Improving recommendations for genomic medicine: building an evolutionary process from clinical practice advisory documents to guidelines.

Genomic sequencing and multigene panel tests are moving rapidly into clinical practice for a range of indications, but the evidence to guide appropriate use is currently limited. Well-crafted advice is needed to reduce unjustified practice variation, minimize risk of error and harm to patients, and encourage best practices. In the absence of definitive evidence, provisional advice can be helpful if it clarifies the potential benefits and risks of different courses of action and identifies the knowledge gaps most important to address in future research. This paper proposes an evolutionary process starting with clinical practice advisory documents (CPADs) and culminating in clinical practice guidelines (CPGs), using two case examples to illustrate the need for this process. When evidence is limited, CPADs can clarify current practice options and identify key knowledge gaps. Added evidence can then support updates to the CPADs over time. Ultimately CPADs can provide the foundation for definitive CPGs as the evidence base matures. This approach addresses an important challenge in genomics and may be applicable to other fields in which technology and practice are outpacing evidence generation.

Practice Implications of Expanded Genetic Testing in Oncology.

Genetic test use in oncology is growing, yet providers' experiences with evolving testing norms and their implications for patient care remain under-explored. In interviews with oncologists and cancer genetics professionals, 22 key informants described the increasing importance of germline results for therapeutic decision-making, preference for ordering tests directly rather than referring, and rapid adoption of cancer gene panels for testing. Implications for informed consent, result interpretation, and patient management were identified. These results suggest concerns raised by the transition of genetic test delivery from cancer genetics professionals to oncologists that must be addressed in practice guidelines and provider training.

Clinician-Stakeholders' Perspectives on Using Patient Portals to Return Lynch Syndrome Screening Results.

Test results for genetic conditions, such as Lynch Syndrome (LS), have traditionally been returned by genetic counselors or other providers who can explain results implications and provide psychosocial support. Returning genetic results through an Electronic Health Record's patient portal may increase the efficiency of returning results and could activate patient follow-up; however, stakeholder input is necessary to determine acceptability and appropriate implementation for LS. Twenty interviews were conducted with clinicians from six specialties involved in LS screening that represent a range of settings. Data were analyzed using directed content analysis and thematic analysis across content categories. Participants felt that patient portals could supplement personal calls, but the potential sensitive nature of LS screening results indicated the need for caution. Others felt that LS results could be returned through portals if there were clear explanations of the result, reputable additional information available within the portal, urging follow up confirmatory testing, and a referral to a genetics specialist. Patient portals were seen as helpful for prompting patient follow-up and providing resources to notify at-risk family members. There is potential for patient portals to return LS screening and other genetic results, however we raise several issues to resolve before implementation is warranted.

Closing the gap between knowledge and clinical application: challenges for genomic translation.

Despite early predictions and rapid progress in research, the introduction of personal genomics into clinical practice has been slow. Several factors contribute to this translational gap between knowledge and clinical application. The evidence available to support genetic test use is often limited, and implementation of new testing programs can be challenging. In addition, the heterogeneity of genomic risk information points to the need for strategies to select and deliver the information most appropriate for particular clinical needs. Accomplishing these tasks also requires recognition that some expectations for personal genomics are unrealistic, notably expectations concerning the clinical utility of genomic risk assessment for common complex diseases. Efforts are needed to improve the body of evidence addressing clinical outcomes for genomics, apply implementation science to personal genomics, and develop realistic goals for genomic risk assessment. In addition, translational research should emphasize the broader benefits of genomic knowledge, including applications of genomic research that provide clinical benefit outside the context of personal genomic risk.

Identifying "ownership" through role descriptions to support implementing universal colorectal cancer tumor screening for Lynch syndrome.

PurposeLynch syndrome cases are underidentified, and universal colorectal cancer tumor screening for Lynch syndrome (UTS) has been recommended. UTS implementation is challenging and few successful examples exist to date, and colorectal cancer patients and at-risk family members exhibit low uptake of genetic services. This study sought to identify the elements that could guide the choice of specialties to implement UTS through three main stages: initiating the screen, returning positive screen results, and providing follow-up.MethodsTo understand stakeholder views on the UTS process, 20 semistructured interviews were conducted with clinicians from six medical specialties crucial for implementing UTS. Data were analyzed using directed content analysis and additional thematic analysis across content categories.ResultsSeveral clinical specialties could fill necessary roles at each of the main stages of UTS implementation. Participants suggested owners based on attributes of specialty roles, clinical settings, and the routes patients take through the system.ConclusionUTS is considered possible in a range of health-care settings, with tailoring. Health systems need to choose who best fills the role's needs based on local resources and processes. These results offer implementation guidance based on role needs, not clinical specialty, in resolving the issue of UTS "ownership."

