—Adul Me S was p edic ed by Me S in childhood beginning a age 5. Howe e , adul ype 2 diabe es melli us and
subclinical a he oscle osis we e no p edic ed by childhood da a un il a e age 8. Body mass index measu emen alone a he
same age poin s p o ided simila findings. (J Am Hea Assoc. 2017;6:e005632. DOI: 10.1161/JAHA.117.005632.)
Key Wo ds: ca o id in ima-media hickness •me abolic synd ome •obesi y • ype 2 diabe es melli us
F om he Resea ch Cen e o Applied and P e en i e Ca dio ascula Medicine (J.K., C.G.M.) and Depa men o Medicine (J.S.A.V., M.J.), Uni e si y o Tu ku,
Finland; Hea Cen e (J.K.) and Di ision o Medicine (J.S.A.V., M.J.), Tu ku Uni e si y Hospi al, Tu ku, Finland; Menzies Ins i u e o Medical Resea ch, Uni e si y
o Tasmania, Hoba , Aus alia (C.G.M., A.V.); Depa men o Pedia ics (A.S.) and Di ision o Epidemiology and Communi y Heal h, School o Public Heal h
(D.R.J.), Uni e si y o Minneso a, Minneapolis, MN; Di ision o Bios a is ics and Epidemiology, Depa men o Pedia ics, Cincinna i Child en’s Hospi al Medical
Cen e and Uni e si y o Cincinna i College o Medicine, Cincinna i, OH (J.W.); Di ision o Ca diology, Depa men o Pedia ics, Cincinna i Child en’s Hospi al
Medical Cen e and Uni e si y o Cincinna i, Cincinna i, OH (E.U.); Depa men o Pedia ics, Uni e si y o Minneso a Masonic Child en’s Hospi al, Minneapolis,
MN (J.S.); Di ision o Public Heal h Sciences, Wake Fo es Uni e si y School o Medicine, Wins on-Salem, NC (R.P.); Mu doch Child en’s Resea ch Ins i u e,
Royal Child en’s Hospi al, Pa k ille, Aus alia (M.A.S., T.D.); Depa men o Pedia ics, Uni e si y o Melbou ne, Pa k ille, Aus alia (M.A.S., T.D.); Depa men o
Epidemiology, College o Public Heal h, Uni e si y o Iowa, Iowa Ci y, IA (T.B.); Depa men o Epidemiology, Tulane Cen e o Ca dio ascula Heal h, Tulane
Uni e si y School o Public Heal h and T opical Medicine, New O leans, LA (G.B.); Depa men s o Epidemiology and Bios a is ics and Bioin o ma ics, Tulane
Uni e si y Heal h Sciences Cen e , Tulane Uni e si y, New O leans, LA (L.B.); Depa men o Pedia ics, Uni e si y o Tampe e School o Medicine and Tampe e
Uni e si y Hospi al, Tampe e, Finland (N.H.-K.); Depa men o Clinical Physiology and Nuclea Medicine, Uni e si y o Tu ku and Tu ku Uni e si y Hospi al, Tu ku,
Finland (O.R.).
Co espondence o: Juha Koskinen, MD, PhD, Resea ch Cen e o Applied and P e en i e Ca dio ascula Medicine, Uni e si y o Tu ku, Kiinamyllynka u 10,
FIN-20520, Tu ku, Finland. E-mail: jkkosk@u u.fi
Recei ed Janua y 19, 2017; accep ed June 14, 2017.
ª2017 The Au ho s. Published on behal o he Ame ican Hea Associa ion, Inc., by Wiley. This is an open access a icle unde he e ms o he C ea i e Commons
A ibu ion-NonComme cial License, which pe mi s use, dis ibu ion and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed and is no used o
comme cial pu poses.
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 1
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om
Me abolic synd ome (Me S) is a cons ella ion o
me abolically in e ela ed a iables, including obesi y,
hype ension, dyslipidemia, hype glycemia, and, in some
analyses, also including hype insulinemia.
1
I is well known
ha adul s wi h Me S a e a inc eased isk o ype 2 diabe es
melli us (T2DM) and ca dio ascula disease (CVD).
2
The
po en ial impo ance o childhood Me S has been ou lined
in a consensus s a emen om he Ame ican Hea Associ-
a ion
3
ha no ed he need o addi ional esea ch in child en
and adolescen s in o de o cla i y i s ela ion o he
de elopmen o adul ca dio ascula isk and disease.
3
Defining he age when childhood me abolic isk exposu e
begins o be associa ed wi h adul ca dio-me abolic isk and
a he oscle osis would help ocus pedia ic ca egi e s on
p e en i e s a egies, including e alua ion and in e en ion.
Using longi udinal da a om a collabo a i e s udy, we ha e
p e iously shown a ela ion be ween pedia ic Me S and adul
Me S, T2DM, and high ca o id a e y in ima-media hickness
(cIMT), a subclinical ma ke o a he oscle osis.
4
Howe e , he
s udy did no conside he specific age o ages in you h when
he associa ion begins o be ope a i e o whe he o e weigh
alone in childhood p edic s adul ou comes di e en ially
acco ding o age o measu emen .
In he p esen s udy, we used da a om 5803 indi iduals in
4 la ge, p ospec i e coho s udies pa icipa ing in he
In e na ional Childhood Ca dio ascula Coho (i3C) Conso -
ium
5
ha ha e ollowed pa icipan s om childhood in o
adul hood. The objec i e o he s udy is o examine he age in
childhood when he ela ionship o childhood Me S and
o e weigh (acco ding o childhood Me S c i e ia) is fi s
associa ed wi h adul Me S, T2DM, and cIMT. Because he e
is no s anda d defini ion o pedia ic Me S, we compa ed 3
p e iously published defini ions.
4,6
Me hods
De ailed s udy cha ac e is ics and me hods o he 4 coho s
a e desc ibed elsewhe e. These p e ious epo s also include
analyses o loss o ollow-up o show ha he ep esen a-
i eness o he coho s was main ained.
5,7–12
Da a we e analyzed in 5803 pa icipan s om 4 longi u-
dinal coho s udies (YFS [Ca dio ascula Risk in Young Finns
S udy], BHS [Bogalusa Hea S udy], PLRS [P ince on Lipid
Resea ch S udy], and IS [Minneso a Insulin S udy]) ha
measu ed isk ac o s o Me S in childhood and adul hood.
Each s udy was app o ed by he app op ia e ins i u ional
e iew boa ds, and w i en in o med consen o assen was
ob ained om all he s udy pa icipan s aged >18 o assen
and consen om hei pa en s o pa icipan s aged <18.
Da a om mo e han 1 age (maximum, 1 isi pe
pa icipan pe age g oup) we e en e ed in o he childhood
analyses om he 5803 pa icipan s (eg, in YFS, a pa icipan
examined a age 6, 9, and 12 yea s had da a en e ed in o he
analyses om all 3 ages). Fo subjec s wi h mul iple ollow-up
isi s in adul hood, da a om he mos ecen isi we e used
o maximize he leng h o ollow-up.
