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1.  Brain tissue volumes in the general population of the elderly The AGES-Reykjavik Study 
NeuroImage  2011;59(4):3862-3870.
Imaging studies have reported conflicting findings on how brain structure differs with age and sex. This may be explained by discrepancies and limitations in study population and study design. We report a study on brain tissue volumes in one of the largest cohorts of individuals studied to date of subjects with high mean age (mean±standard deviation (SD) 76±6 years). These analyses are based on magnetic resonance imaging (MRI) scans acquired at baseline on 4303 non-demented elderly, and 367 who had a second MRI, on average 2.5±0.2 years later. Tissue segmentation was performed with an automatic image analysis pipeline. Total brain parenchymal (TBP) volume decreased with increasing age while there was an increase in white matter hyperintensities (WMH) in both sexes. A reduction in both normal white matter (NWM) - and grey matter (GM) volume contributed to the brain shrinkage. After adjusting for intra-cranial volume, women had larger brain volumes compared to men (3.32%, p<0.001) for TBP volume in the cross-sectional analysis. The longitudinal analysis showed a significant age-sex interaction in TBP volume with a greater rate of annual change in men (−0.70%, 95%CI: −0.78% to −0.63%) than women (−0.55%, 95%CI: −0.61% to −0.49%). The annual change in the cross-sectional data was approximately 40% less than the annual change in the longitudinal data and did not show significant age-sex interaction. The findings indicate that the cross-sectional data underestimate the rate of change in tissue volumes with age as the longitudinal data show greater rate of change in tissue volumes with age for all tissues.
PMCID: PMC4712156  PMID: 22119006
Brain volume; White matter hyperintensities; Atrophy; Magnetic resonance imaging; Population based; AGES-Reykjavik study
2.  Incidence and prevalence of total joint replacements due to osteoarthritis in the elderly: risk factors and factors associated with late life prevalence in the AGES-Reykjavik Study 
Total joint replacements (TJRs) should be considered as one of few definite endpoints in osteoarthritis research. We analyzed factors associated with late-life prevalence and risk factors for incidence of TJRs due to osteoarthritis in a population based cohort.
After exclusion of inflammatory arthritis and fractures as causes of TJR, 5170 participants in the AGES-Reykjavik Study (mean age (SD) 76.4(6), 58 % females) were included for osteoarthritis studies. Three thousand one hundred thirty-three of them had a follow-up visit 5 years later.
The prevalence of having at least one joint replacement operation due to OA was 13.6 % and the yearly incidence was 1.4 %/year during the five-year follow-up. Factors positively associated with late life prevalence of TJR included BMI, hand OA severity, female gender, finger length ratio and spine BMD. Risk factors for TJRs in the incidence group were symptoms at initial visit, prior TJR in the contralateral joint and BMI. Much stronger associations were seen for TKR than for THR with discriminatory analysis showing an AUC 0.71 for late life prevalence and 0.84 for the incidence.
This study illustrates the importance of the different information expressed by late life prevalence vs. incidence on the factors associated with severe osteoarthritis of the knee and hip. The observation that prior TJR is a risk factor for subsequent TJR in the contralateral joint has not been described previously. The high power predictions for TKR suggest that a predictive model may be feasible, particularly if it can be extended by the addition of further predictive variables, perhaps through genetic, biomarker or imaging data.
PMCID: PMC4711057  PMID: 26759053
Osteoarthritis; Arthroplasty; Epidemiology; Risk factors
3.  Segmental Kidney Volumes Measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging and Their Association With CKD in Older People 
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a potentially powerful tool for analysis of kidney structure and function. The ability to measure functional and hypofunctional tissues could provide important information in groups at risk for chronic kidney disease (CKD) like the elderly.
Study Design
Observational study with a cross-sectional design.
Setting & Participants
493 volunteers (72–94 years old; 278 women; mean estimated glomerular filtration rate [eGFR], 67±15 ml/min/1.73 m2; 40% with CKD) in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study.
DCE-MRI kidney segmentation data.
Outcomes & Measurements
eGFR, urine albumin-creatinine ratio (ACR), and risk factors for and complications of CKD.
After adjustment for age, sex and height, eGFR was related to kidney volume (ΔR2=0.19; P<0.001), cortex volume (ΔR2=0.14; P<0.001), medulla volume (ΔR2=0.18; P<0.001) and volume percentages of fibrosis (ΔR2=0.03; P<0.001) and fat (ΔR2=0.01; P=0.03). In similarly adjusted models, log(ACR) was related to kidney volume (ΔR2=0.02; P<0.001) and fibrosis volume percentage (ΔR2=0.03; P<0.001). Using multivariable regression models adjusted for eGFR, ACR, age, sex, and height, kidney volume was related positively to body mass index (β=29.9±2.1 ml [SE]; P<0.001), smoking (β=19.7±7.7 ml; P=0.01) and diabetes mellitus (β=14.8±7.1 ml; P=0.04) and negatively to hematocrit (β=−4.4±2.1 ml; P=0.04 [model R2=0.72; P<0.001]); relations were per 1-SD greater value of the variable. Fibrosis volume percentage was associated positively with body mass index (β=0.28±0.03; P<0.001), cardiac output (β=0.15±0.03; P<0.001), and heart rate (β=0.08±0.03; P=0.01) and negatively with hematocrit (β=−0.07±0.3; P=0.02) and augmentation index (β=−0.06±0.03; P=0.04 [model R2=0.49; p<0.001]); again, relatins are per 1-SD greater value of the variable.
