Fmily Prctice, 2015, Vol. 32, No. 6, 646 651 doi:10.1093/fmpr/cmv080 Advnce Access publiction 17 October 2015 Helth Service Reserch Overweight cn be used s tool to guide cse-finding for crdiovsculr risk ssessment Ann W de Boer,b, *, Renée de Mutsert, Mrtin den Heijer,c, John W Jukem d, Frits R Rosendl, Jenet W Blom b nd Willem J J Assendelft b,e ; for the NEO study group Deprtment of Clinicl Epidemiology nd b Deprtment of Public Helth nd Primry Cre, Leiden University Medicl Center, Leiden, c Deprtment of Internl Medicine, VU Medicl Center, Amsterdm, d Deprtment of Crdiology, Leiden University Medicl Center, Leiden nd e Deprtment of Primry nd Community cre, Rdboud University Medicl Center, Nijmegen, The Netherlnds. *Correspondence to Ann W de Boer, Deprtment of Clinicl Epidemiology, Leiden University Medicl Center, PO Box 9600, 2300 RC Leiden, The Netherlnds; E-mil:.w.de_boer@lumc.nl Abstrct Bckground. In generl prctice, it is too time-consuming to invite ll ptients for crdiovsculr risk ssessment. Objective. To exmine how mny ptients with n indiction for tretment with crdiovsculr mediction cn be identified by d hoc cse-finding when ll ptients with overweight/obesity re invited for risk ssessment. Methods. A cross-sectionl nlysis of the bseline mesurements of the Netherlnds Epidemiology of Obesity study, popultion-bsed prospective cohort study in 6673 persons ged 45 65 yers. We clculted the proportion of prticipnts with tretment indiction using the risk prediction Systemtic COronry Risk Evlution (SCORE-NL 2011), for len, overweight nd obese prticipnts. Prticipnts with history of crdiovsculr disese, dibetes mellitus or rheumtoid rthritis or using crdiovsculr mediction were not eligible for d hoc cse-finding becuse they were lredy identified s being t risk nd/or hd been treted. Results. Of the study popultion, 30% hd lredy been identified nd/or treted with crdiovsculr mediction nd were therefore not eligible for d hoc cse-finding. Of the eligible prticipnts, 47% were len, 41% overweight nd 12% obese. Of the prticipnts with overweight, 12% hd tretment indiction nd of the prticipnts with obesity, 19% hd tretment indiction. Of ll prticipnts with tretment indiction 24% were not yet treted. Of ll prticipnts with new tretment indiction, 70% hd overweight or obesity. Conclusions. Of the prticipnts with tretment indiction, 24% were not yet treted. Inviting ptients with overweight/obesity for crdiovsculr risk ssessment my help to detect 70% of these residul ptients with tretment indiction. Key words: Crdiovsculr diseses, generl prctice, overweight, primry prevention, risk ssessment, risk fctors. Introduction To clculte the risk of crdiovsculr disese (CVD) nd corresponding tretment indiction, severl risk estimtion systems hve been developed for primry prevention bsed on crdiovsculr risk fctors (e.g. Frminghm, SCORE, QRISK, PROCAM) (1). Crdiovsculr risk ssessment in generl prctice is time-consuming, with on verge first consulttion of 20 minutes for history The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, plese e-mil: journls.permissions@oup.com. 646
Overweight s tool to guide cse-finding 647 tking nd exmintion of the ptient nd second consulttion of 20 minutes to discuss the results (2,3). Therefore, t present in the Netherlnds, not ll ptients re invited for risk ssessment; however, high-risk ptients re usully identified first, either bsed on more progrmmtic pproch or by d hoc cse-finding. In progrmmtic pproch, for exmple, ll ptients of 45 yers or older re invited to complete risk questionnire (4). Ptients t incresed risk re dvised to consult their GP for crdiovsculr risk ssessment. However, this method is time-consuming nd it is reported tht only 36% of ptients t risk responds to the invittion (4). Ad hoc cse-finding mong generl prctice ttendnts is the most commonly used pproch, which is less expensive nd hs better coverge since potentil high-risk ptients re invited for crdiovsculr risk ssessment during regulr consulttion for other resons. However, disdvntge of d hoc cse-finding is tht it is uncler wht strtegy cn best be followed to identify high-risk ptients efficiently, in