De ails o he me hods used o he measu emen o
weigh , heigh , blood p essu e (BP), lipid le els, glucose and
insulin le els, cIMT, and o he co a ia es in each coho s udy
a e p o ided elsewhe e.
5,7–12
Heigh and weigh we e mea-
su ed a all ime poin s. Body mass index (BMI) was calcula ed
om he o mula: weigh (kg)/heigh (m)
2
. A andom ze o
sphygmomanome e was used o measu e BP. Venous blood
samples we e aken a e a 12-hou as om he an ecubi al
ein. In YFS a baseline, se um choles e ol and iglyce ides
we e measu ed using ully enzyma ic Boeh inge CHOD-PAP
ki s wi h an OLLI 3000 analyze . Subsequen ly, Olympus
Sys em eagen analyze in a clinical chemis y analyze
(AU400; Olympus, Tokyo, Japan) was used o de e mine lipid
le els. Se um high-densi y lipop o ein (HDL) choles e ol was
measu ed by he dex an sulpha e 500 000 me hod. Low-
densi y lipop o ein choles e ol was calcula ed using he
F iedewald o mula.
13
In BHS, HDL-choles e ol and iglyc-
e ides we e measu ed using chemical p ocedu es wi h a
Technicon Au o Analyze II (Technicon Ins umen Co p,
Ta y own, NY), acco ding o he labo a o y manual o he
Lipid Resea ch Clinics p og am. Since his ime, hese
a iables we e de e mined by enzyma ic p ocedu es
14
using
he Abbo VP ins umen (Abbo Labo a o ies, No h
Chicago, IL). In PLRS da a, all se um lipid measu emen s
we e pe o med wi h s anda d me hods in Cen e s o Disease
Con ol and P e en ion–s anda dized labo a o ies.
15
Child-
hood glucose le els we e measu ed wi h an ABA-100 sys em
by using he hexokinase me hod. In adul hood, glucose le els
we e measu ed wi h a Dade Dimension Xpand sys em by
using he hexokinase/glucose-6-phospha e dehyd ogenase
me hod.
15,16
In IS, se um lipids we e analyzed in he
Uni e si y o Minneso a labo a o y wi h a Cobas FARA. HDL-
choles e ol was de e mined a e p ecipi a ion o non-HDL
lipop o eins wi h a magnesium/dex an p ecipi a ing eagen .
Clinical Pe spec i e
Wha Is New?
•The da a om his s udy p o ide help o in o m he iming
o ini ia ing clinical sc eening o ca dio ascula isk ac o s.
Wha A e he Clinical Implica ions?
•E alua ion o me abolic isk ac o le els p o ide meaning ul
p edic ion o adul ou comes a ound he ime o pube y onse .
•Using body mass index alone p o ides essen ially simila
esul s compa ed o he con en ional me abolic synd ome
model.
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 2
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om
T iglyce ides we e de e mined wi h a s anda d glyce ol
blanked enzyma ic iglyce ide me hod. Blood samples we e
analyzed o glucose wi h a Beckman Glucose Analyze II
(Beckman Ins umen s Inc, Fulle on, CA). Insulin samples
we e de e mined wi h a adioimmunoassay ki (Equa e RIA;
Binax Co p, Po land, ME). B-mode ul asound s udies o he
le ca o id a e y we e pe o med a ollow-ups using
s anda dized p o ocols in each s udy. In YFS, o assess
in aindi idual ep oducibili y o ul asound measu emen s, 57
subjec s we e e-examined 3 mon hs a e he ini ial isi . The
a e age absolu e di e ence and SD be ween measu emen s
was 0.050.04 mm. In BHS, 75 pa icipan s unde wen
epea ul asound examina ions 10 o 12 days a e hei
ini ial isi o de e mine in aindi idual ep oducibili y. The
a e age absolu e di e ence and SD be ween measu emen s
o all cIMT segmen s was 0.050.03 mm. In IS, ep o-
ducibili y o he cIMT showed a mean di e ence (SD) o
0.020.03 o analysis sepa a ed by 1 week.
Defini ion o Me S and I s Componen s in
Childhood
Table 1 lis s he componen s and alues o he 3 Me S
defini ions used in his s udy. BMI was used as he measu e o
adiposi y because wais ci cum e ence was no a ailable a
baseline in all coho s. Fas ing insulin was used when glucose
was no a ailable o he YFS, BHS, o IS coho s a baseline.
We gene a ed age-, sex-, ace-, coho -, and s udy-yea –
specific pe cen iles o BMI, sys olic and dias olic BPs, HDL-
choles e ol, iglyce ides, insulin, and glucose.
Fo he modified Na ional Choles e ol Educa ion P og am
(Me SNCEP75) defini ion, a pa icipan was ca ego ized as
ha ing Me S i he o she had any 3 o he ollowing 5
componen s: BMI o wais ci cum e ence ≥75 h pe cen ile;
sys olic o dias olic BP ≥75 h pe cen ile; HDL-choles e ol
≤25 h pe cen ile; iglyce ides ≥75 h pe cen ile; o insulin/
glucose ≥75 h pe cen ile.
The second childhood Me S defini ion used age- and sex-
s anda dized pedia ic cu poin s a ailable in he li e a u e o
deno e each componen isk ac o (Me SPed).
4
A pa icipan
was ca ego ized as ha ing Me S i he o she ulfilled
o e weigh plus any 2 o 4 emaining isk componen
c i e ia. O e weigh o obesi y we e defined acco ding o he
Cole classifica ion.
17
P ehype ension o hype ension was
defined acco ding o he Fou h Repo on High Blood
P essu e in Child en and Adolescen s om he Na ional High
Blood P essu e Educa ion P og am.
18
Low HDL-choles e ol
and high iglyce ides we e defined using cu poin s
p oposed om g ow h-cu e da a ha we e linked o adul
defini ions.
19
Hype glycemia was defined as plasma glucose
≥5.60 mmol/L (100 mg/dL).
20
Hype insulinemia was
defined when glucose was una ailable as ha ing insulin
le els abo e age-, sex-, ace-, s udy-coho –, and s udy-yea –
specific 75 h pe cen ile.
The hi d Me S defini ion (Me SCook) was desc ibed by
Cook e al
21
using he Na ional Choles e ol Educa ion
P og am (Adul T ea men Panel III) defini ion modified o
age. O e weigh o obesi y and ele a ed BP was defined as
BMI o sys olic o dias olic BP ≥90 h pe cen ile. Ele a ed
alues o iglyce ides we e defined a le els a o abo e
1.695 mmol/L (150 mg/dL) and o glucose le els a o
abo e 5.6 mmol/L (100 mg/dL); dec eased le els o HDL-
choles e ol we e defined as le els a o below 1.036 mmol/L
(40 mg/dL). When glucose was no a ailable, we used
hype insulinemia (≥90 h pe cen ile). Finally, a con inuous
Me S sco e o child en was cons uc ed based on a sex- and
ace-specific algo i hm de i ed om confi ma o y ac o
analysis o da a om he Na ional Heal h and Nu i ion
Examina ion Su ey.
22
Pa icipan s wi h missing glucose da a
we e excluded om he con inuous Me S analyses.
