Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care.

OBJECTIVE: To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations. STUDY DESIGN: In-depth interviews were conducted with parents, audio-recorded and transcribed. A structured codebook was applied to each transcript, after which iterative memoing was used to identify themes. RESULTS: Fifty-four parents participated, including 17 (31.5%) whose child received a diagnosis through research. Themes describing parents' expectations and experiences of genomic diagnosis research included (1) the extent to which parents' motivations for participation focused on their hope that it would directly benefit their child, (2) the ways in which parents' frustrations regarding the research process confused the dual clinical and research goals of their participation, and (3) the limited clinical benefits parents ultimately experienced for their children. CONCLUSIONS: Our results suggest that parents of undiagnosed children seeking enrollment in genomic diagnosis research are at risk of a form of therapeutic misconception-in this case, diagnostic misconception. These findings indicate the need to examine the processes and procedures associated with this research to communicate appropriately and balance the potential burdens and benefits of study participation.

Rare Disease, Advocacy and Justice: Intersecting Disparities in Research and Clinical Care.

Rare genetic diseases collectively impact millions of individuals in the United States. These patients and their families share many challenges including delayed diagnosis, lack of knowledgeable providers, and limited economic incentives to develop new therapies for small patient groups. As such, rare disease patients and families often must rely on advocacy, including both self-advocacy to access clinical care and public advocacy to advance research. However, these demands raise serious concerns for equity, as both care and research for a given disease can depend on the education, financial resources, and social capital available to the patients in a given community. In this article, we utilize three case examples to illustrate ethical challenges at the intersection of rare diseases, advocacy and justice, including how reliance on advocacy in rare disease may drive unintended consequences for equity. We conclude with a discussion of opportunities for diverse stakeholders to begin to address these challenges.

Developer Perspectives on Potential Harms of Machine Learning Predictive Analytics in Health Care: Qualitative Analysis.

BACKGROUND: Machine learning predictive analytics (MLPA) is increasingly used in health care to reduce costs and improve efficacy; it also has the potential to harm patients and trust in health care. Academic and regulatory leaders have proposed a variety of principles and guidelines to address the challenges of evaluating the safety of machine learning-based software in the health care context, but accepted practices do not yet exist. However, there appears to be a shift toward process-based regulatory paradigms that rely heavily on self-regulation. At the same time, little research has examined the perspectives about the harms of MLPA developers themselves, whose role will be essential in overcoming the "principles-to-practice" gap. OBJECTIVE: The objective of this study was to understand how MLPA developers of health care products perceived the potential harms of those products and their responses to recognized harms. METHODS: We interviewed 40 individuals who were developing MLPA tools for health care at 15 US-based organizations, including data scientists, software engineers, and those with mid- and high-level management roles. These 15 organizations were selected to represent a range of organizational types and sizes from the 106 that we previously identified. We asked developers about their perspectives on the potential harms of their work, factors that influence these harms, and their role in mitigation. We used standard qualitative analysis of transcribed interviews to identify themes in the data. RESULTS: We found that MLPA developers recognized a range of potential harms of MLPA to individuals, social groups, and the health care system, such as issues of privacy, bias, and system disruption. They also identified drivers of these harms related to the characteristics of machine learning and specific to the health care and commercial contexts in which the products are developed. MLPA developers also described strategies to respond to these drivers and potentially mitigate the harms. Opportunities included balancing algorithm performance goals with potential harms, emphasizing iterative integration of health care expertise, and fostering shared company values. However, their recognition of their own responsibility to address potential harms varied widely. CONCLUSIONS: Even though MLPA developers recognized that their products can harm patients, public, and even health systems, robust procedures to assess the potential for harms and the need for mitigation do not exist. Our findings suggest that, to the extent that new oversight paradigms rely on self-regulation, they will face serious challenges if harms are driven by features that developers consider inescapable in health care and business environments. Furthermore, effective self-regulation will require MLPA developers to accept responsibility for safety and efficacy and know how to act accordingly. Our results suggest that, at the very least, substantial education will be necessary to fill the "principles-to-practice" gap.