ddition only short consulttion is plnned for the ctul reson for the encounter. As consequence, d hoc cse-finding is often neglected nd high-risk ptients with tretment indiction my remin untreted. Further optimiztion of the yield of cse-finding my reduce time nd costs relted to crdiovsculr risk mngement; however, the identifying fctor needs to be obtined within few seconds during regulr consulttion. Overweight my be promising cndidte becuse this is visible nd (combined with simple mesurements) esily obtined risk fctor. Therefore, we imed to exmine how mny ptients with tretment indiction cn be identified when ll ptients with overweight or obesity re invited for crdiovsculr risk ssessment by d hoc cse-finding. Hereto we used the dt of the Netherlnds Epidemiology of Obesity (NEO) study, popultion-bsed prospective cohort study including len, overweight nd obese prticipnts (5). This study popultion llowed us to clculte the gin in identifiction of ptients with tretment indiction when using weight s guidnce for d hoc cse-finding. Methods Study design nd study popultion The NEO study is popultion-bsed prospective cohort study in persons ged 45 65 yers with n oversmpling of prticipnts with body mss index (BMI) 27 kg/m 2. The study design hs been described elsewhere (5). Prticipnts with self-reported BMI 27 kg/m 2 were recruited from the greter re of Leiden, the Netherlnds, vi GPs, municipl registers nd dvertisements. In one municiplity (Leiderdorp), ll inhbitnts ged 45 65 yers were invited, irrespective of their BMI, to llow for reference distribution of BMI. Prior to the NEO study visit, prticipnts were sked to complete questionnire including questions bout demogrphics, lifestyle nd clinicl informtion. During the bseline visit t the NEO study centre of the Leiden University Medicl Center (LUMC), severl mesurements were performed, including physicl exmintion nd blood smpling. This study is cross-sectionl nlysis of the bseline mesurements of the NEO study. The study ws pproved by the Medicl Ethics Committee of the LUMC nd ll prticipnts gve informed consent. systolic blood pressure (SBP), totl cholesterol/high-density lipoprotein (TC/HDL) rtio, smoking sttus, dibetes mellitus (DM), first-degree fmily history of CVD, physicl ctivity, BMI, estimted glomerulr filtrtion rte (egfr), poor metbolic control nd lbuminuri (6). The method of SCORE-NL 2011 is described in more detil in online Supplementry Dt. Prticipnts without history of CVD, DM or rheumtoid rthritis (RA) nd without using ntihypertensive or lipid-lowering drugs were eligible for d hoc cse-finding. The rtionle for this selection is tht ll other prticipnts re regulrly ssessed due to being t incresed risk or hve lredy been identified with tretment indiction. We defined prevlent CVD s history of ngin pectoris, myocrdil infrction (MI), stroke, ortic neurysm nd peripherl rteril disese s reported in the questionnire. First-degree fmily history of MI or stroke ws reported in the questionnire in five ge groups: before ge 50 yers, 50 60 yers, 60 70 yers, fter ge 70 yers nd ge unknown. In SCORE-NL 2011, n event before ge 60 yers (one member) nd before ge 65 yers (two members) is used s dditionl risk fctor. For the ltter, we used CVD event before ge 70 yers. We defined newly discovered DM s fsting plsm glucose 7.0 mmol/l or non-fsting glucose 11.1 mmol/l (7) nd history of DM s hving self-reported history of DM or using glucoselowering therpy. Poor metbolic control ws defined s hemoglobin A1c (HbA1c) 7% (8,9). We defined prticipnts with RA who regulrly visit physicin, s prticipnts using disese-modifying ntirheumtic drugs, such s methotrexte, sulfslzine, immunosuppressive drugs nd biophrmceuticls. Physicl ctivity ws ssessed with the Short QUestionnire to ASsess Helth-enhncing physicl ctivity (10), with sedentry lifestyle s being zero dys per week physiclly ctive for t lest 30 minutes with t lest moderte intensity. Smoking sttus ws dichotomized into current smokers nd nonsmokers (including former smokers). Body weight nd height were mesured during the study visit with clibrted scle nd verticlly fixed, clibrted tpe mesure during the study visit. The