Table 1. Me S Defini ions and Thei Componen s Used in This S udy
Me S Defini ion O e weigh Ele a ed BP High T iglyce ide Le el Low-HDL Choles e ol
Glucose/Insulin
Abno mali y
Me SNCEP75 (any 3
componen s)
BMI ≥75 h pe cen ile Sys olic and/o dias olic
BP ≥75 h pe cen ile
T iglyce ides ≥75 h
pe cen ile
HDL-choles e ol
≤25 h pe cen ile
Glucose o insulin
le el ≥75 h
pe cen ile
Me SCook (any 3
componen s)
BMI ≥90 h pe cen ile Sys olic and/o dias olic
BP ≥90 h pe cen ile o
>130/85 mm Hg
≥150 mg/dL ≤40 mg/dL Glucose ≥100 mg/
dL o insulin ≥90 h
pe cen ile
Me SPed
(o e weigh +any 2
componen s)
Cole classi ica ion NHBPEP-classi ica ion G ow h cu e
dependen *
G ow h cu e
dependen *
Glucose ≥100 mg/
dL o insulin ≥90 h
pe cen ile
BP indica es blood p essu e; Me S, me abolic synd ome; NCEP, Na ional Choles e ol Educa ion P og am; NHBPEP, he Na ional High Blood P essu e Educa ion P og am.
*A ailable only om age o 6 yea s onwa d.
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 3
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om
Defini ion o Me S in Adul hood
Me S in adul hood was defined by he diagnos ic c i e ia
p o ided by a join s a emen om he In e na ional Diabe es
Fede a ion Task Fo ce on Epidemiology and P e en ion,
Na ional Hea , Lung and Blood Ins i u e, he Ame ican Hea
Associa ion, he Wo ld Hea Fede a ion, he In e na ional
A he oscle osis Socie y, and he In e na ional Associa ion o
he S udy o Obesi y.
23
Me S was diagnosed when 3 o mo e
o he ollowing 5 c i e ia we e p esen : wais ci cum e ence
cu poin s o ≥102 cm o men and ≥88 cm o women o
define abdominal obesi y; iglyce ides ≥1.695 mmol/L
(150 mg/dL); HDL-choles e ol <1.036 mmol/L (40 mg/dL)
in men o <1.295 mmol/L (50 mg/dL) in women; BP ≥130/
≥85 mm Hg o BP-lowe ing medica ion; o as ing glucose
≥5.6 mmol/L (100 mg/dL).
Defini ion o T2DM in Adul hood
Pa icipan s we e classified as ha ing T2DM i hey: (1) had a
as ing plasma glucose ≥7.0 mmol/L (≥126 mg/dL); (2) had
a glycohemoglobin (A1C) le el o ≥6.5% (48 mmol/mol); (3)
epo ed ecei ing o al hypoglycemic agen s and/o insulin
injec ions and did no ha e ype 1 diabe es melli us; o (4)
epo ed a his o y o physician-diagnosed T2DM. Women who
epo ed ha ing physician-diagnosed diabe es melli us only
du ing he e m o hei p egnancy we e conside ed o ha e
had ges a ional diabe es melli us.
Defini ion o High cIMT in Adul hood
Consis en wi h p e ious epo s,
24
high cIMT in adul hood
was defined as a maximum cIMT ≥90 h pe cen ile o age-,
sex-, ace-, s udy-yea –, and s udy-coho –specific alues
(YFS, BHS). Fo IS, high cIMT in adul hood was defined as a
mean alue ≥90 h pe cen ile (age, sex, ace, and s udy yea )
because maximum alues we e no a ailable. Da a on cIMT
we e no a ailable o he PLRS coho and we e excluded
om he analyses examining high cIMT.
S a is ical Analysis
The YFS coho examined child en om specific bi h coho s
wi h 3-yea in e als (ages 3, 6, 9, 12, 15, and 18 yea s a
baseline su ey), whe eas he o he s udies had pa icipan s
a ying ac oss all ages om 3 o 18 yea s. The e o e, dic a ed
by YFS being he la ges coho , indi iduals om BHS, PLRS,
and IS a age g oups o 3 o 4, 5 o 7, 8 o 10, 11 o 13, 14 o 16,
and 17 o 18 yea s we e included in he espec i e age g oups
wi h he 3-, 6-, 9-, 12-, 15-, and 18-yea -olds om YFS. To ake
in o accoun possible di e ences a ibu ed o age, sex, ace,
and secula ends in isk ac o s, s udy coho , and di e en
me hodology age-, sex-, ace-, s udy-yea –, and s udy-coho –
specific isk ac o pe cen iles we e gene a ed o childhood
isk ac o s. Age- and sex-adjus ed ANOVA o con inuous
a iables and logis ic eg ession o ca ego ical a iables was
used o compa e cha ac e is ics among he s udy g oups. Fo
main analyses, di e en mul i a ia e echniques (Poisson
eg ession wi h ime o se , mul inomial eg ession, Cox
p opo ional haza ds a ios, and logis ic eg ession) we e used
o calcula e isk a ios (RR) and 95% confidence in e als (95%
CI). Conclusions d awn om he esul s we e essen ially simila
independen o he me hod used. In he Resul s sec ion, he
alues om he logis ic eg ession a e shown, which had he
lowes Akaike and Bayesian c i e ion in o ma ion alues. All
eg ession analyses using da a om bo h sexes we e adjus ed
wi h sex and all eg ession models combining da a om se e al
coho s we e addi ionally adjus ed o s udy coho , and yea o
minimize he e ec o he e ogenei y o he pa icipan s
a ibu ed o geog aphy and physiology. Because o almos no
T2DM e en s we e obse ed in he 2 younges age g oups, we
collapsed hese 2 g oups (3–4 and 5–7 yea olds) in o 1 age
g oup (3–7 yea olds) when analyzing u u e isk o T2DM.
S a is ical analyses we e pe o med wi h SAS so wa e ( e sion
9.4; SAS Ins i u e, Ca y, NC). S a is ical significance was
in e ed as P<0.05.
Resul s
Clinical Cha ac e is ics
Table 2 shows he numbe o childhood isi s in each s udy
coho and he clinical cha ac e is ics o he s udy subjec s.
MeanSD ollow-up ime was 22.39.5 yea s. PLRS had he
oldes and IS had he younges pa icipan s a adul ollow-up.
Subjec s we e p edominan ly whi es (76%) and blacks (24%).
Childhood insulin le els, Me SNCEP75, and adul hood Me S did
no ha e significan di e ences among he g oups (P>0.16).
O he wise s a is ically significan di e ences in clinical cha -
ac e is ics we e obse ed among he s udy g oups (Palways
<0.05). The no mali y assump ions o he esiduals we e
assessed by examining his og ams o he esiduals and no mal
p obabili y plo s. The esiduals we e no mally dis ibu ed.