Automatic segmentations were not validated by histology. The limited age range prevented meaningful interpretation of age effects on measured data or the automatic segmentation procedure.
Kidney volume, cortex volume, and hypofunctional volume fraction assessed by DCE-MRI may provide information about CKD risk and prognosis beyond that provided by eGFR and urine ACR.
PMCID: PMC4272676  PMID: 25022339
Automatic segmentation; magnetic resonance imaging (MRI); chronic kidney disease (CKD); fibrosis; dynamic contrast enhancement (DCE); kidney imaging; segmental kidney volume; hypofunctional tissue
4.  GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy 
The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.
We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.
In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10−7) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10−8) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10−10).
We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.
PMCID: PMC4296168  PMID: 25199915
Longevity; GWAS; FOXO3; APOE.
5.  Feasibility of Using Pseudo-Continuous Arterial Spin Labeling Perfusion in a Geriatric Population at 1.5 Tesla 
PLoS ONE  2015;10(12):e0144743.
To evaluate the feasibility of using pseudo-continuous arterial spin labeling (pCASL) perfusion in a geriatric population at 1.5-Tesla.
Materials and Methods
In 17 participants (mean age 78.8±1.63 years) we assessed; 1) inter-session repeatability and reliability of resting state perfusion in 27 brain regions; 2) brain activation using finger-tapping as a means to evaluate the ability to detect flow differences; 3) reliability by comparing cerebral blood flow (CBF) with pCASL to CBF with phase contrast (PC-MR).
The CBF (mean±standard deviation (SD)) for the whole brain grey matter (GM) was 40.6±8.4 and 41.4±8.7 ml/100g/min for the first and second scan respectively. The within-subject standard deviation (SDw), the repeatability index (RI) and intra-class correlation coefficient (ICC) across the 27 regions ranged from 1.1 to 7.9, 2.2 to 15.5 and 0.35 to 0.98 respectively. For whole brain GM the SDw, RI and ICC were 1.6, 3.2 and 0.96 respectively. The between-subject standard deviation (SDB) was larger than the SDw for all regions. Comparison of CBF at rest and activation on a voxel level showed significantly higher perfusion during finger tapping in the motor- and somatosensory regions. The mean CBF for whole brain GM was 40.6±8.4 ml/100g/min at rest and 42.6±8.6 ml/100g/min during activation. Finally the reliability of pCASL against the reference standard of PC-MR was high (ICC = 0.80). The mean CBF for whole brain measured with PC-MRI was 54.3±10.1 ml/100g/min and 38.3±7.8 ml/100g/min with pCASL.
The results demonstrate moderate to high levels of repeatability and reliability for most brain regions, comparable to what has been reported for younger populations. The performance of pCASL at 1.5-Tesla shows that region-specific perfusion measurements with this technique are feasible in studies of a geriatric population.
PMCID: PMC4687637  PMID: 26659363
6.  The Alcohol Paradox: Light-to-Moderate Alcohol Consumption, Cognitive Function, and Brain Volume 
Studies of older persons show consumption of light-to-moderate amounts of alcohol is positively associated with cognitive function and, separately, is negatively associated with total brain volume (TBV). This is paradoxical as generally, cognitive function is positively associated with TBV. We examined the relationships of TBV, global cognitive function (GCF), and alcohol consumption in a population-based cohort of 3,363 men and women (b. 1907–1935) participating in the Age Gene/Environment Susceptibility-Reykjavik Study (2002–2006) and who were free of dementia or mild cognitive impairment
Drinking status (never, former, and current) and current amount of alcohol consumed were assessed by questionnaire. GCF is a composite score derived from a battery of cognitive tests. TBV, standardized to head size, is estimated quantitatively from brain magnetic resonance imaging.
Among women and not men, adjusting for demographic and cardiovascular risk factors, current drinkers had significantly higher GCF scores than abstainers and former drinkers (p < .0001); and GCF was associated with amount consumed. TBV was not associated with drinking status or amount consumed in men or women. GCF and TBV did significantly differ in their associations across alcohol categories (p interaction < .001). Within categories of alcohol intake, GCF and TBV were positively associated.
