Changes in cholesterol and triglyceride concentrations in the Vanguard population of the Carotene and Retinol Efficacy Trial (CARET).

BACKGROUND: The Beta-Carotene and Retinol Efficacy Trial (CARET) was terminated 21 months ahead of schedule due to an excess of lung cancers. Deaths from cardiovascular disease also increased (relative risk=1.26 (95% confidence interval (CI) 0.99-1.61)) in the group assigned to a combination of 30 mg beta-carotene and 25 000 IU retinyl palmitate (vitamin A) daily. The basis for increased cardiovascular mortality is unexplained. DESIGN: We analyzed data on serum lipids, available for 1474 CARET Vanguard participants who were enrolled in the two CARET pilot studies and transitioned to the Vanguard study. Total cholesterol and triglycerides were measured 2 months prior to, 4 and 12 months following randomization, and annually thereafter for up to 7 y. INTERVENTION: In the asbestos-exposed pilot (N = 816), participants were assigned to beta-carotene and retinol or to placebo; in the smokers pilot (N = 1029), participants were assigned to beta-carotene, retinol, a combination, or placebo. RESULTS: Serum cholesterol showed a decline over time in both arms; serum triglycerides had a continuous decline over time in the placebo arm, but an initial increase that persisted in the active arm. Both serum cholesterol concentrations (P < 0.0003) and serum triglycerides (P < 0.0001) were significantly higher in the participants receiving vitamin A and/or a combination of vitamin A and beta-carotene (n = 863) as compared to the placebo group (n = 611). Those in this active intervention group had an average cholesterol concentration 5.3 mg/dl (0.137 mmol/l) higher than those in the placebo arm. CONCLUSION: The differences in cholesterol and triglyceride concentrations between the groups following randomization may account in part for the unexpected excess in cardiovascular deaths seen in the active intervention arm of CARET.

Assessment of human cancer risk: challenges for alternative approaches.

The ILSI/HESI Workshop on Alternatives to Carcinogenicity Testing aims to develop and apply new methods for assessment of potential carcinogenic risk to humans from various chemicals. The Workshop represents a major cooperative scientific effort. The long-term goals should be to greatly enhance the efficiency and reliability of such testing and to supplant, not just supplement, lifetime rodent bioassays. There are now well-established frameworks for risk assessment and risk management, putting risks into public health context and engaging stakeholders. The Lave-Omenn value-of-information model provides a useful way to assess the social costs and benefits of different strategies for testing large numbers of chemicals.

Predictors of serum selenium in cigarette smokers and the lack of association with lung and prostate cancer risk.

Epidemiological studies have suggested that low levels of selenium are associated with a higher incidence of both lung and prostate cancer. We analyzed the selenium serum concentration in 356 Carotene and Retinol Efficacy Trial (CARET) participants who later developed lung cancer and 356 matched controls and in 235 prostate cancer cases and 456 matched controls. Serum samples were obtained a mean of 4.7 years before diagnosis for both tumor types. Controls were matched to cases by year of randomization, age, smoking status, treatment arm, exposure population (asbestos workers or cigarette smokers), and year of blood draw. In the control population (n = 820), significant predictors of low serum selenium concentration were current smoking status and East Coast locations of the study center. Overall, there was no significant difference in mean serum selenium in lung cancer cases versus controls (11.91 microg/dl versus 11.77 microg/dl) or prostate cancer cases versus controls (11.48 microg/dl versus 11.43 microg/dl). No statistically significant trend in odds ratio was seen across quartiles of serum selenium for lung cancer (P = 0.49) or prostate cancer (P = 0.69). In a subpopulation of 174 prostate cancer patients who had clinical and pathological staging material reviewed, there was no association between serum selenium and Gleason score or clinical or pathological stage. In the CARET population of current and former smokers consuming an ad libitum diet, the serum concentration of selenium was not a risk factor for either lung cancer or prostate cancer.

The new millennium: values, perceptions of risk, and the key roles of science and technology.

Radiation protection and management of radioactive waste streams and products are certain to be important areas of public policy, worker education, and technology development in the new millennium. Overriding values of freedom, sustainability, transparency, and public participation in decision making about technology's benefits and risks will shape the public policy agenda. Early engagement of stakeholders in the identification and assessment of risks and in communications about risk management will be beneficial in most cases. Putting specific environmental problems into broader public health and ecologic context will be helpful to all parties and will improve decisions about how best to utilize precious resources and enhance public confidence in the process and the outcomes.

