Accounting for relatedness in family based genetic association studies.

OBJECTIVE: Assess the differences in point estimates, power and type 1 error rates when accounting for and ignoring family structure in genetic tests of association. METHODS: We compare by simulation the performance of analytic models using variance components to account for family structure and regression models that ignore relatedness for a range of possible family based study designs (i.e., sib pairs vs. large sibships vs. nuclear families vs. extended families). RESULTS: Our analyses indicate that effect size estimates and power are not significantly affected by ignoring family structure. Type 1 error rates increase when family structure is ignored, as density of family structures increases, and as trait heritability increases. For discrete traits with moderate levels of heritability and across many common sampling designs, type 1 error rates rise from a nominal 0.05 to 0.11. CONCLUSION: Ignoring family structure may be useful in screening although it comes at a cost of a increased type 1 error rate, the magnitude of which depends on trait heritability and pedigree configuration.

Relationship between vascular calcification and bone mineral density in the Old-order Amish.

Vascular calcification and osteoporosis are common age-related processes that are influenced by both genetic and nongenetic factors. Whether common genes underlie these processes is not known. We measured coronary artery calcification (CAC), aortic calcification (AC), and bone mineral density (BMD) in 682 men and women from large Old-Order Amish families. We assessed the heritabilities of these traits and then evaluated, using variance decomposition procedures, whether variation in the traits was influenced by a common set of genes (i.e., pleiotropy). Significant heritabilities were detected for BMD of the femoral neck and spine (0.65, 0.63) and CAC and AC (0.43, 0.42). Mean BMD did not differ significantly across quartiles of either CAC or AC in either sex. In neither the total group nor any single subgroup (men, women, postmenopausal women) did any of the genetic or environmental correlations between BMD and vascular calcification achieve statistical significance. However, subjects with a history of cardiovascular disease (CVD) events had significantly lower BMD at the femoral neck compared to subjects who reported no prior history of CVD (age-, sex-, body mass index-, and family structure-adjusted P = 0.003). We detected no evidence for shared genes affecting the joint distribution of bone and vascular calcification. However, our results do reveal a lower BMD in subjects with a prior history of CVD in the Old-Order Amish.

Predictors of length of stay after coronary stenting.

BACKGROUND: Postprocedure length of stay (LOS) remains an important determinant of medical costs after coronary stenting. Variables that predict LOS in this setting have not been well characterized. METHODS: We evaluated 359 consecutive patients who underwent coronary stenting with antiplatelet therapy. Sequential multiple linear regression (MLR) models were constructed with use of 4 types of variables to predict log-transformed LOS: preprocedure, intraprocedure, and postprocedure factors and adverse outcomes. RESULTS: Preprocedure factors alone explained more than one third of the variability in postprocedure LOS (adjusted R(2) = 0.37). The addition of procedural variables added little to the model (adjusted R(2) = 0.39). Entering nonoutcome postprocedure variables significantly enhanced the predictive capacity of the model, explaining more than half the variability in postprocedure LOS (adjusted R(2) = 0.54). In the final model, addition of outcome variables increased its predictive capacity only slightly (adjusted R(2) = 0.61). In this model, significant preprocedure factors included: myocardial infarction (MI) within 24 hours, MI within 1 to 30 days, women with peripheral vascular disease, intravenous heparin, and chronic atrial fibrillation. High-risk intervention was the only significant intraprocedure variable. Significant postprocedure factors included periprocedure ischemia; cerebrovascular accident or transient ischemic attack; treatment with intravenous heparin or nitroglycerin or intra-aortic balloon pump; and need for blood transfusion. Significant adverse outcomes included contrast nephropathy, gastrointestinal bleeding, arrhythmia, vascular complication, and repeat angiography. CONCLUSION: This prediction model identifies a number of potentially reversible factors responsible for prolonging LOS and may enable the development of more accurate risk-adjusted methods with which to improve or compare care.

Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography.