trined stff reported the height in centimetre; body weight ws rounded to 100 g, 1 kg ws subtrcted to correct for the weight of clothing. BMI ws clculted by dividing weight (in kilogrm) by the squre of height (in metre). Overweight ws defined ccording to the World Helth Orgniztion s BMI 25 30 kg/m 2 nd obesity s BMI 30 kg/m 2 (11). Wist circumference (WC) ws mesured between the border of the lower costl mrgin nd the ilic crest rounded to 0.1 cm. An incresed WC ws defined s WC 102 cm for men nd WC 88 cm for women (12). SBP ws mesured three times on the right rm by n utomtic monitor fter 10 minutes rest in sitting position. The men of these mesurements ws used in the nlyses. Blood smples were tken fter n overnight fst. Serum cholesterol concentrtions, glucose, HbA1c nd cretinine were determined in the centrl clinicl chemicl lbortory of the LUMC. Albuminuri ws defined s n lbumin/cretinine rtio 2.5 mg/mmol for men nd 3.5 mg/mmol for women. egfr ws clculted using the Modifiction of Diet in Renl Disese (13). A reduced egfr ws defined s egfr < 60 ml/min/1.73 m 2 in prticipnts ged <65 yers, nd egfr < 45 ml/min/1.73 m 2 in prticipnts ged 65 yers. Dt collection in the NEO study We used SCORE-NL 2011 to clculte the 10-yer CVD risk for prticipnts eligible for d hoc cse-finding; this includes sex, ge, Sttisticl nlysis In the NEO study, there is n oversmpling of prticipnts with BMI 27 kg/m 2. To correctly represent the generl popultion,
648 Fmily Prctice, 2015, Vol. 32, No. 6 prticipnts were weighted towrds the BMI distribution of the prticipnts from the Leiderdorp municiplity (14,15) whose BMI distribution ws similr to the BMI distribution of the Dutch generl popultion (16). Hereto, prticipnts with BMI < 27 kg/m 2, who were under-represented in the study popultion, received greter weight in the nlyses. All results were bsed on weighted nlyses. Consequently, the results pply to popultion-bsed study without oversmpling of prticipnts with BMI 27 kg/m 2. For prticipnts eligible for d hoc cse-finding, we clculted the predicted 10-yer CVD risk nd tretment indiction ccording to SCORE-NL 2011. Differences in proportions were tested using the Person s chi-squre test. We lso clculted the proportion of prticipnts with new tretment indiction of ll ptients with tretment indiction for primry prevention, nd the proportion of prticipnts with tretment indiction of ll prticipnts with n incresed WC. The first 863 prticipnts included in the study completed questionnire tht did not contin questions bout fmily history of CVD; these prticipnts were considered s hving no first-degree reltive with CVD event. However, we lso performed sensitivity nlysis considering these prticipnts s hving two first-degree reltives with CVD event before 65 yers of ge. All nlyses re strtified by BMI ctegory into BMI < 25 kg/ m 2, BMI 25 30 kg/m 2 nd BMI 30 kg/m 2. Only proportions, not counts, could be reported due to the weighted nlysis. For ll nlyses, STATA sttisticl softwre (Sttcorp, College Sttion, TX), version 12 ws used. Results Of the 6673 persons included in the NEO study, 5215 hd BMI 27 kg/m 2. The individul prticipnts were weighted towrds the BMI distribution of the generl Dutch popultion. After weighting, 42% of the prticipnts hd BMI < 25 kg/m 2, 42% BMI 25 30 kg/ m 2, nd 16% BMI 30 kg/m 2. Six percentge of the prticipnts were excluded due to missing dt for SCORE risk prediction. The weighted bseline chrcteristics of the prticipnts included in the present nlysis strtified by BMI ctegory re shown in Tble 1. Prticipnts with overweight or obesity hd higher SBP, higher TC/HDL rtio nd more newly dignosed DM compred with len prticipnts. The eligibility for d hoc cse-finding nd the 10-yer CVD risk nd tretment indiction ws clculted. Of the totl study popultion, 30% of the prticipnts were lredy identified nd/or treted. With incresing levels of BMI, more prticipnts were lredy identified nd/or treted nd not eligible for d hoc cse-finding, i.e. 20% of the prticipnts with BMI < 25 kg/m 2 were lredy identified nd/or treted, 32% with BMI 25 30 kg/m 2 nd 49% with BMI 30 kg/m 2. This ws minly due to higher proportion of prticipnts