ELSI Publications and Products Database

Understanding the social factors that influence the translation of genetic information to improved human health is a major objective of genomics research (Grand Challenges II-5,II-6 and III-1). One current approach for applying genomics to public health is to raise social awareness of family history as an independent, major risk factor for common diseases of adulthood in order to motivate appropriate preventive actions. This research will evaluate whether such public health measures translate into long-term health benefits for individuals having strong genomic predisposition to coronary heart disease (CHD). The Pawtucket Heart Health Program (PHHP) was a community-based intervention that substantially and specifically raised community awareness about familial predisposition to CHD. We propose to conduct a controlled epidemiologic study in order to evaluate whether this community-level awareness of family history translates into a survival advantage for adults having a strong genomic predisposition to CHD. We hypothesize that adults with a 1st degree family history of early-onset CHD who live in the community enriched with awareness about familial predisposition to CHD will survive longer than those from the control community. Using PHHP household interview records accrued between 1989 and 1992, baseline serologic and physical exam data and National Death Index follow-up data, we propose to conduct a 15-year longitudinal survival study (n=696) as the empirical basis for addressing our main hypothesis. Results from this study will provide timely empirical data regarding the potential impact that raising social awareness of genomic predisposition to CHD will have on population health.

This research project proposes to determine who actually chooses to obtain susceptibility genotyping for Alzheimer's disease (AD) and what the consequences of that information would be. Subjects will be randomized to one of two arms of study. In the Control arm, risk will be estimated based upon family history. In the Intervention arm, risk will be estimated by family history and by genotyping APOE, a common susceptibility polymorphism. Three clinical centers of care (Atlanta, New York City, and Cleveland) will enroll adult offspring of persons with AD; and using a carefully monitored protocol of counseling, assess the benefits and risks of providing this information. Determination of APOE status will be used in a format that parallels likely clinical usage and will permit the development of guidelines for clinicians for genetic testing, risk assessment and appropriate counseling scenarios. APOE determination and counseling, because of its inherent uncertainties, is an ideal model to develop new guidelines for whether and how best to use susceptibility gene markers in this and other diseases where such markers are or will be available in the future.

Project Summary/Abstract - The Risk Evaluation and Education for Alzheimer's Disease (REVEAL) Study is an ongoing series of multi-site randomized controlled trials that provide empirical data to address ethical, social and translational issues in genetic susceptibility testing for common diseases. Such work has become increasingly important given the expansion of genome-wide association studies identifying genetic risk factors for common diseases and corresponding efforts to commercialize genetic testing using these markers. Our paradigm for these trials is disclosure of Apolipoprotein E (APOE) genotype as part of risk assessment for Alzheimer's disease (AD) to unaffected individuals. In previous funding cycles we have enrolled 1000 participants in three separate trials, and our multi-disciplinary team has been highly productive in analyzing many aspects of the psychological impact and health behavior changes of receiving genetic risk information. We now propose the first translational genetics study to focus upon the situation where mild early symptoms of a disease (phenotype) and known genetic marker (genotype) information can be used together to produce more imminent risk projections. To do this, we will develop genotype specific risk curves for patients with Mild Cognitive Impairment, a condition where the APOE epsilon 4 allele is associated with more rapid progression to AD and differential response to certain pharmacological treatments. We will carry out a new randomized clinical trial to examine the impact of "imminent risk assessment" (i.e., risk of conversion to AD within 3 years) in these individuals and their care partners. We also propose to develop and validate a novel instrument, which we call the Capacity Assessment Tool for Genetic Testing, to reliably assess an individual's capacity to consent to genetic testing, which will be useful for clinicians and researchers working with neuropsychiatric diseases. Finally, we propose to systematically study the long-term psychological impact and health behavior changes in participants who learned their APOE genotype in earlier cycles of the REVEAL Study, some of whom were enrolled as early as 2000. These data will help inform policy and practice regarding the use of genetic risk information for common, complex diseases. Public Health Relevance: REVEAL IV Project Narrative: In this continuation of the REVEAL Study, we will conduct a new randomized clinical trial to determine the psychological and health behavior changes associated with disclosing APOE genotype and 3-year risk estimates to persons with mild memory problems. We will also create a new instrument that clinicians and researchers can use to reliably evaluate a patient's capacity to consent to genetic testing and examine long-term impact of genetic risk assessment by following REVEAL Study patients 2-10 years following disclosure.