Childhood Me S and O e weigh P edic ing he
Risk o Adul Me S
Tables 3 and 4 show RRs and 95% CIs (sexes combined and
sepa a ely, espec i ely) acco ding o child age (ages 3–18,
di ided in o 3-yea in e als) o childhood Me S p edic ion o
adul Me S. Childhood Me S was a significan p edic o o
adul Me S om ages 5 (RR, 2.43–3.39 wi h 95% CI 1.74–
3.40 and 1.68–6.83, espec i ely) o 18 yea s (RR, 3.64–
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 4
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om
5.13; 95% CI, 2.90–4.56 and 3.23–8.15, espec i ely) o he
3defini ions, excep ha he associa ion in males using he
Me SCook defini ion did no become significan un il 8 yea s
(RR, 4.62; 95% CI, 2.41–8.83). Nex , we emo ed BMI om
he Me SNCEP75 c i e ia; he esul s based on any 2 o he
emaining componen s emained essen ially simila o
Me SNCEP75. Finally, a mul i a iable model including all
indi idual Me SNCEP75 isk ac o s was cons uc ed. All
Me SNCEP75 componen s we e significan p edic o s
be ween ages 5 o 18 yea s (Table 5). When s udy coho s
we e analyzed sepa a ely, he RRs o childhood Me S in
p edic ing adul hood Me S we e consis en wi h Table 3
( esul s shown in Table 6).
Childhood Me S P edic ing he Risk o Adul
T2DM
Because o low numbe o T2DM e en s, we collapsed 2
younges age g oups (3–4 and 5–7 yea olds) in o 1 age
g oup (3–7 yea olds). Childhood Me S became a significan
Table 2. Cha ac e is ics o S udy Subjec s a Thei Fi s Obse a ion in Childhood and Thei Mos Recen Obse a ion in
Adul hood
BHS IS PLRS YFS
PValue*
All Coho s
N 1983 322 562 2936 5803
Childhood da a
Age, y 11.23.5 14.31.6 12.63.1 10.93.9 <0.0001 11.84.0
Age ange, y 3 o 18 11 o 18 6 o 18 3 o 18 3 o 18
E hinici y (whi e/black %) 62/38 78/22 71/29 100/0 <0.0001 76/24
BMI, kg/m
2
19.34.5 22.85.2 19.94.4 17.93.0 <0.0001 19.24.3
Sys olic BP, mm Hg 10211 1089 10413 11111 <0.0001 10612
Dias olic BP, mm Hg 5013 5613 6311 6510 <0.0001 5614
Glucose, mmol/L 4.60.5 4.90.4 4.80.44 4.70.7 <0.0001 4.60.5
Insulin, mU/L 10.48.2 11.58.8  10.06.8 0.16 10.47.6
T iglyce ides, mmol/L 0.780.40 1.010.58 0.850.42 0.770.35 <0.0001 0.790.40
HDL-choles e ol, mmol/L 1.500.44 1.130.25 1.390.32 1.600.32 <0.0001 1.510.40
Childhood Me S, %
Me SNCEP75 20 20 20 19 0.16 19
Me SPed 9 14 4 3 <0.0001 6
Me SCook 5 9 14 3 <0.0001 5
Con inuous Me S sco e (mean) 0.950.78 0.100.69 0.710.78 0.670.63 <0.0001 0.830.80
Adul hood da a
Age, y 31.38.0 23.32.5 42.16.8 34.48.1 <0.0001 33.28.5
Age ange, y 19 o 51 19 o 35 19 o 57 21 o 50 19 o 57
BMI, kg/m
2
27.57.1 26.46.5 28.76.9 25.34.7 <0.0001 26.56.2
Sys olic BP, mm Hg 11413 11010 12015 11914 <0.0001 11614
Dias olic BP, mm Hg 6911 6510 7911 7311 <0.0001 7111
Glucose, mmol/L 4.70.9 4.80.8 5.01.5 5.20.9 <0.0001 4.91.0
T iglyce ides, mmol/L 1.320.95 1.090.63 1.521.47 1.300.94 <0.0001 1.310.97
HDL-choles e ol, mmol/L 1.280.40 1.190.28 1.180.38 1.350.34 <0.0001 1.300.37
Me S, % 20 9 32 25 0.009 23
T2DM, % 1 0 5 2.5 0.17 2
cIMT mean, mm  0.4430.057  0.6030.097 <0.0001 0.5910.104
cIMT maximum, mm 0.7190.192  0.6430.101 <0.0001 0.6720.148
Values a e mean (SD), unless o he wise men ioned. BHS indica es he Bogalusa Hea S udy; BMI, body mass index; BP, blood p essu e; cIMT, ca o id in ima-media hickness; HDL, high-
densi y lipop o ein; IS, he Insulin S udy; Me S, me abolic synd ome; PLRS, he P ince on Lipid Resea ch S udy; YFS, he Ca dio ascula Risk in Young Finns S udy.
*Age- and sex-adjus ed P alues om g oup compa isons.
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 5
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om

p edic o o adul T2DM a age 8 yea s (RR, 2.85–4.14; 95%
CI, 1.12–7.24 and 1.37–12.4, espec i ely) and con inued
h ough age 18 (RR, 7.63; 95% CI, 3.85–15.1 and 1.98–10.2,
espec i ely) wi h he Me SCook, and Me SPed me hods.
De ailed esul s a e shown in Table 7. Significan associa ions
be ween childhood Me S and adul hood T2DM we e obse ed
om 14 yea s onwa d by he Me SNCEP75 me hod (RR, 3.59;
95% CI, 2.09–6.16). When sexes we e analyzed sepa a ely
(Table 8), he associa ion in emales be ween childhood Me S
and adul T2DM was inconsis en and spo adic, wi h
Me SCook significan a age 11 o 13, Me SPed and
Me SNCEP75 significan a age 14 o 16, and Me SPed and
Me SCook significan a age 17 o 18. Simila esul s wi h
childhood Me S ela ion o adul T2DM we e ob ained by
using o e weigh alone (Table 9). O he Me SNCEP75 isk
ac o s did no show consis en associa ion wi h adul T2DM.
When s udy coho s we e analyzed sepa a ely, he ou come
was un eliable, because o almos no ou come e en s
(Table 10).
Childhood Me S P edic ing he Risk o Adul High
cIMT
Childhood Me S measu ed by all me hods p edic ed adul -
hood high cIMT 2- o 4- old in he 11 o 18 age g oups.
De ailed RR and 95% CI a e p esen ed in Table 11. The esul s
we e he same when sexes we e analyzed sepa a ely
(Table 12). When BMI was emo ed om he Me SNCEP75
c i e ia, he associa ion was no longe s a is ically significan
in he 11 o 16 emale age g oups (P>0.13). F om he
Me SNCEP75 isk ac o s, only high BMI showed consis en
associa ion wi h adul cIMT om he age o 11 onwa d
(Table 13). High BP was associa ed wi h la e in ima-media
hickness a ages 5 o 7, high insulin a ages 11 o 16, and
high iglyce ides and low HDL choles e ol a ages 14 o 18.
When indi idual coho s we e analyzed (Table 14), high adul
cIMT was p edic ed only in YFS and BHS o 11- o 18-yea -
olds.
