James H. Dwyer

Estimating Mediated Effects in Prevention Studies

The purpose of this article is to describe statistical procedures to assess how prevention and intervention programs achieve their effects. The analyses require the measurement of intervening or mediating variables hypothesized to represent the causal mechanism by which the prevention program achieves its effects. Methods to estimate mediation are illustrated in the evaluation of a health promotion program designed to reduce dietary cholesterol and a school-based drug prevention program. The methods are relatively easy to apply and the information gained from such analyses should add to our understanding of prevention.

Oxygenated Carotenoid Lutein and Progression of Early Atherosclerosis The Los Angeles Atherosclerosis Study

Background—Carotenoids are hypothesized to explain some of the protective effects of fruit and vegetable intake on risk of cardiovascular disease. The present study assessed the protective effects of the oxygenated carotenoid lutein against early atherosclerosis. Methods and Results—Epidemiology: Progression of intima-media thickness (IMT) of the common carotid arteries over 18 months was determined ultrasonographically and was related to plasma lutein among a randomly sampled cohort of utility employees age 40 to 60 years (n=480). Coculture: The impact of lutein on monocyte response to artery wall cell modification of LDL was assessed in vitro by quantification of monocyte migration in a coculture model of human intima. Mouse models: The impact of lutein supplementation on atherosclerotic lesion formation was assessed in vivo by assigning apoE-null mice to chow or chow plus lutein (0.2% by weight) and LDL receptor-null mice to Western diet or Western diet plus lutein. IMT progression declined with increasing quintile of plasma lutein (P for trend=0.007, age-adjusted;P =0.0007, multivariate). Covariate-adjusted IMT progression (mean±SEM) was 0.021±0.005 mm in the lowest quintile of plasma lutein, whereas progression was blocked in the highest quintile (0.004±0.005 mm;P =0.01). In the coculture, pretreatment of cells with lutein inhibited LDL-induced migration in a dose-dependent manner (P <0.05). Finally, in the mouse models, lutein supplementation reduced lesion size 44% in apoE-null mice (P =0.009) and 43% in LDL receptor-null mice (P =0.02). Conclusions—These epidemiological, in vitro, and mouse model findings support the hypothesis that increased dietary intake of lutein is protective against the development of early atherosclerosis.

Effects of Program Implementation on Adolescent Drug Use Behavior The Midwestern Prevention Project (MPP)

This study evaluated the relationship between level of program implementation and change in adolescent drug use behavior in the Midwestern Prevention Project (MPP), a school- and community-based program for drug abuse prevention. Trained teachers implemented the pro gram with transition year students. Implementation was measured by teacher self-report and validated by research staff reports. Adolescent drug use was measured by student self-report; an expired air measure of smoking was used to increase the accuracy of self-reported drug use. Regression analyses were used to evaluate adherence; exposure, or amount of implementation; and reinvention. Results showed that all schools assigned to the program condition adhered to the research by implementing the program. Exposure had a significant effect on minimizing the increase in drug use from baseline to one year. Exposure also had a larger magnitude of intervention effect than experimental group assignment. Reinvention did not affect drug use. Results are discussed in terms of research assumptions about quality of program implementation, and possible school-level predictors of implementation.

Parallel developmental trajectories of sensation seeking and regular substance use in adolescents.

This study applied piecewise latent growth modeling to longitudinal survey data from 2 different samples of adolescents (N=1,002 and N=1,206) to examine the hypothesis that development of sensation seeking in middle school would predict development of substance use (cigarettes, alcohol, and marijuana) in middle school and high school. Results showed that sensation seeking had strong predictive value for both concurrent and distal marijuana and alcohol use in both samples; however, initial level of sensation seeking predicted initial level of cigarette use during high school in 1 sample only. White participants scored consistently higher on both initial level and rate of increase in sensation seeking than did participants of other ethnicities. Advantages of this methodology are discussed in the context of substance use research.

