Original Article
Disclosure of APOE Genotype for Risk of Alzheimer's Disease
N Engl J Med 2009; 361:245-254July 16, 2009
- Abstract
Background
The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and their family members has been discouraged. We examined the effect of genotype disclosure in a prospective, randomized, controlled trial.
Methods
We randomly assigned 162 asymptomatic adults who had a parent with Alzheimer's disease to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, and test-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure.
Results
There were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group, P=0.84), depression (8.8 and 8.7, respectively; P=0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondary comparisons between the nondisclosure group and a disclosure subgroup of subjects carrying the APOE ε4 allele (which is associated with increased risk) also revealed no significant differences. However, the ε4-negative subgroup had a significantly lower level of test-related distress than did the ε4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the ε4-positive and ε4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons).
Conclusions
The disclosure of APOE genotyping results to adult children of patients with Alzheimer's disease did not result in significant short-term psychological risks. Test-related distress was reduced among those who learned that they were APOE ε4–negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. (ClinicalTrials.gov number, NCT00571025.)
Media in This Article
Figure 1
Enrollment and Outcomes.Table 1
Characteristics of the Subjects at Baseline.Article Activity
- Article
Knowledge of the results of genetic-susceptibility testing may cause anxiety, depression, and other types of distress. Nevertheless, gene variants that are associated with risks of common diseases are being rapidly discovered, and genetic testing is now marketed to consumers.1-3 A variant of the gene APOE, which encodes apolipoprotein E, is associated with an increased susceptibility to Alzheimer's disease,4 and we thought that testing for the presence of this gene would be useful for evaluating the effect of genetic-risk assessment.4 By consensus, APOE testing is not currently recommended for asymptomatic persons; a major concern is the emotional effect of risk disclosure.5-8
In the Risk Evaluation and Education for Alzheimer's Disease (REVEAL) study, we hypothesized that persons who learned about their APOE genotype through an education-and-disclosure protocol would not have greater symptoms of anxiety, depression, or test-related distress than those not receiving such information.
Methods
Study Population and Instruments
We recruited adult children of a living or deceased parent with Alzheimer's disease through self-referral or telephone calls to families in research registries.9 As part of the screening process, we interviewed the subjects and administered standardized tests to evaluate their cognitive ability, academic achievement, and levels of anxiety and depression. We excluded subjects who scored 1.3 SD below norms on the Repeatable Battery for the Assessment of Neuropsychological Status or the Wide Range Achievement Test 3; higher than 20 on the Beck Anxiety Inventory (BAI), which ranges from 0 to 63, with higher scores indicating greater anxiety; or higher than 26 on the Center for Epidemiological Studies Depression Scale (CES-D), which ranges from 0 to 60, with higher scores indicating greater depression. Ancestry was determined by self-report obtained through a multiple-choice question, with the following options: white, American Indian, Asian, black, and Hispanic; we prespecified the designation of “other” in the event that a subject selected more than one option.
The BAI10,11 is a 21-item scale designed to distinguish symptoms of anxiety from those of depression and to be sensitive to change. This test is based on self-reported severity of a given anxiety symptom during the previous week, with a clinical cutoff score of 16 (moderate anxiety). The CES-D12,13 measures depressive symptoms in studies of nonclinical populations, with a clinical cutoff score of 16 to 20.14,15 We estimated that 5-point differences on either the BAI or the CES-D would be a sensitive indicator of clinically meaningful change and that with a sample of 46 persons per group, the study would have a statistical power of 80% to detect this difference on either scale. The Impact of Event Scale (IES) is a 15-item self-report instrument assessing test-related distress16,17 that is commonly used in genetics research. The scores range from 0 to 75, with higher scores indicating greater distress.18-25 A total score of 20 to 40 may indicate significant distress, and a 5-point difference is a conservative measure of clinically meaningful change. We also developed a series of original questions to gauge changes in risk perception, positive and negative effects of the genetic disclosure, and whether the subject would make the same decision again to undergo genetic testing.
Study Design
The REVEAL study group — an interdisciplinary team of experts in clinical trials, neurology, genetics, genetic counseling, health psychology, biostatistics, and bioethics — designed the study, drawing on surveys conducted with relatives of patients with Alzheimer's disease.26-28 We created risk curves for the disclosure process that were specific for age and sex, showing the lifetime cumulative incidence of Alzheimer's disease and the remaining risk of Alzheimer's disease for each subject (cumulative incidence from current age to the age of 85 years).29
The study was conducted from 2000 through 2003 at sites in Boston, Cleveland, and New York. It was approved by the institutional review board at each center and was coordinated by a board-certified or board-eligible genetic counselor at each site. Informed consent was obtained first by telephone, then in writing (Figure 1Figure 1
Enrollment and Outcomes., and the Supplementary Appendix, available with the full text of this article at NEJM.org). A 90-minute, semiscripted group session that was led by the genetic counselor described the limitations of APOE testing, the absence of a medical benefit of such testing, and the format for communication of the risk. All subjects later met individually with the genetic counselor for the drawing of blood samples, which were sent to Athena Diagnostics for APOE genotyping. Subjects were then randomly assigned to receive the genotyping results (the disclosure group) or not to receive the results (the nondisclosure group). Subjects in the nondisclosure group were individually shown two charts: one showing the incidence of Alzheimer's disease in the general population according to age and another showing the sex- and age-specific incidence of the disease among first-degree relatives of patients with Alzheimer's disease.29 Subjects in the disclosure group were shown the same curves with an additional line for their genotype-specific risk (Fig. 1 in the Supplementary Appendix). They also received their lifetime cumulative incidence risk by the age of 85 years. Subjects were told their APOE genotype and were given written reports of their lifetime cumulative incidence risk and remaining incident risk.29 Outcome Measures
The prespecified primary outcomes were changes in subjects' anxiety and depression symptoms, as measured by the BAI and the CES-D, respectively. The prespecified secondary outcome was test-related distress, as measured by the IES.