BACKGROUND: Electron-beam CT (EBCT) quantification of coronary artery calcification (CAC) allows noninvasive assessment of coronary atherosclerosis. We undertook a follow-up study to determine whether CAC extent, measured at the time of angiography by EBCT, predicted future hard cardiac events, comprising cardiac death and nonfatal myocardial infarction (MI). We also assessed the potential of selected coronary artery disease (CAD) risk factors, prior CAD event history (MI or revascularization), and angiographic findings (number of diseased vessels and overall disease burden) to predict subsequent hard events. METHODS AND RESULTS: Two hundred eighty-eight patients who underwent contemporaneous coronary angiography and EBCT scanning were contacted after a mean of 6.9 years. Vital status and history of MI during follow-up were determined. Cox proportional hazards models were used to compare the predictive ability of CAC extent with selected CAD risk factors, CAD event history, and angiographic findings. Median CAC score was 160 (range 0 to 7633). The 22 patients who experienced hard events during follow-up were older and had more extensive CAC and angiographic disease (P<0.05). Only 1 of 87 patients with CAC score <20 experienced a subsequent hard event during follow-up. Event-free survival was significantly higher for patients with CAC scores <100 than for those with scores >/=100 (relative risk 3.20; 95% CI 1.17 to 8.71). When a stepwise multivariable model was used, only age and CAC extent predicted hard events (risk ratios 1.72 and 1.88, respectively; P<0.05). CONCLUSIONS: In patients undergoing angiography, CAC extent on EBCT is highly predictive of future hard cardiac events and adds valuable prognostic information.

Gender- and age-dependent relationships between the E-selectin S128R polymorphism and coronary artery calcification.

Development and progression of atherosclerosis involves recruitment and binding of circulating leukocytes to areas of inflammation within the vascular endothelium mediated by a diverse array of cellular adhesion molecules. A polymorphism in the endothelial-leukocyte adhesion molecule 1 (E-selectin) gene has been implicated in early-onset, angiographically defined, severe atherosclerotic disease because it profoundly affects ligand recognition and binding specificity, resulting in a significant increase in cellular adhesion. Relationships between the E-selectin S128R polymorphism and coronary artery calcification (CAC), a marker of atherosclerosis detected with noninvasive electron beam computed tomography, were examined in 294 asymptomatic women aged 40--88 years and 314 asymptomatic men aged 30--80 years from the Epidemiology of Coronary Artery Calcification Study. The E-selectin polymorphism was not associated with presence of CAC in men of any age or in women over age 50. In women 50 years of age or younger the E-selectin polymorphism was significantly associated with presence of CAC after adjustment for age, body mass index, systolic blood pressure, ratio of total cholesterol to high-density lipoprotein cholesterol, and smoking. The significant association between E-selectin and CAC in women 50 years of age or younger may suggest that the 128R allele is a risk factor for coronary atherosclerosis in younger asymptomatic women, who typically have lower levels of traditional risk factors and reduced adhesion molecule expression due to the presence of higher levels of endogenous hormones.

Electron-beam computed tomography in the diagnosis of coronary artery disease: a meta-analysis.

BACKGROUND: Electron-beam computed tomography (EBCT) is a new, noninvasive method of detecting coronary artery calcification that is being increasingly advocated as a diagnostic test for coronary artery disease (CAD). Before its clinical use is justified, however, the overall accuracy of EBCT must be better defined. OBJECTIVE: To estimate the accuracy of EBCT in diagnosing obstructive CAD. DATA SOURCES: English-language studies from January 1, 1979, through February 29, 2000, were retrieved using MEDLINE and Current Contents databases, bibliographies, and expert consultation. STUDY SELECTION: We included a study if it (1) used EBCT as a diagnostic test; (2) reported cases in absolute numbers of true-positive, false-positive, true-negative, and false-negative results; and (3) used coronary angiography as the reference standard for diagnosing obstructive CAD (defined as > or = 50% diameter stenosis). DATA EXTRACTION: Data were extracted from the included articles by 2 independent reviewers. DATA SYNTHESIS: Weighted pooled analysis and summary receiver operating characteristic (ROC) curve analysis were used to determine sensitivity and specificity rates. Results from 9 studies with 1662 subjects were included. Pooled sensitivity for EBCT was 92.3% (95% confidence interval [CI], 90.7%-94.0%) and pooled specificity was 51.2% (95% CI, 47.5%-54.9%). Maximum joint sensitivity and specificity for EBCT from its summary ROC curve was 75%. As the threshold for defining an abnormal test varied, sensitivity and specificity changed. For a threshold that resulted in a sensitivity of 90%, specificity was 54%; when sensitivity was 80%, specificity rose to 71%. CONCLUSION: The performance of EBCT as a diagnostic test for obstructive CAD is reasonable based on sensitivity and specificity rates from its summary ROC curve.

