PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (54)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
Document Types
1.  Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis 
Wormser, David | Angelantonio, Emanuele Di | Kaptoge, Stephen | Wood, Angela M | Gao, Pei | Sun, Qi | Walldius, Göran | Selmer, Randi | Verschuren, WM Monique | Bueno-de-Mesquita, H Bas | Engström, Gunnar | Ridker, Paul M | Njølstad, Inger | Iso, Hiroyasu | Holme, Ingar | Giampaoli, Simona | Tunstall-Pedoe, Hugh | Gaziano, J Michael | Brunner, Eric | Kee, Frank | Tosetto, Alberto | Meisinger, Christa | Brenner, Hermann | Ducimetiere, Pierre | Whincup, Peter H | Tipping, Robert W | Ford, Ian | Cremer, Peter | Hofman, Albert | Wilhelmsen, Lars | Clarke, Robert | de Boer, Ian H | Jukema, J Wouter | Ibañez, Alejandro Marín | Lawlor, Debbie A | D'Agostino, Ralph B | Rodriguez, Beatriz | Casiglia, Edoardo | Stehouwer, Coen DA | Simons, Leon A | Nietert, Paul J | Barrett-Connor, Elizabeth | Panagiotakos, Demosthenes B | Björkelund, Cecilia | Strandberg, Timo E | Wassertheil-Smoller, Sylvia | Blazer, Dan G | Meade, Tom W | Welin, Lennart | Svärdsudd, Kurt | Woodward, Mark | Nissinen, Aulikki | Kromhout, Daan | Jørgensen, Torben | Tilvis, Reijo S | Guralnik, Jack M | Rosengren, Annika | Taylor, James O | Kiechl, Stefan | Dagenais, Gilles R | Gerry, F | Fowkes, R | Wallace, Robert B | Khaw, Kay-Tee | Shaffer, Jonathan A | Visser, Marjolein | Kauhanen, Jussi | Salonen, Jukka T | Gallacher, John | Ben-Shlomo, Yoav | Kitamura, Akihiko | Sundström, Johan | Wennberg, Patrik | Kiyohara, Yutaka | Daimon, Makoto | de la Cámara, Agustin Gómez | Cooper, Jackie A | Onat, Altan | Devereux, Richard | Mukamal, Kenneth J | Dankner, Rachel | Knuiman, Matthew W | Crespo, Carlos J | Gansevoort, Ron T | Goldbourt, Uri | Nordestgaard, Børge G | Shaw, Jonathan E | Mussolino, Michael | Nakagawa, Hidaeki | Fletcher, Astrid | Kuller, Lewis H | Gillum, Richard F | Gudnason, Vilmundur | Assmann, Gerd | Wald, Nicholas | Jousilahti, Pekka R | Greenland, Philip | Trevisan, Maurizio | Ulmer, Hanno | Butterworth, Adam S | Folsom, Aaron R | Davey-Smith, George | Hu, Frank B | Danesh, John | Tipping, Robert W | Ford, Charles E | Simpson, Lara M | Walldius, Göran | Jungner, Ingmar | Folsom, Aaron R | Demerath, Ellen W | Franceschini, Nora | Lutsey, Pamela L | Panagiotakos, Demosthenes B | Pitsavos, Christos | Chrysohoou, Christina | Stefanadis, Christodoulos | Shaw, Jonathan E | Atkins, Robert | Zimmet, Paul Z | Barr, Elizabeth LM | Knuiman, Matthew W | Whincup, Peter H | Wannamethee, S Goya | Morris, Richard W | Willeit, Johann | Kiechl, Stefan | Weger, Siegfried | Oberhollenzer, Friedrich | Wald, Nicholas | Ebrahim, Shah | Lawlor, Debbie A | Gallacher, John | Ben-Shlomo, Yoav | Yarnell, John WG | Casiglia, Edoardo | Tikhonoff, Valérie | Greenland, Philip | Shay, Christina M | Garside, Daniel B | Nietert, Paul J | Sutherland, Susan E | Bachman, David L | Keil, Julian E | de Boer, Ian H | Kizer, Jorge R | Psaty, Bruce M | Mukamal, Kenneth J | Nordestgaard, Børge G | Tybjærg-Hansen, Anne | Jensen, Gorm B | Schnohr, Peter | Giampaoli, Simona | Palmieri, Luigi | Panico, Salvatore | Pilotto, Lorenza | Vanuzzo, Diego | de la Cámara, Agustin Gómez | Simons, Leon A | Simons, Judith | McCallum, John | Friedlander, Yechiel | Gerry, F | Fowkes, R | Price, Jackie F | Lee, Amanda J | Taylor, James O | Guralnik, Jack M | Phillips, Caroline L | Wallace, Robert B | Kohout, Frank J | Cornoni-Huntley, Joan C | Guralnik, Jack M | Blazer, Dan G | Guralnik, Jack M | Phillips, Caroline L | Phillips, Caroline L | Guralnik, Jack M | Khaw, Kay-Tee | Wareham, Nicholas J | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Rothenbacher, Dietrich | Wennberg, Patrik | Jansson, Jan-Håkan | Nissinen, Aulikki | Donfrancesco, Chiara | Giampaoli, Simona | Woodward, Mark | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | D'Agostino, Ralph B | Vasan, Ramachandran S | Fox, Caroline S | Pencina, Michael J | Daimon, Makoto | Oizumi, Toshihide | Kayama, Takamasa | Kato, Takeo | Bladbjerg, Else-Marie | Jørgensen, Torben | Møller, Lars | Jespersen, Jørgen | Dankner, Rachel | Chetrit, Angela | Lubin, Flora | Svärdsudd, Kurt | Eriksson, Henry | Welin, Lennart | Lappas, Georgios | Rosengren, Annika | Lappas, Georgios | Welin, Lennart | Svärdsudd, Kurt | Eriksson, Henry | Lappas, Georgios | Bengtsson, Calle | Lissner, Lauren | Björkelund, Cecilia | Cremer, Peter | Nagel, Dorothea | Strandberg, Timo E | Salomaa, Veikko | Tilvis, Reijo S | Miettinen, Tatu A | Tilvis, Reijo S | Strandberg, Timo E | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Rodriguez, Beatriz | Dekker, Jacqueline M | Nijpels, Giel | Stehouwer, Coen DA | Hu, Frank B | Sun, Qi | Rimm, Eric B | Willett, Walter C | Iso, Hiroyasu | Kitamura, Akihiko | Yamagishi, Kazumasa | Noda, Hiroyuki | Goldbourt, Uri | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | Kauhanen, Jussi | Salonen, Jukka T | Kurl, Sudhir | Tuomainen, Tomi-Pekka | Poppelaars, Jan L | Deeg, Dorly JH | Visser, Marjolein | Meade, Tom W | De Stavola, Bianca Lucia | Hedblad, Bo | Nilsson, Peter | Engström, Gunnar | Verschuren, WM Monique | Blokstra, Anneke | de Boer, Ian H | Shea, Steven J | Meisinger, Christa | Thorand, Barbara | Koenig, Wolfgang | Döring, Angela | Verschuren, WM Monique | Blokstra, Anneke | Bueno-de-Mesquita, H Bas | Wilhelmsen, Lars | Rosengren, Annika | Lappas, Georgios | Fletcher, Astrid | Nitsch, Dorothea | Kuller, Lewis H | Grandits, Greg | Tverdal, Aage | Selmer, Randi | Nystad, Wenche | Mussolino, Michael | Gillum, Richard F | Hu, Frank B | Sun, Qi | Manson, JoAnn E | Rimm, Eric B | Hankinson, Susan E | Meade, Tom W | De Stavola, Bianca Lucia | Cooper, Jackie A | Bauer, Kenneth A | Davidson, Karina W | Kirkland, Susan | Shaffer, Jonathan A | Shimbo, Daichi | Kitamura, Akihiko | Iso, Hiroyasu | Sato, Shinichi | Holme, Ingar | Selmer, Randi | Tverdal, Aage | Nystad, Wenche | Nakagawa, Hidaeki | Miura, Katsuyuki | Sakurai, Masaru | Ducimetiere, Pierre | Jouven, Xavier | Bakker, Stephan JL | Gansevoort, Ron T | van der Harst, Pim | Hillege, Hans L | Crespo, Carlos J | Garcia-Palmieri, Mario R | Kee, Frank | Amouyel, Philippe | Arveiler, Dominique | Ferrières, Jean | Schulte, Helmut | Assmann, Gerd | Jukema, J Wouter | de Craen, Anton JM | Sattar, Naveed | Stott, David J | Cantin, Bernard | Lamarche, Benoît | Després, Jean-Pierre | Dagenais, Gilles R | Barrett-Connor, Elizabeth | Bergstrom, Jaclyn | Bettencourt, Richele R | Buisson, Catherine | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Trevisan, Maurizio | Hofman, Albert | Ikram, M Arfan | Tiemeier, Henning | Witteman, Jacqueline CM | Tunstall-Pedoe, Hugh | Tavendale, Roger | Lowe, Gordon DO | Woodward, Mark | Devereux, Richard | Yeh, Jeun-Liang | Ali, Tauqeer | Calhoun, Darren | Ben-Shlomo, Yoav | Davey-Smith, George | Onat, Altan | Can, Günay | Nakagawa, Hidaeki | Sakurai, Masaru | Nakamura, Koshi | Morikawa, Yuko | Njølstad, Inger | Mathiesen, Ellisiv B | Løchen, Maja-Lisa | Wilsgaard, Tom | Sundström, Johan | Ingelsson, Erik | Michaëlsson, Karl | Cederholm, Tommy | Gaziano, J Michael | Buring, Julie | Ridker, Paul M | Gaziano, J Michael | Ridker, Paul M | Ulmer, Hanno | Diem, Günter | Concin, Hans | Rodeghiero, Francesco | Tosetto, Alberto | Wassertheil-Smoller, Sylvia | Manson, JoAnn E | Marmot, Michael | Clarke, Robert | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimaki, Mika | Ridker, Paul M | Buring, Julie | Ford, Ian | Robertson, Michele | Ibañez, Alejandro Marín | Feskens, Edith | Geleijnse, Johanna M | Kromhout, Daan | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S | Angelantonio, Emanuele Di | Franco, Oscar H | Gao, Pei | Gobin, Reeta | Haycock, Philip | Kaptoge, Stephen | Seshasai, Sreenivasa R Kondapally | Lewington, Sarah | Pennells, Lisa | Rapsomaniki, Eleni | Sarwar, Nadeem | Thompson, Alexander | Thompson, Simon G | Walker, Matthew | Watson, Sarah | White, Ian R | Wood, Angela M | Wormser, David | Zhao, Xiaohui | Danesh, John
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
doi:10.1093/ije/dys086
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
2.  Atherosclerotic Risk Factors and Their Association With Hospital Mortality Among Patients With First Myocardial Infarction (from the National Registry of Myocardial Infarction) 
The American journal of cardiology  2012;110(9):1256-1261.
Few studies have examined associations between atherosclerotic risk factors and short-term mortality after first myocardial infarction (MI). Histories of 5 traditional atherosclerotic risk factors at presentation (diabetes, hypertension, smoking, dyslipidemia, and family history of premature heart disease) and hospital mortality were examined among 542,008 patients with first MIs in the National Registry of Myocardial Infarction (1994 to 2006). On initial MI presentation, history of hypertension (52.3%) was most common, followed by smoking (31.3%). The least common risk factor was diabetes (22.4%). Crude mortality was highest in patients with MI with diabetes (11.9%) and hypertension (9.8%) and lowest in those with smoking histories (5.4%) and dyslipidemia (4.6%). The inclusion of 5 atherosclerotic risk factors in a stepwise multivariate model contributed little toward predicting hospital mortality over age alone (C-statistic = 0.73 and 0.71, respectively). After extensive multivariate adjustments for clinical and sociodemographic factors, patients with MI with diabetes had higher odds of dying (odds ratio [OR] 1.23, 95% confidence interval [CI] 1.20 to 1.26) than those without diabetes and similarly for hypertension (OR 1.08, 95% CI 1.06 to 1.11). Conversely, family history (OR 0.71, 95% CI 0.69 to 0.73), dyslipidemia (OR 0.62, 95% CI 0.60 to 0.64), and smoking (OR 0.85, 95% CI 0.83 to 0.88) were associated with decreased mortality (C-statistic = 0.82 for the full model). In conclusion, in the setting of acute MI, histories of diabetes and hypertension are associated with higher hospital mortality, but the inclusion of atherosclerotic risk factors in models of hospital mortality does not improve predictive ability beyond other major clinical and sociodemographic characteristics.
doi:10.1016/j.amjcard.2012.06.025
PMCID: PMC4494670  PMID: 22840346
3.  Number of Coronary Heart Disease Risk Factors and Mortality in Patients With First Myocardial Infarction 
JAMA  2011;306(19):2120-2127.