The rapid identification of genetic risk factors for common, complex diseases poses great opportunities and challenges for public health. Genetic information is increasingly being utilized as part of commercial efforts, including direct-to-consumer (DTC) genetic testing to provide risk information on common diseases to consumers. Very few empirical data have been gathered to understand the characteristics of DTC test consumers, the psychological, behavioral and health impact, and the ethical, legal and social issues associated with DTC services. In the proposed research, we will survey users of the two leading US companies providing DTC genetic testing (23andMe and Navigenics) regarding their response to genetic tests for common diseases of interest, including heart disease, diabetes, Alzheimer's disease, arthritis, and breast, colon, lung and prostate cancers. Each company now has thousands of customers and each anticipates extensive sales in coming years. Each has agreed to allow our group to survey consumers using third-party data collection and analysis procedures that will enable an independent consideration of the benefits and risks of DTC testing in this format. The companies have also agreed to provide genetic test information (with respondents' permission) for analyses. A total of 1000 consumers (500 from each company) will be surveyed via the Internet before receipt of genetic test results, and we will survey this sample again at 1-2 weeks and six months following receipt of results. To carry out the proposed research, we have assembled an interdisciplinary team of experts with backgrounds in medicine, genetic testing policy and practice, health communication, genetic counseling, health psychology, health law, bioethics and web survey design. Many team members have collaborated on prior, related ELSI-funded research. Our aims are as follows: 1) to describe who seeks genetic testing and why, collecting information on demographics, motivations for seeking testing, and understanding of genetics; 2) to describe the impact of DTC genetic testing, including psychological impact, risk perceptions and comprehension, and personal utility of services; and 3) to assess what consumers do with their genetic information in the domains of health behaviors, insurance changes, information seeking, and communication with family and health care providers. This study will produce results that can be translated into recommendations to guide practice and policy in this rapidly emerging area. PUBLIC HEALTH RELEVANCE: Genetic information is increasingly being utilized as part of commercial efforts, including direct-to-consumer (DTC) genetic testing to provide risk information on common diseases to consumers. We will survey customers of the two leading DTC genetic test services in the U.S., using independent third party data collection and analysis to provide data on who is ordering these tests and why, and what its benefits and risks may be. This study will produce results that can be translated into recommendations to guide practice and policy in this rapidly emerging area.

The Risk Evaluation and Education for Alzheimer's Disease (REVEAL) Study is an ongoing, multi-site research project that is designed to evaluate the psychological and behavioral impact of genetic risk assessment with disclosure of APOE, a susceptibility polymorphism for Alzheimer's disease. In the first funding cycle of the REVEAL Study, we developed a novel risk assessment methodology and conducted a randomized clinical trial in which 162 first degree relatives of patients with AD received genetic risk assessment with or without APOE disclosure. The results of this trial suggested that genotype information could be disclosed safely with a highly structured protocol. In the (current) funding cycle of the REVEAL Study, we adjusted our risk curves to incorporate data on African Americans, and we have enrolled 297 subjects into a second randomized trial to examine the impact of genetic risk assessment with a brief, more clinically feasible protocol in comparison to a more conventional genetic counseling protocol. Preliminary results suggest that the brief protocol is as safe and effective in educating participants as the conventional protocol, so it will be used exclusively in the next phase of our research. In the next funding cycle of the REVEAL Study we propose to combine genotype and phenotype information, creating new risk estimates that incorporate the presence or absence of mild cognitive impairment (MCI), an amnestic condition which increases the probability of developing AD. Because APOE also increases the risk of cardiovascular disease, we will also study disclosure of genetic pleiotropy by enrolling 256 subjects, including 60 MCI subjects, into a new randomized clinical trial that compares the impact of providing risk information on two diseases to providing risk information on just one. We will add outcome measures that explore themes of race and social identity among participants volunteering for genetic risk assessment. We will also re-examine participants from the first two funding cycles to assess the long-term impact of genetic risk assessment and disclosure for AD up to 10 years following disclosure. This study will have an impact on public health by informing policy makers and clinicians about safe and effective ways to integrate genetic discoveries into the practice of medicine. .

This project will develop a new multidisciplinary undergraduate course in the ethical, legal, and social implications of the Human Genome Project. The course will offer a case-study oriented approach, focusing on representative genetic diseases, genetic programs, or episodes in the history of genetics, which will allow students to learn to identify and assess emerging issues and apply and test the analytical skills they develop as the course precedes. The course will serve as a model which can be exported to other colleges or universities. It will be offered in conjunction with a Faculty Summer Seminar involving eight pairs of teachers competitively selected from applicants from other liberal arts institutions. These teachers will be trained to carry their learning from this summer experience back to their home institutions, where they will be expected to introduce a similar course and serve as regional disseminators of course materials and methods. The course materials, developed by a distinguished advisory board, will be made available to other institutions as part of the ongoing Ethics Institute publication/media series, 'Dartmouth Teaching Resources in Applied and Professional Ethics.'