We administered the BAI and the CES-D before randomization and 6 weeks, 6 months, and 1 year after disclosure or nondisclosure of risk. We administered the IES at 6 weeks, 6 months, and 1 year. The primary analysis compared the two randomized groups. A secondary analysis compared the subgroup of subjects in the disclosure group who were informed that they carried at least one ε4 allele, which is associated with an increased risk of Alzheimer's disease (the ε4-positive subgroup), with either a subgroup of subjects who were informed that they did not carry an ε4 allele (the ε4-negative subgroup) or with the nondisclosure group.
Safety Monitoring
Throughout the study, genetics counselors monitored all subjects for adverse psychological effects. We created an independent external ethics and safety board to review the protocol, monitor study progress, and establish criteria for the reporting of adverse events to the institutional review board at each site. For example, subjects whose BAI or CES-D scores were more than 16 or increased by more than 15 points were immediately interviewed, with referral as appropriate. The chair of the ethics and safety board reviewed the results annually to screen for adverse or unanticipated events.
Statistical Analysis
We used two-sided t-tests or chi-square tests to compare baseline variables between the two initial randomization groups (the disclosure group and the nondisclosure group) and between the nondisclosure group and the ε4-positive and ε4-negative subgroups. We compared the rate of withdrawal from the study among the groups. Prespecified primary analyses compared scores on the BAI and the CES-D in the disclosure group with those in the nondisclosure group and included data from all time points, with the use of longitudinal analysis of mixed-effects models that were adjusted for age, sex, years of education, time, and baseline outcome score (if available). In the intention-to-treat analysis, missing values were calculated with the Markov chain Monte Carlo method of multiple imputation with the use of PROC MI statistical software, version 9.1 (SAS Institute).
To assess trends over time, we added interaction terms between group and time as covariates to longitudinal models. The model for the primary analysis was also run separately for each time point. This process was repeated for the IES scores. All three outcomes were then examined in the same manner for the two disclosure subgroups and the nondisclosure group. Although the study was not originally powered for equivalence testing, equivalence was demonstrated post hoc when a confidence interval for a group difference did not include 5 points in either direction.30 We examined raw changes in scores on each outcome measure to calculate the percentage of subjects whose changes in scores exceeded clinically significant thresholds (Fig. 3 in the Supplementary Appendix).
Results
Subjects
Of the subjects who participated in the informational interview and educational session, 61% and 84%, respectively, underwent phlebotomy (Figure 1). Twelve subjects withdrew from the study after phlebotomy and before randomization, and seven subjects with low neurocognitive scores and two subjects with high depression scores were excluded. The remaining 162 subjects were randomly assigned in a 2:1 ratio to either the disclosure group (111 subjects) or the nondisclosure group (51 subjects) (Table 1Table 1
Characteristics of the Subjects at Baseline.).After randomization, 14 subjects withdrew from the study, citing study-related reasons. Of the variables listed in Table 1, only the baseline BAI score showed a trend toward an association with withdrawal from the study (i.e., those who were less anxious were more likely to withdraw; P=0.07). Some subjects in the nondisclosure group were dissatisfied at not receiving their genotyping results; of these subjects, 8 (16%) withdrew, as did 6 subjects (5%) in the disclosure group (P=0.04). Of the 53 subjects in the ε4-positive subgroup, 3 (6%) withdrew from the study, as did 3 of 58 subjects (5%) in the ε4-negative subgroup. Of the 111 subjects in the disclosure group, 3 (3%) had the ε4/ε4 genotype, 46 (41%) had the ε3/ε4 genotype, 53 (48%) had the ε3/ε3 genotype, 5 (4%) had the ε2/ε3 genotype, and 4 (4%) had the ε2/ε4 genotype; none of the subjects had the ε2/ε2 genotype. Subjects with the ε4/ε4 genotype were given a higher risk estimate13 but were included in the ε4-positive group in analyses. Data that were collected after randomization but before withdrawal were included in the analyses.
For the end points of scores on the BAI and the CES-D, adjusted group means for the disclosure and nondisclosure groups did not differ significantly either with the use of the time-averaged longitudinal model or at any individual time point (Table 2Table 2
Measures of Anxiety, Depression, and Test-Related Distress in the Randomized Groups.). Changes from baseline in time-averaged scores for anxiety and depression did not differ significantly between the two groups: for the anxiety score, 4.5 in the disclosure group and 4.4 in the nondisclosure group (P=0.84); and for the depression score, 8.8 and 8.7, respectively (P=0.98).Interaction analyses indicated that between-group differences in scores were stable over time. We designed the prespecified analyses to allow detection of significant differences, and observing none, we then carried out a post hoc analysis for equivalence by examining 95% confidence intervals. All the confidence intervals excluded a difference of 5 points or more for scores on both the BAI (within 3 points) and the CES-D (within 2 points). Post-disclosure scores on the BAI and the CES-D were strongly associated with respective baseline scores on these measures (P<0.001 for both comparisons).