Low Serum Cholesterol and Mortality Which Is the Cause and Which Is the Effect

BACKGROUND Many studies have reported an association between a low or lowered blood total cholesterol (TC) level and subsequent nonatherosclerotic disease incidence or death. The question of whether low TC is a true risk factor or alternatively a consequence of occult disease at the time of TC measurement remains unsettled. To shed new light onto this problem, we analyzed TC change over a 6- year period (from exam 1 in 1965 through 1968 to exam 3 in 1971 through 1974) in relation to subsequent 16-year mortality in a cohort of Japanese American men. METHODS AND RESULTS The study was based on 5941 men 45 to 68 years of age without prior history of coronary heart disease, stroke, cancer, or gastrointestinal-liver disease at exam 1 who also participated in exam 3 of the Honolulu Heart Program. The association of TC change with mortality end points was investigated with two different approaches (continuous and categorical TC change) with standard survival analysis techniques. Falling TC level was accompanied by a subsequent increased risk of death caused by some cancers (hemopoietic, esophageal, and prostate), noncardiovascular noncancer causes (particularly liver disease), and all causes. The risk-factor-adjusted rate of all-cause mortality was 30% higher (relative risk, 1.30; 95% CI, 1.06 to 1.59) among persons with a decline from middle (180 to 239 mg/dL) to low (< 180 mg/dL) TC than in persons remaining at a stable middle level. By contrast, there was no significant increase in all-cause mortality risk among cohort men with stable low TC levels. Nonillness mortality (deaths caused by trauma and suicide) was not related to either TC change or the average of TC levels in exams 1 and 3. CONCLUSIONS These results add strength to the reverse-causality proposition that catabolic diseases cause TC to decrease.

Progression of Carotid Intima-Media Thickness and Plasma Antioxidants: The Los Angeles Atherosclerosis Study

Objective—Recent epidemiologic and animal model data suggest that oxygenated carotenoids are protective against early atherosclerosis. We assessed the association between atherosclerotic progression, measured by carotid intima-media thickness (IMT), and plasma levels of oxygenated and hydrocarbon carotenoids, tocopherols, retinol, and ascorbic acid. Methods and Results—Participants were from an occupational cohort of 573 middle-aged women and men who were free of symptomatic cardiovascular disease at baseline. Ultrasound examination of the common carotid arteries, lipid level determination, and risk factor assessment were performed at baseline and 18-month follow-up. Plasma levels of antioxidants were determined at baseline only. Change in IMT was related to baseline plasma antioxidant levels in regression models controlling for covariates. In models adjusted for age, sex, and smoking status, 18-month change in IMT was significantly inversely related to the 3 measured oxygenated carotenoids (lutein, &bgr;-cryptoxanthin, zeaxanthin; P <0.02 for all) and one hydrocarbon carotenoid, &agr;-carotene (P =0.003). After adjusting for additional cardiac risk factors and potential confounders, including high-sensitivity C-reactive protein, these associations remained significant (P <0.05). Conclusions—These findings suggest that higher levels of plasma oxygenated carotenoids (lutein, zeaxanthin, &bgr;-cryptoxanthin) and &agr;-carotene may be protective against early atherosclerosis.

Analysis of data from group-randomized trials with repeat observations on the same groups

This study used Monte Carlo simulations to evaluate the performance of alternative models for the analysis of group-randomized trials having more than two time intervals for data collection. The major distinction among the models tested was the sampling variance of the intervention effect. In the mixed-model ANOVA, the sampling variance of the intervention effect is based on the variance among group x time-interval means. In the random coefficients model, the sampling variance of the intervention effect is based on the variance among the group-specific slopes. These models are equivalent when the design includes only two time intervals, but not when there are more than two time intervals. The results indicate that the mixed-model ANOVA yields unbiased estimates of sampling variation and nominal type I error rates when the group-specific time trends are homogenous. However, when the group-specific time trends are heterogeneous, the mixed-model ANOVA yields downwardly biased estimates of sampling variance and inflated type I error rates. In contrast, the random coefficients model yields unbiased estimates of sampling variance and the nominal type I error rate regardless of the pattern among the groups. We discuss implications for the analysis of group-randomized trials with more than two time intervals.