Context
Few studies have examined the association between the number of coronary heart disease risk factors and outcomes of acute myocardial infarction in community practice.
Objective
To determine the association between the number of coronary heart disease risk factors in patients with first myocardial infarction and hospital mortality.
Design
Observational study from the National Registry of Myocardial Infarction, 1994-2006.
Patients
We examined the presence and absence of 5 major traditional coronary heart disease risk factors (hypertension, smoking, dyslipidemia, diabetes, and family history of coronary heart disease) and hospital mortality among 542 008 patients with first myocardial infarction and without prior cardiovascular disease.
Main Outcome Measure
All-cause in-hospital mortality.
Results
A majority (85.6%) of patients who presented with initial myocardial infarction had at least 1 of the 5 coronary heart disease risk factors, and 14.4% had none of the 5 risk factors. Age varied inversely with the number of coronary heart disease risk factors, from a mean age of 71.5 years with 0 risk factors to 56.7 years with 5 risk factors (P for trend <.001). The total number of in-hospital deaths for all causes was 50 788. Unadjusted in-hospital mortality rates were 14.9%, 10.9%, 7.9%, 5.3%, 4.2%, and 3.6% for patients with 0, 1, 2, 3, 4, and 5 risk factors, respectively. After adjusting for age and other clinical factors, there was an inverse association between the number of coronary heart disease risk factors and hospital mortality adjusted odds ratio (1.54; 95% CI, 1.23-1.94) among individuals with 0 vs 5 risk factors. This association was consistent among several age strata and important patient subgroups.
Conclusion
Among patients with incident acute myocardial infarction without prior cardiovascular disease, in-hospital mortality was inversely related to the number of coronary heart disease risk factors.
doi:10.1001/jama.2011.1654
PMCID: PMC4494683  PMID: 22089719
4.  Design of the Value of Imaging in Enhancing the Wellness of Your Heart (VIEW) Trial and the Impact of Uncertainty on Power 
Background
Although observational evidence has suggested that the measurement of CAC may improve risk stratification for cardiovascular events and thus help guide the use of lipid-lowering therapy, this contention has not been evaluated within the context of a randomized trial. The Value of Imaging in Enhancing the Wellness of Your Heart (VIEW) trial is proposed as a randomized study in participants at low intermediate risk of future coronary heart disease (CHD) events to evaluate whether coronary artery calcium (CAC) testing leads to improved patient outcomes.
Purpose
To describe the challenges encountered in designing a prototypical screening trial and to examine the impact of uncertainty on power.
Methods
The VIEW trial was designed as an effectiveness clinical trial to examine the benefit of CAC testing to guide therapy on a primary outcome consisting of a composite of non-fatal myocardial infarction, probable or definite angina with revascularization, resuscitated cardiac arrest, non-fatal stroke (not transient ischemic attack (TIA)), CHD death, stroke death, other atherosclerotic death, or other cardiovascular disease (CVD) death. Many critical choices were faced in designing the trial, including: (1) the choice of primary outcome, (2) the choice of therapy, (3) the target population with corresponding ethical issues, (4) specifications of assumptions for sample size calculations, and (5) impact of uncertainty in these assumptions on power/sample size determination.
Results
We have proposed a sample size of 30,000 (800 events) which provides 92.7% power. Alternatively, sample sizes of 20,228 (539 events), 23,138 (617 events) and 27,078 (722 events) provide 80, 85, and 90% power. We have also allowed for uncertainty in our assumptions by computing average power integrated over specified prior distributions. This relaxation of specificity indicates a reduction in power, dropping to 89.9% (95% confidence interval (CI): 89.8 to 89.9) for a sample size of 30,000. Samples sizes of 20,228, 23,138, and 27,078 provide power of 78.0% (77.9 to 78.0), 82.5% (82.5 to 82.6), and 87.2% (87.2 to 87.3), respectively.
Limitations
These power estimates are dependent on form and parameters of the prior distributions.
Conclusions
Despite the pressing need for a randomized trial to evaluate the utility of CAC testing, conduct of such a trial requires recruiting a large patient population, making efficiency of critical importance. The large sample size is primarily due to targeting a study population at relatively low risk of a CVD event. Our calculations also illustrate the importance of formally considering uncertainty in power calculations of large trials as standard power calculations may tend to overestimate power.
doi:10.1177/1740774512436882
PMCID: PMC4475283  PMID: 22333998
cardiovascular disease (CVD); coronary heart disease (CHD); coronary artery calcium (CAC); disease prevention; statistical power; Bayes
5.  The Use of Coronary Artery Calcium Testing to Guide Aspirin Utilization for Primary Prevention: Estimates from the Multi-Ethnic Study of Atherosclerosis 
Background
Aspirin for the primary prevention of coronary heart disease (CHD) is only recommended for individuals at high risk for CHD although the majority of CHD events occur in individuals who are low to intermediate risk.