Coronary artery calcification measured at electron-beam CT: agreement in dual scan runs and change over time.

PURPOSE: To use a recently described regression approach to evaluate agreement in the quantity of coronary artery calcification (CAC) with two consecutive acquisitions (dual scan runs) at electron-beam computed tomography (CT) in a quality-control program and to assess the change in CAC quantity over time in an individual. MATERIALS AND METHODS: A total of 1,376 asymptomatic research participants, who were not selected because they were at high risk for coronary artery disease, were examined for the quantity of CAC with dual scan runs at electron-beam CT. With these data, 95% limits of agreement were established and used to evaluate differences between scan runs performed approximately 3.5 years apart in 81 participants. RESULTS: The 95% limits of agreement depended on the mean quantity of CAC in the dual scan runs. Of the 81 participants whose examinations were approximately 3.5 years apart, 59 (73%) had no apparent change in CAC between the two examinations, 21 (26%) had large increases suggesting progression of CAC, and one (1%) had a large decrease suggesting regression of CAC. CONCLUSION: The demonstrated method can be used to evaluate both agreement in dual scan runs and change in quantity of CAC over time.

Association of fibrinogen with quantity of coronary artery calcification measured by electron beam computed tomography.

Increased plasma fibrinogen concentration is an independent risk factor for cardiovascular disease. Fibrinogen is the main coagulation protein in plasma, a determinant of blood viscosity, and can act as a cofactor for platelet aggregation. In this study of middle-aged men and women, we examined the association between plasma fibrinogen concentration and coronary artery calcification (CAC), a marker of preclinical coronary atherosclerosis. Two hundred twenty-eight participants were selected from the community-based Epidemiology of Coronary Artery Calcification Study, in which CAC was measured noninvasively by electron beam computed tomography. One hundred fourteen participants (57 men) were selected because they had high quantities of CAC; the remaining 114 participants (57 men) were selected because they had no detectable CAC. Logistic regression models were used to investigate the association between plasma fibrinogen concentration and high quantity of CAC. In men, an increase of 1 standard deviation in fibrinogen concentration was associated with a statistically significant odds ratio of 1.6 (95% CI 1.1 to 2.5) for a high quantity of CAC. In women, the corresponding odds ratio was 2.5 (95% CI 1.6 to 4.1). Inferences from sex-specific bivariate logistic models for odds ratios adjusted individually for each coronary risk factor and C-reactive protein were similar to those from the univariate models. In women, there was also a significant interaction between fibrinogen concentration and age. According to the models, younger women with high plasma fibrinogen were more likely to have high quantities of CAC than were younger women with low plasma fibrinogen. The strength of this association was diminished in older women.

The interface of genetics and public health: research and educational challenges.

As the target date for the sequencing of the human genome approaches, there is growing recognition that public health practice, research, and education will be impacted by new genetic technologies and information and that a multidisciplinary approach is required. Research in the emerging field of public health genetics encompasses a broad range of disciplines and will increasingly involve the interactions among the investigators in these fields. An overview of these areas of research is provided, with illustrative examples. Education in public health genetics needs to address a variety of audiences, including public health graduate students and practitioners, students from related disciplines, and health care professionals. Two new graduate programs at the Universities of Michigan and Washington and training opportunities for public health professionals are described. These educational efforts must be ongoing so that the potential of genetic technology and information can be appropriately used to benefit the health of all.

Probabilistic model for prediction of angiographically defined obstructive coronary artery disease using electron beam computed tomography calcium score strata.

BACKGROUND: Electron beam CT (EBCT) is an accurate, noninvasive method to detect and quantify coronary artery calcification, a marker of coronary artery disease (CAD). This investigation examined the accuracy of EBCT to detect obstructive CAD (> or =50% stenosis) and determined the optimal strata for quantity of coronary artery calcification to facilitate clinical decision-making. METHODS AND RESULTS: Clinical research patients (n=213) were examined with coronary angiography and EBCT (angiography group), and 765 research participants were examined with only EBCT (nonangiography group). Of the angiography group, 53% had obstructive CAD. After adjustment for verification bias, the estimated sensitivity and specificity for calcium score > or =1 were 97.0% and 72.4%, respectively. Likelihood ratios for strata of calcium score associated with obstructive CAD were calculated in each sex and 2 age groups. Among those > or =50 years old, the same 4 strata of EBCT calcium scores were identified in each sex; likelihood ratios ranged from 0.03 (calcium score 0) to 12.85 (calcium score > or =200). The same 3 strata EBCT calcium scores were identified in each sex among those <50 years old; likelihood ratios ranged from 0.13 (calcium score 0) to 190 (calcium score > or =100). CONCLUSIONS: A calcium score > or =200 among those > or =50 years old and calcium score > or =100 among those <50 years old provided strong evidence that patients of either sex had obstructive CAD. A calcium score of 0 provided strong evidence that patients > or =50 years old did not have obstructive CAD.

