Obtaining Informed Consent for Genetic Studies: The Multiethnic Study of Atherosclerosis

Abstract

Studies of DNA may yield important information about atherosclerosis. To determine how often study participants' consent to examine DNA is denied and the factors associated with that denial, information was collected on participants in the US Multiethnic Study of Atherosclerosis (MESA) during 2000–2004. Permission was sought for preparation of DNA, transformation of cells into cell lines, evaluation of genes related to heart and other health conditions, and access to DNA by private companies. Of the 5,494 participants at entry, 897 (16.3%) refused consent for some items and 247 (4.5%) completely denied consent. At a second examination 18 months later, 819 (15.0%) partially refused and 229 (4.2%) completely denied consent. Age among men (odds ratio per 10 years = 0.68, 95% confidence interval: 0.54, 0.85; p = 0.004), ethnicity (odds ratio for African American = 2.34, 95% confidence interval: 1.66, 3.32; p < 0.001), and field center (p < 0.001) were associated with complete denial. For those giving partial consent, the most common item refused was access to DNA by private companies (baseline: 99%; second examination: 90%); younger age, male gender, and African-American ethnicity were associated with refusal. The authors concluded that a small percentage of participants in epidemiologic studies refuse consent for DNA studies, and the majority are concerned about sharing their DNA data with industry.

Research involving DNA has become increasingly commonplace. Genotyping helps stratify patients according to the risk of a disease, genotyping clarifies the role of specific genes in the causation of complex disorders, and gene-expression profiling is used to assess disease prognosis and guide therapy (1). Genetic studies are particularly applicable to atherosclerosis, which is a classic example of a complex, multigenic disorder affected by numerous domains, such as metabolism, nutrients, hemostasis, and inflammation. An examination of relevant genes in persons early in the course of atheromatous disease may identify factors involved in the pathogenesis and progression of the disorder and serves to build hypotheses for future research (2).

Privacy issues and other concerns about genetic research may lead to reluctance by study participants to give consent for studies of their DNA despite their willingness to participate in other study components; this reluctance may influence the representativeness of the resulting study sample. It is thus important to determine how often participants refuse to have their DNA examined and the factors that influence that decision. The frequency with which persons deny consent for DNA studies, and why they withhold consent, has not been addressed by most population-based studies. A few exceptions are the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project, which reported that 2.2 percent of eligible participants refused consent for academic genetic research (3); the National Health and Nutrition Examination Survey, which noted that about 15 percent of participants declined to have their blood samples included in a national repository for genetic research (4); and the Takashima study, which observed that participation rates for the genetic component were 4.7–9.3 percent lower than those for the nongenetic component (5).

The incidence and prevalence of cardiovascular disease differ among racial and ethnic groups. A study that includes several of these groups may enable assessment of ethnic, age, and sex differences in subclinical disease prevalence, risk of progression, and rates of clinical cardiovascular disease. The Multiethnic Study of Atherosclerosis (MESA) is an ongoing, longitudinal study focused on recognition of risk factors for the prevalence and progression of subclinical vascular disease (6). Participating in MESA are 6,814 Caucasians, African Americans, Hispanics, and Chinese Americans enrolled in six centers in the United States. In this paper, we describe the frequency of full and partial consent for genetic research in this population-based sample, identify factors related to provision of partial consent, and suggest approaches that may improve the protections and acceptability of genetic research.

MATERIALS AND METHODS

MESA participants were free of a history of clinical cardiovascular disease and were enrolled in 2000–2001 at six field centers: Columbia University, New York, New York; Johns Hopkins University, Baltimore, Maryland; Northwestern University, Chicago, Illinois; University of California, Los Angeles, California; University of Minnesota, Minneapolis, Minnesota; and Wake Forest University, Winston-Salem, North Carolina. Participants were men and women who identified themselves as Caucasian, Asian, African American, or Hispanic and were between the ages of 45 and 84 years. They were recruited from the geographic boundaries of each field center by randomly selecting names listed in census tracts, in telephone exchanges, in church membership rosters, by motor vehicle departments, in the Health Care Financing Administration database, and in union rosters (details of recruitment procedures may be found at www.mesa-nhlbi.org, paragraph 4.2). Blood samples were obtained to measure a variety of factors implicated in atherogenesis, including lipids and other nutrients, clotting proteins, and metabolites. In addition, blood was obtained for the preparation of DNA for subsequent genetic studies. At a second examination approximately 18 months later, additional blood and DNA sampling was performed along with follow-up examinations for atherosclerosis. Participants were enrolled according to protocols approved by each site's local institutional review board.