Childhood Con inuous Me S Sco e P edic ing he
Risk o Adul Me S, T2DM, and High cIMT
The associa ion be ween childhood con inuous Me S and
adul hood ou comes is shown in Table 15, wi h he analyses
limi ed o hose wi h childhood glucose da a. The esul s we e
simila o he 3 Me S me hods (ie, significan o adul Me S a
all ages and significan o T2DM and cIMT a adolescen
ages). When sexes we e analyzed sepa a ely, p edic ion o he
adul Me S was significan om age 5 onwa d (RR, 2.14; 95%
CI, 1.19–3.85 o males and RR, 3.79; 95% CI, 1.89–7.77 o
emales) and high cIMT om age 11 onwa d (RR, 2.02; 95% CI,
1.20–3.37 o males and RR, 1.82; 95% CI, 1.11–2.98 o
Table 3. RRs and Thei 95% CIs o Childhood Me S P edic ing he Risk o Adul hood Me S
Age a Childhood Measu emen in Yea s (No. o Me S E en s in Adul hood/No. o Subjec s)
3 o4(N=74/422) 5 o 7 (N=144/859) 8 o 10 (N=238/1054) 11 o 13 (N=351/1410) 14 o 16 (N=316/1334) 17 o 18 (N=275/949)
RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue
Me SNCEP75
(yes/no)
1.77 (0.98–3.20) 0.060 2.43 (1.74–3.40) <0.0001 3.21 (2.51–4.11) <0.0001 2.91 (2.37–3.58) <0.0001 3.26 (2.66–3.99) <0.0001 3.64 (2.90–4.56) <0.0001
Me SPed
(yes/no)*
  3.17 (1.92–5.22) <0.0001 2.76 (2.01–3.80) <0.0001 3.18 (2.46–4.11) <0.0001 3.68 (2.84–4.76) <0.0001 3.20 (2.28–4.51) <0.0001
Me SCook
(yes/no)
1.50 (0.57–3.92) 0.40 3.39 (1.68–6.83) 0.0006 4.08 (2.62–6.35) <0.0001 3.79 (2.57–5.58) <0.0001 4.10 (2.84–5.93) <0.0001 5.13 (3.23–8.15) <0.0001
All models a e adjus ed o sex, s udy coho , and yea . CI indica es 95% confidence in e al; Me S, me abolic synd ome, RR, isk a io.
*Me SPed was defined only o subjec s aged 6 o 18 yea s.
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 6
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om
Table 4. Sex-Specific RRs and Thei 95% CIs o Childhood Me S P edic ing he Risk o Adul hood Me S
Males
Age in Yea s (No. o Subjec s)
3 o4(N=44/203) 5 o 7 (N=85/376) 8 o 10 (N=119/461) 11 o 13 (N=180/655) 14 o 16 (N=171/620) 17 o 18 (N=132/438)
RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue
Me S a ian s
Me SNCEP75
(yes/no)
1.91 (0.88–4.15) 0.10 1.85 (1.16–2.97) 0.010 3.28 (2.29–4.69) <0.0001 3.13 (2.33–4.22) <0.0001 3.62 (2.72–4.82) <0.0001 3.96 (2.83–5.53) <0.0001
Me SPed
(yes/no)*
  3.36 (1.54–7.30) 0.0022 3.68 (2.32–5.84) <0.0001 4.03 (2.73–5.95) <0.0001 4.30 (2.97–6.23) <0.0001 3.33 (2.02–5.49) <0.0001
Me SCook
(yes/no)
0.79 (0.17–3.86) 0.77 2.19 (0.77–6.19) 0.14 4.62 (2.41–8.83) <0.0001 4.75 (2.55–8.85) <0.0001 3.60 (2.14–6.03) <0.0001 4.13 (2.24–7.61) <0.0001
Me SNCEP75
†
(yes/no, omi ing
BMI om he
Me S de ini ion)
1.48 (0.75–2.94) 0.26 1.72 (1.14–2.60) 0.009 2.21 (1.61–3.02) <0.0001 2.59 (1.98–3.38) <0.0001 2.52 (1.95–3.25) <0.0001 2.88 (2.16–3.84) <0.0001
Females
3 o4(N=30/219) 5 o 7 (N=59/483) 8 o 10 (N=119/593) 11 o 13 (N=171/755) 14 o 16 (N=145/714) 17 o 18 (N=143/511)
RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue
Me S a ian s
Me SNCEP75
(yes/no)
1.61 (0.63–4.09) 0.31 3.22 (1.99–5.21) <0.0001 3.17 (2.24–4.46) <0.0001 2.78 (2.07–3.72) <0.0001 2.94 (2.20–3.91) <0.0001 3.46 (2.54–4.72) <0.0001
Me SPed (yes/no)   2.93 (1.52–5.65) 0.0013 2.11 (1.35–3.32) 0.0011 2.64 (1.86–3.74) <0.0001 3.20 (2.22–4.61) <0.0001 3.13 (1.96–5.00) <0.0001
Me SCook
(yes/no)
2.48 (0.73–8.41) 0.15 4.65 (1.81–11.9) 0.0014 3.68 (2.00–6.77) <0.0001 3.45 (2.07–5.73) <0.0001 4.72 (2.80–7.97) <0.0001 6.99 (3.41–14.3) <0.0001
Me SNCEP75
†
(yes/no, omi ing
BMI om he
Me S de ini ion)
1.13 (0.50–2.52) 0.76 2.94 (1.85–4.67) <0.0001 2.65 (1.93–3.65) <0.0001 2.63 (2.01–3.43) <0.0001 2.34 (1.82–3.01) <0.0001 2.12 (1.62–2.77) <0.0001
All models a e adjus ed o sex, s udy coho , and yea . BMI indica es body mass index; CI, 95% confidence in e al; Me S, me abolic synd ome; RR, isk a io.
*Me SPed was defined only o subjec s aged 6 o 18 yea s.
†
Me S s a us was ulfilled i he o she ulfilled any 2 o he emaining Me S componen s (blood p essu e, iglyce ides, o glucose/insulin abo e 75 h pe cen ile and high-densi y lipop o ein choles e ol below 25 h pe cen ile).
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 7
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om
Table 5. Mul i a iable RRs and Thei 95% CIs o Childhood Me S Risk Fac o s P edic ing he Risk o Adul hood Me S
Risk Fac o (Yes/
No)*
Age a Childhood Measu emen in Yea s (No. o Me S E en s in Adul hood/No. o Subjec s)
3 o4 5 o7 8 o10 11 o13 14 o16 17 o18
RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue
High BMI 75 1.20 (0.67–2.13) 0.53 2.39 (1.73–3.29) <0.0001 2.49 (1.97–3.13) <0.0001 2.89 (2.38–3.51) <0.0001 3.21 (2.66–3.87) <0.0001 3.51 (2.84–4.33) <0.0001
High BP 75 1.15 (0.69–1.92) 0.59 1.62 (1.20–2.20) 0.002 2.11 (1.70–2.64) <0.0001 1.61 (1.34–1.93) <0.0001 1.22 (1.02–1.45) 0.03 1.57 (1.30–1.91) <0.0001
High insulin 75 1.14 (0.67–1.94) 0.63 2.01 (1.46–2.77) <0.0001 1.77 (1.39–2.25) <0.0001 2.28 (1.86–2.79) <0.0001 2.14 (1.77–2.59) <0.0001 1.86 (1.50–2.29) <0.0001
High iglyce ides
75
1.37 (0.78–2.41) 0.26 1.70 (1.23–2.36) 0.001 1.83 (1.44–2.33) <0.0001 2.14 (1.75–2.61) <0.0001 2.28 (1.89–2.75) <0.0001 2.00 (1.62–2.46) <0.0001
Low HDL 75 2.09 (1.23–3.55) 0.006 2.13 (1.54–2.94) <0.0001 1.91 (1.51–2.42) <0.0001 2.27 (1.87–2.77) <0.0001 1.88 (1.56–2.28) <0.0001 1.98 (1.61–2.44) <0.0001
All models a e adjus ed o sex, s udy coho , and yea . BMI indica es body mass index; BP, blood p essu e; CI, 95% confidence in e al; HDL, high-densi y lipop o ein; Me S, me abolic synd ome; RR, isk a io.