Progression of coronary artery calcification: a pilot study.

OBJECTIVE: To describe individual changes in the quantity of coronary artery calcification (CAC) measured by electron beam computed tomography (CT) and determine the rate of change in the quantity of CAC during a 3.5-year period. MATERIAL AND METHODS: Eighty-eight consecutive participants (51 men at least 30 years of age and 37 women at least 40 years of age) from a community-based CAC study were invited for a follow-up examination. Established coronary artery disease risk factors were studied at baseline. CAC score was measured by electron beam CT at baseline and follow-up. RESULTS: Of the 88 invited participants, 82 (93%) returned for a follow-up examination. Considerable variation existed among the participants in the extent of CAC score change. On average, CAC score increased over time by an estimated 24% each year (P<0.05). The relative increase in CAC score over time was significantly lower for older than for younger participants but did not vary significantly by sex. CONCLUSION: The ability to recruit follow-up participants in this pilot study and to detect significant change in CAC score over time provides evidence that electron beam CT is useful for studying progression of CAC in a sample and may be a valuable procedure for assessing the effectiveness of clinical interventions designed to retard progression of coronary atherosclerosis.

Potential of quantity of coronary artery calcification to identify new risk factors for asymptomatic atherosclerosis.

The goals of this study of adults asymptomatic for coronary artery disease (CAD) were to examine the relations between established CAD risk factors and quantity of coronary artery calcification (CAC) in three arterial locations using generalized linear mixed models and to estimate the variability in quantity of CAC explained by established CAD risk factors and the variability due to noise or artifact in the measure. The community-based sample included 740 asymptomatic adults (378 women) aged 20-59 years without hypertension or diabetes. Participants were recruited from Rochester, Minnesota, between 1990 and 1994. Quantity of CAC in three arterial locations was detected noninvasively by electron beam computed tomography. Sex, arterial location, age, body size, blood pressure, lipid metabolism, and smoking were significantly (p < 0.05) associated with quantity of CAC. Age was more strongly associated with quantity of CAC in the left than in the right coronary or circumflex arterial locations (p < 0.005). In each sex, risk factors together explained less than 40% of the variability in quantity of CAC. Noise or artifact in the measure accounted for only a small proportion of unexplained variability. Future studies of new risk factors for artery-specific quantity of CAC and its progression could provide additional etiologic insights into the atherosclerotic process.

The prevalence of anti-latex IgE antibodies among registered nurses.

BACKGROUND: Recent studies have reported that the prevalence of latex allergy among volunteer populations of health care workers ranges from 2% to 25%. To date, no epidemiologic study has investigated the prevalence of latex allergy and its relationship to possible risk factors among nurses. METHODS: Registered nurses (n = 741) in a large metropolitan hospital participated in a latex allergy prevalence study. Latex exposure data were obtained through self-administered questionnaires. Blood samples were classified as positive or negative for anti-latex IgE antibodies. Associations between potential risk factors for latex allergy and anti-latex antibodies were assessed. RESULTS: The participation rate was 90.6% among eligible nurses. Sixty-five samples were positive for a prevalence of 8.9% (95% confidence interval, 6.7 to 10.8). No differences in latex positivity among five nursing specialties were noted. Logistic regression indicated that after adjusting for age and sex, the following factors were significantly associated with latex seropositivity: nonwhite race (odds ratio [OR] = 4.2), reported histories of penicillin allergy (OR = 2.2), pruritic skin (OR = 2.2), conjunctivitis (OR = 3.0), localized urticaria (OR = 1.8), hay fever (OR = 2.1), avocado allergy (OR = 9.9), and ragweed allergy (OR = 3.4). CONCLUSIONS: The prevalence of latex sensitization appeared to be substantial (8.9%) among the nurses studied, and the prevalence did not vary by nursing specialty. The factors associated with latex positivity in the logistic regression model correctly classified 81.3% of the nurses with a sensitivity and specificity of 66.7% and 82.7%, respectively.

