Missing Heritability in the Tails of Quantitative Traits? A Simulation Study on the Impact of Slightly Altered True Genetic Models

Objective: Genome-wide association studies have identified robust associations between single nucleotide polymorphisms and complex traits. As the proportion of phenotypic variance explained is still limited for most of the traits, larger and larger meta-analyses are being conducted to detect additional associations. Here we investigate the impact of the study design and the underlying assumption about the true genetic effect in a bimodal mixture situation on the power to detect associations. Methods: We performed simulations of quantitative phenotypes analysed by standard linear regression and dichotomized case-control data sets from the extremes of the quantitative trait analysed by standard logistic regression. Results: Using linear regression, markers with an effect in the extremes of the traits were almost undetectable, whereas analysing extremes by case-control design had superior power even for much smaller sample sizes. Two real data examples are provided to support our theoretical findings and to explore our mixture and parameter assumption. Conclusions: Our findings support the idea to re-analyse the available meta-analysis data sets to detect new loci in the extremes. Moreover, our investigation offers an explanation for discrepant findings when analysing quantitative traits in the general population and in the extremes. Copyright (C) 2011 S. Karger AG, Base

Signs of subclinical coronary atherosclerosis in relation to risk factor distribution in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR)

AIMS: Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR). METHODS AND RESULTS: The measured CAC in 2220 MESA participants were compared with those in 3,126 HNR participants with the inclusion criteria such as age 45-75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC > 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC > 0 of 0.78 [95% confidence interval (CI): 0.72-0.85] after adjustment for known risk factors. Consequently, among participants with CAC > 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19-1.63), since many HNR participants have small (near zero) CAC values. CONCLUSIONS: The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort

Coronary age as a risk factor in the modified Framingham risk score

BACKGROUND: Clinical guidelines emphasize risk assessment as vital to patient selection for medical primary intervention. However, risk assessment methods are restricted in their ability to predict further coronary events. The most widely accepted tool in the United States is the Framingham risk score. In these equations age is a powerful risk factor. Although the extent of coronary atherosclerosis increases with age, there is large inter-individual variability in the rate of development and progression of this disease. This fact limits the utility of Framingham scoring when applied to individuals. Electron beam tomography (EBT), which measures coronary calcium, provides a non-invasive method for assessing coronary plaque burden, thus offering the possibility of providing a more accurate estimate of an individual's "arterial age" than from chronological age alone. METHODS: In this paper we discuss a new and simple method for incorporating the coronary calcium score (CCS) to modify the Framingham Risk Assessment (FRA). Using this method, a coronary artery calcium (CAC) age equivalent is generated that replaces chronological age in Framingham scoring. RESULTS AND DISCUSSION: Using a percentile table of CCS scores by age group and sex, individuals are matched to the age group whose calcium score most closely approximates their own individual score. The original 10-year absolute risk score of a 65-year old man with a CCS of 6 based on chronological age is 10%, whereas the modified absolute risk score based on CAC age equivalents is 2%. CONCLUSION: Our approach of replacing chronological age with CAC age equivalents in the Framingham equations possesses simplicity of application combined with precision. Physicians can easily derive adjusted Framingham risk scores and prescribe intervention methods based on patients' ten-year risks. The adjusted ten-year risks are likely to be more accurate than unadjusted risks since they are based on coronary calcium score information. The modified FRA approach not only may increase the predicted risk for some patients, but also may decrease the predicted risk for others, making it a more precise adjustment than other methods

Secondhand Smoke Exposure and Coronary Artery Calcification among Nonsmoking Participants of a Population-Based Cohort

Background: Secondhand smoke (SHS) consists of fine particulate matter, carcinogens, and various toxins that affect large parts of the population. SHS increases the risk for acute cardiovascular events and may contribute to the development of atherosclerosis