At each of the two MESA examinations, participants were asked to read and sign consent forms describing the procedures to be performed at that examination (refer to the Appendix). All protocols were described to the participants orally. Staff were trained in administering informed consent at central training events. With regard to the DNA portion of the consent, staff were instructed to read each specific option and make certain that participants had sufficient time to think about their responses. Questions that staff were unable to answer were referred to an investigator; if answers were not readily forthcoming and participants had doubts about consenting to a particular item, the “no” response was ticked. Although the consent forms differed slightly from site to site according to the dictates of the local institutional review boards, five of the six sites asked participants to grant or refuse permission for each of the following five items:

1. Preparation of DNA from blood cells

2. Transformation of blood cells to cell lines (baseline examination only)

3. Administration of tests of genes related specifically to heart and vascular disease (main goals)

4. Administration of tests of genes related to other health conditions (secondary goals)

5. Access to participant DNA by researchers from private companies who might want to develop diagnostic tests or new therapies

For item 5, participants were told that their names or any identifying information would not be given to private-company researchers, and they were specifically informed that neither they nor their heirs would benefit financially from sharing their DNA with private companies. At these five sites, participants were specifically informed that their DNA would not be sold to anyone.

Participants could give full consent (agree to all five items), partial consent (agree to certain specific items and refuse others), or complete denial of consent for all DNA analyses. At site 6, participants were asked to grant or refuse permission for the following four items at the baseline examination only: 1) preparation and testing of DNA for primary or secondary study aims, 2) creation of cells lines, 3) release of their genetic results to them, and 4) reporting of their genetic results to their physician. Because the consent data from this site were collected differently, its participants were excluded from this analysis.

Statistical analyses were conducted by using consent data from the baseline and first follow-up examinations. Multivariate analyses were performed with Stata 8.0 software (Stata Corporation, College Station, Texas) by using logistic regression with empirical standard errors. All variables used were specified a priori, although exploratory analyses were conducted to find potential interactions. The particular interactions considered were with either gender or ethnicity against any variable present in the model. If a strong (p < 0.05) interaction was detected in the primary analysis, it was then included in all other analyses regardless of its statistical significance. The interactions were tested by forward selection from the base model. When reporting the interaction found between age and gender, the odds ratio for age among women requires a linear combination of the effect of age among men and the interaction. Also shown is the interaction to denote the magnitude of the differences between men and women, as well as the linear combination to test whether there is a statistically significant age effect within women.

Consent was coded 0, whereas denial of consent was coded 1; thus, the odds ratios were interpreted as the odds of denial of consent. For regressions on change in consent status over time, adjustments were made for the same variables. Some of the outcomes were sufficiently infrequent so as to justify interpreting the odds ratios as relative risks. Separate regressions were run for change from providing full consent and change to denial of consent. In all instances, p values should be taken as measures of relative strength because this study is exploratory, and no attempts were made to account for multiple testing. When possible, missing consent data at the follow-up examination were replaced with participants' complete data from the baseline examination.

RESULTS

The five centers included in this analysis recruited 5,494 participants. Full consent for DNA studies was given by 4,350 (79.2 percent) and partial consent by 897 (16.3 percent), and 247 (4.5 percent) refused to have their DNA prepared or used in any way. Table 1 lists the characteristics of those consenting to full or partial use or completely denying DNA consent at the baseline visit. Although there did not appear to be an association with age without adjustment for other variables, there were significant differences among ethnicities (p < 0.001). Higher percentages of subjects who self-identified as Asian (9 percent) or African American (8 percent) denied consent than Caucasian (3 percent) or Hispanic (1 percent) participants. There were also significant differences among field centers regarding the percentage that denied consent, with site 5 participants most likely to deny consent and site 4 subjects most likely to give consent; these differences persisted even after adjustment for ethnic composition at each site. Neither self-perception of health, a family history of cardiovascular disease, nor yearly gross family income was associated with provision of consent. In a multivariate analysis (table 2), age among men, ethnicity, and field center remained strongly predictive of consent status, with older participants being less likely to deny consent and African Americans being 2.3-fold more likely than Caucasians to deny consent.

Table 3 shows the percentages of subjects refusing each of the consent items, both at baseline and at the second examination, among those who gave partial consent for use of their DNA. As is evident, the item most frequently refused was the sharing of participant DNA with private companies. Table 4 shows the results of a multivariate analysis of data for the 1,138 participants who refused this use of their DNA at study entry. Age among men (odds ratio (OR) per 10 years = 0.83, 95 percent confidence interval (CI): 0.74, 0.93; p = 0.001), ethnicity (Asian, African American, and Hispanic compared with Caucasian), site, and yearly gross family income (more than $12,000 but less than $50,000) were significant predictors of refusal for industry sharing. Further exploration of the data showed that the income association was driven primarily by Caucasians and, to a lesser extent, by Chinese participants.