with history of DM, RA or CVD nd higher proportion of prticipnts using ntihypertensive or lipid-lowering drugs in the groups with higher BMI (Tble 2, Fig. 1). Overll, 80% of the prticipnts eligible for d hoc cse-finding hd low CVD risk, 13% n intermedite risk nd 4% high risk bsed on the SCORE function, nd 3% hd definite tretment indiction bsed on single high-risk fctor. Of ll eligible prticipnts, tretment ws indicted in 10% (19% of the men, 4% of the women). Of the eligible prticipnts with BMI 25 30 kg/m 2, 12% (18% of the men, 6% of the women) hd tretment indiction nd of the eligible prticipnts with BMI 30 kg/m 2, 19% (35% of the men, Tble 1. Bseline chrcteristics of the prticipnts of the NEO study, ged 45 65 yers, recruited in 2008 12 nd strtified by BMI group BMI (kg/m 2 ) <25 25 30 30 (42%) (42%) (16%) Age (yers) 56 (3) 56 (6) 56 (10) Sex (% men) 35 54 44 BMI (kg/m 2 ) 22.6 (0.8) 27.1 (1.4) 33.9 (6.6) Smoking (% current) 15 17 16 SBP (mmhg) 127 (9) 132 (17) 134 (29) TC/HDL rtio 3.4 (0.6) 4.2 (1.3) 4.4 (2.2) Newly discovered DM (%) 1 3 5 HbA1c (%) 6.1 (0.8) 6.1 (0.8) 6.3 (1.2) ACR 0.6 (0.1) 1.1 (2.5) 3.6 (28.6) egfr (ml/min/1.73 m 2 ) 85 (7) 85 (14) 86 (26) Reduced egfr (%) b 2 2 3 First-degree fmily history of CVD 1 member ged <60 yers (%) 21 22 23 1 member ged <65 yers (%) 36 34 36 2 members ged <65 yers (%) 8 8 10 Sedentry lifestyle (%) c 3 5 8 Dt re expressed s men (SD) or %. ACR, lbumin/cretinine rtio; SD, stndrd devition. Results re bsed on weighted nlyses nd therefore represent the generl popultion. b Reduced egfr: egfr < 60 ml/min/1.73 m 2 in ptients ged <65 yers, egfr < 45 ml/min/1.73 m 2 in ptients ged 65 yers. c Sedentry lifestyle: being zero dys per week physiclly ctive for t lest 30 minutes with t lest moderte intensity. Tble 2. Eligibility for d hoc cse-finding for crdiovsculr risk ssessment in prticipnts ged 45 65 yers of the NEO study, strtified by BMI group BMI (kg/m 2 ) <25 25 30 30 (42%) (42%) (16%) % (95% CI) % (95% CI) % (95% CI) Eligible for d hoc cse- 80 (77 83) 68 (66 70) 51 (50 53) finding Not eligible for d hoc cse- 20 (17 23) 32 (30 34) 49 (47 50) finding b History of DM or RA 2 (1 3) 4 (3 5) 12 (11 13) History of CVD 5 (3 6) 7 (5 8) 9 (8 10) Use of ntihypertensive or lipid-lowering drugs 18 (15 21) 29 (27 31) 45 (44 47) CI, confidence intervl. Results re bsed on weighted nlyses. b More thn one reson cn be present in the prticipnts not eligible for d hoc cse-finding. 6% of the women) hd tretment indiction (Tble 3). When combining ll eligible prticipnts with overweight or obesity (BMI 25 kg/m 2 ), 14% (men 21%, women 6%) hd tretment indiction. When considering ll prticipnts with tretment indiction (including those lredy using primry preventive mediction nd those with new tretment indiction), 24% were not yet treted,
Overweight s tool to guide cse-finding 649 Figure 1. Eligibility for d hoc cse-finding for crdiovsculr risk ssessment nd crdiovsculr tretment indiction clculted by SCORE-NL 2011 in prticipnts ged 45 65 yers of the NEO study (results re bsed on weighted nlyses). For ll prticipnts within BMI group, the percentge is shown of prticipnts not eligible nd the percentge eligible for d hoc cse-finding. Not eligible for d hoc cse-finding were prticipnts with history of CVD, DM or RA, or who re using ntihypertensive or lipid-lowering drugs. The percentge of the prticipnts eligible for d hoc cse-finding is divided into prticipnts with nd without tretment indiction Tble 3. SCORE risk ctegories nd corresponding tretment indiction for prticipnts ged 45 65 yers of the NEO study, who were eligible for d hoc cse-finding for crdiovsculr risk ssessment, strtified by BMI group i.e. 26% of the prticipnts with BMI < 25 kg/m 2, 26% with BMI 25 30 kg/m 2 nd 20% with BMI 30 kg/m 2 (P = 0.19). Of ll prticipnts with new tretment indiction, 70% hd overweight or obesity. Of ll prticipnts eligible for d hoc cse-finding, 32% hd n incresed WC; of those with n incresed WC, 14% hd tretment indiction. Of the 863 prticipnts who did not report their fmily history, only 60 prticipnts were both eligible for d hoc cse-finding nd fell in the ctegory intermedite risk, in