Perceived utility and disutility of genomic sequencing for pediatric patients: Perspectives from parents with diverse sociodemographic characteristics.

Given the limited therapeutic options for most rare diseases diagnosed through genomic sequencing (GS) and the proportion of patients who remain undiagnosed even after GS, it is important to characterize a broader range of benefits and potential harms of GS from the perspectives of families with diverse sociodemographic characteristics. We recruited parents of children enrolled in the Undiagnosed Diseases Network. Parents completed an in-depth interview, and we conducted a comparative content analysis of the data. Parents (n = 30) were demographically diverse, with 43.3% identifying as Hispanic, 33.3% primarily Spanish-speaking, and widely variable household income and education. Parents reported minimal changes in their child's health status following GS but did report a range of other forms of perceived utility, including improvements in their child's healthcare management and access, in their own psychological well-being, and in disease-specific social connections and research opportunities. Parents who received a diagnosis more frequently perceived utility across all domains; however, disutility also was reported by both those with and without a diagnosis. Impacts depended on multiple mediating factors, including parents' underlying expectations and beliefs, family sociodemographic characteristics, individual disease characteristics, and prior healthcare access. Our study suggests that the perceived utility of GS varies widely among parents and may depend on multiple individual, sociodemographic, and contextual factors that are relevant for pre- and post-GS counseling, for value assessment of GS, and for policymaking related to access to new genomic technologies.

Perspectives of Rare Disease Social Media Group Participants on Engaging With Genetic Counselors: Mixed Methods Study.

BACKGROUND: Social media provides a potential avenue for genetic counselors to address gaps in access to reliable genetics information for rare disease communities. However, only limited research has examined patient and family attitudes toward engaging with genetic counselors through social media. OBJECTIVE: Our study assessed the attitudes of members of rare disease social media groups toward engaging with genetic counselors through social media, characteristics associated with greater interest, and the benefits and potential pitfalls of various approaches to such engagement. METHODS: We conducted a mixed methods survey of patients and family members recruited from a systematic sample of rare disease Facebook groups. Patient characteristics and their associations with interest in engagement with genetic counselors were evaluated using univariate and bivariate statistics. Responses to open-ended questions were analyzed using thematic content analysis. RESULTS: In total, 1053 individuals from 103 rare disease groups participated. The median overall interest in engaging with genetic counselors on social media was moderately high at 7.0 (IQR 4.0-9.0, range 0-10). No past experience with a genetic counselor was associated with greater interest in engaging with one through social media (µ=6.5 vs 6.0, P=.04). Participants expressed greatest interest (median 9.0, IQR 5.0-10.0) in engagement models allowing direct communication with genetic counselors, which was corroborated by the majority (n=399, 61.3%) of individuals who responded to open-ended questions explicitly stating their interest in 1-on-1 interactions. When asked what forms of support they would request from genetic counselors through social media, participants desired individualized support and information about how to access services. However, participants also expressed concerns regarding privacy and confidentiality. CONCLUSIONS: Patients and family members in rare disease social media groups appear interested in engaging with genetic counselors through social media, particularly for individualized support. This form of engagement on social media is not meant to replace the current structure and content of genetic counseling (GC) services, but genetic counselors could more actively use social media as a communication tool to address gaps in knowledge and awareness about genetics services and gaps in accessible patient information. Although encouraging, concerns regarding privacy and feasibility require further consideration, pointing to the need for professional guidelines in this area.

"It seems like COVID-19 now is the only disease present on Earth": living with a rare or undiagnosed disease during the COVID-19 pandemic.