The difference in associations of alcohol intake to brain structure and function suggests there may be unmeasured factors that contribute to maintaining better GCF relative to TBV. However, at higher levels of reasonable alcohol consumption, there may be factors leading to reduced brain volume.
PMCID: PMC4271023  PMID: 24994845
Alcohol consumption; Brain aging; Epidemiology; Imaging; Cognitive aging.
8.  B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies 
Europace  2014;16(10):1426-1433.
B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
Methods and results
We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56–1.76], P < 0.0001 and 1.18 (95% CI, 1.11–1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ2 = 17.0; CRP, χ2 = 10.5; BNP and CRP, χ2 = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022–0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322–0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
PMCID: PMC4197895  PMID: 25037055
Atrial fibrillation; Risk prediction; Epidemiology; Biomarker; B-type natriuretic peptide; C-reactive protein
9.  Pulse Pressure Relation to Aortic and Left Ventricular Structure in Older People in the AGES-Reykjavik Study 
Hypertension  2014;64(4):756-761.
High pulse pressure, a major cardiovascular risk factor, has been attributed to medial elastic fiber degeneration and aortic dilation, which transfers hemodynamic load to stiffer collagen. However, recent studies suggest higher pulse pressure is instead associated with smaller aortic diameter. Thus, we sought to elucidate relations of pulse pressure with aortic stiffness and aortic and cardiac dimensions. We used magnetic resonance imaging to examine relations of pulse pressure with lumen area and wall stiffness and thickness in the thoracic aorta and left ventricular structure in 526 participants (72 to 94 years of age, 295 women) in the community-based Age, Gene/Environment Susceptibility-Reykjavik Study. In a multivariable model that adjusted for age, sex, height, weight, and standard vascular risk factors, central pulse pressure had a negative relation with aortic lumen area (all effects expressed as mm Hg/SD; B=−8.1±1.2, P<0.001) and positive relations with left ventricular end-diastolic volume (B=3.8±1.0, P<0.001), carotid-femoral pulse wave velocity (B=3.6±1.0, P<0.001), and aortic wall area (B=3.0±1.2, P=0.015). Higher pulse pressure in older people is associated with smaller aortic lumen area and greater aortic wall stiffness and thickness and left ventricular volume. Relations of larger ventricular volume and smaller aortic lumen with higher pulse pressure suggest mismatch in hemodynamic load accommodation by the heart and aorta in older people.
PMCID: PMC4162768  PMID: 25024287
aortic stiffness; hypertension; pulse wave velocity; pulse pressure; magnetic resonance imaging
10.  Joint effect of mid- and late-life blood pressure on the brain 
Neurology  2014;82(24):2187-2195.
We hypothesized that in participants with a history of hypertension, lower late-life blood pressure (BP) will be associated with more brain pathology.
Participants are 4,057 older men and women without dementia with midlife (mean age 50 ± 6 years) and late-life (mean age 76 ± 5 years) vascular screening, cognitive function, and brain structures on MRI ascertained as part of the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study.
The association of late-life BP to brain measures depended on midlife hypertension history. Higher late-life systolic and diastolic BP (DBP) was associated with an increased risk of white matter lesions and cerebral microbleeds, and this was most pronounced in participants without a history of midlife hypertension. In contrast, in participants with a history of midlife hypertension, lower late-life DBP was associated with smaller total brain and gray matter volumes. This finding was reflected back in cognitive performance; in participants with midlife hypertension, lower DBP was associated with lower memory scores.
In this large population-based cohort, late-life BP differentially affects brain pathology and cognitive performance, depending on the history of midlife hypertension. Our study suggests history of hypertension is critical to understand how late-life BP affects brain structure and function.