Patient safety in genomic medicine: an exploratory study.

PURPOSE: Concerns about patient safety and the potential for medical error are largely unexplored for genetic testing, despite the expansion of test use. In this preliminary qualitative study, we sought the views of genetics professionals about error and patient safety concerns in genomic medicine and factors that might mitigate them. METHODS: Twelve semistructured interviews with experienced genetics professionals were conducted. Transcripts were analyzed using selective coding for issues related to error definition, mitigation, and communication. Additional thematic analysis captured themes across content categories. RESULTS: Key informants suggested that the potential for adverse events exists in all phases of genetic testing, from ordering to analysis, interpretation, and follow-up. A perceived contributor was lack of physician knowledge about genetics, resulting in errors in test ordering and interpretation. The limitations and uncertainty inherent to rapidly evolving technology were also seen as contributing factors. Strategies to prevent errors included physician education, availability of genetic experts for consultation, and enhanced communication such as improved test reports and electronic decision support. CONCLUSION: Genetic testing poses concerns for patient safety due to errors and the limitations of current tests. As genomic tests are integrated into medical care, anticipating and addressing patient safety concerns identified by these key informants will be crucial.Genet Med 18 11, 1136-1142.

Generating a taxonomy for genetic conditions relevant to reproductive planning.

As genome or exome sequencing (hereafter genome-scale sequencing) becomes more integrated into standard care, carrier testing is an important possible application. Carrier testing using genome-scale sequencing can identify a large number of conditions, but choosing which conditions/genes to evaluate as well as which results to disclose can be complicated. Carrier testing generally occurs in the context of reproductive decision-making and involves patient values in a way that other types of genetic testing may not. The Kaiser Permanente Clinical Sequencing Exploratory Research program is conducting a randomized clinical trial of preconception carrier testing that allows participants to select their preferences for results from among broad descriptive categories rather than selecting individual conditions. This paper describes (1) the criteria developed by the research team, the return of results committee (RORC), and stakeholders for defining the categories; (2) the process of refining the categories based on input from patient focus groups and validation through a patient survey; and (3) how the RORC then assigned specific gene-condition pairs to taxonomy categories being piloted in the trial. The development of four categories (serious, moderate/mild, unpredictable, late onset) for sharing results allows patients to select results based on their values without separately deciding their interest in knowing their carrier status for hundreds of conditions. A fifth category, lifespan limiting, was always shared. The lessons learned may be applicable in other results disclosure situations, such as incidental findings.

A comparison of institutional review board professionals' and patients' views on consent for research on medical practices.

BACKGROUND/AIMS: In the context of research on medical practices, which includes comparative effectiveness research and pragmatic clinical trials, empirical studies have begun to raise questions about the extent to which institutional review boards' interpretations and applications of research regulations align with patients' values. To better understand the similarities and differences between these stakeholder groups, we compare and contrast two surveys: one of institutional review board professionals and one of patients, which examine views on consent for research on medical practices. METHODS: We conducted online surveys of two target populations between July 2014 and March 2015. We surveyed 601 human subjects research professionals out of 1500 randomly selected from the Public Responsibility in Medicine and Research membership list (40.1% response rate), limiting analysis to 537 respondents who reported having had institutional review board experience. We also surveyed 120 adult patients out of 225 approached at subspecialty clinics in Spokane, Washington (53.3% response rate). Our survey questions probed attitudes about consent in the context of research on medical practices using medical record review and randomization. The patient survey included three embedded animated videos to explain these concepts. RESULTS: A majority of institutional review board professionals distinguished between consent preferences for medical record review and randomization, ranked clinicians as the least preferred person to obtain participant consent (54.6%), and viewed written or verbal permission as the minimum acceptable consent approach for research on medical practices using randomization (87.3%). In contrast, most patients had similar consent preferences for research on medical practices using randomization and medical record review, most preferred to have consent conversations with their doctors rather than with researchers for studies using randomization (72.6%) and medical record review (67.0%), and only a few preferred to see research involving randomization (16.8%) or medical record review (13.8%) not take place if obtaining written or verbal permission would make the research too difficult to conduct. Limitations of our post hoc analysis include differences in framing, structure, and language between the two surveys and possible response bias. CONCLUSION: Our findings highlight a need to identify appropriate ways to integrate patient preferences into prevailing regulatory interpretations as institutional review boards increasingly apply research regulations in the context of research on medical practices. Dialogue between institutional review boards and research participants will be an important part of this process and should inform future regulatory guidance.

Participants' Role Expectations in Genetics Research and Re-consent: Revising the Theory and Methods of Mental Models Research Relating to Roles.