PURPOSE: Patients with rare and undiagnosed diseases (RUDs) face significant health challenges, which may be exacerbated during the COVID-19 pandemic. The goal of this study was to identify specific impacts of the pandemic on RUD patients, and targets for improving support and health-care access. METHODS: We conducted an online survey of RUD patients and their family members from 21 April to 8 June 2020, recruited from 76 Facebook groups for RUDs. Questions assessed patient characteristics and impacts of the pandemic on RUD diagnosis and management. RESULTS: Respondents (n = 413), including 274 RUD patients and 139 family members, were predominantly female and white, though income varied. Impacts of the pandemic included (1) barriers to accessing essential health care, (2) specific impacts of restrictive COVID-19 visitation policies on ability to advocate in health-care settings, (3) uncertainty and fear regarding COVID-19 risk, (4) exacerbated physical and mental health challenges, (5) magnified impacts of reduced educational and therapeutic services, and (6) unexpected positive changes due to the pandemic. CONCLUSION: There are specific, serious challenges affecting RUD patients and families during the COVID-19 pandemic. There is an urgent need to develop approaches to mitigate these challenges both during and beyond the pandemic.

Opportunities and pitfalls of social media research in rare genetic diseases: a systematic review.

PURPOSE: Social media may be particularly valuable in research in rare genetic diseases because of the low numbers of patients and the rare disease community's robust online presence. The goal of this systematic review was to understand how social media is currently used in rare disease research and the characteristics of the participants in these studies. METHODS: We conducted a systematic review of six databases to identify studies published in English between January 2004 and November 2020, of which 120 met inclusion criteria. RESULTS: Most studies were observational (n = 114, 95.0%) and cross-sectional (n = 107, 89.2%), and more than half (n = 69, 57.5%) utilized only surveys. Only 101 rare diseases were included across all studies. Participant demographics, when reported, were predominantly female (70.1% ± 22.5%) and white (85.0% ± 11.0%) adult patients and caregivers. CONCLUSION: Despite its potential benefits in rare disease research, the use of social media is still methodologically limited and the participants reached may not be representative of the rare disease population by gender, race, age, or rare disease type. As scholars explore using social media for rare disease research, careful attention should be paid to representativeness when studying this diverse patient community.

"Doctors can read about it, they can know about it, but they've never lived with it": How parents use social media throughout the diagnostic odyssey.

Parents of children with undiagnosed conditions struggle to obtain information about how to treat and support their children. It can be particularly challenging to find communities and other parents who share their experiences and can provide emotional and informational support. This study sought to characterize how parents use social media, both throughout the diagnostic odyssey and post-diagnosis, to meet their informational, social, and emotional support needs. We conducted qualitative semi-structured interviews with 14 parents from the Stanford site of the Undiagnosed Diseases Network (UDN), including five whose children had received a diagnosis through study participation. Interview recordings were analyzed using inductive, team-based coding and thematic analysis based in grounded theory using Dedoose qualitative analysis software. Through this process, we identified four key themes related to social media use. First, parents struggled to find the "right" community, often seeking out groups of similar patients based on symptoms or similar conditions. Second, though they found much valuable information through social media about caring for their child, they also struggled to interpret the relevance of the information to their own child's condition. Third, the social support and access to other patients' and families' lived experiences were described as both highly valued and emotionally challenging, particularly in the case of poor outcomes for similar families. Finally, parents expressed the need to balance concerns about their child's privacy with the value of transparency and data sharing for diagnosis. Our results suggest that the needs and experiences of undiagnosed patients and families differ from those with diagnosed diseases and highlight the need for support in best utilizing social media resources at different stages of the diagnostic odyssey.

A Typology of Existing Machine Learning-Based Predictive Analytic Tools Focused on Reducing Costs and Improving Quality in Health Care: Systematic Search and Content Analysis.