PMCID: PMC4113458  PMID: 24898928
11.  Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium 
Moayyeri, Alireza | Hsu, Yi-Hsiang | Karasik, David | Estrada, Karol | Xiao, Su-Mei | Nielson, Carrie | Srikanth, Priya | Giroux, Sylvie | Wilson, Scott G. | Zheng, Hou-Feng | Smith, Albert V. | Pye, Stephen R. | Leo, Paul J. | Teumer, Alexander | Hwang, Joo-Yeon | Ohlsson, Claes | McGuigan, Fiona | Minster, Ryan L. | Hayward, Caroline | Olmos, José M. | Lyytikäinen, Leo-Pekka | Lewis, Joshua R. | Swart, Karin M.A. | Masi, Laura | Oldmeadow, Chris | Holliday, Elizabeth G. | Cheng, Sulin | van Schoor, Natasja M. | Harvey, Nicholas C. | Kruk, Marcin | del Greco M, Fabiola | Igl, Wilmar | Trummer, Olivia | Grigoriou, Efi | Luben, Robert | Liu, Ching-Ti | Zhou, Yanhua | Oei, Ling | Medina-Gomez, Carolina | Zmuda, Joseph | Tranah, Greg | Brown, Suzanne J. | Williams, Frances M. | Soranzo, Nicole | Jakobsdottir, Johanna | Siggeirsdottir, Kristin | Holliday, Kate L. | Hannemann, Anke | Go, Min Jin | Garcia, Melissa | Polasek, Ozren | Laaksonen, Marika | Zhu, Kun | Enneman, Anke W. | McEvoy, Mark | Peel, Roseanne | Sham, Pak Chung | Jaworski, Maciej | Johansson, Åsa | Hicks, Andrew A. | Pludowski, Pawel | Scott, Rodney | Dhonukshe-Rutten, Rosalie A.M. | van der Velde, Nathalie | Kähönen, Mika | Viikari, Jorma S. | Sievänen, Harri | Raitakari, Olli T. | González-Macías, Jesús | Hernández, Jose L. | Mellström, Dan | Ljunggren, Östen | Cho, Yoon Shin | Völker, Uwe | Nauck, Matthias | Homuth, Georg | Völzke, Henry | Haring, Robin | Brown, Matthew A. | McCloskey, Eugene | Nicholson, Geoffrey C. | Eastell, Richard | Eisman, John A. | Jones, Graeme | Reid, Ian R. | Dennison, Elaine M. | Wark, John | Boonen, Steven | Vanderschueren, Dirk | Wu, Frederick C.W. | Aspelund, Thor | Richards, J. Brent | Bauer, Doug | Hofman, Albert | Khaw, Kay-Tee | Dedoussis, George | Obermayer-Pietsch, Barbara | Gyllensten, Ulf | Pramstaller, Peter P. | Lorenc, Roman S. | Cooper, Cyrus | Kung, Annie Wai Chee | Lips, Paul | Alen, Markku | Attia, John | Brandi, Maria Luisa | de Groot, Lisette C.P.G.M. | Lehtimäki, Terho | Riancho, José A. | Campbell, Harry | Liu, Yongmei | Harris, Tamara B. | Akesson, Kristina | Karlsson, Magnus | Lee, Jong-Young | Wallaschofski, Henri | Duncan, Emma L. | O'Neill, Terence W. | Gudnason, Vilmundur | Spector, Timothy D. | Rousseau, François | Orwoll, Eric | Cummings, Steven R. | Wareham, Nick J. | Rivadeneira, Fernando | Uitterlinden, Andre G. | Prince, Richard L. | Kiel, Douglas P. | Reeve, Jonathan | Kaptoge, Stephen K.
Human Molecular Genetics  2014;23(11):3054-3068.
Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10−8) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10−14). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10−6 also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
PMCID: PMC4038791  PMID: 24430505
12.  Spousal Loss and Cognitive Function in Later Life: A 25-year Follow-up in the AGES-Reykjavik Study 
American Journal of Epidemiology  2014;179(6):674-683.
The aim of this study was to investigate the associations between loss of a life partner and the development of dementia and decline in cognitive function in later life. We used an Icelandic cohort of 4,370 participants in the Age, Gene/Environment Susceptibility-Reykjavik Study who were living as married in 1978 (born in 1907–1935) and were either still married (unexposed cohort) or widowed (exposed cohort) at follow-up (in 2002–2006). We ascertained history of marital status and spouse's death by record linkage to the Registry of the Total Population, Statistics Iceland. The outcome measures were as follows: 1) dementia and mild cognitive impairment; and 2) memory, speed of processing, and executive function. During the observation period, 3,007 individuals remained married and 1,363 lost a spouse through death. We did not find any significant associations between loss of a spouse and our outcome variables, except that widowed women had poorer executive function (mean = −0.08) during the first 2 years after their husbands’ deaths compared with still-married women (mean = 0.09). Our findings do not support the notion that the risk of dementia is increased following the loss of a spouse, yet women demonstrate a seemingly temporary decline in executive function following the death of a partner.
PMCID: PMC3939848  PMID: 24444551
dementia; executive function; marital status; memory; psychological stress
13.  Assessment of Incident Spine and Hip Fractures in Women and Men using Finite Element Analysis of CT Scans 
Finite element analysis of computed tomography (CT) scans provides non-invasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a five-year case-control study of 1110 women and men over age 65 from the AGES-Reykjavik cohort (case = incident spine or hip fracture; control = no incident spine or hip fracture, respectively). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that, for incident radiographically-confirmed spine fractures (n=167), the age-adjusted odds ratio for vertebral strength was significant for women (2.8, 95% CI: 1.8–4.3) and men (2.2, 95% CI: 1.5–3.2), and for men, remained significant (p=0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n=171), the age-adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI: 2.6–6.9) and men (3.5, 95% CI: 2.3–5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p=0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD-based interventional thresholds for osteoporosis and at corresponding pre-established thresholds for “fragile bone strength” (spine: women ≤ 4,500 N, men ≤ 6,500 N; hip: women ≤ 3,000 N, men ≤ 3,500 N). Since it is well established that individuals over age 65 who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have “fragile bone strength” at the hip or spine should also be considered at high risk of fracture.