The rise of large cohort-based health research that includes genetic components has increased the communication challenges for researchers. Controversies have been amplified over requirements for re-consent, return of results, and privacy protections, among other issues. This study extended research on the impact that the perceived role of "research participant" might have on communication expectations to illuminate research participants' preferences for re-consent. The study employed an online survey of participants in a long-standing cancer genetics registry. Results confirmed previous exploratory findings that research participants endorse multiple mental models of participant roles in research (doctor-patient, collaborator, donor, legal contract, etc.). Regression analyses indicated that high and low salience of different models of the role of research participant are related to different communication expectations. However, the pattern of relationships among roles is relevant. The results of the regression analysis also indicated that preference for mandatory re-consent and its relationship to mental models of roles are related to attitudes of trust, benefits, and informational risks. The discussion identifies implications as including the use of explicit approaches to address role relationships in communication with research participants. It also points to implications for methodological approaches in mental model research.

Attitudes Toward Risk and Informed Consent for Research on Medical Practices: A Cross-sectional Survey.

BACKGROUND: The U.S. Office for Human Research Protections has proposed that end points of randomized trials comparing the effectiveness of standard medical practices are risks of research that would require disclosure and written informed consent, but data are lacking on the views of potential participants. OBJECTIVE: To assess attitudes of U.S. adults about risks and preferences for notification and consent for research on medical practices. DESIGN: Cross-sectional survey conducted in August 2014. SETTING: Web-based questionnaire. PATIENTS: 1095 U.S. adults sampled from an online panel (n = 805) and an online convenience river sample (n = 290). MEASUREMENTS: Attitudes toward risk, informed consent, and willingness to participate in 3 research scenarios involving medical record review and randomization of usual medical practices. RESULTS: 97% of respondents agreed that health systems should evaluate standard treatments. Most wanted to be asked for permission to participate in each of 3 scenarios (range, 75.2% to 80.4%), even if it involved only medical record review, but most would accept nonwritten (oral) permission or general notification if obtaining written permission would make the research too difficult to conduct (range, 70.2% to 82.7%). Most perceived additional risk from each scenario (range, 64.0% to 81.6%). LIMITATION: Use of hypothetical scenarios and a nonprobability sample that was not fully representative of the U.S. population. CONCLUSION: Most respondents preferred to be asked for permission to participate in observational and randomized research evaluating usual medical practices, but they are willing to accept less elaborate approaches than written consent if research would otherwise be impracticable. These attitudes are not aligned with proposed regulatory guidance. PRIMARY FUNDING SOURCE: National Center for Advancing Translational Sciences at the National Institutes of Health.

Addressing the Challenges of Research With Small Populations.

Public health policy relies on accurate data, which are often unavailable for small populations, especially indigenous groups. Yet these groups have some of the worst health disparities in the United States, making it an ethical imperative to explore creative solutions to the problem of insufficient data. We discuss the limits of widely applied methods of data aggregation and propose a mixed-methods approach to data borrowing as a way to augment sample sizes. In this approach, community partners assist in selecting related populations that make suitable "neighbors" to enlarge the data pool. The result will be data that are substantial, accurate, and relevant to the needs of small populations, especially for health-related policy and decision-making at all levels.

Patient Perspectives on the Learning Health System: The Importance of Trust and Shared Decision Making.

We conducted focus groups to assess patient attitudes toward research on medical practices in the context of usual care. We found that patients focus on the implications of this research for their relationship with and trust in their physicians. Patients view research on medical practices as separate from usual care, demanding dissemination of information and in most cases, individual consent. Patients expect information about this research to come through their physician, whom they rely on to identify and filter associated risks. In general, patients support this research, but worry that participation in research involving randomization may undermine individualized care that acknowledges their unique medical histories. These findings suggest the need for public education on variation in practice among physicians and the need for a collaborative approach to the governance of research on medical practices that addresses core values of trust, transparency, and partnership.

Patient Recommendations for the Content and Design of Electronic Returns of Genetic Test Results: Interview Study Among Patients Who Accessed Their Genetic Test Results via the Internet.