*High BMI, BP, insulin, iglyce ides ≥age, sex, ace, s udy coho , and yea -specific 75 h pe cen ile and low HDL ≤25 h pe cen ile.
Table 6. RRs and Thei 95% CIs o Childhood Me S P edic ing Risk o Me S in Adul hood S a ified by S udy Coho
Age (y)
3 o4 5 o7 8 o10 11 o13 14 o16 17 o18
RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue
YFS
Me SNCEP75
(yes/no)
1.76 (0.96–3.22) 0.063 2.25 (1.52–3.35) <0.0001 2.89 (2.13–3.93) <0.0001 2.61 (1.98–3.44) <0.0001 3.06 (2.34–4.02) <0.0001 3.27 (2.45–4.36) <0.0001
BHS
Me SNCEP75
(yes/no)
2.53 (0.12–93.3) 0.61 2.98 (1.52–5.85) 0.001 3.59 (2.26–5.71) <0.0001 3.38 (2.33–4.89) <0.0001 3.13 (2.22–4.40) <0.0001 4.16 (2.77–6.26) <0.0001
IS
Me SNCEP75
(yes/no)
      2.86 (0.91–9.00) 0.07 9.05 (3.51–23.4) <0.0001 6.78 (1.88–24.0) 0.0033
PLRS
Me SNCEP75
(yes/no)
  2.17 (0.29–15.9) 0.44 6.44 (2.15–19.2) 0.0009 4.01 (1.95–8.25) 0.0002 3.37 (1.38–8.18) 0.0072 5.55 (1.76–17.5) 0.0035
Models adjus ed o sex. BHS indica es he Bogalusa Hea S udy; CI, 95% confidence in e al; IS, he Insulin S udy; Me S, me abolic synd ome; PLRS, he P ince on Lipid Resea ch S udy; RR, isk a io; YFS, he Ca dio ascula Risk in Young
Finns S udy.
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 8
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om
emales) o bo h males and emales. Because o he small
numbe o diabe es melli us cases, esul s we e inconsis en
in significance bu consis en in di ec ion. The isk o T2DM
was significan o 8 o 10- and 14 o 16-yea -old males (RR,
4.19; 95% CI, 1.16–15.1 and RR, 3.40; 95% CI, 1.72–6.71,
espec i ely) and o 8 o 10- and o 17 o 18-yea -old
emales (RR, 3.43; 95% CI, 1.32–8.86 and RR, 2.99; 95% CI,
1.34–6.68, espec i ely).
Discussion
The esul s om his s udy demons a e ha childhood Me S
and o e weigh in bo h males and emales seems o p edic
inc eased isk o adul Me S om age 5 yea s onwa d. In
addi ion, childhood Me S iden ifies child en om ages 8 o
14 yea s onwa d who a e a inc eased isk o adul T2DM
and ea ly subclinical a he oscle osis measu ed by cIMT.
Simila esul s we e ound when an Me S sco e, using Me S
componen s as con inuous a iables, was subs i u ed o he
Me S, which uses dicho omized componen s o define isk.
We and o he s ha e assessed pedia ic Me S as a isk
ac o o adul Me S, T2DM, and high cIMT in coho s
consis ing o bo h child en and adolescen s. A p ospec i e
s udy o o me s uden s om he P ince on lipid esea ch
s udy epo ed ha child en aged 5 o 19 yea s wi h Me S
we e mo e likely o ha e Me S, T2DM, and clinical CVD 25 o
30 yea s la e as adul s.
10,25
Simila associa ions we e
obse ed in he YFS and BHS s udies conce ning Me S,
T2DM, and cIMT.
4,6
Howe e , he numbe o pa icipan s in
hose s udies was oo small o be able o conside age-
s a ified analyses, and li le is cu en ly known abou he age
when childhood Me S exposu e begins o ela e o adul isk.
The p esen s udy, wi h a coho o 5803 indi iduals, shows
ha a significan ela ion be ween childhood Me S and adul
Me S begins as ea ly as age 5 (ou da a a ea lie ages a e
spa se and we he e o e do no conside hem defini i e), and
he ela ion o T2DM and subclinical a he oscle osis begins in
ea ly adolescence. In con as o he p esen s udy, a 10-yea
longi udinal s udy o 1604 Pima Indians aged 5 o 19 yea s
wi h da a ob ained a age 26 yea s showed ha clus e ing o
CVD isk ac o s in 3 childhood age g oups (5–9, 10–14, and
15–19 yea s) inc eased he isk o ea ly T2DM.
26
The sligh ly
younge age a which a ela ion o adul T2DM was ecognized
may be ela ed o he known inc eased isk o de elopmen
o diabe es melli us in he Pima popula ion.
A s anda d uni e sal me hod o defining pedia ic Me S is
no a ailable, and he c i e ia cu en ly used ha e been
a iably adop ed om adul s anda ds.
3
In he p esen epo ,
we show ha he esul s be ween 3 di e en pedia ic Me S
defini ions we e essen ially simila in p edic ing adul Me S,
T2DM, and cIMT. In addi ion, he cMe S sco e, using isk
ac o s as con inuous a iables, esul ed in findings simila
Table 7. RRs and Thei 95% CIs o Childhood Me S P edic ing he Risk o Adul hood T2DM
Age a Childhood Measu emen in Yea s (No. o T2DM E en s in Adul hood/No. o Subjec s)
3 o7*(N=12/1281) 8 o 10 (N=19/1054) 11 o 13 (N=26/1410) 14 o 16 (N=34/1334) 17 o 18 (N=34/949)
RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue
Me SNCEP75 (yes/no) 1.54 (0.58–2.50) 0.33 1.46 (0.64–3.48) 0.38 1.67 (0.86–3.23) 0.13 3.59 (2.09–6.16) <0.0001 2.61 (1.50–4.56) 0.0007
Me SPed (yes/no)
†
1.64 (0.20–13.0) 0.63 2.85 (1.12–7.24) 0.027 3.21 (1.59–6.46) 0.0011 5.15 (2.74–9.68) <0.0001 7.63 (3.85–15.1) <0.0001
Me SCook (yes/no) 3.73 (0.73–16.9) 0.09 4.14 (1.37–12.4) 0.011 5.57 (2.52–12.3) <0.0001 5.54 (2.61–11.7) <0.0001 4.50 (1.98–10.2) 0.0003
All models a e adjus ed o sex, s udy coho , and yea . CI indica es 95% confidence in e al; Me S, me abolic synd ome; RR, isk a io; T2DM, ype 2 diabe es melli us.