PMCID: PMC3925753  PMID: 23956027
osteoporosis; fracture risk assessment; biomechanics; bone QCT
14.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
PMCID: PMC4140093  PMID: 24929828
15.  Longitudinal and Circumferential Strain of the Proximal Aorta 
Accurate assessment of mechanical properties of the proximal aorta is a requisite first step for elucidating the pathophysiology of isolated systolic hypertension. During systole, substantial proximal aortic axial displacement produces longitudinal strain, which we hypothesize causes variable underestimation of ascending aortic circumferential strain compared to values in the longitudinally constrained descending aorta.
Methods and Results
To assess effects of longitudinal strain, we performed magnetic resonance imaging in 375 participants (72 to 94 years old, 204 women) in the Age, Gene/Environment Susceptibility‐Reykjavik Study and measured aortic circumferential and longitudinal strain. Circumferential ascending aortic area strain uncorrected for longitudinal strain was comparable in women and men (mean [95% CI], 8.3 [7.8, 8.9] versus 7.9 [7.4, 8.5]%, respectively, P=0.3). However, longitudinal strain was greater in women (8.5±2.5 versus 7.0±2.5%, P<0.001), resulting in greater longitudinally corrected circumferential ascending aortic strain (14.4 [13.6, 15.2] versus 13.0 [12.4, 13.7]%, P=0.010). Observed circumferential descending aortic strain, which did not require correction (women: 14.0 [13.2, 14.8], men: 12.4 [11.6, 13.2]%, P=0.005), was larger than uncorrected (P<0.001), but comparable to longitudinally corrected (P=0.12) circumferential ascending aortic strain. Carotid‐femoral pulse wave velocity did not correlate with uncorrected ascending aortic strain (R=−0.04, P=0.5), but was inversely related to longitudinally corrected ascending and observed descending aortic strain (R=−0.15, P=0.004; R=−0.36, P<0.001, respectively). Longitudinal strain was also inversely related to carotid‐femoral pulse wave velocity and other risk factors for higher aortic stiffness including treated hypertension.
Longitudinal strain creates substantial and variable errors in circumferential ascending aortic area strain measurements, particularly in women, and should be considered to avoid misclassification of ascending aortic stiffness.
PMCID: PMC4338743  PMID: 25523153
aortic stiffness; ascending aorta; carotid‐femoral pulse wave velocity; circumferential strain; longitudinal strain
16.  Mid-life physical activity preserves lower extremity function in older adults: Age Gene/Environment Susceptibility (AGES) - Reykjavik Study 
To examine the long-term association between mid-life physical activity (PA) and lower extremity function (LEF) in late-life.
A longitudinal study with an average of 25 years of follow up.
A large community-based population of 4753 men and women (mean age 76±6 yrs) residing in Reykjavik, Iceland.
On the basis of weekly hours of regular PA reported at the mid-life examination, participants were classified as “Active” and “Inactive”. Measures of LEF in late-life included gait speed from 6m walk (meter per second, m/s), Timed Up and Go (TUG, second), and Knee Extension (KE) strength (kg) tests. Linear regression analysis was used to examine the association.
Participants who were active in mid-life had significantly better LEF (faster gait speed,, β = 0.05, p ≤ 0.001; faster TUG time, β = −0.53, p ≤ 0.001; stronger KE strength, β = 1.3, p ≤ 0.001) in late-life compared with those who were not active in mid-life, after adjusting for socio-demographic and cardiovascular risk factors. After adjustment for cognitive function in late life (speed of processing, memory, and executive function), participants who were active in mid-life still had significantly faster gait speed (β = 0.04, p ≤ 0.001), faster TUG time (β = −0.34, p ≤ 0.001), and greater KE strength (β = 0.87, p ≤ 0.001) in old age compared with those who were not active in mid-life.
Regular PA reported in mid-life is associated with better performance of LEF in later life, even after controlling for late life cognitive function.
PMCID: PMC4205047  PMID: 23320618
mid-life physical activity; mobility; aging; cognitive function; lower extremity function
17.  Profile and health-related quality of life of Ghanaian stroke survivors 
Stroke is a leading cause of mortality with a major effect on health-related quality of life (HRQoL). There are no previous studies exploring HRQoL among stroke survivors in Ghana, despite the increasing public health significance of the disease in this country. Here we describe the profile of and factors associated with HRQoL among stroke survivors in Ghana.
This was a cross-sectional study involving 156 stroke survivors and 156 age- and sex-matched, apparently healthy controls. A robust HRQoL questionnaire involving seven domains was used to collect data from the study participants. Clinical epidemiology data were also collected from stroke survivors on parameters such as stroke severity and risk factors. Statistical analyses were performed on the interrelationships among the study variables.