Methods and Results
To estimate the potential of coronary artery calcium (CAC) scoring to guide aspirin use for primary prevention of CHD, we studied 4229 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were not on aspirin at baseline and were free of diabetes. Using data from median 7.6-year follow-up, five-year number-needed-to-treat (NNT5) estimations were calculated by applying an 18% relative CHD reduction to the observed event rates. This was contrasted to 5-year number-needed-to-harm (NNH5) estimations based on the risk of major bleeding reported in an aspirin meta-analysis. Results were stratified by a 10% 10-year CHD Framingham Risk Score (FRS). Individuals with CAC ≥ 100 had an estimated net benefit with aspirin regardless of their traditional risk status (estimated NNT5 of 173 for individuals <10% FRS and 92 for individuals ≥ 10% FRS, estimated NNH5 of 442 for a major bleed). Conversely, individuals with zero CAC had unfavorable estimations (estimated NNT5 of 2,036 for individuals <10% FRS and 808 for individuals ≥ 10% FRS, estimated NNH5 of 442 for a major bleed). Gender specific and age-stratified analyses showed similar results.
Conclusion
For the primary prevention of CHD, MESA participants with CAC ≥ 100 had favorable risk/benefit estimations for aspirin use while participants with zero CAC were estimated to receive net harm from aspirin.
doi:10.1161/CIRCOUTCOMES.113.000690
PMCID: PMC4412344  PMID: 24803472
Aspirin; imaging; prevention; coronary disease
6.  Vulnerable Blood in High Risk Vascular Patients: Study Design and Methods 
Contemporary clinical trials  2014;38(1):121-129.
BACKGROUND
Basic research suggests that rapid increases in circulating inflammatory and hemostatic blood markers may trigger or indicate impending plaque rupture and coronary thrombosis, resulting in acute ischemic heart disease (IHD) events. However, these associations are not established in humans.
METHODS AND RESULTS
The Biomarker Risk Assessment in Vulnerable Outpatients (BRAVO) Study will determine whether levels of inflammatory and hemostatic biomarkers rapidly increase during the weeks prior to an acute IHD event in people with lower extremity peripheral artery disease (PAD). The BRAVO Study will determine whether biomarker levels measured immediately prior to an IHD event are higher than levels not preceding an IHD event; whether participants who experience an IHD event (cases) have higher biomarker levels immediately prior to the event and higher biomarker levels at each time point leading up to the IHD event than participants without an IHD event (controls); and whether case participants have greater increases in biomarkers during the months leading up to the event than controls. BRAVO enrolled 595 patients with PAD, a population at high risk for acute IHD events. After a baseline visit, participants returned every two months for blood collection, underwent an electrocardiogram to identify new silent myocardial infarctions, and were queried about new hospitalizations since their prior study visit. Mortality data were also collected. Participants were followed prospectively for up to three years.
CONCLUSIONS
BRAVO results will provide important information about the pathophysiology of IHD events and may lead to improved therapies for preventing IHD events in high-risk patients.
doi:10.1016/j.cct.2014.03.009
PMCID: PMC4082976  PMID: 24721480
7.  CORONARY ARTERY CALCIUM IN RELATION TO INITIATION AND CONTINUATION OF CARDIOVASCULAR PREVENTIVE MEDICATIONS: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) 
Background
Whether measuring and reporting of coronary artery calcium scores (CACS) might lead to changes in cardiovascular risk management is not established. In this observational study we examined whether high baseline CACS were associated with the initiation as well continuation of new lipid lowering medication (LLM), blood pressure lowering medication (BPLM) and regular aspirin (ASA) use in a multi-ethnic population-based cohort.
Methods and Results
MESA is a prospective cohort study of 6814 participants free of clinical cardiovascular disease at entry who underwent CAC testing at baseline examination (exam 1). Information on LLM, BPLM and regular ASA usage was also obtained at baseline, and at exams 2 and 3 (average of 1.6 and 3.2 years after baseline respectively). In this study we examined: 1) initiation of these medications at exam 2 among participants not taking these medications at baseline; and 2) continuation of medication use to exam 3 among participants already on medication at baseline. Among MESA participants, initiation of LLM, BPLM and ASA was greater in those with higher CACS After taking into account age, gender, race, MESA site, LDL cholesterol, diabetes mellitus, BMI, smoking status, hypertension, systolic blood pressure, and SES (income, education and health insurance), the risk ratios for medication initiation comparing those with CACS>400 vs. CACS=0 were 1.53 (95% CI: 1.08, 2.15) for LLM, 1.55 (1.10-- 2.17) for BPLM, and 1.32 (1.03–1.69) for ASA initiation, respectively. The risk ratios for medication continuation among those with CAC>400 vs. CACS=0 were 1.10 (95% CI: 1.01–1.20) for LLM, 1.05 (1.02–1.08) for BPLM, and 1.14 (1.04- 1.25) for ASA initiation, respectively.
Conclusion
CACS>400 was associated with a higher likelihood of initiation and continuation of LLM, BPLM and ASA. The association was weaker for continuation than for initiation of these preventive therapies.
doi:10.1161/CIRCOUTCOMES.109.893396
PMCID: PMC4402976  PMID: 20371760
Coronary artery calcification; Computed tomography; Medications; Adherence; Prevention
8.  Attention to Detail in the Selection of Words in Epidemiologic Research Reports 
American Journal of Epidemiology  2014;179(7):795-796.
A recent article in the Journal by Whelton et al. (Am J Epidemiol. 2013;178(7):1076–1084) prompted this commentary about the use of the word “elevated” in medical reports. We believe that the word used in that particular report should have been “higher.” The exposure variable was not actually elevated according to what we understand the word to mean in epidemiologic research. Consistent with the elimination of the inappropriate use of elevated and according to correct clinical chemistry usage, we suggest that the word “level” should also have been avoided in that context. We discuss the specific example of C-reactive protein in the article by Whelton et al. Appropriate word selection underpinning accurate reporting should avoid unnecessarily misleading readers about the meaning of epidemiologic findings.
doi:10.1093/aje/kwu008
PMCID: PMC3969539  PMID: 24557814
accuracy in reporting; C-reactive protein; medical publishing
9.  Using the Coronary Artery Calcium Score to Guide Statin Therapy 
Background
The coronary artery calcium score (CAC) predicts future coronary heart disease (CHD) events and could be used to guide primary prevention interventions, but CAC measurement has costs and exposes patients to low-dose radiation.