Although the majority of participants gave the same permissions for use of their DNA at both examinations, a number of them changed their minds about one or more aspects of DNA use. There were 117 subjects (2.1 percent) who had agreed to some elements of consent at examination 1 and refused consent to those elements at examination 2. Conversely, 135 (2.5 percent) participants gave consent for elements at the second examination after refusing at the first one. The specific elements for which consent changed, and the percentages of participants who changed their minds, are shown in table 5. Of those who changed their consent, 8.2 percent were Asians and 8.1 percent were African Americans compared with 2.9 percent Caucasians and 1.5 percent Hispanics (p < 0.001). Multivariate analysis showed that site (p = 0.052) and education (p = 0.029) were strongly associated with a positive change in consent status. Education was primarily driven by the high school category (OR = 4.36, 95 percent CI: 1.33, 14.27). Ethnicity (p < 0.001) and site (p < 0.001) were associated with change from consent to refusal, with African Americans more likely than Caucasians to change to refusal (OR = 2.89, 95 percent CI: 1.74, 4.77).

With regard to consent for DNA use by industry, older men (OR per 10 years = 1.30, 95 percent CI: 1.07, 1.58; p = 0.007) were more likely to give consent when they had previously refused this consent, whereas age had a slighter effect on women (OR per 10 years = 1.12, 95 percent CI: 0.96, 1.33; p = 0.157). Center also had a significant association with change to positive industry consent status (p < 0.001). African Americans were marginally less likely than Caucasians to change to a positive consent status (OR = 0.79, 95 percent CI: 0.58, 1.08; p = 0.144) but significantly more likely to refuse this permission when they had previously consented (OR = 2.25, 95 percent CI: 1.74, 2.97; p < 0.001).

DISCUSSION

In MESA, only a small number of subjects completely denied consent for DNA studies (247 participants, or 4.5 percent). African Americans constituted the majority of this group (53 percent), similar to the findings of the National Health and Nutrition Examination Survey (4), which analyzed the sociodemographic predictors of willingness to participate in genetic research in a representative sample of the US population and found the lowest consent rates in the group of non-Hispanic Blacks. Prior authors have attributed a lesser willingness of African Americans to participate in research to previous abuses of human subjects, especially of Blacks in the Tuskegee syphilis studies (7, 8), although we were unable to assess the reasons for individual decisions to deny consent for DNA testing in the current study.

The majority of participants agreed to all of the proposed genetic applications, but the element most commonly refused was access for researchers from private firms. Participation in research is often motivated by altruism, and participants in other studies have expressed concerns that private firms might profit from the time and samples they have donated (9). Reluctance to participate may also stem from fears of disclosure of personal information to the private sector, with the potential for future discrimination in employment or insurance. Pullman and Latus (10) proposed that private companies negotiate an upfront benefit-sharing agreement in exchange for the privilege of collecting DNA. Perhaps if participants were assured that private companies would maintain absolute confidentiality and that profits from the study of their DNA would be used to advance the health of the public, they would be more willing to consent to this component of genetic studies.

Our findings suggest that, when MESA participants were asked the same questions at two different times 18 months apart, a small percentage (4.6 percent) changed their directive on the use of DNA. The numbers of participants who withdrew consent between visits and who initially denied consent but then agreed were roughly equal. Although reasons for these changes are not known, it is possible that some of these subjects forgot whether they had previously agreed or disagreed or simply were not strongly committed to either course. Participants were not reminded of their initial consent directive at the second visit. Alternatively, some participants might have become more informed about DNA research during the interval between examinations, prompting a change in their acceptance of the research. Such issues might be explored in subsequent research on consent for use of DNA and changes in participants' attitudes over time.

The current consent process may not be sufficient to minimize study participants' perceived risks of genetic research. The risks of genetic research are often influenced by what subjects disclose to others after their research participation has ended (11). Wendler et al. (11) suggest that research subjects may be especially likely to forget past genetic research, and they question whether institutional review boards and genetic researchers should take steps to help subjects remember key aspects of their participation. Some studies state that researchers should allow participants to take a more active part in decision making and their interests (12–14). According to the National Bioethics Advisory Commission (15), current US federal regulations can protect subjects' rights and interests and, at the same time, permit well-designed research to proceed using materials already in storage as well as those newly collected. The Commission also states, “ … most research using human biological materials is likely to be considered of minimal risk because much of it focuses on research that is not clinically relevant to the sample source … ” (15, p. 67). Karen Cox (16) found that the difficulties with decision making among patients who were in the process of recruitment to anticancer drug trials were probably related to a lack of background information on which to base their decision about trial participation and a lack of knowledge and understanding of the research.