The objective of the proposed study is to determine whether computer-based education is as effective as practitioner-based education for increasing understanding of genetic testing for breast cancer. The primary study hypothesis is that comprehension scores on a test of immediate recall of information about genetic screening for breast cancer will be as high for patients informed by computer-based education as by practitioner-based education. The secondary hypotheses are that knowledge will affect intent to receive testing and that computer-based education is less costly than practitioner-based education. This study will test these hypotheses by a randomized controlled clinical trial using 150 women at high risk for familial breast cancer at two study sites. Consenting eligible subjects will be randomized to receive either education by computer or by genetic counselor. Immediately following the educational intervention, subjects will be given a multiple choice test of comprehension. Scores on this test will be measured, and group means will be compared. Intent to receive testing for the breast cancer susceptibility gene will be measured before and after the education intervention, and results will be compared to assess the effect of knowledge on intention to undergo genetic screening. Costs of computer- based education will be compared to practitioner-based education.

The long term goal of this project is to improve patient understanding about breast cancer risk and genetic testing. This project will conduct a clinical trial to evaluate the effectiveness of a CD-ROM, called 'Counseling by Computer: Breast Cancer Risk and Genetic Testing', at educating women about breast cancer risk, and options and implications of genetic testing. This project will take 36 months to complete and involves two specific aims: 1) to evaluate the effectiveness of the CD-ROM at educating women about breast cancer risk, and the options and implications of genetic testing through a randomized, pretest-posttest control-group, crossover trial of 210 patients at three study sites. [In preparation for this trial, 40 women (at least 1/4 of whom are minorities) will be recruited from a general internal medical clincial and breast cancer support group to evaluate the useability and effectiveness of the CD-ROM. This feedback will be used to refine the CD-ROM and study instruments.]; and 2) to evaluate the impact of a prior computer- based educational session on subsequent interactions between patients and genetic counselors. Comparisons will be made between those educated by a genetic counselor alone, and those educated by a computer prior to their session with a genetic counselor, by measuring: the amount of time spent with a genetic counselor; the quality and quantity of questions directed to the genetic counselor; patient's and genetic counselor's satisfaction; and perceived effectiveness of the counseling session.

This study will explore the ethical choices of a small group of genetic counselors and physicians. Drawing on previous research and the questions and case material from a larger study of clinicians' ethical decision-making about genetic information and prenatal and genetic testing, (see Wertz, below) the proposed research will provide data about the ethical choices, reasoning, thoughts, and feelings of clinicians. The research entails interviews; qualitative analysis of the interview data will focus on similarities and differences among respondents, with particular attention to gender differences, if any, and differences between MS-prepared genetic counselors and physicians. Participant observation at genetic counselor training courses will complement the interviews. The long-range aim of the study is to supplement existing and ongoing research by providing a detailed picture of the ways clinicians think and make choices about new genetic information.

This study will develop and validate (1) alternative methods for administering informed consent (IC) procedures to a diverse population of women at increased risk for breast cancer, and 2) standardized instruments to evaluate the effect of alternative methods on both comprehension and willingness to participate in research that includes screening for BRCA1/2 mutations. The study focuses on the 'informed' part of informed consent and reflects the principles and methods of cognitive-based theories of decision making and risk communication. The study will be conducted in three stages. In stage 1, counseling protocols and IC forms used in pervious research that involved BRCA1/2 screening will be compiled and evaluated. During stage two a control condition that reflects 'best current IC practices' will be developed along with two experimental conditions based on the deliberations of expert and lay panels. Also during stage 2, a standardized instrument to evaluate change in subjects' knowledge and beliefs about breast cancer and BRCA1/2 screening will be developed. In Stage 3 a standardized instrument will be administered to 456 first-degree relatives of women recently diagnosed with breast cancer before they are randomly assigned to and after they receive one of the IC conditions. Both process and outcome evaluation data will be collected. Outcomes will include changes in knowledge, attitudes and beliefs about breast cancer and genetic screening as well as willingness to participate in a research study that would include BRCA1/2 testing.

In order to gather important data on the psychosocial and behavioral aspects and sequelae of genetic counseling protocols for hereditary cancer, this investigation will study a consecutive series of approximately 1,000 index cases of Colorectal Cancer (CRC), identified at the UTMDACC, who will be offered molecular testing for hereditary nonpolyposis colon cancer (HNPCC) and participation in the study. From this series, approximately 65 carriers of HNPCC mutations, and 225 first degree relatives (FDRs) of those index cases will be enrolled. Spouses of FDRs (c.100) also will be enrolled in the psychosocial portion of the study. Finally, we will follow a sample of noncarrier index cases for psychosocial assessment in order to have carriers and noncarriers at all levels of the design. Major endpoints of the study will include completion of molecular testing; adherence to surveillance recommendations among carrier and noncarrier FDRs; and psychosocial indicators of distress and well-being. Four pilot studies will address important qualitative issues: a telephone 'counseling line' to deal with questions, concerns and problems; audiotaped counseling sessions as an educational intervention; process analysis of counseling sessions; and field trips to registry families to study family dynamics in risk notification and genetic counseling.