Methods and Results
We estimated the cost-effectiveness of measuring CAC and prescribing statin therapy based on the resulting score under a range of assumptions using an established model enhanced with CAC distribution and risk estimates from the Multi-Ethnic Study of Atherosclerosis (MESA). Ten years of statin treatment for 10,000 55-year-old women with high cholesterol (10-year CHD risk=7.5%) was projected to prevent 32 myocardial infarctions, cause 70 cases of statin-induced myopathy, and add 1,108 years to total life-expectancy. Measuring CAC and targeting statin treatment to the 2,500 women with CAC>0 would provide 45% of the benefit (+501 life-years), but CAC measurement would cost $2.25 million and cause 9 radiation-induced cancers. Treat All was preferable to CAC screening in this scenario and across a broad range of other scenarios (CHD risk=2.5-15%) when statin assumptions were favorable ($0.13/pill and no quality of life penalty). When statin assumptions were less favorable ($1.00/pill and disutility=0.00384), CAC screening with statin treatment for persons with CAC>0 was cost-effective (<$50,000/quality-adjusted life-year) in this scenario, in 55-year old men with CHD risk=7.5%, and in other intermediate risk scenarios (CHD risk=5-10%). Our results were critically sensitive to statin cost and disutility, and relatively robust to other assumptions. Alternate CAC treatment thresholds (>100 or >300) were generally not cost-effective.
Conclusions
CAC testing in intermediate risk patients can be cost-effective, but only if statins are costly or significantly impact quality of life.
doi:10.1161/CIRCOUTCOMES.113.000799
PMCID: PMC4156513  PMID: 24619318
coronary; atherosclerosis; economics; calcium; statins
10.  Prospective Associations of Coronary Heart Disease Loci in African Americans Using the MetaboChip: The PAGE Study 
PLoS ONE  2014;9(12):e113203.
Background
Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.
Methods and Results
Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium.
Conclusions
Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.
doi:10.1371/journal.pone.0113203
PMCID: PMC4277270  PMID: 25542012
11.  Interpretation of the Coronary Artery Calcium Score in Combination with Conventional Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Circulation  2013;128(10):10.1161/CIRCULATIONAHA.113.002598.
Background
The coronary artery calcium (CAC) score predicts coronary heart disease (CHD) events, but methods for interpreting the score in combination with conventional CHD risk factors have not been established.
Methods and Results
We analyzed CAC scores and CHD risk factor measurements from 6757 Black, Chinese, Hispanic and white men and women aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC was associated with age, sex, race-ethnicity, and all conventional CHD risk factors. Multivariable models using these factors predicted the presence of CAC (C-statistic = 0.789) and degree of elevation (16% of variation explained), and can be used to update a “pre-test” CHD risk estimate, such as the 10-year Framingham Risk Score, that is based on an individual’s conventional risk factors. In scenarios where a high CAC score is expected, a moderately elevated CAC score of 50 is reassuring (e.g., reducing risk from 10% to 6% in a healthy older white man); but when a low/zero CAC score is expected, even with identical pre-test CHD risk, the same CAC score of 50 may be alarmingly high (e.g., increasing risk from 10% to 20% in a middle-aged black woman with multiple risk factors). Both the magnitude and direction of the shift in risk varied markedly with pre-test CHD risk and with the pattern of risk factors.
Conclusions
Knowing what CAC score to expect for an individual patient, based on their conventional risk factors, may help clinicians decide when to order a CAC test and how to interpret the results.
doi:10.1161/CIRCULATIONAHA.113.002598
PMCID: PMC3840900  PMID: 23884352
coronary disease; calcium; imaging; epidemiology
12.  Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate Risk Individuals. The Multi-Ethnic Study of Atherosclerosis 
Context
Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial Index (ABI), brachial flow-mediated dilation (FMD), high sensitivity C -reactive protein (hs-CRP) and family history (FH) of coronary heart disease (CHD) have been reported to improve on the Framingham risk score (FRS) for prediction of CHD. However, there are no direct comparisons of these markers for risk prediction in a single cohort.
Objective
We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate risk participants (5 % < FRS < 20%) in the Multi-Ethnic Study of Atherosclerosis (MESA).
Design, Setting and Participants
Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2011. Probability- weighted Cox proportional hazard models were used to estimate hazard ratios (HR). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare incremental contributions of each marker when added to the FRS + race/ethnicity.
Main Outcome Measures
Incident CHD defined as MI, angina followed by revascularization, resuscitated cardiac arrest or CHD death. Incident CVD additionally included stroke or CVD death.
Results
After median follow-up of 7.6 years (IQR 7.3 – 7.8 years), 94 CHD and 123 CVD events occurred. CAC, ABI, hs-CRP and FH were independently associated with incident CHD in multivariable analyses [HR (95%CI: 2.60(1.94-3.50), 0.79(0.66-0.95), 1.28(1.00-1.64) and 2.18(1.38-3.42) respectively]. CIMT and FMD were not associated with incident CHD in multivariable analyses [HR (95%CI) 1.17(0.95- 1.45) and 0.95(0.78 −1.14) respectively]. Although the addition of the markers individually to the FRS +race/ethnicity improved the AUC, CAC afforded the highest increment (0.623 vs. 0.784) while FMD afforded the least [0.623 vs. 0.639]. For incident CHD, the NRI with CAC was 0.659, FMD 0.024, ABI 0.036, CIMT 0.102, FH 0.160 and hs-CRP 0.079. Similar results were obtained for incident CVD.
Conclusion
CAC, ABI, hs-CRP and FH are independent predictors of incident CHD/CVD in intermediate risk individuals. CAC provides superior discrimination and risk reclassification compared with other risk markers.
doi:10.1001/jama.2012.9624
PMCID: PMC4141475  PMID: 22910756
13.  N-terminal Pro-B-Type Natriuretic Peptide, Left Ventricular Mass, and Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2012;5(6):727-734.
Background
Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with clinically overt heart failure (HF). However, whether it provides additive prognostic information for incident HF beyond traditional risk factors and left ventricular (LV) mass index among multi-ethnic asymptomatic individuals has not yet been determined. We studied the associations of plasma NT-proBNP and magnetic resonance imaging defined LV mass index with incident HF in an asymptomatic multi-ethnic population.