There were no significant differences between the nondisclosure group and the two disclosure subgroups (ε4-positive and ε4-negative) in the overall model on the BAI or the CES-D at any time point (Table 3Table 3
Measures of Anxiety, Depression, and Test-Related Distress in the Nondisclosure Group and in the Two Disclosure Subgroups with Known APOE ε4 Status. and Table 4Table 4
Differences in Measures of Anxiety, Depression, and Test-Related Distress among the Nondisclosure Group and the Two Disclosure Subgroups with Known APOE ε4 Status.), with all 95% confidence intervals excluding a difference of 5 points or more. We observed no significant differences between the nondisclosure group and the ε4-positive group over time using the longitudinal model or at any time point. Adjusted means were very similar to unadjusted means. (Tables show only adjusted means; raw means are shown in Fig. 2 in the Supplementary Appendix.)Adjusted mean IES scores for the disclosure and nondisclosure groups did not differ significantly at any time point or over time (6.9 in the disclosure group and 7.5 in the nondisclosure group, P=0.61). All 95% confidence intervals excluded clinically meaningful differences of 5 points or more, except for the scores at 6 months, which showed a trend toward less distress in the disclosure group. Adjusted IES scores in the ε4-negative subgroup were lower than those in the nondisclosure group at 6 months (P=0.01), with a similar trend over time (P=0.09) (Table 4). A comparison of IES scores in the ε4-negative group with those in the ε4-positive group showed significant differences over time (4.8 in the ε4-negative group vs. 8.5 in the ε4-positive group, P=0.01) and at 6 weeks (P=0.02) and 6 months (P=0.01), with a marginally significant difference at 12 months (P=0.06).
On the IES, we could not demonstrate equivalence to within 5 points with 95% confidence at any time point for comparisons between the nondisclosure group and the ε4-negative subgroup or between the ε4-positive subgroup and the ε4-negative subgroup. A comparison of the nondisclosure group with the ε4-positive subgroup showed no significant differences over time or at any time point. A difference of 5 points could be excluded with 95% confidence at 6 months, 12 months, and over time but not at 6 weeks, when scores for distress were higher in the ε4-positive subgroup. The results of all intention-to-treat analyses were similar to the results of analyses that included only subjects for whom scores at all time points were available (data not shown).
There was no significant change in our findings after adjustment for race, years of education, marital status, study site, referral source, family history, caregiver status, or mean age of the affected parent at the onset of disease. Lower overall BAI scores were associated with lower baseline BAI scores (P<0.001) and also with self-referral to the study (P=0.002). Lower overall CES-D scores were associated with lower baseline CES-D scores (P<0.001), with a younger age at the onset of the parent's symptoms of Alzheimer's disease (P=0.003), and with self-referral (P=0.008). Lower overall IES scores were associated with male sex (P=0.01). No other covariates were significantly associated with outcome.
Subjects in the ε4-positive group were more likely than those in either the nondisclosure group or the ε4-negative subgroup to report a high perceived risk and an overall negative effect of learning their genotype (Table 1 in the Supplementary Appendix). This finding suggests that the subjects in the ε4-positive group understood the information they received with respect to risk and that they had some negative feelings about receiving their results. Nevertheless, subjects in the ε4-positive subgroup were no less likely than those in the ε4-negative group to say that they would undergo testing again.
The distributions of changes in scores were similar among the two disclosure subgroups and the overall disclosure group at all time points (Fig. 3 in the Supplementary Appendix). Outcome scores, combined with prespecified safety criteria, triggered an assessment of adverse psychological effects in 13 subjects: 3 in the nondisclosure group, 4 in the ε4-negative subgroup, and 6 in the ε4-positive group (4 with the ε3/ε4 genotype and 2 with the ε4/ε4 genotype). None of the subjects attributed their psychological state to concern about disclosure but instead cited personal events or experiences, such as family illness and job-related stress, that were not related to the study.
Discussion
Subjects who were randomly assigned to undergo risk assessment with APOE disclosure did not have greater anxiety, depression, or test-related distress than those who were assigned to undergo risk assessment without APOE disclosure. Post hoc equivalence within 5 points was demonstrated at all visits over time for all outcomes, with the exception of the 6-month time point for the secondary outcome of the IES score, which showed a trend toward less distress in the disclosure group.
Subjects who learned they were ε4-positive and were therefore at increased risk for Alzheimer's disease showed no more anxiety, depression, or test-related distress than those who did not learn their genotype, although strict equivalence could not be demonstrated for test-related distress at 6 weeks, which reflected, in part, transient test-related distress among ε4-positive subjects at this time point. The comparison of subjects in the ε4-positive subgroup with those in the ε4-negative subgroup revealed significant but not clinically meaningful differences on test-related distress, driven by reduced distress among ε4-negative subjects at 6 months and 12 months. The change in the IES score from baseline to 6 weeks also differed significantly between the ε4-positive subgroup and the ε4-negative subgroup, which we partly attributed to an increase in distress in the ε4-positive group. On all outcome measures, mean scores in the two disclosure subgroups and the overall disclosure group were well below clinical thresholds for concern. Subjects with outcome scores above prespecified safety thresholds were evenly distributed among the nondisclosure group and the ε4-positive and ε4-negative subgroups, and these subjects did not cite genotype disclosure as contributing to their psychological distress.
Additional questions about risk perception and the effect of testing 6 weeks after disclosure suggested that subjects understood that their risk was higher or lower according to their genotype, and they had the expected negative or positive feelings about this news. Thus, subjects were not immune to the negative implications of learning that they had an increased risk, but these feelings were not associated with clinically significant psychological distress.
These data support the psychological safety of disclosing data regarding genetic-counseling protocols to screened adult children of patients with Alzheimer's disease who request such information, despite the frightening nature of the disease and the fact that disclosure has no clear medical benefit. Larger studies that follow subjects for more than 1 year will be required to detect uncommon and long-term effects, such as delayed emotional repercussions and injudicious life decisions.
APOE is the most robust risk marker available for Alzheimer's disease4; it is also associated with impaired memory among persons without dementia31 and with progression to Alzheimer's disease among persons with mild cognitive impairment.32 Surveys33-35 indicate that the public is interested in APOE genotyping and that 15% of primary care physicians who treat patients with Alzheimer's disease have already received requests for genotyping. If APOE genotyping is discovered to predict treatment efficacy or a risk of side effects, the level of interest is likely to increase.