which fmily history my influence the tretment indiction. In sensitivity nlysis, when we considered these prticipnts s hving two first-degree reltives with CVD event before 65 yers of ge, this hd no mrked effect on our results, i.e. 14% of the eligible prticipnts with BMI 25 30 kg/m 2 hd tretment indiction nd 19% of the eligible prticipnts with BMI 30 kg/m 2 hd tretment indiction. BMI (kg/m 2 ) <25 25 30 30 (47%) (41%) (12%) SCORE-NL 2011 (6) Tretment indiction % (95% CI) % (95% CI) % (95% CI) Low risk No tretment 85 (82 88) 75 (73 78) 76 (74 78) Intermedite risk b No tretment 8 (6 11) 12 (10 14) 6 (5 7) Tretment 2 (1 3) 3 (2 4) 9 (7 10) High risk No tretment 0 (0 1) 0 (0 0) Tretment 2 (1 4) 5 (4 6) 6 (5 7) Definite indiction c Tretment 2 (1 3) 4 (3 5) 4 (3 5) Totl* Tretment 6 (4 8) 12 (10 14) 19 (17 21) Due to rounding, percentges my not dd up to 100%. CI, confidence intervl. Results re bsed on weighted nlyses. b Tretment in the intermedite group is dependent on dditionl risk fctors (6). c SBP > 180 mmhg or TC > 8 mmol/l or TC/HDL rtio > 8 or triglycerides >10. *Chi-squre test, P 0.001. Discussion This study used dt from lrge popultion-bsed prospective cohort study with ll the informtion present to clculte the 10-yer CVD risk nd corresponding tretment indiction. We imed to identify high-risk ptients for crdiovsculr risk ssessment by d hoc cse-finding mong ptients visiting their GP for other resons. We observed tht with higher levels of BMI more prticipnts were lredy identified with high risk or disese by the GP, leding to tretment. However, 24% of the prticipnts with tretment indiction were not yet identified nd treted. In the prticipnts eligible for d hoc cse-finding, 12% of the prticipnts with overweight nd 19% of the prticipnts with obesity hd tretment indiction. Importntly, most of them were men. Hence, the risk of eight ptients with overweight or five ptients with obesity needs to be ssessed to detect one ptient with tretment indiction.
650 Fmily Prctice, 2015, Vol. 32, No. 6 When the results re pplied to stndrd generl prctice in the Netherlnds (2400 ptients registered, 590 ptients ged 45 64 yers old), 413 ptients re eligible for d hoc cse-finding. Of the 50 ptients tht would hve obesity (BMI 30 kg/m 2 ), 9 ptients would hve tretment indiction. When ptients with overweight (BMI 25 30 kg/m 2 ) could lso be identified, then 219 ptients (BMI 25 kg/m 2 ) would be selected for further risk ssessment, of which 31 with tretment indiction. To our knowledge, few studies hve exmined the yield of identifiction of high-risk ptients by d hoc cse-finding in generl prctice. Previous studies minly focused on improving the risk estimtion systems or on the development of progrmmtic pproch for identifiction of high-risk ptients. For exmple, in the Prevention Consulttion, progrmmtic pproch in the Netherlnds for the prevention nd erly detection of CVD, DM nd chronic kidney disese (CKD), risk questionnire is sent to ll ptients ged 45 70 yers, nd ptients with high-risk score re referred to their GP for extensive mesurements including crdiovsculr risk ssessment. As result, 20% of the ptients who visited their GP with high-risk score hd crdiovsculr tretment indiction, DM or CKD (4). An dvntge of our pproch, identifying high-risk ptients by d hoc cse-finding, is tht it costs less in terms of time nd money to invite ptients for risk ssessment. A prospective modelling study compred different screening strtegies to identify high-risk ptients with the invittion of ll ptients ged 40 79 yers. When ptients ged 40 79 yers with overweight (BMI 27, 5 kg/m 2 or WC > 94 cm in men or WC > 80 cm in women) re identified for crdiovsculr risk ssessment, 70% of the CVD events cn be prevented tht would hve been prevented when ll ptients hd been invited for risk ssessment (with number needed to intervene to prevent one new CVD event of 100) (17). This my imply tht, compred with inviting ll ptients, mjor proportion of the preventble CVD events re prevented when only ptients with overweight re identified. Strengths of this study re the lrge smple size, nd the extensive nd uniform mesurements of ll informtion needed