Disclosing Individual Results in Dementia Research: A Proposed Study Participant's Bill of Rights.

This Study Participant's Bill of Rights is a call to action for researchers in Alzheimer's disease and related dementias (ADRD) to proactively design clinical studies that provide the option for research participants to learn their individual research results if they choose, and in a manner that ensures study integrity. This Bill of Rights was crafted by a committee of study participants, care partners, representatives of dementia advocacy organizations, and other stakeholders in dementia research for the Advisory Group on Risk Education for Dementia (AGREEDementia). The framework developed by the Multi-Regional Clinical Trials (MRCT) Return of Individual Research Results provides a useful context for researchers to plan their studies and disclosure.

The Advisory Group on Risk Evidence Education for Dementia: Multidisciplinary and Open to All.

The brain changes of Alzheimer's disease and other degenerative dementias begin long before cognitive dysfunction develops, and in people with subtle cognitive complaints, clinicians often struggle to predict who will develop dementia. The public increasingly sees benefits to accessing dementia risk evidence (DRE) such as biomarkers, predictive algorithms, and genetic information, particularly as this information moves from research to demonstrated usefulness in guiding diagnosis and clinical management. For example, the knowledge that one has high levels of amyloid in the brain may lead one to seek amyloid reducing medications, plan for disability, or engage in health promoting behaviors to fight cognitive decline. Researchers often hesitate to share DRE data, either because they are insufficiently validated or reliable for use in individuals, or there are concerns about assuring responsible use and ensuring adequate understanding of potential problems when one's biomarker status is known. Concerns include warning people receiving DRE about situations in which they might be compelled to disclose their risk status potentially leading to discrimination or stigma. The Advisory Group on Risk Evidence Education for Dementia (AGREEDementia) welcomes all concerned with how best to share and use DRE. Supporting understanding in clinicians, stakeholders, and people with or at risk for dementia and clearly delineating risks, benefits, and gaps in knowledge is vital. This brief overview describes elements that made this group effective as a model for other health conditions where there is interest in unfettered collaboration to discuss diagnostic uncertainty and the appropriate use and communication of health-related risk information.

Alzheimer's Disease: Risk Tests and the Medical Record.

Although the medical record is the centerpiece of modern medical care, its usefulness is diminished by the reluctance of people to disclose important health information, such as a higher risk for Alzheimer's disease, to their doctors. Steps should be taken now to ensure that the medical record, the repository of one's health information, can continue to serve the needs of the medical community and of patients.

Cost-Effectiveness of Risk-Stratified Colorectal Cancer Screening Based on Polygenic Risk: Current Status and Future Potential.

BACKGROUND: Although uniform colonoscopy screening reduces colorectal cancer (CRC) mortality, risk-based screening may be more efficient. We investigated whether CRC screening based on polygenic risk is a cost-effective alternative to current uniform screening, and if not, under what conditions it would be. METHODS: The MISCAN-Colon model was used to simulate a hypothetical cohort of US 40-year-olds. Uniform screening was modeled as colonoscopy screening at ages 50, 60, and 70 years. For risk-stratified screening, individuals underwent polygenic testing with current and potential future discriminatory performance (area under the receiver-operating curve [AUC] of 0.60 and 0.65-0.80, respectively). Polygenic testing results were used to create risk groups, for which colonoscopy screening was optimized by varying the start age (40-60 years), end age (70-85 years), and interval (1-20 years). RESULTS: With current discriminatory performance, optimal screening ranged from once-only colonoscopy at age 60 years for the lowest-risk group to six colonoscopies at ages 40-80 years for the highest-risk group. While maintaining the same health benefits, risk-stratified screening increased costs by $59 per person. Risk-stratified screening could become cost-effective if the AUC value would increase beyond 0.65, the price per polygenic test would drop to less than $141, or risk-stratified screening would lead to a 5% increase in screening participation. CONCLUSIONS: Currently, CRC screening based on polygenic risk is unlikely to be cost-effective compared with uniform screening. This is expected to change with a greater than 0.05 increase in AUC value, a greater than 30% reduction in polygenic testing costs, or a greater than 5% increase in adherence with screening.

"Well, good luck with that": reactions to learning of increased genetic risk for Alzheimer disease.

PURPOSE: Apolipoprotein-E (APOE) genetic testing to estimate risk for developing late-onset Alzheimer disease is increasingly being offered without prior genetic counseling or preparation. Consumer interest continues to grow, raising the question of how best to conduct such testing. METHODS: Twenty-six semistructured interviews were carried out to study the reactions of individuals who had already learned of their higher risk after APOE testing had been done because of a family history of Alzheimer disease, or from genetic tests done for other health-related or general-interest reasons. RESULTS: Adverse psychological reactions were reported by a substantial fraction of the participants, including those who had specifically sought testing, those for whom the information came as a surprise, those with a family history, and those with no known history. Still, nearly all of those interviewed said that they had benefited in the long term from lifestyle changes, often learned from online sources, that they subsequently made. CONCLUSION: The results show that people should be prepared prior to any genetic testing and allowed to opt out of particular tests. If testing is carried out and a higher risk is revealed, they should be actively assisted in deciding how to proceed.