Although visions of personalized medicine suggest that genetic risk markers will empower patients to improve their health through preventive practices and early interventions,36 there is concern that the understanding of risk among both the lay public and medical professionals is exceedingly poor,37 that genetic tests offering probabilistic estimates for risks of common diseases in the absence of a family history or environmental risks may be misunderstood, and that the psychological harm of such misunderstanding may outweigh the benefits, particularly with disorders such as Alzheimer's disease, for which no medical interventions are available.38-40 These concerns are amplified by the recent emergence of companies offering direct-to-consumer genetic testing, with most of them evaluating single-nucleotide polymorphisms that indicate the APOE genotype,1-3 in the absence of guidelines for deciding which associations between genes and disease have sufficient clinical validity and usefulness to justify disclosure and with no gauge of the effect of such disclosure. Caution is thus warranted, and empirical data are valuable.
Our study is limited in that it concerns a single polymorphism that is robustly associated with Alzheimer's disease. In addition, most of the subjects were of fairly homogeneous and similar ancestry. If APOE genotyping had been provided without genetic counseling or to subjects who had no family history of Alzheimer's disease, the results might have been different. In addition, the exclusion of subjects with low neurocognitive scores and high depression scores may have influenced the results. Within these constraints, our results suggest that disclosure of genotyping information provides a benefit to those who are negative for a susceptibility variant and causes transient, modest distress to those with a positive result.
Supported by grants (R01-HG/AG02213, to Dr. Green; and R01-AG09029, to Dr. Farrer) from the Ethical, Legal and Social Implications (ELSI) Branch of the National Human Genome Research Institute and the National Institute on Aging (NIA); by an NIA Mentoring Award (K24 AG027841, to Dr. Green); by a grant (P30-AG13846) from the Boston University Alzheimer's Disease Center; by a grant (M01-RR00533) from the Boston University General Clinical Research Center; and by a grant (P50-HG003391, to Duke University) from the Centers of Excellence in ELSI Research.
Drs. Relkin and Farrer report receiving consulting fees from Smart Genetics, which provided direct-to-consumer APOE genotyping from March 2008 through October 2008, when it ceased operations. No other potential conflict of interest relevant to this article was reported.
We thank Joe Massaro, Ph.D., Suzanne Hendrix, Ph.D., and Steve Piantadosi, Ph.D., for their helpful comments on the manuscript.
Source Information
From Boston University School of Medicine (R.C.G., T.B., L.A.F.), Boston University School of Public Health (R.C.G., L.A.C., C.C., L.A.F.), and Harvard Medical School Genetics Training Program (R.C.G.) — all in Boston; the University of Michigan School of Public Health, Ann Arbor (J.S.R.); Weill Cornell Medical College, New York (N.R.R.); Case Western Reserve University School of Medicine, Cleveland (P.J.W., M.B.); Columbia University School of Medicine, New York (S.L.E.); the University of British Columbia, Vancouver Hospital and Health Sciences Centre, Vancouver, BC, Canada (A.D.S.); Indiana University School of Medicine, Indianapolis (K.A.Q.); and Duke University, Durham, NC (R.C.-D.).
Address reprint requests to Dr. Green at Boston University School of Medicine, 715 Albany St., L-320, Boston, MA 02118, or at rcgreen@bu.edu.
Members of the Risk Evaluation and Education for Alzheimer's Disease (REVEAL) Study Group are listed in the Appendix.
Appendix
Members of the REVEAL study group are as follows: G. Annas, Boston University School of Medicine, Boston; D. Bhatt, Cleveland Clinic Foundation, Cleveland; B. Biesecker, Johns Hopkins School of Public Health, Baltimore; D. Blacker, Harvard School of Public Health, Boston; E. Cox, Weill Cornell Medical College, New York; K. Christensen, University of Michigan School of Public Health, Ann Arbor; J.G. Davis, Weill Cornell Medical College, New York; G.-A. Fasaye, Howard University, Washington, DC; P. Griffith, Morehouse School of Medicine, Atlanta; S. Hiraki, Boston University School of Medicine, Boston; E. Juengst, Case Western Reserve University School of Medicine, Cleveland; J. Karlawish, University of Pennsylvania School of Bioethics, Philadelphia; E. Linnenbringer, University of Michigan, Ann Arbor; T. Marteau, Kings College, London; E. Neimeister, Weill Cornell Medical College, New York; T. Obisesan, Howard University, Washington, DC; R. Petersen, Mayo Alzheimer's Disease Research Center, Rochester, MN; S. Post, Case Western Reserve University School of Medicine, Cleveland; L. Ravdin, Weill Cornell Medical College, New York; R.P. Reilly, Shriver Center, Waltham, MA; D. Roter, Johns Hopkins Bloomberg School of Public Health, Baltimore; C. Royal, Duke University, Durham, NC; R. Stern, Boston University School of Medicine, Boston; E. Topol, Cleveland Clinic Lerner College of Medicine, Cleveland; W. Uhlmann, University of Michigan, Ann Arbor: M. Williams, Morehouse School of Medicine, Atlanta; L. Wright, Medical College of Georgia, Athens.