Progression of coronary calcification in healthy postmenopausal women

BACKGROUND: Coronary artery calcium score incrementally improves coronary risk prediction beyond that provided by conventional risk factors. Limited information is available regarding rates of progression of coronary calcification in women, particularly those with baseline scores above zero. Further, determinants of progression of coronary artery calcification in women are not well understood. This study prospectively evaluated rates and determinants of progression of coronary artery calcium score in a group of healthy postmenopausal women. METHODS: We determined coronary calcium score by computed tomography and recorded demographic, lifestyle and health characteristics of 914 postmenopausal women, a subset of those enrolled in the Women's Health Initiative Observational Study. The 305 women with calcium score ≥10 Agatston units at baseline were invited for repeat scan. This analysis includes the 94 women who underwent second scans. RESULTS: Mean age of study participants was 65 ± 9 years (mean ± SD), body mass index was 26.1 ± 6.1 kg/m(2), and baseline calcium score was 162 ± 220 Agatston units. Mean interval between scans was 3.3 ± 0.7 years. A wide range of changes in coronary calcium score was observed, from -53 to +452 Agatston units/year. Women with lower scores at baseline had smaller annual increases in absolute calcium score. Coronary calcium scores increased 11, 31 and 79 Agatston units/year among women with baseline calcium score in the lowest, middle and highest tertiles. In multivariate analysis, age was not an independent predictor of absolute change in coronary calcium score. Hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) use at baseline was a negative predictor (p = 0.015), whereas baseline calcium score was a strong, positive predictor (p < 0.0001) of progression of coronary calcification. CONCLUSION: Among postmenopausal women with coronary calcium score ≥ 10 Agatston units, rates of change of coronary calcium score varied widely. In multivariate analysis, statin use was a negative independent determinant, whereas baseline calcium score was a strong positive predictor of annual change in coronary calcium score

Predictive value of coronary calcifications for future cardiac events in asymptomatic patients with diabetes mellitus: A prospective study in 716 patients over 8 years

<p>Abstract</p> <p>Background</p> <p>To establish an efficient prophylaxis of coronary artery disease reliable risk stratification is crucial, especially in the high risk population of patients suffering from diabetes mellitus. This prospective study determined the predictive value of coronary calcifications for future cardiovascular events in asymptomatic patients with diabetes mellitus.</p> <p>Methods</p> <p>We included 716 patients suffering from diabetes mellitus (430 men, 286 women, age 55.2 ± 15.2 years) in this study. On study entry all patients were asymptomatic and had no history of coronary artery disease. In addition, all patients showed no signs of coronary artery disease in ECG, stress ECG or echocardiography. Coronary calcifications were determined with the Imatron C 150 XP electron beam computed tomograph. For quantification of coronary calcifications we calculated the Agatston score. After a mean observation period of 8.1 ± 1.1 years patients were contacted and the event rate of cardiac death (CD) and myocardial infarction (MI) was determined.</p> <p>Results</p> <p>During the observation period 40 patients suffered from MI, 36 patients died from acute CD. The initial Agatston score in patients that suffered from MI or died from CD (475 ± 208) was significantly higher compared to those without cardiac events (236 ± 199, p < 0.01). An Agatston score above 400 was associated with a significantly higher annualised event rate for cardiovascular events (5.6% versus 0.7%, p < 0.01). No cardiac events were observed in patients with exclusion of coronary calcifications. Compared to the Framingham risk score and the UKPDS score the Agatston score showed a significantly higher diagnostic accuracy in the prediction of MI with an area under the ROC curve of 0.77 versus 0.68, and 0.71, respectively, p < 0.01.</p> <p>Conclusion</p> <p>By determination of coronary calcifications patients at risk for future MI and CD could be identified within an asymptomatic high risk group of patients suffering from diabetes mellitus. On the other hand future events could be excluded in patients without coronary calcifications.</p

Calcium scoring using 64-slice MDCT, dual source CT and EBT: a comparative phantom study