The mean ages of the stroke survivors and healthy controls were 58.0 (standard deviation, 11.4) and 57.6 (standard deviation, 12.0) years, respectively. Fifty-three percent (86) of the stroke survivors had mild stroke and 35.3% (55) had moderate stroke, whereas 12.2% (19) had severe stroke. Ischemic infarction was the prevalent stroke subtype (78.1%). Hypertension was the most common risk factor (89%) among the stroke survivors, followed by diabetes (29%). HRQoL scores ranged from 57.7% (cognitive domain) to 80.0% (spirit domain) for stroke survivors, whereas HRQoL scores of the control group ranged from 65.6% (cognitive domain) to 85.2% (soul domain). For each HRQoL domain, significantly higher scores were observed for the control group compared with the stroke survivors, at P<0.05. Determinants of HRQoL of stroke survivors in multivariate analysis included age, stroke severity, poststroke duration, stroke recurrence, frequency of laughter, and negative emotions.
The most affected HRQoL domains are of the physical, psychoemotional, and cognitive domains. Rehabilitation of stroke patients in this region should include interventions targeted at these domains and modifying the statistical determinants of HRQoL where possible.
PMCID: PMC4199965  PMID: 25336935
quality of life; stroke; domain; Ghana
18.  Coronary artery calcium and physical performance as determinants of mortality in older age: the AGES-Reykjavik Study 
International journal of cardiology  2013;168(3):2094-2099.
Coronary artery calcium (CAC) and physical performance have been shown to be associated with mortality, but it is not clear whether one of them modifies the association. We investigated the association between the extent of CAC and physical performance among older individuals and explored these individual and combined effects on cardiovascular disease (CVD) and non-CVD mortality.
We studied 4074 participants of the AGES-Reykjavik Study who were free from coronary heart disease, had a CAC score calculated from computed tomography scans and had data on mobility limitations and gait speed at baseline in 2002-2006 at a mean age of 76 years. Register-based mortality was available until 2009.
Odds for mobility limitation and slow gait increased according to the extent of CAC. Altogether 645 persons died during the follow-up. High CAC, mobility limitation and slow gait were independent predictors of CVD and non-CVD mortality. The joint effect of CAC and gait speed on non-CVD mortality was synergistic, i.e. compared to those with low CAC and normal gait, the joint effect of high CAC and slow gait exceeded the additive effect of these individual exposures on non-CVD mortality. For CVD mortality, the effect was additive i.e. the joint effect of high CAC and slow gait did not exceed the sum of the individual exposures.
The extent of CAC and decreased physical performance were independent predictors of mortality and the joint presence of these risk factors increased the risk of non-CVD mortality above and beyond the individual effects.
PMCID: PMC3674198  PMID: 23414742
atherosclerosis; coronary artery calcification; cardiovascular disease risk factors; aging; mortality; epidemiology
19.  Similarities and differences between sexes in regional loss of cortical and trabecular bone in the mid-femoral neck: The AGES-Reykjavik Longitudinal Study 
The risk of hip fracture rises rapidly with age, and is notably higher in women. After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density. To better understand the extent to which femoral neck density and structure change with age in each sex, we have carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density to investigate changes in regional cortical thickness, as well as cortical and trabecular bone mineral density at the mid-femoral neck. Segmental QCT analysis was used to assess bone measurements in two anatomic sub-regions, the supero-lateral (superior) and infero-medial (inferior). A total of 400 older individuals (100 men and 300 women, aged 66–90 years) who were participants in the AGES-Reykjavik study, were studied. Participants had two QCT scans of the hip over a median follow-up of 5.1 yr. (mean baseline age 74 yr.). Changes in bone values during follow-up were estimated from mixed effects regression models. At baseline women had lower bone values in the superior region than men. At follow-up all bone values were lower in women, except cortical vBMD inferiorly. The relative losses in all bone values estimated in the superior region were substantially (about threefold) and significantly greater compared to those estimated in the inferior region in both sexes. Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck DXA-like results. The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men.
PMCID: PMC3779495  PMID: 23609070
Cortical thickness; proximal end of femur; aging; longitudinal; QCT
20.  Prevalence and Prognosis of Unrecognized Myocardial Infarction Determined by Cardiac Magnetic Resonance in Older Adults 
Unrecognized myocardial infarction (MI) is prognostically important but electrocardiography (ECG), the main epidemiology tool for detection, is insensitive to MI.
Determine prevalence and mortality risk for unrecognized MI (UMI) detected by cardiac magnetic resonance (CMR) or ECG.
ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004–January 2007) using ECG or CMR to detect UMI.
Community dwelling participants in Iceland over age 67.
936 participants (ages 67–93 years) including 670 who were randomly selected and 266 with diabetes.
Main Outcome Measures
MI prevalence and mortality through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI).