- References
References
1
Wolfberg AJ . Genes on the Web -- direct-to-consumer marketing of genetic testing. N Engl J Med 2006;355:543-545
Full Text | Web of Science | Medline2
Hunter DJ ,Khoury MJ ,Drazen JM . Letting the genome out of the bottle -- will we get our wish? N Engl J Med 2008;358:105-107
Full Text | Web of Science | Medline3
Offit K . Genomic profiles for disease risk: predictive or premature? JAMA 2008;299:1353-1355
CrossRef | Web of Science | Medline4
Farrer LA ,Cupples LA ,Haines JL , et al. Effects of age, sex and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA 1997;278:1349-1356
CrossRef | Web of Science | Medline5
Farrer LA ,Brin MF ,Elsas L , et al. Statement on use of apolipoprotein E testing for Alzheimer disease. JAMA 1995;274:1627-1629
CrossRef | Web of Science6
Post SG ,Whitehouse PJ ,Binstock RH , et al. The clinical introduction of genetic testing for Alzheimer disease: an ethical perspective. JAMA 1997;277:832-836
CrossRef | Web of Science | Medline7
McConnell LM ,Koenig BA ,Greely HT ,Raffin TA . Genetic testing and Alzheimer disease: has the time come? Nat Med 1998;4:757-759
CrossRef | Web of Science | Medline8
Relkin NR ,Tanzi R ,Breitner J , et al. Apolipoprotein E genotyping in Alzheimer's disease. Lancet 1996;347:1091-1095
Web of Science | Medline9
Roberts JS ,Barber M ,Brown TM , et al. Who seeks genetic susceptibility testing for Alzheimer's disease: findings from a multisite, randomized clinical trial. Genet Med 2004;6:197-203
CrossRef | Web of Science | Medline10
Beck AT, Steer RA. Beck Depression Inventory. New York: Psychological Corporation, 1987.
11
Beck AT ,Epstein N ,Brown G ,Steer RA . An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56:893-897
CrossRef | Web of Science | Medline12
Radloff LS . The CES-D Scale: A self report depression scale for research in the general population. Appl Psychol Meas 1977;1:385-401
CrossRef13
Santor DA ,Zuroff DC ,Ramsay JO ,Cervantes P ,Palacios J . Examining scale discriminability in the BDI and CES-D as a function of depressive severity. Psychol Assess 1995;7:131-139
CrossRef | Web of Science14
Vernon SW ,Gritz ER ,Peterson SK , et al. Correlates of psychologic distress in colorectal cancer patients undergoing genetic testing for hereditary colon cancer. Health Psychol 1997;16:73-86
CrossRef | Web of Science | Medline15
Lerman D ,Narod S ,Schulman K , et al. BRCA1 testing in families with hereditary breast-ovarian cancer: a prospective study of patient decision making and outcomes. JAMA 1996;275:1885-1892
CrossRef | Web of Science | Medline16
Horowitz M ,Wilner N ,Alvarez MA . Impact of Event Scale: a measure of subjective stress. Psychosom Med 1979;41:209-218
Web of Science | Medline17
Zilberg NJ ,Weiss DS ,Horowitz MJ . Impact of Event Scale: a cross-validation study and some empirical evidence supporting a conceptual model of stress response syndromes. J Consult Clin Psychol 1982;50:407-414
CrossRef | Web of Science | Medline18
Payne K ,Nicholls S ,McAllister M ,Macleod R ,Donnai D ,Davies LM . Outcome measurement in clinical genetics services: a systematic review of validated measures. Value Health 2008;11:497-508
CrossRef | Web of Science | Medline19
DudokdeWit AC ,Tibben A ,Duivenvoorden HJ ,Niermeijer MF ,Passchier J . Predicting adaptation to presymptomatic DNA testing for late onset disorders: who will experience distress? J Med Genet 1998;35:745-754
CrossRef | Web of Science | Medline20
Michie S ,Bobrow M ,Marteau TM . Predictive genetic testing in children and adults: a study of emotional impact. J Med Genet 2001;38:519-526
CrossRef | Web of Science | Medline21
Thewes B ,Meiser B ,Hickie IB . Psychometric properties of the Impact of Event Scale amongst women at increased risk for hereditary breast cancer. Psychooncology 2001;10:459-468
CrossRef | Web of Science | Medline22
Meiser B ,Butow P ,Friedlander M , et al. Psychological impact of genetic testing in women from high-risk breast cancer families. Eur J Cancer 2002;38:2025-2031
Web of Science | Medline23
Schwartz MD ,Peshkin BN ,Hughes C ,Main D ,Isaacs C ,Lerman C . Impact of BRCA1/BRCA2 mutation testing on psychologic distress in a clinic-based sample. J Clin Oncol 2002;20:514-520
CrossRef | Web of Science | Medline24
Smith CO ,Lipe HP ,Bird TD . Impact of presymptomatic genetic testing for hereditary ataxia and neuromuscular disorders. Arch Neurol 2004;61:875-880
CrossRef | Web of Science | Medline25
Meiser B ,Collins V ,Warren R , et al. Psychological impact of genetic testing for hereditary non-polyposis colorectal cancer. Clin Genet 2004;66:502-511
CrossRef | Web of Science | Medline26
Roberts JS . Anticipating response to predictive genetic testing for Alzheimer's disease: a survey of first-degree relatives. Gerontologist 2000;40:43-52
CrossRef | Web of Science | Medline27
Roberts JS ,Connell CM ,Cisewski D ,Hipps YG ,Demissie S ,Green RC . Differences between African Americans and whites in their perceptions of Alzheimer disease. Alzheimer Dis Assoc Disord 2003;17:19-26
CrossRef | Web of Science | Medline28
Hipps YG ,Roberts JS ,Farrer LA ,Green RC . Differences between African Americans and whites in their attitudes toward genetic testing for Alzheimer's disease. Genet Test 2003;7:39-44
CrossRef | Web of Science | Medline29
Cupples LA ,Farrer L ,Sadovnick D ,Relkin N ,Whitehouse P ,Green RC . Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: the REVEAL study. Genet Med 2004;6:192-196
CrossRef | Web of Science | Medline30
Jones B ,Jarvis P ,Lewis JA ,Ebbutt AF . Trials to assess equivalence: the importance of rigorous methods. BMJ 1996;313:36-39[Erratum, BMJ 1996;313:550.]