BACKGROUND: Considerable effort has been devoted to the development of artificial intelligence, including machine learning-based predictive analytics (MLPA) for use in health care settings. The growth of MLPA could be fueled by payment reforms that hold health care organizations responsible for providing high-quality, cost-effective care. Policy analysts, ethicists, and computer scientists have identified unique ethical and regulatory challenges from the use of MLPA in health care. However, little is known about the types of MLPA health care products available on the market today or their stated goals. OBJECTIVE: This study aims to better characterize available MLPA health care products, identifying and characterizing claims about products recently or currently in use in US health care settings that are marketed as tools to improve health care efficiency by improving quality of care while reducing costs. METHODS: We conducted systematic database searches of relevant business news and academic research to identify MLPA products for health care efficiency meeting our inclusion and exclusion criteria. We used content analysis to generate MLPA product categories and characterize the organizations marketing the products. RESULTS: We identified 106 products and characterized them based on publicly available information in terms of the types of predictions made and the size, type, and clinical training of the leadership of the companies marketing them. We identified 5 categories of predictions made by MLPA products based on publicly available product marketing materials: disease onset and progression, treatment, cost and utilization, admissions and readmissions, and decompensation and adverse events. CONCLUSIONS: Our findings provide a foundational reference to inform the analysis of specific ethical and regulatory challenges arising from the use of MLPA to improve health care efficiency.

Barriers and Facilitators to Real-world Implementation of the Diabetes Prevention Program in Large Healthcare Systems: Lifestyle Coach Perspectives.

BACKGROUND: Group-based lifestyle change programs based on the Diabetes Prevention Program (DPP) are associated with clinically significant weight loss and decreases in cardiometabolic risk factors. However, these benefits depend on successful real-world implementation. Studies have examined implementation in community settings, but less is known about integration in healthcare systems, and particularly in large, multi-site systems with the potential for extended reach. OBJECTIVE: To examine the barriers and facilitators to successful DPP implementation in a large multi-site healthcare system. DESIGN: Semi-structured interviews, based on the RE-AIM framework, were conducted in person for 30-90 min each. PARTICIPANTS: Past and present DPP lifestyle coaches in the healthcare system identified using purposive sampling. APPROACH: Thematic analysis of qualitative data to identify key factors influencing the success of DPP implementation. An iterative consensus process was used to model the relationships among factors. KEY RESULTS: We conducted 33 interviews across 20 clinic sites serving 12 counties. Participants described six key factors as potential barriers or facilitators to implementation, including (1) Broader Context, including the surrounding physical and sociodemographic context; (2) Institutional Context, including finances, infrastructure, and personnel; (3) Program Provision, including curriculum, administration, cost, goals, and visibility; (4) Recruitment Process, including screening and referrals; (5) Lifestyle Coaches, including their characteristics, behaviors, and morale; and (6) Cohort, including group attrition/retention and interpersonal dynamics. These factors were both highly interconnected in their impact on implementation and widely variable across sites within the healthcare system, as illustrated in our multi-level conceptual framework. CONCLUSIONS: This study identified key factors that could serve as barriers or facilitators in the implementation of DPP in large healthcare systems, from the perspective of lifestyle coaches. With further examination, the conceptual model presented here may be used for planning and managing the implementation of group-based behavioral interventions in these settings.

Supporting caregivers during hematopoietic cell transplantation for children with primary immunodeficiency disorders.