Of 936 participants, 91 had recognized MI (RMI; 9.7% CI 8–12%), and 157 had UMI by CMR (17%; CI 14–19%) which was more prevalent than the 46 UMI by ECG (5%; CI 4–6%, p<0.001). Diabetic participants had more UMI by CMR than UMI by ECG (n=72; 21%; CI 17–26% vs. n=15; 4%; CI 2–7%, p<0.001). UMI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 33% (CI 23–43%) of individuals with RMI died (30 of 91) and 28% (CI 21–35%) with UMI died (44 of 157), both higher rates than the 17% (CI 15–20%) with no MI that died (119 of 688). UMI by CMR improved risk stratification for mortality over RMI (NRI: 0.34; CI 0.16–0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (HR 1.45 CI 1.02–2.06, absolute risk increase (ARI) 8%) and significantly improved risk stratification for mortality, NRI 0.16 (CI 0.01–0.31)) but UMI by ECG did not (HR 0.88, CI 0.45–1.73 ARI −2%; NRI: −0.05; CI −0.17–0.05). Compared to those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; CI, 28–43% or 56/157 vs.73%; CI 63–82% or 66/91; p<0.001).
In a community-based cohort, the prevalence of UMI by CMR was higher than the prevalence of recognized MI or UMI by ECG, and was associated with increased mortality risk.
PMCID: PMC4137910  PMID: 22948699
21.  Persistence of the effect of birth size on dysglycaemia and type 2 diabetes in old age: AGES-Reykjavik Study 
Age  2012;35(4):1401-1409.
We studied the effect of birth size on glucose and insulin metabolism among old non-diabetic individuals. We also explored the combined effect of birth size and midlife body mass index (BMI) on type 2 diabetes in old age. Our study comprised 1,682 Icelanders whose birth records included anthropometrical data. The same individuals had participated in the prospective population-based Reykjavik Study, where BMI was assessed at a mean age of 47 years, and in the AGES-Reykjavik Study during 2002 to 2006, where fasting glucose, insulin and HbA1c were measured and homeostasis model assessment for the degree of insulin resistance (HOMA-IR) calculated at a mean age of 75.5 years. Type 2 diabetes was determined as having a history of diabetes, using glucose-modifying medication or fasting glucose of >7.0 mmol/l. Of the participants, 249 had prevalent type 2 diabetes in old age. Lower birth weight and body length were associated with higher fasting glucose, insulin, HOMA-IR and HbA1c among old non-diabetic individuals. Higher birth weight and ponderal index at birth decreased the risk for type 2 diabetes in old age, odds ratio (OR), 0.61 [95 % confidence interval (CI), 0.48–0.79] and 0.96 (95 % CI, 0.92–1.00), respectively. Compared with those with high birth weight and low BMI in midlife, the odds of diabetes was almost five-fold for individuals with low birth weight and high BMI (OR, 4.93; 95 % CI, 2.14–11.37). Excessive weight gain in adulthood might be particularly detrimental to the health of old individuals with low birth weight.
PMCID: PMC3705119  PMID: 22588637
Aging; Birth size; Type 2 diabetes; Dysglycaemia; Birth weight; AGES-Reykjavik Study
22.  Migraine, depression, and brain volume 
Neurology  2013;80(23):2138-2144.
To examine the joint association of migraine headache and major depressive disorder on brain volume in older persons without dementia.
Participants (n = 4,296, 58% women) from the population-based Age, Gene/Environment Susceptibility–Reykjavik Study were assessed for migraine headache in 1967–1991 (age 51 years [range 33–65]) according to modified International Classification of Headache Disorders–II criteria. In 2002–2006 (age 76 years [range 66–96]), lifetime history of major depressive disorder (depression) was diagnosed according to DSM-IV criteria, and full-brain MRI was acquired, which was computer postprocessed into total brain volume (TBV) (gray matter [GM], white matter [WM], white matter hyperintensities) and CSF volume for each study subject. We compared brain tissue volumes by headache categories with or without depression using linear regression, adjusting for intracranial volume and other factors.
Compared with the reference group (no headache, no depression) TBV and WM and GM volumes were smaller in those with both migraine and depression (TBV −19.2 mL, 95% confidence interval [CI] −35.3, −3.1, p = 0.02; WM −12.8 mL, CI −21.3, −4.3, p = 0.003; GM −13.0 mL, CI −26.0, 0.1, p = 0.05) but not for those with migraine alone (TBV 0.4 mL, WM 0.2 mL, GM 0.6 mL) or depression alone (TBV −3.9 mL, WM −0.9 mL, GM −2.9 mL).
Reporting both migraine and major depressive disorder was associated with smaller brain tissue volumes than having one or neither of these conditions. Migraineurs with depression may represent a distinct clinical phenotype with different long-term sequelae. Nonetheless, the number of subjects in the current study is relatively small and these findings need to be confirmed in future studies.