CrossRef | Web of Science | Medline31
Small BJ ,Rosnick CB ,Fratiglioni L ,Backman L . Apolipoprotein E and cognitive performance: a meta-analysis. Psychol Aging 2004;19:592-600
CrossRef | Web of Science | Medline32
Petersen RC . Mild cognitive impairment: current research and clinical implications. Semin Neurol 2007;27:22-31
CrossRef | Web of Science | Medline33
Roberts JS ,LaRusse SA ,Katzen H , et al. Reasons for seeking genetic susceptibility testing among first-degree relatives of people with Alzheimer disease. Alzheimer Dis Assoc Disord 2003;17:86-93
CrossRef | Web of Science | Medline34
Neumann PJ ,Hammitt JK ,Mueller C , et al. Public attitudes about genetic testing for Alzheimer's disease. Health Aff (Millwood) 2001;20:252-264
CrossRef | Web of Science | Medline35
Chase GA ,Geller G ,Havstad SL ,Holtzman NA ,Bassett SS . Physicians' propensity to offer genetic testing for Alzheimer's disease: results from a survey. Genet Med 2002;4:297-303
CrossRef | Web of Science | Medline36
Collins FS ,Green ED ,Guttmacher AE ,Guyer MS . A vision for the future of genomics research. Nature 2003;422:835-847
CrossRef | Web of Science | Medline37
Julian-Reynier C ,Welkenhuysen M ,Hagoel L ,Decruyenaere M ,Hopwood P . Risk communication strategies: state of the art and effectiveness in the context of cancer genetic services. Eur J Hum Genet 2003;11:725-736
CrossRef | Web of Science | Medline38
Khoury MJ ,McCabe LL ,McCabe ERB . Population screening in the age of genomic medicine. N Engl J Med 2003;348:50-58
Full Text | Web of Science | Medline39
Haga SB, Khoury MJ, Burke W. Genomic profiling to promote a healthy lifestyle: not ready for prime time. Nat Genet 2003;34:347-50.
40
Burke W ,Psaty BM . Personalized medicine in the era of genomics. JAMA 2007;298:1682-1684
CrossRef | Web of Science | Medline
- Citing Articles (63)
Citing Articles
1
Timothy Caulfield, Amy L. McGuire. (2012) Direct-to-Consumer Genetic Testing: Perceptions, Problems, and Policy Responses. Annual Review of Medicine 63:1, 23-33
CrossRef2
Felix Kork, André Gentsch, Jan Holthues, Rainer Hellweg, Vera Jankowski, Martin Tepel, Walter Zidek, Joachim Jankowski. (2012) A biomarker for severity of Alzheimer’s disease: 1 H-NMR resonances in cerebrospinal fluid correlate with performance in mini-mental-state-exam. Biomarkers 17:1, 36-42
CrossRef3
Amy C. Sturm, Kandamurugu Manickam. (2012) Direct-to-Consumer Personal Genomic Testing: A Case Study and Practical Recommendations for “Genomic Counseling”. Journal of Genetic Counseling
CrossRef4
Graham Mazereeuw, Krista L. Lanctôt, Sarah A. Chau, Walter Swardfager, Nathan Herrmann. (2012) Effects of omega-3 fatty acids on cognitive performance: a meta-analysis. Neurobiology of Aging
CrossRef5
Alice K. Hawkins, Anita Ho. (2012) Genetic Counseling and the Ethical Issues Around Direct to Consumer Genetic Testing. Journal of Genetic Counseling
CrossRef6
Steven K. Hoge, Paul S. Appelbaum. (2012) Ethics and neuropsychiatric genetics: a review of major issues. The International Journal of Neuropsychopharmacology1-11
CrossRef7
Wendy R. Uhlmann. (2012) National Society of Genetic Counselors Natalie Weissburger Paul Lifetime Achievement Award Address: The Power of Connecting. Journal of Genetic Counseling
CrossRef8
T Caulfield. (2012) DTC genetic testing: pendulum swings and policy paradoxes. Clinical Genetics 81:1, 4-6
CrossRef9
W. Glannon. 2012. Neuroethics/Brain Imaging. , 216-224.
CrossRef10
M. Arribas-Ayllon. (2011) The ethics of disclosing genetic diagnosis for Alzheimer's disease: do we need a new paradigm?. British Medical Bulletin 100:1, 7-21
CrossRef11
Ilona M. Kopits, Clara Chen, J. Scott Roberts, Wendy Uhlmann, Robert C. Green. (2011) Willingness to Pay for Genetic Testing for Alzheimer's Disease: A Measure of Personal Utility. Genetic Testing and Molecular Biomarkers 15:12, 871-875
CrossRef12
Laura M. Beskow, Emily E. Namey, R. Jean Cadigan, Tracy Brazg, Julia Crouch, Gail E. Henderson, Marsha Michie, Daniel K. Nelson, Holly K. Tabor, Benjamin S. Wilfond. (2011) Research Participants' Perspectives on Genotype-Driven Research Recruitment. Journal of Empirical Research on Human Research Ethics: An International Journal 6:4, 3-20
CrossRef13
B. A. Tarini, K. P. Tercyak, B. S. Wilfond. (2011) Commentary: Children and Predictive Genomic Testing: Disease Prevention, Research Protection, and Our Future. Journal of Pediatric Psychology 36:10, 1113-1121
CrossRef14
Misha Angrist. (2011) You never call, you never write: why return of ‘omic’ results to research participants is both a good idea and a moral imperative. Personalized Medicine 8:6, 651-657
CrossRef15
JS Roberts, KD Christensen, RC Green. (2011) Using Alzheimer's disease as a model for genetic risk disclosure: implications for personal genomics. Clinical Genetics 80:5, 407-414
CrossRef16
Elvira M. Zilliacus, Bettina Meiser, Elizabeth A. Lobb, Patrick J. Kelly, Kristine Barlow-Stewart, Judy A. Kirk, Alan D. Spigelman, Linda J. Warwick, Katherine M. Tucker. (2011) Are videoconferenced consultations as effective as face-to-face consultations for hereditary breast and ovarian cancer genetic counseling?. Genetics in Medicine 13:11, 933-941