Psychosocial Stress and Cardiovascular Disease: Pathophysiological Links

Abstract The remarkable decline in cardiovascular disease (CVD) experienced in developed countries over the last 40 years appears to have abated. Currently, many CVD patients continue to show cardiac events despite optimal treatment of traditional risk factors. This evidence suggests that additional interventions, particularly those aimed at nontraditional factors, might be useful for continuing the decline. Psychosocial stress is a newly recognized (nontraditional) risk factor that appears to contribute to all recognized mechanisms underlying cardiac events, specifically, (a) clustering of traditional cardiovascular risk factors, (b) endothelial dysfunction, (c) myocardial ischemia, (d) plaque rupture, (e) thrombosis, and (f) malignant arrhythmias. A better understanding of the behavioral and physiologic associations between psychosocial stress and CVD will assist researchers in identifying effective approaches for reducing or reversing the damaging effects of stress and may lead to further reductions of CVD morbidity and mortality.

Oral Magnesium Supplementation Inhibits Platelet-Dependent Thrombosis in Patients With Coronary Artery Disease

The use of magnesium in the treatment of acute myocardial infarction remains controversial despite preliminary experimental evidence that magnesium plays a beneficial role as a regulator of thrombosis. This study examines whether oral magnesium treatment inhibits platelet-dependent thrombosis (PDT) in patients with coronary artery disease (CAD). In a randomized prospective, double-blind, crossover, and placebo-controlled study, 42 patients with CAD (37 men, 5 women, mean age 68 +/- 9 years) on aspirin received either magnesium oxide tablets (800 to 1,200 mg/day) or placebo for 3 months (phase 1) followed by a 4-week wash-out period, and the crossover treatment for 3 months (phase 2). PDT, platelet aggregation, platelet P-selectin flow cytometry, monocyte tissue factor procoagulant activity (TF-PCA), and adhesion molecule density were assessed before and after each phase. PDT was evaluated by an ex vivo perfusion model using the Badimon chamber. Median PDT was significantly reduced by 35% in patients who received magnesium versus placebo (delta change from baseline -24 vs 26 mm2/mm; p = 0.02, respectively). There was no significant effect of magnesium treatment on platelet aggregation, P-selectin expression, monocyte TF-PCA, or adhesion molecules. Oral magnesium treatment inhibited PDT in patients with stable CAD. This effect appears to be independent of platelet aggregation or P-selectin expression, and is evident despite aspirin therapy. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in patients with CAD.

Longitudinal effects of the midwestern prevention project on regular and experimental smoking in adolescents

The purpose of this study was to compare longitudinal smoking prevention program effects estimated on a population-based cohort sample of sixth- and seventh-grade students (average n per year = 4,664) using different schools as units of analysis (middle/junior high school as the school of origin or high school as the endpoint school of intervention). Fifty schools in 15 school districts were demographically matched and assigned to either a school and community-based program for prevention of cigarette, alcohol, and marijuana use, or a health education as usual control group. Smoking was measured by questionnaires administered to the students. An expired air (CO) measure of smoking was also administered to increase accuracy of self-reports. Program effects were estimated with regression analyses, controlling for school-level socioeconomic status, racial/ethnic make-up, urbanicity, and grade. Using school of origin as the unit of analysis, program effects showed 1 year net reductions of -8, -6, and -5% in prevalence rates of smoking in the last month, last week, and last 24 hr; 2-year program effects showed similar net reductions of -6, -5, and -3% (Ps less than 0.10-0.001). Analyses with endpoint school as the unit showed slightly weaker effects at the 2-year follow-up, the year during which 64% of students had moved to a junior high or high school. The findings are discussed in terms of the potential contamination of experimental groups in longitudinal studies from school consolidations, family mobility, and feeder patterns to high schools, and the different smoking environments represented by middle, junior high, and high schools.