BACKGROUND: Genetic test results will be increasingly made available electronically as more patient-facing tools are developed; however, little research has been done that collects data on patient preferences for content and design before creating results templates. OBJECTIVE: This study identifies patient preferences for the electronic return of genetic test results, including what considerations should be prioritized for content and design. METHODS: Following user-centered design methods, 59 interviews were conducted by using semistructured protocols. The interviews explored the content and design issues of patient portals that facilitated the return of test results to patients. We interviewed patients who received electronic results for specific types of genetics tests (pharmacogenetic tests, hereditary blood disorder tests, and tests for the risk of heritable cancers) or electronically received any type of genetic or nongenetic test results. RESULTS: In general, many of participants felt that there always needed to be some clinician involvement in electronic result returns and that electronic coversheets with simple summaries would be helpful for facilitating this. Coversheet summaries could accompany, but not replace, the more detailed report. Participants had specific suggestions for such results summaries, such as only reporting the information that was the most important for patients to understand, including next steps, and doing so by using clear language that is free of medical jargon. Electronic result returns should also include explicit encouragement for patients to contact health care providers about questions. Finally, many participants preferred to manage their care by using their smartphones, particularly in instances when they needed to access health information on the go. CONCLUSIONS: Participants recommended that a patient-friendly front section should accompany the more detailed report and made suggestions for organization, content, and wording. Many used their smartphones regularly to access test results; therefore, health systems and patient portal software vendors should accommodate smartphone app design and web portal design concomitantly when developing platforms for returning results.

Implementing Precision Medicine: The Ethical Challenges.

Precision medicine aims to individualize care by understanding differences in genetics, lifestyle, and environment. Pharmacogenomics and cancer genetics represent two promising areas for this approach. Pharmacogenomic tests have the potential to direct drug prescribing to increase safety and effectiveness because individuals vary on a genetic basis in their response to many drugs. Similarly, tests to identify people with an inherited cancer risk can guide prevention. For both, a few tests have entered clinical practice and more are under development. Implementation challenges include the limited evidence base available to guide clinical use and the lack of data from diverse populations. Accordingly, ongoing research should prioritize procedures that enhance the trustworthiness of clinical practice guidelines and create decision support for clinicians and patients that address their needs and accommodate flexibility. Each step involves choices with ethical implications.

Research on Medical Practices: Why Patients Consider Participating and the Investigational Misconception.

Understanding how patients decide whether to enroll in research can help improve educational materials, protocols, and recruitment rates. However, little is known about patients' willingness to participate in research on medical practices (ROMP), or studies comparing interventions within usual care. We assessed willingness to consider participating in ROMP by surveying 1095 adults in the United States, of whom 834 answered at least one open-ended question about their reasons for being willing or unwilling to consider participating in two scenarios involving ROMP. Most respondents were willing to consider participating in the research scenarios. The most commonly cited reasons for being willing to consider participating included benefit to others and oneself; the top reasons for being unwilling to consider participating included belief that the research was unsafe and an unfavorable view of experimentation. Responses also revealed misconceptions about ROMP among both those who were willing and unwilling to consider participating. Because these misconceptions may present an obstacle to recruiting participants in ROMP, there may be a need for educational initiatives to clarify the nature of these types of studies.

Participant views on consent in cancer genetics research: preparing for the precision medicine era.

The Precision Medicine Initiative (PMI) has created considerable discussions about research participant issues including re-consent and how and when to incorporate the patient experience into clinical trials. Within the changing landscape of genetic and genomic research, the preferences of participants are lacking yet are needed to inform policy. With the growing use of biobanks intended to support studies, including the national research cohort proposed under the PMI, understanding participant preferences, including re-consent, is a pressing concern. The Participant Issues Project (PIP) addresses this gap, and here we present data on participant attitudes regarding re-consent and broad consent in research studies. PIP study participants came from the Northwest Cancer Genetics Registry and included cancer patients, relatives, and controls. Thirty telephone interviews were conducted and analyzed using content and thematic analysis. Results indicate that in some scenarios, re-consent is needed. Most participants agreed that re-consent was necessary when the study direction changed significantly or a child participant became an adult, but not if the genetic variant changed. Most participants' willingness to participate in research would not be affected if the researcher or institution profited or if a broad consent form were used. Participants emphasized re-consent to provide information and control of the use of their data, now relevant for tailored treatment, while also prioritizing research as important. In the era of precision medicine, it is essential that policy makers consider participant preferences with regard to use of their materials and that participants understand genetic and genomic research and its harms and benefits as well as what broad consent entails, including privacy and re-identification risks.

Developing Governance for Federated Community-based EHR Data Sharing.

Bi-directional translational pathways between scientific discoveries and primary care are crucial for improving individual patient care and population health. The Data QUEST pilot project is a program supporting data sharing amongst community based primary care practices and is built on a technical infrastructure to share electronic health record data. We developed a set of governance requirements from interviewing and collaborating with partner organizations. Recommendations from our partner organizations included: 1) partner organizations can physically terminate the link to the data sharing network and only approved data exits the local site; 2) partner organizations must approve or reject each query; 3) partner organizations and researchers must respect local processes, resource restrictions, and infrastructures; and 4) partner organizations can be seamlessly added and removed from any individual data sharing query or the entire network.