CrossRef17
Y. Takata, M. Kikukawa, H. Hanyu, S. Koyama, S. Shimizu, T. Umahara, H. Sakurai, T. Iwamoto, K. Ohyashiki, J. H. Ohyashiki. (2011) Association Between ApoE Phenotypes and Telomere Erosion in Alzheimer's Disease. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
CrossRef18
C. S. Bloss, B. F. Darst, E. J. Topol, N. J. Schork. (2011) Direct-to-consumer personalized genomic testing. Human Molecular Genetics 20:R2, R132-R141
CrossRef19
L. Jostins, J. C. Barrett. (2011) Genetic risk prediction in complex disease. Human Molecular Genetics 20:R2, R182-R188
CrossRef20
Heidi Carmen Howard, Pascal Borry. (2011) Is there a doctor in the house?. Journal of Community Genetics
CrossRef21
E Genin, D Hannequin, D Wallon, K Sleegers, M Hiltunen, O Combarros, M J Bullido, S Engelborghs, P De Deyn, C Berr, F Pasquier, B Dubois, G Tognoni, N Fiévet, N Brouwers, K Bettens, B Arosio, E Coto, M Del Zompo, I Mateo, J Epelbaum, A Frank-Garcia, S Helisalmi, E Porcellini, A Pilotto, P Forti, R Ferri, E Scarpini, G Siciliano, V Solfrizzi, S Sorbi, G Spalletta, F Valdivieso, S Vepsäläinen, V Alvarez, P Bosco, M Mancuso, F Panza, B Nacmias, P Bossù, O Hanon, P Piccardi, G Annoni, D Seripa, D Galimberti, F Licastro, H Soininen, J-F Dartigues, M I Kamboh, C Van Broeckhoven, J C Lambert, P Amouyel, D Campion. (2011) APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Molecular Psychiatry 16:9, 903-907
CrossRef22
Susanne B. Haga, Madeline M. Carrig, Julianne M. O’Daniel, Lori A. Orlando, Ley A. Killeya-Jones, Geoffrey S. Ginsburg, Alex Cho. (2011) Genomic Risk Profiling: Attitudes and Use in Personal and Clinical Care of Primary Care Physicians Who Offer Risk Profiling. Journal of General Internal Medicine 26:8, 834-840
CrossRef23
A. Wilde, B. Meiser, P. B. Mitchell, D. Hadzi-Pavlovic, P. R. Schofield. (2011) Community interest in predictive genetic testing for susceptibility to major depressive disorder in a large national sample. Psychological Medicine 41:08, 1605-1613
CrossRef24
Tom Valeo. (2011) When to Test for AD Genetics: New Guidelines Offer Guidance. Neurology Today 11:16, 1
CrossRef25
Hyman M. Schipper. (2011) Presymptomatic apolipoprotein E genotyping for Alzheimer's disease risk assessment and prevention. Alzheimer's and Dementia 7:4, e118-e123
CrossRef26
Timothy Caulfield. (2011) Direct-to-consumer testing: if consumers are not anxious, why are policymakers?. Human Genetics 130:1, 23-25
CrossRef27
Kenneth Offit. (2011) Personalized medicine: new genomics, old lessons. Human Genetics 130:1, 3-14
CrossRef28
Jill S Goldman, Susan E Hahn, Jennifer Williamson Catania, Susan Larusse-Eckert, Melissa Barber Butson, Malia Rumbaugh, Michelle N Strecker, J Scott Roberts, Wylie Burke, Richard Mayeux, Thomas Bird. (2011) Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genetics in Medicine 13:6, 597-605
CrossRef29
Felix W. Frueh, Henry T. Greely, Robert C. Green, Stuart Hogarth, Sue Siegel. (2011) The future of direct-to-consumer clinical genetic tests. Nature Reviews Genetics 12:7, 511-515
CrossRef30
Kurt D Christensen, J Scott Roberts, Wendy R Uhlmann, Robert C Green. (2011) Changes to perceptions of the pros and cons of genetic susceptibility testing after APOE genotyping for Alzheimer disease risk. Genetics in Medicine 13:5, 409-414
CrossRef31
Samir B. Damani, Eric J. Topol. (2011) Emerging Genomic Applications in Coronary Artery Disease. JACC: Cardiovascular Interventions 4:5, 473-482
CrossRef32
Serge Gauthier, Christopher Patterson, Michael Gordon, Jean-Paul Soucy, François Schubert, Antoine Leuzy. (2011) Commentary on “Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.” A Canadian perspective. Alzheimer's and Dementia 7:3, 330-332
CrossRef33
Joanna H Fanos, Susan Gronka, Joanne Wuu, Christine Stanislaw, Peter M Andersen, Michael Benatar. (2011) Impact of presymptomatic genetic testing for familial amyotrophic lateral sclerosis. Genetics in Medicine 13:4, 342-348
CrossRef34
Tracey Holsinger, Malaz Boustani, David Abbot, John W Williams. (2011) Acceptability of dementia screening in primary care patients. International Journal of Geriatric Psychiatry 26:4, 373-379
CrossRef35
Caroline F Wright, Alison Hall, Ron L Zimmern. (2011) Regulating direct-to-consumer genetic tests: What is all the fuss about?. Genetics in Medicine 13:4, 295-300
CrossRef36
Bloss, Cinnamon S., Schork, Nicholas J., Topol, Eric J., . (2011) Effect of Direct-to-Consumer Genomewide Profiling to Assess Disease Risk. New England Journal of Medicine 364:6, 524-534
Full Text37
Cassandra Willyard. (2011) People prove impervious to anxiety from genetic tests. Nature
CrossRef38
Massimo F.L. Pomponi, Giovanni Gambassi, Massimiliano Pomponi, Annamaria Di Gioia, Carlo Masullo. (2011) Why docosahexaenoic acid and aspirin supplementation could be useful in women as a primary prevention therapy against Alzheimer's disease?. Ageing Research Reviews 10:1, 124-131