BACKGROUND: Caregivers of children with primary immunodeficiency disorders (PIDs) experience significant psychological distress during their child's hematopoietic cell transplantation (HCT) process. OBJECTIVES: This study aims to understand caregiver challenges and identify areas for health care system-level improvements to enhance caregiver well-being. METHODS: In this mixed-methods study caregivers of children with PIDs were contacted in August to November 2017 through online and electronic mailing lists of rare disease consortiums and foundations. Caregivers were invited to participate in an online survey assessing sociodemographic variables, the child's medical characteristics, psychosocial support use, and the World Health Organization-5 Well-Being Index. Open-ended questions about health care system improvements were included. Descriptive statistics and linear multivariate regression analyses were conducted. A modified content analysis method was used to code responses and identify emergent themes. RESULTS: Among the 80 caregiver respondents, caregivers had a median age of 34 years (range, 23-62 years) and were predominantly female, white, and married with male children given a diagnosis of severe combined immune deficiency. In the adjusted regression model lower caregiver well-being was significantly associated with lower household income and medical complications. Challenges during HCT include maintaining relationships with partners and the child's healthy sibling or siblings, managing self-care, and coping with feelings of uncertainty. Caregivers suggested several organizational-level solutions to enhance psychosocial support, including respite services, online connections to other PID caregivers, and bedside mental health services. CONCLUSIONS: Certain high-risk subpopulations of caregivers might need more targeted psychosocial support to reduce the long-term effect of the HCT experience on their well-being. Caregivers suggested several organizational-level solutions for provision of this support.

Implementation of a group-based diabetes prevention program within a healthcare delivery system.

BACKGROUND: Group-based Diabetes Prevention Programs (DPP), aligned with recommendations from the Centers for Disease Control and Prevention, promote clinically significant weight loss and reduce cardio-metabolic risks. Studies have examined implementation of the DPP in community settings, but less is known about its integration in healthcare systems. In 2010, a group-based DPP known as the Group Lifestyle Balance (GLB) was implemented within a large healthcare delivery system in Northern California, across three geographically distinct regional administration divisions of the organization within 12 state counties, with varying underlying socio-demographics. The regional divisions implemented the program independently, allowing for natural variation in its real-world integration. We leveraged this natural experiment to qualitatively assess the implementation of a DPP in this healthcare system and, especially, its fidelity to the original GLB curriculum and potential heterogeneity in implementation across clinics and regional divisions. METHODS: Using purposive sampling, we conducted semi-structured interviews with DPP lifestyle coaches. Data were analyzed using mixed-method techniques, guided by an implementation outcomes framework consisting of eight constructs: acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, and sustainability. RESULTS: We conducted 33 interviews at 20 clinics across the three regional administrative divisions. Consistencies in implementation of the program were found across regions in terms of satisfaction with the evidence base (acceptability), referral methods (adoption), eligibility criteria (fidelity), and strategies to increase retention and effectiveness (sustainability). Heterogeneity in implementation across regions were found in all categories, including: the number and frequency of sessions (fidelity); program branding (adoption); lifestyle coach training (adoption), and patient-facing cost (cost). Lifestyle coaches expressed differing attitudes about curriculum content (acceptability) and suitability of educational level (appropriateness). While difficulties with recruitment were common across regions (feasibility), strategies used to address these challenges differed (sustainability). CONCLUSIONS: Variation exists in the implementation of the DPP within a large multi-site healthcare system, revealing a dynamic and important tension between retaining fidelity to the original program and tailoring the program to meet the local needs. Moreover, certain challenges across sites may represent opportunities for considering alternative implementation to anticipate these barriers. Further research is needed to explore how differences in implementation domains impact program effectiveness.

Collecting Practice-level Data in a Changing Physician Office-based Ambulatory Care Environment: A Pilot Study Examining the Physician induction interview Component of the National Ambulatory Medical Care Survey.

Objective This report examines ways to improve National Ambulatory Medical Care Survey (NAMCS) data on practice and physician characteristics in multispecialty group practices. Methods From February to April 2013, the National Center for Health Statistics (NCHS) conducted a pilot study to observe the collection of the NAMCS physician interview information component in a large multispecialty group practice. Nine physicians were randomly sampled using standard NAMCS recruitment procedures; eight were eligible and agreed to participate. Using standard protocols, three field representatives conducted NAMCS physician induction interviews (PIIs) while trained ethnographers observed and audio recorded the interviews. Transcripts and field notes were analyzed to identify recurrent issues in the data collection process. Results The majority of the NAMCS items appeared to have been easily answered by the physician respondents. Among the items that appeared to be difficult to answer, three themes emerged: (a) physician respondents demonstrated an inconsistent understanding of "location" in responding to questions; (b) lack of familiarity with administrative matters made certain questions difficult for physicians to answer; and (c) certain primary care­oriented questions were not relevant to specialty care providers. Conclusions Some PII survey questions were challenging for physicians in a multispecialty practice setting. Improving the design and administration of NAMCS data collection is part of NCHS' continuous quality improvement process.