Methods and Results
A total of 5597 multi-ethnic participants without clinically apparent cardiovascular disease underwent baseline measurement of NT-proBNP and were followed for 5.5±1.1 years. Among them, 4163 also underwent baseline cardiac magnetic resonance imaging. During follow-up, 111 participants experienced incident HF. Higher NT-proBNP was significantly associated with incident HF, independent of baseline age, sex, ethnicity, systolic blood pressure, diabetes mellitus, smoking, estimated glomerular filtration rate, medications (anti-hypertensive and statin), LV mass index, and interim myocardial infarction (hazard ratio: 1.95 per 1U log NT-proBNP increment, 95% CI 1.54–2.46, P<0.001). This relationship held among different ethnic groups, non-Hispanic whites, African-Americans, and Hispanics. Most importantly, NT-proBNP provided additive prognostic value beyond both traditional risk factors and LV mass index for predicting incident HF (integrated discrimination index=0.046, P<0.001; net reclassification index; 6-year risk probability categorized by <3%, 3–10%, >10% =0.175, P=0.019; category-less net reclassification index=0.561, P<0.001).
Conclusions
Plasma NT-proBNP provides incremental prognostic information beyond traditional risk factors and the magnetic resonance imaging-determined LV mass index for incident symptomatic HF in an asymptomatic multi-ethnic population.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005487.
doi:10.1161/CIRCHEARTFAILURE.112.968701
PMCID: PMC4124746  PMID: 23032197
N-terminal pro-B-type natriuretic peptide; heart failure; left ventricular mass
14.  Discordance between non-HDL-cholesterol and LDL-particle measurements: Results from the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2013;229(2):517-523.
Background
Cardiovascular risk assessment incorporates measurement of atherogenic lipids such as non-HDL cholesterol (non-HDL-C). It remains uncertain under which circumstances atherogenic lipoprotein enumeration such as LDL particle number (LDL-P) differs from simultaneously acquired non-HDL-C.
Methods
Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) were deemed LDL-P>non-HDL-C discordant if they exhibited higher LDL-P than expected for simultaneously measured non-HDL-C, given the observed distribution of both in MESA. Conversely, a lower LDL-P than would be suggested from non-HDL-C characterized LDL-P
Results
Discordance was observed among 44% of subjects. LDL-P>non-HDL-C compared to LDL-P
Conclusions
Our results demonstrated that disagreement between LDL-P and non-HDL-C was common and significantly associated with several clinical characteristics. In the setting of discordance, LDL-P was more closely associated with CIMT and CAC than non-HDL-C, though observed differences were small.
doi:10.1016/j.atherosclerosis.2013.03.012
PMCID: PMC4066302  PMID: 23591415
cholesterol; lipoproteins; risk assessment; LDL-particle number; apolipoprotein B
Background
We evaluated 25 repolarization‐related ECG variables for the risk of coronary heart disease (CHD) death in 52 994 postmenopausal women from the Women's Health Initiative study.
Methods and Results
Hazard ratios from Cox regression were computed for subgroups of women with and without cardiovascular disease (CVD). During the average follow‐up of 16.9 years, 941 CHD deaths occurred. Based on electrophysiological considerations, 2 sets of ECG variables with low correlations were considered as candidates for independent predictors of CHD death: Set 1, Ѳ(Tp|Tref), the spatial angle between T peak (Tp) and normal T reference (Tref) vectors; Ѳ(Tinit|Tterm), the angle between the initial and terminal T vectors; STJ depression in V6 and rate‐adjusted QTp interval (QTpa); and Set 2, TaVR and TV1 amplitudes, heart rate, and QRS duration. Strong independent predictors with over 2‐fold increased risk for CHD death in women with and without CVD were Ѳ(Tp|Tref) >42° from Set 1 and TaVR amplitude >−100 μV from Set 2. The risk for these CHD death predictors remained significant after multivariable adjustment for demographic/clinical factors. Other significant predictors for CHD death in fully adjusted risk models were Ѳ(Tinit|Tterm) >30°, TV1 >175 μV, and QRS duration >100 ms.
Conclusions
Ѳ(Tp|Tref) angle and TaVR amplitude are associated with CHD mortality in postmenopausal women. The use of these measures to identify high‐risk women for further diagnostic evaluation or more intense preventive intervention warrants further study.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.
doi:10.1161/JAHA.114.001005
PMCID: PMC4310391  PMID: 25074699
coronary heart disease; electrocardiography; mortality; repolarization; risk factors
Background
The association between high‐density lipoprotein cholesterol (HDL‐C) and coronary heart disease (CHD) events is not well described in individuals with very high levels of HDL‐C (>80 mg/dL).
Methods and Results
Using pooled data from 6 community‐based cohorts we examined CHD and total mortality risks across a broad range of HDL‐C, including values in excess of 80 mg/dL. We used Cox proportional hazards models with penalized splines to assess multivariable, adjusted, sex‐stratified associations of HDL‐C with the hazard for CHD events and total mortality, using HDL‐C 45 mg/dL and 55 mg/dL as the referent in men and women, respectively. Analyses included 11 515 men and 12 925 women yielding 307 245 person‐years of follow‐up. In men, the association between HDL‐C and CHD events was inverse and linear across most HDL‐C values; however at HDL‐C values >90 mg/dL there was a plateau effect in the pattern of association. In women, the association between HDL‐C and CHD events was inverse and linear across lower values of HDL‐C, however at HDL‐C values >75 mg/dL there were no further reductions in the hazard ratio point estimates for CHD. In unadjusted models there were increased total mortality risks in men with very high HDL‐C, however mortality risks observed in participants with very high HDL‐C were attenuated after adjustment for traditional risk factors.
Conclusions
We did not observe further reductions in CHD risk with HDL‐C values higher than 90 mg/dL in men and 75 mg/dL in women.
doi:10.1161/JAHA.113.000519
PMCID: PMC4187512  PMID: 24627418
CHD events; total mortality; very‐high HDL‐C
Clinical cardiology  2012;36(1):15-20.