*Because o low numbe o ou comes, 2 younges age g oups we e collapsed in o 1 age g oup.
†
Me SPed was defined only o subjec s aged 6 o 18 yea s.
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 9
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om
Re e ences
1. Rea en GM. Ban ing lec u e 1988. Role o insulin esis ance in human disease.
Diabe es. 1988;37:1595–1607.
2. Wilson PW, D’Agos ino RB, Pa ise H, Sulli an L, Meigs JB. Me abolic synd ome
as a p ecu so o ca dio ascula disease and ype 2 diabe es melli us.
Ci cula ion. 2005;112:3066–3072.
3. S einbe ge J, Daniels SR, Eckel RH, Hayman L, Lus ig RH, McC indle B,
Mie us-Snyde ML; Ame ican Hea Associa ion A he oscle osis, Hype ension,
Council on Ca dio ascula Nu sing, and Council on Nu i ion, Physical Ac i i y.
P og ess and challenges in me abolic synd ome in child en and adolescen s: a
scien ific s a emen om he Ame ican Hea Associa ion A he oscle osis,
Hype ension, and Obesi y in he Young Commi ee o he Council on
Ca dio ascula Disease in he Young; Council on Ca dio ascula Nu sing; and
Council on Nu i ion, Physical Ac i i y, and Me abolism. Ci cula ion.
2009;119:628–647.
4. Magnussen CG, Koskinen J, Chen W, Thomson R, Schmid MD, S ini asan SR,
Ki imaki M, Ma sson N, Kahonen M, Lai inen T, Tai onen L, Ronnemaa T,
Viika i JS, Be enson GS, Juonala M, Rai aka i OT. Pedia ic me abolic synd ome
p edic s adul hood me abolic synd ome, subclinical a he oscle osis, and ype
2 diabe es melli us bu is no be e han body mass index alone: he Bogalusa
Hea S udy and he Ca dio ascula Risk in Young Finns S udy. Ci cula ion.
2010;122:1604–1611.
5. Dwye T, Sun C, Magnussen CG, Rai aka i OT, Scho k NJ, Venn A, Bu ns TL,
Juonala M, S einbe ge J, Sinaiko AR, P ineas RJ, Da is PH, Woo JG, Mo ison
JA, Daniels SR, Chen W, S ini asan SR, Viika i JS, Be enson GS. Coho p ofile:
he In e na ional Childhood Ca dio ascula Coho (i3C) Conso ium. In J
Epidemiol. 2013;42:86–96.
6. Magnussen CG, Che iyan S, Sabin MA, Juonala M, Koskinen J, Thomson R,
Skil on MR, Kahonen M, Lai inen T, Tai onen L, Hu i-Kahonen N, Viika i JS,
Rai aka i OT. Con inuous and dicho omous me abolic synd ome defini ions in
you h p edic adul ype 2 diabe es and ca o id a e y in ima media hickness:
he Ca dio ascula Risk in Young Finns S udy. J Pedia . 2016;171:103.e3.
7. Rai aka i OT, Juonala M, Kahonen M, Tai onen L, Lai inen T, Maki-To kko N,
Ja isalo MJ, Uha i M, Jokinen E, Ronnemaa T, Ake blom HK, Viika i JS.
Ca dio ascula isk ac o s in childhood and ca o id a e y in ima-media
hickness in adul hood: he Ca dio ascula Risk in Young Finns S udy. JAMA.
2003;290:2277–2283.
8. Rai aka i OT, Juonala M, Ronnemaa T, Kel ikangas-Ja inen L, Rasanen L,
Pie ikainen M, Hu i-Kahonen N, Tai onen L, Jokinen E, Ma niemi J, Jula A,
Telama R, Kahonen M, Leh imaki T, Ake blom HK, Viika i JS. Coho p ofile: he
Ca dio ascula Risk in Young Finns S udy. In J Epidemiol. 2008;37:1220–
1226.
9. Be enson GS, S ini asan SR, Bao W, Newman WP, T acy RE, Wa igney WA.
Associa ion be ween mul iple ca dio ascula isk ac o s and a he oscle osis
in child en and young adul s. The Bogalusa Hea S udy. N Engl J Med.
1998;338:1650–1656.
10. Mo ison JA, F iedman LA, G ay-McGui e C. Me abolic synd ome in childhood
p edic s adul ca dio ascula disease 25 yea s la e : he P ince on Lipid
Resea ch Clinics Follow-up S udy. Pedia ics. 2007;120:340–345.
11. Mo ison JA, Glueck CJ, Ho n PS, Ye amaneni S, Wang P. Pedia ic iglyce ides
p edic ca dio ascula disease e en s in he ou h o fi h decade o li e.
Me abolism. 2009;58:1277–1284.
12. Sinaiko AR, Jacobs DR, S einbe ge J, Mo an A, Luepke R, Rocchini AP,
P ineas RJ. Insulin esis ance synd ome in childhood: associa ions o he
euglycemic insulin clamp and as ing insulin wi h a ness and o he isk
ac o s. JPedia . 2001;139:700–707.
13. F iedewald WT, Le y RI, F ed ickson DS. Es ima ion o he concen a ion o
low-densi y lipop o ein choles e ol in plasma, wi hou use o he p epa a i e
ul acen i uge. Clin Chem. 1972;18:499–502.
14. Chen W, S ini asan SR, Li S, Xu J, Be enson GS. Me abolic synd ome a iables a
low le els in childhood a e beneficially associa ed wi h adul hood ca dio ascula
isk: he Bogalusa Hea S udy. Diabe es Ca e. 2005;28:126–131.
15. Mo ison JA, Kelly K, Ho i z R, Khou y P, Laska zewski PM, Mellies MJ, Glueck
CJ. Pa en -o sp ing and sibling lipid and lipop o ein associa ions du ing and
a e sha ing o household en i onmen s: he P ince on school dis ic amily
s udy. Me abolism. 1982;31:158–166.
16. Pa en RL, Hewi D, Waldman GT, Jones G, Li le JA. Associa ions o plasma
high-densi y lipop o ein choles e ol wi h clinical chemis y da a. Ci cula ion.
1980;62:41.
17. Cole TJ, Bellizzi MC, Flegal KM, Die z WH. Es ablishing a s anda d defini ion o
child o e weigh and obesi y wo ldwide: in e na ional su ey. BMJ.
2000;320:1240–1243.
18. Na ional High Blood P essu e Educa ion P og am Wo king G oup on High
Blood P essu e in Child en and Adolescen s. The ou h epo on he
diagnosis, e alua ion, and ea men o high blood p essu e in child en and
adolescen s. Pedia ics. 2004;114:555–576.
19. Cook S, Auinge P, Huang TT. G ow h cu es o ca dio-me abolic isk ac o s
in child en and adolescen s. J Pedia . 2009;155:S6.e15-26.