Cost Effectiveness of Age-Specific Screening Intervals for People With Family Histories of Colorectal Cancer.

BACKGROUND & AIMS: Relative risk of colorectal cancer (CRC) decreases with age among individuals with a family history of CRC. However, no screening recommendations specify less frequent screening with increasing age. We aimed to determine whether such a refinement would be cost effective. METHODS: We determined the relative risk for CRC for individuals based on age and number of affected first-degree relatives (FDRs) using data from publications. For each number of affected FDRs, we used the Microsimulation Screening Analysis model to estimate costs and effects of colonoscopy screening strategies with different age ranges and intervals. Screening was then optimized sequentially, starting with the youngest age group, and allowing the interval of screening to change at certain ages. Strategies with an incremental cost effectiveness ratio below $100,000 per quality-adjusted life year were considered cost effective. RESULTS: For people with 1 affected FDR (92% of those with a family history), screening every 3 years beginning at an age of 40 years is most cost effective. If no adenomas are found, the screening interval can gradually be extended to 5 and 7 years, at ages 45 and 55 years, respectively. From a cost-effectiveness perspective, individuals with more affected FDRs should start screening earlier and at shorter intervals. However, frequency can be reduced if no abnormalities are found. CONCLUSIONS: Using a microsimulation model, we found that for individuals with a family history of CRC, it is cost effective to gradually increase the screening interval if several subsequent screening colonoscopies have negative results and no new cases of CRC are found in family members.

Impact of a Patient-Facing Enhanced Genomic Results Report to Improve Understanding, Engagement, and Communication.

"The objective of this study was to" test the effectiveness of an enhanced genomic report on patient-centered outcome domains including communication, engagement and satisfaction. "Study design utilized" a prospective, randomized, mixed-methods desctiptive study of a whole genome sequencing results report, GenomeCOMPASS™, that was accessed by providers through the electronic health record and by patients through the associated patient portal. "The study was set in" an integrated healthcare delivery system in central Pennsylvania. "Eighty-four" parents of 46 children with undiagnosed Intellectual Disability, Autism Spectrum Disorder and/or multiple congenital anomalies who had participated in a previous study offering whole genome sequencing for their affected child were invited to enroll. Fifty-two parents enrolled. Following a traditional genetics results informing visit, the study coordinator stratified families by diagnostic result and uninformative result and then randomized families within each group to an intervention arm to receive the GenomeCOMPASS™ report or to the usual care arm to receive a summary letter from the medical geneticist. A letter inviting enrollment included a baseline survey, which once returned, constituted enrollment. Surveys were administered at 3 months post-genetics visit. At 6 months, the usual care arm crossed over to receive the intervention and were administered an additional survey at 3 months. Qualitative interviews were conducted following survey completion to augment the survey data regarding the patient centered outcomes of interest. Patient reported outcomes including communication, engagement, empowerment and satisfaction. In the intervention arm, GenomeCOMPASS™ reports were released to 14 families (N = 28 parents) and of those 21 (75%) returned 3 month surveys. In the usual care arm, 12 families (N = 24 parents) received usual care summary letters and of those 20 (83%) returned 3 month surveys. At crossover, GenomeCOMPASS™ reports were released to 20 individuals and 15 (75%) returned 3 month surveys. Qualitative interviews were conducted with 5 individuals. Use of the GenomeCOMPASS™ report was reported by this small group of parents to improve communication with providers and non-health professionals such as educators and therapists and led to increased engagement and high satisfaction. Providers and others involved in the children's care also endorsed the report's effectiveness. Reports that addressed negative findings, i.e. uninformative results, were not found to be useful. Although the number of users was small, this study supports that customizable template reports may provide a useful and durable source of information that can support and enhance the information provided by genetics professionals in traditional face-to-face encounters. TRIAL REGISTRATION: Clinicaltrials.gov (Record 2013-0594).

Evaluation of a Web-based decision aid for people considering the APOE genetic test for Alzheimer risk.