Introduction
Given the results of the JUPITER trial, statin initiation may be considered for individuals with elevated high sensitivity C-reactive protein (CRP). However, if followed prospectively, many individuals with elevated CRP may become statin-eligible, limiting the impact of elevated CRP as a treatment indication. This analysis estimates the proportion of people with elevated CRP that become statin eligible over time.
Methods
We followed 2,153 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of cardiovascular disease (CVD) and diabetes with LDL-cholesterol (LDL-C) <130 mg/dL at baseline to determine the proportion who become eligible for statins over 4.5 years. The proportion eligible for statin therapy, defined by the National Cholesterol Education Program (NCEP) 2004 updated guidelines, was calculated at baseline and during follow-up stratified by baseline CRP level (≥2 mg/L).
Results
At baseline, 47% of the 2,153 participants had elevated CRP. Among participants with elevated CRP, 29% met NCEP criteria for statins, compared to 28% without elevated CRP at baseline. By 1.5 years later, 26% and 22% (p=0.09) of those with and without elevated CRP at baseline reached NCEP LDL-C criteria and/or had started statins, respectively. These increased to 42% and 39% (p=0.24) at 3 years and 59% and 52% (p=0.01) at 4.5 years following baseline.
Conclusions
A substantial proportion of those with elevated CRP did not achieve NCEP based statin eligibility over 4.5 years of follow-up. These findings suggest that many patients with elevated CRP may not receive the benefits of statins if CRP is not incorporated into the NCEP screening strategy.
doi:10.1002/clc.22046
PMCID: PMC3953418  PMID: 22886783
Psychosomatic medicine  2012;75(2):137-143.
Objective
Attention control conditions are used to balance nonspecific attention in randomized trials of behavioral interventions. Very little guidance is available in the literature about which behavioral interventions and outcomes merit an attention control. The primary aim of the present paper is to demonstrate a scenario in which use of attention control in a behavioral randomized trial was unnecessary and possibly detrimental.
Methods
Exploratory analyses were performed in a randomized controlled trial that tested whether a patient-centered telephone counseling (PC) intervention reduced low-density lipoprotein cholesterol (LDL-C) levels in 355 participants with peripheral arterial disease (PAD), compared to attention control (AC) and usual care (UC) conditions. The PC intervention was designed to activate participants to ask their physician for lipid-lowering medication and/or increase dose intensity, increase medication adherence, and reduce fat intake. The AC condition involved attention-matched phone-delivered health education, and the UC condition consisted of an educational pamphlet.
Results
At 12-month follow-up, mean LDL-C changes were −11.1, and −6.8 mg/dl in the UC and AC conditions, respectively (p=.17). The proportion of participants who increased use or dose intensity of medication was significantly lower in AC than UC, 17.5% versus 30.5% (p=0.03). No significant difference between AC and UC were observed on other outcomes.
Conclusions
The AC had significantly worse medication outcomes and there was no indication of a therapeutic effect on other endpoints. Implications for use of attention control in behavioral randomized trials are discussed.
doi:10.1097/PSY.0b013e3182765dd2
PMCID: PMC3570637  PMID: 23197844
Attention control; control groups; placebo; behavioral interventions; randomized controlled trials
Breast cancer research and treatment  2013;139(3):10.1007/s10549-013-2578-y.
An increased risk of breast cancer has been reported in patients with non-melanomatous skin cancer (NMSC), but this association has not been studied in a large, multi-geographic population. We utilized data from the Women's Health Initiative observational study to assess whether history of NMSC is associated with breast cancer risk. This analysis included 70,246 postmenopausal White and Hispanic women aged 50–79, in which 4,247 breast cancer cases were identified over a mean (SD) of 11.3 (3.2) years. Baseline information was collected on demographics, medical history, sun exposure, and vitamin D intake. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95 % confidence intervals (CIs). The relationship between NMSC and breast cancer was examined as a time-dependent exposure using updated information on NMSC gathered during follow-up visits. All statistical tests were two sided. There were 5,595 women diagnosed with NMSC at study entry. The annualized rate of breast cancer was 0.64 % among women with a history of NMSC and 0.55 % among women with no history of NMSC. The multivariable-adjusted HR for breast cancer among women with a history of NMSC versus no history of NMSC was 1.07 (95 % CI 0.95–1.20, P = 0.27). Further evaluation stratified by tumor characteristics showed an increased risk of lymph node-positive disease, HR = 1.30 (95 % CI 1.01–1.67, P = 0.04), and regional-stage disease, HR = 1.33 (95 % CI 1.05–1.70, P = 0.02), among women with NMSC. There was no significant overall association between NMSC and breast cancer; however, there was an increased risk of more advanced-stage breast cancer which needs further exploration.
doi:10.1007/s10549-013-2578-y
PMCID: PMC3869388  PMID: 23760856
Non-melanomatous skin cancer; Breast cancer; Women's Health Initiative; Cohort study; Cancer risk
American Journal of Epidemiology  2012;176(6):473-481.
The discrimination of a risk prediction model measures that model's ability to distinguish between subjects with and without events. The area under the receiver operating characteristic curve (AUC) is a popular measure of discrimination. However, the AUC has recently been criticized for its insensitivity in model comparisons in which the baseline model has performed well. Thus, 2 other measures have been proposed to capture improvement in discrimination for nested models: the integrated discrimination improvement and the continuous net reclassification improvement. In the present study, the authors use mathematical relations and numerical simulations to quantify the improvement in discrimination offered by candidate markers of different strengths as measured by their effect sizes. They demonstrate that the increase in the AUC depends on the strength of the baseline model, which is true to a lesser degree for the integrated discrimination improvement. On the other hand, the continuous net reclassification improvement depends only on the effect size of the candidate variable and its correlation with other predictors. These measures are illustrated using the Framingham model for incident atrial fibrillation. The authors conclude that the increase in the AUC, integrated discrimination improvement, and net reclassification improvement offer complementary information and thus recommend reporting all 3 alongside measures characterizing the performance of the final model.
doi:10.1093/aje/kws207
PMCID: PMC3530349  PMID: 22875755
area under curve; biomarkers; discrimination; risk assessment; risk factors
JACC. Cardiovascular imaging  2012;5(9):923-930.