Purpose Assessment of calcium scoring (Ca-scoring) on a 64-slice multi-detector computed tomography (MDCT) scanner, a dual-source computed tomography (DSCT) scanner and an electron beam tomography (EBT) scanner with a moving cardiac phantom as a function of heart rate, slice thickness and calcium density. Methods and materials Three artificial arteries with inserted calcifications of different sizes and densities were scanned at rest (0 beats per minute) and at 50–110 beats per minute (bpm) with an interval of 10 bpm using 64-slice MDCT, DSCT and EBT. Images were reconstructed with a slice thickness of 0.6 and 3.0 mm. Agatston score, volume score and equivalent mass score were determined for each artery. A cardiac motion susceptibility (CMS) index was introduced to assess the susceptibility of Ca-scoring to heart rate. In addition, a difference (Δ) index was introduced to assess the difference of absolute Ca-scoring on MDCT and DSCT with EBT. Results Ca-score is relatively constant up to 60 bpm and starts to decrease or increase above 70 bpm, depending on scoring method, calcification density and slice thickness. EBT showed the least susceptibility to cardiac motion with the smallest average CMS-index (2.5). The average CMS-index of 64-slice MDCT (9.0) is approximately 2.5 times the average CMS-index of DSCT (3.6). The use of a smaller slice thickness decreases the CMS-index for both CT-modalities. The Δ-index for DSCT at 0.6 mm (53.2) is approximately 30% lower than the Δ-index for 64-slice MDCT at 0.6 mm (72.0). The Δ-indexes at 3.0 mm are approximately equal for both modalities (96.9 and 102.0 for 64-slice MDCT and DSCT respectively). Conclusion Ca-scoring is influenced by heart rate, slice thickness and modality used. Ca-scoring on DSCT is approximately 50% less susceptible to cardiac motion as 64-slice MDCT. DSCT offers a better approximation of absolute calcium score on EBT than 64-slice MDCT when using a smaller slice thickness. A smaller slice thickness reduces the susceptibility to cardiac motion and reduces the difference between CT-data and EBT-data. The best approximation of EBT on CT is found for DSCT with a slice thickness of 0.6 mm

Incremental value of the CT coronary calcium score for the prediction of coronary artery disease

Objectives:: To validate published prediction models for the presence of obstructive coronary artery disease (CAD) in patients with new onset stable typical or atypical angina pectoris and to assess the incremental value of the CT coronary calcium score (CTCS). Methods:: We searched the literature for clinical prediction rules for the diagnosis of obstructive CAD, defined as≥50% stenosis in at least one vessel on conventional coronary angiography. Significant variables were re-analysed in our dataset of 254 patients with logistic regression. CTCS was subsequently included in the models. The area under the receiver operating characteristic curve (AUC) was calculated to assess diagnostic performance. Results:: Re-analysing the variables used by Diamond & Forrester yielded an AUC of 0.798, which increased to 0.890 by adding CTCS. For Pryor, Morise 1994, Morise 1997 and Shaw the AUC increased from 0.838 to 0.901, 0.831 to 0.899, 0.840 to 0.898 and 0.833 to 0.899. CTCS significantly improved model performance in each model. Conclusions:: Validation demonstrated good diagnostic performance across all models. CTCS improves the prediction of the presence of obstructive CAD, independent of clinical predictors, and should be considered in its diagnostic work-up. © 2010 The Author(s)

Small coronary calcifications are not detectable by 64-slice contrast enhanced computed tomography

Recently, small calcifications have been associated with unstable plaques. Plaque calcifications are both in intravascular ultrasound (IVUS) and multi-slice computed tomography (MSCT) easily recognized. However, smaller calcifications might be missed on MSCT due to its lower resolution. Because it is unknown to which extent calcifications can be detected with MSCT, we compared calcification detection on contrast enhanced MSCT with IVUS. The coronary arteries of patients with myocardial infarction or unstable angina were imaged by 64-slice MSCT angiography and IVUS. The IVUS and MSCT images were registered and the arteries were inspected on the presence of calcifications on both modalities independently. We measured the length and the maximum circumferential angle of each calcification on IVUS. In 31 arteries, we found 99 calcifications on IVUS, of which only 47 were also detected on MSCT. The calcifications missed on MSCT (n = 52) were significantly smaller in angle (27° ± 16° vs. 59° ± 31°) and length (1.4 ± 0.8 vs. 3.7 ± 2.2 mm) than those detected on MSCT. Calcifications could only be detected reliably on MSCT if they were larger than 2.1 mm in length or 36° in angle. Half of the calcifications seen on the IVUS images cannot be detected on contrast enhanced 64-slice MSCT angiography images because of their size. The limited resolution of MSCT is the main reason for missing small calcifications