The consent form for the MESA study allowed participants to permit or refuse certain potential uses of their DNA. An explanation of each of these aspects of the research was available to participants when they received the consent forms, but how well the subjects understood the questions is unknown. Although staff received general training in administering consent forms, specific instruction with regard to genetic studies was not given. Differences in presentation of the material, experience of field center personnel, and relationships between specific institutions and their constituent populations may account for the variation among field centers in the percentages of participants consenting. Some of this variability might be lessened by standardized training across field centers (17, 18) but would require confirmation in a future study. In order for subjects to make informed, reasonable, and independent decisions about participating in research, adequate and sufficient information provided in a nondirective manner is of the utmost importance (19). In an investigation that compared consent rates for genetic and nongenetic studies in a Japanese population, more persons opted out of the genetic studies (5). However, providing educational material in the form of lectures and explanatory meetings significantly decreased the dropout rate from the genetic studies. Kegley (20) affirmed that cultural, ethnic, gender, religious, and other differences influence patients in their decision making but that there is also the possibility that investigators do not facilitate good informed consent in genetic decision making.

A limitation of our study, as in most epidemiologic studies, is that the population recruited for MESA may not be representative of the population at large. Inclusion of participants was constrained by requirements for specific numbers of individuals drawn from the various ethnic, gender, and age groups at the six centers. Therefore, our results may not be generalizable to other populations selected by using different criteria. The higher educational level of our participants compared with those in the National Health and Nutrition Examination Survey (4) (68 percent vs. 35 percent with some college or beyond) is consistent with known biases toward higher-educated persons being more likely to participate in research, but it limits the generalizability of our findings on genetic research primarily to subjects already participating in research studies. On the other hand, each field center used procedures designed to avoid selection bias, resulting in a fairly diverse group of participants. When future studies are planned, our population is well suited for obtaining genetic consent rates.

Our study of MESA participants shows that relatively few deny consent for any use of their DNA, while a much larger proportion refuse some aspects of DNA research, particularly use by private companies. Approaches to reducing rates of refusal or denial of consent to genetic studies should be explored, and may include 1) simplifying consent forms; 2) ensuring that the persons administering the consent document are knowledgeable about the research; and 3) clarifying investigators' research motives, especially those regarding private companies. More extensive public discussion, including education about the value of DNA studies, has been recommended to help persons make truly informed decisions about their participation (19). As in all human research, efforts to build a trusting relationship between staff and study subjects, to recognize that participants are collaborators in our research, and to express our appreciation for their altruistic efforts to improve the health of others are critical to conducting responsible, ethical, and productive human research.

APPENDIX

The following is a sample paragraph from the consent form used at one study site. It describes genetic/DNA testing.

You will be asked to allow genetic testing on the collected blood samples. Your blood samples may be used to prepare DNA or cell lines. Cell lines are blood cells that have been treated so they will live for long periods of time. This genetic testing is necessary to study genes important to the development of heart and blood vessel disease. The DNA will be stored in a central site listed under a code number. Results of your genetic status will not be reported to you unless they have clinical meaning. If we happen to find a gene that is linked to a medically treatable genetic disease, we will contact you if you have given us consent to do so. Results from genetic testing will not be released, placed in your medical record, or shared in any way with your relatives, personal physician, insurance companies, or any other third party unless you authorize MESA staff, in writing, to do so.

I give my permission to:

• YES  NO

• ——  —— Release the findings from tests and examinations to my physician

• ——  —— Prepare DNA from my blood samples

• ——  —— Create a cell line from my blood cells

• ——  —— Test my DNA for genes related to the main goals of the study: heart and blood vessel diseases

• ——  —— Test my DNA for genes related to the secondary goals of the study: other health conditions, such as diabetes, obesity, and cancer

• ——  —— Notify me if a potentially treatable genetic condition is identified

• ——  —— Allow researchers from private companies who wish to develop diagnostic lab tests or pharmaceutical therapies that could benefit many people to have access to my DNA (Note: you or your heirs will not benefit financially from this, nor will your cell line or DNA be sold to anyone)

This research was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute.

Other investigators, staff, and the MESA study participants made valuable contributions.

A full list of participating MESA investigators and institutions can be found at the following website: http://www.mesa-nhlbi.org.

D. G. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest: none declared.

References