PMCID: PMC3716352  PMID: 23700334
23.  Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts 
Background and Purpose
Atrial fibrillation (AF) has been associated with cognitive decline independant of stroke, suggesting additional effects of AF on the brain. We aimed to assess the association between AF and brain function and structure in a general elderly population.
This is a cross-sectional analysis on 4251 non-demented participants (mean age 76 ± 5 years) in the population-based AGES-Reykjavik Study. Medical record data were collected on the presence, subtype and time from first diagnosis of AF; 330 participants had AF. Brain volume measurements, adjusted for intracranial volume, and presence of cerebral infarcts were determined with MRI. Memory, speed of processing and executive function composites were calculated from a cognitive test battery. In a multivariable linear regression model, adjustments were made for demographic, cardiovascular risk factors and cerebral infarcts.
Participants with AF had lower total brain volume compared to those without AF (p<0.001). The association was stronger with persistent/permanent than paroxysmal AF and with increased time from the first diagnosis of the disease. Of the brain tissue volumes, AF was associated with lower volume of gray and white matter (p<0.001 and p=0.008 respectively) but not of white matter hyperintesities (p=0.49). Participants with AF scored lower on tests on memory.
AF is associated with smaller brain volume and the association is stronger with increasing burden of the arrhythmia. These findings suggest that AF has a cumulative negative effect on the brain independent of cerebral infarcts.
PMCID: PMC3632359  PMID: 23444303
atrial fibrillation; brain imaging; cognition; cerebral infarct
24.  Community awareness of stroke in Accra, Ghana 
BMC Public Health  2014;14:196.
Community awareness of stroke, especially the risk factors and warning signs is important in the control of the disease. In sub-Saharan Africa, little is known about community awareness of stroke though the brunt of stroke is currently borne in this region. The aim of the study was to evaluate stroke awareness in Accra (capital city of Ghana) particularly, the risk factors and warning signs.
This was a cross-sectional study involving systematic sampling of 63 households in each of the 11 sub metropolitan areas of Accra. A structured questionnaire was used to collect stroke awareness data from respondents randomly sampled in the selected households. Logistic regression analyses were done to identify predictors of the main outcome variables including recognition of stroke risk factors, stroke warning signs and the organ affected by stroke.
Only 40% (n = 277) of the 693 respondents correctly identified the brain as the organ affected in stroke. Similarly, less than half of the respondents could recognize any of the established stroke risk factors as well as any of the established stroke warning signs. Over 70% (n > 485) of the respondents either believed that stroke is a preventable disease, or lifestyle alterations can be made to reduce the risk of stroke, or stroke requires emergency treatment. In multivariate analysis, predictors of stroke awareness were: age <50 years (OR = 0.56, CI = 0.35-0.92, p = 0.021), presence of a stroke risk factor (OR = 2.37, CI = 1.52-3.71, p < 0.001) and Christian Religion (OR = 14.86, CI = 1.37-161.01, p = 0.03).
Though stroke is perceived as a serious and preventable disease in Accra, community awareness of the risk factors and warning signs is sub-optimal. This indicates that community-based education programs to increase public awareness of stroke could contribute to decreasing the risk of stroke and to increasing the speed of hospital presentation after stroke onset.
PMCID: PMC3943505  PMID: 24559414
Stroke; Risk factors; Warning signs; Brain; Accra
25.  Population Assessment of Future Trajectories in Coronary Heart Disease Mortality 
PLoS ONE  2014;9(1):e85800.
Coronary heart disease (CHD) mortality rates have been decreasing in Iceland since the 1980s, largely reflecting improvements in cardiovascular risk factors. The purpose of this study was to predict future CHD mortality in Iceland based on potential risk factor trends.
Methods and findings
The previously validated IMPACT model was used to predict changes in CHD mortality between 2010 and 2040 among the projected population of Iceland aged 25–74. Calculations were based on combining: i) data on population numbers and projections (Statistics Iceland), ii) population risk factor levels and projections (Refine Reykjavik study), and iii) effectiveness of specific risk factor reductions (published meta-analyses). Projections for three contrasting scenarios were compared: 1) If the historical risk factor trends of past 30 years were to continue, the declining death rates of past decades would level off, reflecting population ageing. 2) If recent trends in risk factors (past 5 years) continue, this would result in a death rate increasing from 49 to 70 per 100,000. This would reflect a recent plateau in previously falling cholesterol levels and recent rapid increases in obesity and diabetes prevalence. 3) Assuming that in 2040 the entire population enjoys optimal risk factor levels observed in low risk cohorts, this would prevent almost all premature CHD deaths before 2040.
The potential increase in CHD deaths with recent trends in risk factor levels is alarming both for Iceland and probably for comparable Western populations. However, our results show considerable room for reducing CHD mortality. Achieving the best case scenario could eradicate premature CHD deaths by 2040. Public health policy interventions based on these predictions may provide a cost effective means of reducing CHD mortality in the future.
PMCID: PMC3897505  PMID: 24465713

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