Electron-beam CT: use of a calibration phantom to reduce variability in calcium quantitation.

PURPOSE: To measure scanner and patient variation in computed tomographic (CT) numbers for electron-beam CT and to determine the ability of calibration phantoms to reduce variability in calcium quantitation. MATERIALS AND METHODS: Two calibration phantoms were imaged to ensure longitudinal homogeneity and to determine the short-term intrascanner variation in CT numbers. Each phantom set was imaged twice a day for 14 weeks to determine intra- and interscanner variation. Data from examinations of 167 patients that included the phantom were analyzed to determine the intra- and interpatient variation in CT numbers of objects with known calcium concentrations. RESULTS: The calibration reduced scanner variations by approximately 25%. The calcium concentration associated with a CT number of 130 HU varied from 77.1 to 136.4 mg/cm3 and was dependent on patient girth, sex, smoking history, and image level. CONCLUSION: Scanner and patient variations in CT numbers in electron-beam CT can be reduced with a calibration phantom. In vitro and in vivo estimates of calcium concentration had a precision of 2% and 7%, respectively.

Quantification of coronary artery calcium by electron beam computed tomography for determination of severity of angiographic coronary artery disease in younger patients.

OBJECTIVES: This study attempted to 1) evaluate five quantitative measures of coronary artery calcium and determine which best agreed with coronary artery disease severity at angiography; and 2) determine optimal quantity cutpoints to distinguish among no, mild and significant disease. BACKGROUND: Coronary artery calcium identified noninvasively by electron beam computed tomography is a sensitive marker for atherosclerosis. Quantitative assessments of calcium could distinguish among patients with no, mild and significant disease in clinical, screening and research settings. METHODS: One hundred sixty patients, 23 to 59 years old, underwent coronary angiography and electron beam computed tomography. Coronary artery calcium was defined as dense (> 130 Hounsfield units) foci > or = 2 mm2 on the tomogram. Regression and receiver operating characteristic analyses were used to evaluate five quantitative measures of calcium as predictors of the largest stenosis in the coronary arteries and to identify optimal cutpoints for distinguishing among disease categories. No disease was defined as no stenosis, mild disease as 10% to 49% diameter stenosis in one or more major branches and significant disease as > or = 50% diameter stenosis in one or more major branches. RESULTS: All measures evaluated performed well. With calcific area as the quantitative measure, the best cutpoint for discriminating between patients with and without disease was the presence of calcium: sensitivity 81%, specificity 86% and overall accuracy 83%. The best cutpoint for discriminating between patients with and without significant disease was 18 mm2: sensitivity 86%, specificity 81% and accuracy 83%. CONCLUSIONS: Because the ranges of calcium quantity overlapped across disease categories, no cutpoints would distinguish among categories with absolute certainty. However, selected cutpoints could rule out disease in most healthy subjects and identify most patients with significant disease.

Quantity of coronary artery calcium detected by electron beam computed tomography in asymptomatic subjects and angiographically studied patients.

OBJECTIVE: To determine the prevalence and quantity of coronary artery calcium (CAC) in asymptomatic subjects from the general population, to identify asymptomatic subjects without risk factors for coronary artery disease (CAD) with CAC scores in the top quartile of the distribution, and to compare CAC scores in patients who underwent angiography with percentiles in asymptomatic subjects of the same age and sex. DESIGN: We studied two samples from Rochester, Minnesota, which consisted of 772 asymptomatic subjects from the general population and 145 patients who underwent angiography, all of whom were 20 to 59 years of age. METHODS: Asymptomatic subjects were classified on the basis of their CAD risk profile. All subjects in both study samples underwent electron beam computed tomography. Age- and sex-specific calcium score percentiles were calculated in the asymptomatic sample. RESULTS: CAC prevalence in the asymptomatic subjects was lower in female than in male subjects and increased with advancing age. Of the asymptomatic sample, 8% had a low-risk profile with calcium scores in the top quartile of the distribution. More patients than expected in the angiography sample had calcium scores above the 50th through 95th score percentiles. CONCLUSION: The quantity of CAC was substantially increased in patients who underwent angiography. Subjects with large amounts of CAC but without known CAD risk factors may be a valuable subset of the population to investigate for previously unidentified CAD risk factors.