An exploratory mixed-methods crossover study comparing DVD- vs. Web-based patient decision support in three conditions: The importance of patient perspectives.

BACKGROUND: The last 15 years have witnessed considerable progress in the development of decision support interventions (DESIs). However, fundamental questions about design and format of delivery remain. METHODS: An exploratory, randomized mixed-method crossover study was conducted to compare a DVD- and Web-based DESI. Randomized participants used either the Web or the DVD first, followed by the alternative format. Participants completed a questionnaire to assess decision-specific knowledge at baseline and a questionnaire and structured qualitative interview after viewing each format. Tracking software was used to capture Web utilization. Transcripts were analyzed using integrated inductive and deductive approaches. Quantitative data were analyzed using exploratory bivariate and multivariate analyses. RESULTS: Exploratory knowledge analyses suggest that both formats increased knowledge, with limited evidence that the DVD increased knowledge more than the Web. Format preference varied across participants: 44% preferred the Web, 32% preferred the DVD and 24% preferred 'both'. Patient discussions of preferences for DESI information structure and the importance of a patients' stage of a given decision suggest these characteristics may be important factors underlying variation in utilization, format preferences and knowledge outcomes. CONCLUSIONS: Our results suggest that both DESI formats effectively increase knowledge. Patients' perceptions of these two formats further suggest that there may be no single 'best' format for all patients. These results have important implications for understanding why different DESI formats might be preferable to and more effective for different patients. Further research is needed to explore the relationship between these factors and DESI utilization outcomes across diverse patient populations.

Redefining Risk and Benefit: Understanding the Decision to Undergo Contralateral Prophylactic Mastectomy.

Rates of contralateral prophylactic mastectomy (CPM) among unilateral breast cancer patients are rapidly increasing; however, there are little data documenting the decision-making process of patients with no known BRCA mutations, who elect this more aggressive treatment. We conducted semistructured interviews with nine newly diagnosed patients who elected CPM over other surgical options. Using grounded theory, we analyzed interview data to identify influential decision-making factors by prevalence and intensity across participants. Decision-making factors included subjective evaluations of risk and benefit, avoidance of future breast cancer surveillance and accompanying worry, and desire to maintain (or improve) breast appearance. Based solely on survival benefit, the decision to undergo CPM might be viewed as unnecessary or even misguided. However, our findings show the importance of psychosocial factors in patients' assessments of risk and benefit, and support the need for additional patient-provider communication regarding these factors.

Beyond barriers: fundamental 'disconnects' underlying the treatment of breast cancer patients' sexual health.

Sexual health concerns represent one of the most frequently experienced and longest-lasting effects of breast cancer treatment, but research suggests that service providers rarely discuss sexual health with their patients. Existing research examining barriers to addressing patients' sexual health concerns has focused on discrete characteristics of the provider-patient interaction without considering the broader context in which these interactions occur. Drawing on the experiences of 21 breast cancer survivors, this paper explores three ways in which fundamental cultural and structural characteristics of the cancer care system in the USA may prevent breast cancer survivors from addressing their sexual health concerns, including: (1) when patients discussed sexual health with their providers, their providers approached sexuality as primarily physical, while participants experienced complex, multidimensional sexual health concerns; (2) specialisation within cancer care services made it difficult for patients to identify the appropriate provider to address their concerns; and (3) the structure of cancer care literally disconnects patients from the healthcare system at the time when sexual side effects commonly emerged. These data suggest that addressing breast cancer survivors' sexual health concerns requires a multifaceted approach to health systems change.