PURPOSE: With the increasing interest in apolipoprotein E (APOE) genetic testing to estimate the risk of developing late-onset Alzheimer disease, new educational tools are needed to help people make the best decision for themselves about whether to undergo this test. This study evaluated an online tool to assist in this decision process. METHODS: A prototype decision aid was studied in a two-part survey that collected data from participants before and after they examined the decision aid. Both surveys had multiple-choice options and opportunities for open-ended responses, yielding quantitative and qualitative information. The responses before and after use of the aid were compared for each participant. RESULTS: A total of 1,262 individuals completed both surveys. The overall effectiveness of the decision aid was shown by three measures: 94% found the decision aid very helpful or somewhat helpful; general knowledge was increased; and some people changed their minds about APOE genetic testing, with 35% shifting to a higher likelihood of undergoing the test and 20% to a lower likelihood. Suggestions for improvements were noted and incorporated into the online tool. CONCLUSION: This decision aid can provide useful educational assistance to many individuals as they consider APOE genetic testing as well as facilitate further discussions with their health-care providers.Genet Med advance online publication 03 November 2016.

Enhancing genomic laboratory reports: A qualitative analysis of provider review.

This study reports on the responses of physicians who reviewed provider and patient versions of a genomic laboratory report designed to communicate results of whole genome sequencing. Semi-structured interviews addressed concept communication, elements, and format of example genome reports. Analysis of the coded transcripts resulted in recognition of three constructs around communication of genome sequencing results: (1) Providers agreed that whole genomic sequencing results are complex and they welcomed a report that provided supportive interpretation information to accompany sequencing results; (2) Providers strongly endorsed a report that included active clinical guidance, such as reference to practice guidelines, if available; and (3) Providers valued the genomic report as a resource that would serve as the basis to facilitate communication of genome sequencing results with their patients and families. Providers valued both versions of the report, though they affirmed the need for a provider-oriented report. Critical elements of the report included clear language to explain the result, as well as consolidated yet comprehensive prognostic information with clear guidance over time for the clinical care of the patient. Most importantly, it appears a report with this design has the potential not only to return results but also serves as a communication tool to help providers and patients discuss and coordinate care over time.

Enhancing genomic laboratory reports from the patients' view: A qualitative analysis.

The purpose of this study was to develop a family genomic laboratory report designed to communicate genome sequencing results to parents of children who were participating in a whole genome sequencing clinical research study. Semi-structured interviews were conducted with parents of children who participated in a whole genome sequencing clinical research study to address the elements, language and format of a sample family-directed genome laboratory report. The qualitative interviews were followed by two focus groups aimed at evaluating example presentations of information about prognosis and next steps related to the whole genome sequencing result. Three themes emerged from the qualitative data: (i) Parents described a continual search for valid information and resources regarding their child's condition, a need that prior reports did not meet for parents; (ii) Parents believed that the Family Report would help facilitate communication with physicians and family members; and (iii) Parents identified specific items they appreciated in a genomics Family Report: simplicity of language, logical flow, visual appeal, information on what to expect in the future and recommended next steps. Parents affirmed their desire for a family genomic results report designed for their use and reference. They articulated the need for clear, easy to understand language that provided information with temporal detail and specific recommendations regarding relevant findings consistent with that available to clinicians.

Family history and the natural history of colorectal cancer: systematic review.

PURPOSE: Family history of colorectal cancer (CRC) is a known risk factor for CRC and encompasses both genetic and shared environmental risks. METHODS: We conducted a systematic review to estimate the impact of family history on the natural history of CRC and adherence to screening. RESULTS: We found high heterogeneity in family-history definitions, the most common definition being one or more first-degree relatives. The prevalence of family history may be lower than the commonly cited 10%, and confirms evidence for increasing levels of risk associated with increasing family-history burden. There is evidence for higher prevalence of adenomas and of multiple adenomas in people with family history of CRC but no evidence for differential adenoma location or adenoma progression by family history. Limited data regarding the natural history of CRC by family history suggest a differential age or stage at cancer diagnosis and mixed evidence with respect to tumor location. Adherence to recommended colonoscopy screening was higher in people with a family history of CRC. CONCLUSION: Stratification based on polygenic and/or multifactorial risk assessment may mature to the point of displacing family history-based approaches, but for the foreseeable future, family history may remain a valuable clinical tool for identifying individuals at increased risk for CRC.

The power of partnerships: the Liverpool school of butterfly and medical genetics.

From the 1950s to the 1970s, a group of physician-researchers forming the 'Liverpool school' made groundbreaking contributions in such diverse areas as the genetics of Lepidoptera and human medical genetics. The success of this group can be attributed to the several different, but interconnected, research partnerships that Liverpool physician Cyril Clarke established with Philip Sheppard, Victor McKusick at Johns Hopkins University, the Nuffield Foundation, and his wife FCo. Despite its notable successes, among them the discovery of the method to prevent Rhesus haemolytic disease of the newborn, the Liverpool School began to lose prominence in the mid-1970s, just as the field of medical genetics that it had helped pioneer began to grow. This paper explores the role of partnerships in making possible the Liverpool school's scientific and medical achievements, and also in contributing to its decline.