OBJECTIVES
The purpose of this study was to assess the prevalence and distribution of coronary artery calcium (CAC) across Framingham Risk Score (FRS) strata and therefore determine FRS levels at which asymptomatic, young to early middle-age individuals could potentially benefit from CAC screening.
BACKGROUND
High CAC burden is associated with increased risk of coronary events beyond the FRS. Expert panel recommendations for CAC screening are based on data obtained in middle-age and older individuals.
METHODS
We included 2,831 CARDIA (Coronary Artery Risk Development in Young Adults) study participants with an age range of 33 to 45 years. The number needed to screen ([NNS] number of people in each FRS stratum who need to be screened to detect 1 person with a CAC score above the specified cut point) was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using a chi-square test.
RESULTS
CAC scores >0 and ≥100 were present in 9.9% and 1.8% of participants, respectively. CAC prevalence and amount increased across higher FRS strata. A CAC score >0 was observed in 7.3%, 20.2%, 19.1%, and 44.8% of individuals with FRSs of 0 to 2.5%, 2.6% to 5%, 5.1% to 10%, and >10%, respectively (NNS = 14, 5, 5, and 2, respectively). A CAC score of ≥100 was observed in 1.3%, 2.4%, and 3.5% of those with FRSs of 0 to 2.5%, 2.6% to 5%, and 5.1% to 10%, respectively (NNS = 79, 41, and 29, respectively), but in 17.2% of those with an FRS >10% (NNS = 6). Similar trends were observed when findings were stratified by sex and race.
CONCLUSIONS
In this young to early middle-age cohort, we observed concordance between CAC prevalence/amount and FRS strata. Within this group, the yield of screening and possibility of identifying those with a high CAC burden (CAC score of ≥100) is low in those with an FRS of ≤10%, but considerable in those with an FRS >10%.
doi:10.1016/j.jcmg.2012.01.022
PMCID: PMC3664953  PMID: 22974805
coronary artery calcium; coronary heart disease; Framingham Risk Score; number needed to screen; risk factors
Purpose
Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors.
Methods
The Electronic Medical Records and GEnomics (eMERGE) network, which includes five biorepositories conducting genome-wide association studies, convened a Return of Results Oversight Committee (RROC) to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision-making.
Results
Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The RROC identified two sex chromosomal anomalies, Klinefelter Syndrome and Turner Syndrome, as well as homozygosity for Factor V Leiden, as findings that could warrant reporting. Views about returning HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of EMRs suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site).
Conclusion
The eMERGE experience reveals the complexity of return of results decision-making and provides a potential deliberative model for adoption in other collaborative contexts.
doi:10.1038/gim.2012.15
PMCID: PMC3723451  PMID: 22361898
Result return; biorepository; electronic medical records; deliberation; context
Jacc. Cardiovascular Imaging  2012;5(2):144-153.
Objectives
We sought to determine whether novel markers not involving ionizing radiation could predict CAC progression in a low-risk population.
Background
Increase in coronary artery calcium (CAC) scores over time (CAC progression) improves prediction of coronary heart disease (CHD) events. Due to radiation exposure, CAC measurement represents an undesirable method for repeated risk assessment, particularly in low predicted risk individuals (Framingham Risk Score [FRS] <10%).
Methods
From 6814 MESA participants, 2620 individuals were classified as low risk for CHD events (FRS <10%), and had follow-up CAC measurement. In addition to traditional risk factors [(RFs) - base model], various combinations of novel-marker models were selected based on data-driven, clinical, or backward stepwise selection techniques.
Results
Mean follow-up was 2.5 years. CAC progression occurred in 574 participants (22% overall; 214 of 1830 with baseline CAC =0, and 360 of 790 with baseline CAC >0). Addition of various combinations of novel markers to the base model (c-statistic =0.711), showed improvements in discrimination of approximately only 0.005 each (c-statistics 0.7158, 0.7160 and 0.7164) for the best-fit models. All 3 best-fit novel-marker models calibrated well but were similar to the base model in predicting individual risk probabilities for CAC progression. The highest prevalence of CAC progression occurred in the highest compared to the lowest probability quartile groups (39.2–40.3% versus 6.4–7.1%).
Conclusions
In individuals at low predicted risk by FRS, traditional RFs predicted CAC progression in the short term with good discrimination and calibration. Prediction improved minimally when various novel markers were added to the model.
doi:10.1016/j.jcmg.2011.11.008
PMCID: PMC3310187  PMID: 22340820
coronary calcium; Framingham risk score; risk factors; progression
Background
Genome wide association studies identified several single nucleotide polymorphisms (SNPs) associated with prevalent coronary heart disease (CHD) but less is known of associations with incident CHD. The association of thirteen published CHD SNPs was examined in five ancestry groups of four large US prospective cohorts.
Methods and Results
The analyses included incident coronary events over 9.1 to 15.7 average follow-up times in up to 26,617 white individuals (6,626 events), 8,018 African Americans (914 events), 1,903 Hispanics (113 events), 3,669 American Indians (595 events) and 885 Asian/Pacific Islanders (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex and ancestry (as needed). Nine loci were statistically associated with incident CHD events in whites: 9p21 (rs10757278, p=4.7 × 10−41), 16q23.1 (rs2549513, p=0.0004), 6p24.1 (rs499818, p=0.0002), 2q36.3 (rs2943634, p=6.7 × 10−6), MTHFDIL (rs6922269, p=5.1 × 10−10), APOE (rs429358, p=2.7 × 10−18), ZNF627 (rs4804611, p=5.0 × 10−8), CXCL12 (rs501120, p=1.4 × 10−6) and LPL (rs268, p=2.7 × 10−17). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals aged 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in African Americans and associations varied in other US minorities.
Conclusions
Prospective analyses of white individuals replicated several reported cross-sectional CHD-SNP associations.
doi:10.1161/CIRCGENETICS.111.960096
PMCID: PMC3293207  PMID: 22042884
9p21 locus; incident coronary heart disease; genetic polymorphisms

Results 1-25 (54)