CrossRef39
Peter J. Neumann, Joshua T. Cohen, James K. Hammitt, Thomas W. Concannon, Hannah R. Auerbach, ChiHui Fang, David M. Kent. (2011) Willingness-to-pay for predictive tests with no immediate treatment implications: a survey of US residents. Health Economicsn/a-n/a
CrossRef40
Sato Ashida, Laura M Koehly, J Scott Roberts, Clara A Chen, Susan Hiraki, Robert C Green. (2010) The role of disease perceptions and results sharing in psychological adaptation after genetic susceptibility testing: the REVEAL Study. European Journal of Human Genetics 18:12, 1296-1301
CrossRef41
Donato Ramani, Chiara Saviane. (2010) Genetic tests: between risks and opportunities. EMBO reports 11:12, 910-913
CrossRef42
Philip B. Mitchell, Bettina Meiser, Alex Wilde, Janice Fullerton, Jennifer Donald, Kay Wilhelm, Peter R. Schofield. (2010) Predictive and Diagnostic Genetic Testing in Psychiatry. Clinics in Laboratory Medicine 30:4, 829-846
CrossRef43
A. L. McGuire, B. J. Evans, T. Caulfield, W. Burke. (2010) Regulating Direct-to-Consumer Personal Genome Testing. Science 330:6001, 181-182
CrossRef44
Martin Richards. (2010) Reading the runes of my genome: a personal exploration of retail genetics. New Genetics and Society 29:3, 291-310
CrossRef45
Sheryl R Torr-Brown. (2010) Regulatory and ethical challenges of personalized medicine. Personalized Medicine 7:5, 465-468
CrossRef46
Colleen M. McBride, Christopher H. Wade, Kimberly A. Kaphingst. (2010) Consumers' Views of Direct-to-Consumer Genetic Information. Annual Review of Genomics and Human Genetics 11:1, 427-446
CrossRef47
Cinnamon S Bloss, Laura Ornowski, Elana Silver, Michele Cargill, Vance Vanier, Nicholas J Schork, Eric J Topol. (2010) Consumer perceptions of direct-to-consumer personalized genomic risk assessments. Genetics in Medicine 12:9, 556-566
CrossRef48
Julianne M. O’Daniel. (2010) The Prospect of Genome-guided Preventive Medicine: A Need and Opportunity for Genetic Counselors. Journal of Genetic Counseling 19:4, 315-327
CrossRef49
J Scott Roberts, Sarah M Tersegno. (2010) Estimating and disclosing the risk of developing Alzheimer’s disease: challenges, controversies and future directions. Future Neurology 5:4, 501-517
CrossRef50
Harald Hampel, Richard Frank, Karl Broich, Stefan J. Teipel, Russell G. Katz, John Hardy, Karl Herholz, Arun L. W. Bokde, Frank Jessen, Yvonne C. Hoessler, Wendy R. Sanhai, Henrik Zetterberg, Janet Woodcock, Kaj Blennow. (2010) Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nature Reviews Drug Discovery 9:7, 560-574
CrossRef51
Oksana A Makeeva, Valentina V Markova, Allen D Roses, Valery P Puzyrev. (2010) An epidemiologic-based survey of public attitudes towards predictive genetic testing in Russia. Personalized Medicine 7:3, 291-300
CrossRef52
Erin Linnenbringer, J Scott Roberts, Susan Hiraki, L Adrienne Cupples, Robert C Green. (2010) “I know what you told me, but this is what I think:” Perceived risk of Alzheimer disease among individuals who accurately recall their genetics-based risk estimate. Genetics in Medicine 12:4, 219-227
CrossRef53
Katie Skeehan, Christopher Heaney, Robert Cook-Deegan. (2010) Impact of gene patents and licensing practices on access to genetic testing for Alzheimer disease. Genetics in Medicine 12, S71-S82
CrossRef54
Philip B. Mitchell, Bettina Meiser, Alex Wilde, Janice Fullerton, Jennifer Donald, Kay Wilhelm, Peter R. Schofield. (2010) Predictive and Diagnostic Genetic Testing in Psychiatry. Psychiatric Clinics of North America 33:1, 225-243
CrossRef55
(2010) Disclosure of the Genetic Risk of Alzheimer's Disease. New England Journal of Medicine 362:2, 181-182
Full Text56
J. Gulcher, K. Stefansson. (2010) Genetic risk information for common diseases may indeed be already useful for prevention and early detection. European Journal of Clinical Investigation 40:1, 56-63
CrossRef57
D. F. Ransohoff, M. J. Khoury. (2010) Personal genomics: information can be harmful. European Journal of Clinical Investigation 40:1, 64-68
CrossRef58
(2010) Current awareness in geriatric psychiatry. International Journal of Geriatric Psychiatry 25:1, i-viii
CrossRef59
Katie Palmer, Massimo Musicco, Carlo Caltagirone. (2010) Are Guidelines Needed for the Diagnosis and Management of Incipient Alzheimer's Disease and Mild Cognitive Impairment?. International Journal of Alzheimer's Disease 2010, 1-7
CrossRef60
Peter C. Wyer, Suzana A. Silva. (2009) Where is the wisdom? I â A conceptual history of evidence-based medicine. Journal of Evaluation in Clinical Practice 15:6, 891-898
CrossRef61
Darren Platt. (2009) When consumers get their genomes. Personalized Medicine 6:6, 669-679
CrossRef62
JAMIE TALAN. (2009) Knowledge of AD Risk Gene Does Not Create Emotional Stress, New Study Finds. Neurology Today 9:16, 18-20
CrossRef63
Kane, Rosalie A., Kane, Robert L., . (2009) Effect of Genetic Testing for Risk of Alzheimer's Disease. New England Journal of Medicine 361:3, 298-299
Full Text
- Letters