20. Jolli e CJ, Janssen I. De elopmen o age-specific adolescen me abolic
synd ome c i e ia ha a e linked o he Adul T ea men Panel III and
In e na ional Diabe es Fede a ion c i e ia. J Am Coll Ca diol. 2007;49:891–
898.
21. Cook S, Wei zman M, Auinge P, Nguyen M, Die z WH. P e alence o a
me abolic synd ome pheno ype in adolescen s: findings om he hi d
Na ional Heal h and Nu i ion Examina ion Su ey, 1988–1994. A ch Pedia
Adolesc Med. 2003;157:821–827.
22. Gu ka MJ, Ice CL, Sun SS, Deboe MD. A confi ma o y ac o analysis o he
me abolic synd ome in adolescen s: an examina ion o sex and acial/e hnic
di e ences. Ca dio asc Diabe ol. 2012;11:128.
23. Albe i KG, Eckel RH, G undy SM, Zimme PZ, Cleeman JI, Dona o KA, F ucha
JC, James WP, Lo ia CM, Smi h SC; In e na ional Diabe es Fede a ion Task
Fo ce on Epidemiology and P e en ion, Ha ional Hea L, Ame ican Hea
Associa ion, Wo ld Hea Fede a ion, In e na ional A he oscle osis Socie y,
In e na ional Associa ion o he S udy o Obesi y. Ha monizing he me abolic
synd ome: a join in e im s a emen o he In e na ional Diabe es Fede a ion
Task Fo ce on Epidemiology and P e en ion; Na ional Hea , Lung, and Blood
Ins i u e; Ame ican Hea Associa ion; Wo ld Hea Fede a ion; In e na ional
A he oscle osis Socie y; and In e na ional Associa ion o he S udy o
Obesi y. Ci cula ion. 2009;120:1640–1645.
24. Magnussen CG, Venn A, Thomson R, Juonala M, S ini asan SR, Viika i JS,
Be enson GS, Dwye T, Rai aka i OT. The associa ion o pedia ic low- and
high-densi y lipop o ein choles e ol dyslipidemia classifica ions and change in
dyslipidemia s a us wi h ca o id in ima-media hickness in adul hood e idence
om he Ca dio ascula Risk in Young Finns S udy, he Bogalusa Hea S udy,
and he CDAH (Childhood De e minan s o Adul Heal h) S udy. J Am Coll
Ca diol. 2009;53:860–869.
25. Mo ison JA, F iedman LA, Wang P, Glueck CJ. Me abolic synd ome in
childhood p edic s adul me abolic synd ome and ype 2 diabe es melli us 25
o 30 yea s la e . J Pedia . 2008;152:201–206.
26. F anks PW, Hanson RL, Knowle WC, Mo e C, Enos G, In an e AM, K ako J,
Looke HC. Childhood p edic o s o young-onse ype 2 diabe es. Diabe es.
2007;56:2964–2972.
27. Reineh T, Wunsch R, Pu e C, Sche ag A. Rela ionship be ween ca o id
in ima-media hickness and me abolic synd ome in adolescen s. J Pedia .
2013;163:327–332.
28. Kelly AS, S einbe ge J, Jacobs DR, Hong CP, Mo an A, Sinaiko AR. P edic ing
ca dio ascula isk in young adul hood om he me abolic synd ome, i s
componen isk ac o s, and a clus e sco e in childhood. In J Pedia Obes.
2011;6:e283–e289.
29. Juhola J, Magnussen CG, Viika i JS, Kahonen M, Hu i-Kahonen N, Jula A,
Leh imaki T, Ake blom HK, Pie ikainen M, Lai inen T, Jokinen E, Tai onen L,
Rai aka i OT, Juonala M. T acking o se um lipid le els, blood p essu e, and
body mass index om childhood o adul hood: he Ca dio ascula Risk in
Young Finns S udy. J Pedia . 2011;159:584–590.
30. S ini asan SR, Mye s L, Be enson GS. P edic abili y o childhood adiposi y and
insulin o de eloping insulin esis ance synd ome (synd ome X) in young
adul hood: he Bogalusa Hea S udy. Diabe es. 2002;51:204–209.
31. Eckel RH, G undy SM, Zimme PZ. The me abolic synd ome. Lance .
2005;365:1415–1428.
32. Goodman E, Daniels SR, Meigs JB, Dolan LM. Ins abili y in he diagnosis o
me abolic synd ome in adolescen s. Ci cula ion. 2007;115:2316–2322.
33. Expe Panel on In eg a ed Guidelines o Ca dio ascula Heal h and Risk
Reduc ion in Child en and Adolescen s; Na ional Hea , Lung, and Blood
Ins i u e. Expe panel on in eg a ed guidelines o ca dio ascula heal h and
isk educ ion in child en and adolescen s: summa y epo . Pedia ics.
2011;128(Suppl 5):S213–S256.
34. Eisenmann JC. On he use o a con inuous me abolic synd ome sco e in
pedia ic esea ch. Ca dio asc Diabe ol. 2008;7:17.
35. Koskinen J, Kahonen M, Viika i JS, Tai onen L, Lai inen T, Ronnemaa T,
Leh imaki T, Hu i-Kahonen N, Pie ikainen M, Jokinen E, Helenius H, Ma sson
N, Rai aka i OT, Juonala M. Con en ional ca dio ascula isk ac o s and
me abolic synd ome in p edic ing ca o id in ima-media hickness p og ession
in young adul s: he Ca dio ascula Risk in Young Finns S udy. Ci cula ion.
2009;120:229–236.
DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 16
Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al
ORIGINAL RESEARCH
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om

Ma kus Juonala
Bazzano, Alison Venn, Jo ma S.A. Viika i, Nina Hu i-Kähönen, Olli Rai aka i, Te ence Dwye and
J , Julia S einbe ge , Ronald P ineas, Ma hew A. Sabin, T udy Bu ns, Ge ald Be enson, Lydia
Juha Koskinen, Cos an G. Magnussen, Alan Sinaiko, Jessica Woo, Elaine U bina, Da id R. Jacobs,
In e na ional Childhood Ca dio ascula Coho Conso ium
Me abolic Synd ome, Type 2 Diabe es Melli us and Ca o id In ima Media Thickness: The
Childhood Age and Associa ions Be ween Childhood Me abolic Synd ome and Adul Risk o
Online ISSN: 2047-9980
Dallas, TX 75231
is published by he Ame ican Hea Associa ion, 7272 G een ille A enue,Jou nal o he Ame ican Hea Associa ionThe doi: 10.1161/JAHA.117.005632
2017;6:e005632; o iginally published Augus 16, 2017;J Am Hea Assoc.
h p://jaha.ahajou nals.o g/con en /6/8/e005632
Wo ld Wide Web a :
The online e sion o his a icle, along wi h upda ed in o ma ion and se ices, is loca ed on he
o mo e in o ma ion. h p://jaha.ahajou nals.o gAccess publica ion. Visi he Jou nal a is an online only OpenJou nal o he Ame ican Hea Associa ionSubsc ip ions, Pe missions, and Rep in s: The
by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om