for clculting the 10-yer CVD risk. A limittion is tht the identifiction of ptients for further risk ssessment by d hoc cse-finding depends on whether ptients regulrly consult their GP. On verge, 74% of the registered ptients visit GP t lest once yer (18), with higher ttendnce rte with higher BMI (19). Though, for GPs it will be chllenging tsk to fit identifiction for crdiovsculr risk ssessment into consulttion tht hs nother reson for the encounter. Another limittion is oversmpling of prticipnts with BMI 27 kg/m 2, which is corrected by weighted nlyses to represent the generl popultion. Without these djustments, the proportion of prticipnts with BMI 27 kg/m 2 would be higher nd therefore the proportion prticipnts with tretment indiction would be higher. In contrst, the weighted results cn be trnslted to the generl popultion. Remrkbly, 30% of ll prticipnts hd lredy been identified nd/or received tretment. This my even be n underestimtion becuse there my hve been eligible prticipnts without tretment indiction whose risk hd lredy been ssessed in generl prctice, resulting in no tretment indiction. Overll, 24% of ll prticipnts with tretment indiction hd not yet been treted, with no differences between BMI groups. Cse-finding by inviting ptients with overweight or obesity does not imply mesuring weight nd height nd clculting BMI t ech consulttion. In prctice, GPs cn visully identify ptients bsed on their perception of the ptient s weight sttus. It is reported tht GPs correctly clssify 75% of overweight ptients (BMI 25 kg/m 2 ) s hving overweight, with higher rtes with incresing BMI levels (20). In our study WC, mesure reflecting bdominl obesity, lso showed similr proportion of prticipnts with tretment indiction compred with BMI. Due to the lower costs nd becuse it is initilly less time-consuming, the most frequently used pproch to identify high-risk ptients for crdiovsculr risk ssessment is d hoc cse-finding. We hypothesized tht ptients with overweight/obesity re n importnt subgroup to identify for further risk ssessment becuse overweight is ssocited with the crdiovsculr risk fctors used in risk estimtion systems nd is esy to obtin. We observed tht with higher levels of BMI more prticipnts hd tretment indiction, some lredy identified nd treted. When ll eligible ptients with overweight/obesity re invited for further risk ssessment, 70% of the residul ptients with tretment indiction could be identified, who would otherwise remin untreted. In conclusion, our findings show tht lthough lrge prt of the prticipnts hd lredy been identified nd treted, inviting ptients with overweight or obesity (especilly men) for crdiovsculr risk ssessment my help to detect substntil dditionl group of ptients with tretment indiction. Supplementry mteril Supplementry mteril is vilble t Fmily Prctice online. Acknowledgements We express our grtitude to ll individuls who prticipte in the Netherlnds Epidemiology of Obesity (NEO) study. We re grteful to ll prticipting GPs for inviting eligible prticipnts. We furthermore thnk ll reserch nurses for collecting the dt nd I de Jonge, MSc, for ll dt mngement of the NEO study. NEO Study Group FRR, RdM, Sski Middeldorp, Ton J Rbelink, Johnnes W A Smit, Johnnes A Romijn, Klus F Rbe, JWJ, Albert de Roos, Sski le Cessie, Pieter S Hiemstr, Mrgreet Kloppenburg, Ton W J Huizing, Hnno Pijl, Jouke T Tmsm, Eelco J P de Koning, WJJA, Pieter H Reitsm, Ko Willems vn Dijk, Aiko P J de Vries, Hildo J Lmb, Ingrid M Jzet, Olf M Dekkers, Nienke R Biermsz, Christ M Cobbert (Leiden University Medicl Center, Leiden, The Netherlnds), MdH, Jcqueline M Dekker nd Brend W Penninx (VU Medicl Center, Amsterdm, The Netherlnds). Declrtion Funding: The NEO study is supported by the prticipting Deprtments, the Division nd the Bord of Directors of the Leiden University Medicl Center, nd by the Leiden University, Reserch Profile Are Vsculr nd Regenertive Medicine. Ethicl pprovl: Protocol P08.109 pproved on 4 August 2008 by the Medicl Ethics Committee of the LUMC. Conflict of interest: none. References 1. Cooney MT, Dudin A, D Agostino R, Grhm IM. 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