Prospects for pharmacogenetics and ecogenetics in the new millennium.

Genetics and genomics are certain to have a large impact in drug development and proper pharmaceutical treatment of subgroups of patients with many specific diseases. We should be able to increase the therapeutic margin for many agents. Genetic variation will also be important in refining estimates of risk from all kinds of environmental agents and in choosing more effective and more cost-effective risk reduction strategies. The linkage of information about genetic variation and information about environmental, nutritional, behavioral, metabolic, medical, and healthcare factors will be necessary to interpret the variation in clinical and public health terms. However, there is a great risk that present federal and state efforts to protect confidentiality and privacy of individual genetic information may make such research infeasible. In Michigan, a Governor's Commission has sought to strike an appropriate balance.

Potential clinical and economic effects of homocyst(e)ine lowering.

BACKGROUND: Elevated total homocyst(e)ine levels (>/=11 micromol/L) have been identified as a potential risk factor for coronary heart disease. However, the benefits expected from lowering homocyst(e)ine levels with folic acid and vitamin B(12) supplementation have yet to be demonstrated in clinical trials. SUBJECTS AND METHODS: We constructed a decision analytic model to estimate the clinical benefits and economic costs of 2 homocyst(e)ine-lowering strategies: (1) "treat all"-no screening, daily supplementation with folic acid (400 microg) and vitamin B(12) (cyanocobalamin; 500 microg) for all; (2) "screen and treat"-screening, followed by daily supplementation with folic acid and vitamin B(12) for individuals with elevated homocyst(e)ine levels. Simulated cohorts of 40-year-old men and 50-year-old women in the general population were evaluated. In the base-case analysis, we assumed that lowering elevated levels would reduce excess coronary heart disease risk by 40%; however, this assumption and others were evaluated across a broad range of potential values using sensitivity analysis. Primary outcomes were discounted costs per life-year saved. RESULTS: Although the treat-all strategy was slightly more effective overall, the screen and treat strategy resulted in a much lower cost per life-year saved ($13,600 in men and $27,500 in women) when compared with no intervention. Incremental cost-effectiveness ratios for the treat-all strategy compared with the screen and treat strategy were more than $500,000 per life-year saved in both cohorts. Sensitivity analysis showed that cost-effectiveness ratios for the screen and treat strategy remained less than $50,000 per life-year saved under several unfavorable scenarios, such as when effective homocyst(e)ine lowering was assumed to reduce the relative risk of coronary heart disease-related death by only 11% in men or 23% in women. CONCLUSIONS: Homocyst(e)ine lowering with folic acid and vitamin B(12) supplementation could result in substantial clinical benefits at reasonable costs. If homocyst-(e)ine lowering is considered, a screen and treat strategy is likely to be more cost-effective than universal supplementation. Arch Intern Med. 2000;160:3406-3412.

Public health genetics: an emerging interdisciplinary field for the post-genomic era.

Public health genetics is an exciting interdisciplinary area that brings all the public health sciences to bear on the emerging challenge of interpreting the medical and public health significance of genetic variation within populations. Sequencing of the human genome will generate an avalanche of genetic information to be linked with information about microbial, chemical, and physical exposures; nutrition, metabolism, lifestyle behaviors, and medications. The public health genetics mini-symposium in this volume includes articles dealing with educational innovations, host-pathogen interactions in infectious diseases, nutrition/genetic interactions in cancers, and population screening for hemochromatosis. Additional topics addressed here are ecogenetics and risk assessment, the genetics of unhealthful behaviors, and ethical and policy issues. Finally, a set of principles for community-based health research in populations is presented as a public health-oriented counterpart to the principle of autonomy and the practice of informed consent that have become key elements of ethics in medical care and medical research with individuals.

The Guide to Community Preventive Services will be influential in academic health centers: education, research and links with practice.

PIP: In both clinical medicine and in public health, programs, services and advice have been built based on individual judgments or professional consensus. There has been a lack of educational commitment, a knowledge base and a practice ethic solidly grounded in research and evaluation. The introduction of the Guide to Community Preventive Services, which has a clear link with the categories of immunizations, counseling services and screening tests, is considered to be influential in academic health centers who are engaged in research and evaluation studies. In addition, principles and guidelines for community-based research will facilitate real-world tests of ideas and guidelines for community preventive services. Performance standards and cost-effectiveness analyses will be expected by all payers and by policy-makers. Moreover, scientific advances, especially in the emerging field of public health genetics, will be incorporated. Thus, academics, practitioners, and employers should join forces to persuade payers to accept evidence-based convergence of related clinical guidelines. Such initiatives will improve the chances for increased investment in preventive medicine and public health.^ieng

Risk estimation and value-of-information analysis for three proposed genetic screening programs for chronic beryllium disease prevention.

Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. We describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and we apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DP beta 1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity (approximately 94%) but low specificity (approximately 70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort, the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD evaluations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.

Barriers and solutions in implementing occupational health and safety services at a large nuclear weapons facility.

The Hanford Nuclear Reservation is one of the U.S. Department of Energy's largest nuclear weapons sites. The enormous changes experienced by Hanford over the last several years, as its mission has shifted from weapons production to cleanup, has profoundly affected its occupational health and safety services. Innovative programs and new initiatives hold promise for a safer workplace for the thousands of workers at Hanford and other DOE sites. However, occupational health and safety professionals continue to face multiple organizational, economic, and cultural challenges. A major problem identified during this review was the lack of coordination of onsite services. Because each health and safety program operates independently (albeit with the guidance of the Richland field operations office), many services are duplicative and the health and safety system is fragmented. The fragmentation is compounded by the lack of centralized data repositories for demographic and exposure data. Innovative measures such as a questionnaire-driven Employee Job Task Analysis linked to medical examinations has allowed the site to move from the inefficient and potentially dangerous administrative medical monitoring assignment to defensible risk-based assignments and could serve as a framework for improving centralized data management and service delivery.

Effects of incentive items on participation in a randomized chemoprevention trial.

Behavioral research has an important role in increasing and maintaining participation in disease prevention trials, both in interventions and in follow-up visits. We conducted a randomized experiment among participants in the lung cancer chemoprevention trial, CARET (Carotene and Retinol Efficacy Trial) to test the effects of providing two incentives on retention. The items used for this study were a Certificate of Appreciation and one of two lapel pins, provided in a 2 2 design. Providing incentives, whether alone or in combination, had no statistically significant effect on retention by the two-year follow-up point. The successful implementation of this randomized incentive study has two implications for future research: (1) study of behavioral interventions and issues is feasible in the context of large controlled trials of disease end-points; and (2) such study is necessary to determine whether selected incentives can increase retention.

Caring for the community: the role of partnerships.

While many members of the public are deeply interested in and supportive of the three traditional missions of academic medicine--education, research, and clinical care, they also want to know what academic health centers (AHCs) are doing to improve the overall health of their communities. Much is already being done toward this goal, but improving communities' health in a measurable way requires a far broader agenda. AHCs must bring together the approaches of medicine and public health, and need to partner with many other players. This agenda must proceed despite all the other challenges that AHCs are currently facing. The author reviews illustrative and emerging national, state, and local efforts, public and private, in both medicine and public health, in partnerships with individuals and institutions in the larger community. He also highlights the physician's role in assisting stakeholders' efforts to deal with health threats from the environment, and offers advice about how such efforts should proceed. He closes by emphasizing the importance of community-based research to learn about the health statuses, problems, and resources of particular communities, and presents a set of principles for such community-based research.

Predictors of participant retention in two chemoprevention feasibility trials.

Retention of participants for intervention and follow-up activities is critical in cancer chemoprevention trials. Little has been published about retention patterns and predictors of retention in prevention studies. The Carotene and Retinol Efficacy Trial (CARET) provides an opportunity to study retention of volunteer participants in a large, long-term clinical trial. Two pilot studies were conducted in different populations to test the feasibility of critical strategies for the long-term study. Thirteen percent of the asbestos-exposed workers and 18% of the smokers became inactive during the pilot study. Of those remaining active, all but 2% of asbestos-exposed workers pilot study participants and 5% of smokers pilot study participants chose to participate in the full-scale efficacy trial. Five baseline predictors of inactivity for the asbestos-exposed participants emerged: being non-White, being a current smoker, having a history of high blood pressure at baseline, reporting two or more increases in symptoms during the placebo run-in, and having higher baseline levels of negative mental health measures (i.e. anxiety, depression, and fatigue). The only significant predictor of inactivity for smoker pilot participants was reporting symptoms during the placebo run-in. The most frequently reported reasons for becoming inactive during the pilot studies were general health issues and problems and symptoms that were seen as specific to the CARET vitamins. These findings suggest areas that could be tested to optimize retention in clinical trials.