A qualitative evaluation of patient and parent experiences with an undiagnosed diseases program.

Previous studies have explored patient experiences before being seen or at the beginning of their evaluation by undiagnosed diseases programs. This study provides additional insight into experiences after participation through in-depth, qualitative evaluation, allowing for reflection of current practice and patient/parent needs. Semi-structured interviews were conducted with patients and parents of patients seen at the University of Alabama at Birmingham (UAB)'s unique, clinically focused Undiagnosed Diseases Program (UDP). Analysis of the interviews was guided by a thematic approach. Participants had undergone a diagnostic odyssey before being evaluated by the UDP and remained hopeful for a diagnosis. They appreciated the opportunity to be seen by the UDP. However, perception of experiences differed based on whether evaluation by the UDP led to a diagnosis. Additionally, while participants were pleased with initial communication, they indicated that there were unmet needs regarding follow-up. Patients and parents of patients believe that participation in an undiagnosed diseases program is the best option for diagnosis. The findings of this study provide a general overview of patient experiences and highlight strengths of the UAB UDP while also emphasizing areas to focus the improvement to optimize the benefit to patients and families with undiagnosed and rare diseases, which could be used helpful in the development of similar clinics.

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.

Medical and psychosocial outcomes of state-funded population genomic screening.

As the uptake of population screening expands, assessment of medical and psychosocial outcomes is needed. Through the Alabama Genomic Health Initiative (AGHI), a state-funded genomic research program, individuals received screening for pathogenic or likely pathogenic variants in 59 actionable genes via genotyping. Of the 3874 eligible participants that received screening results, 858 (22%) responded to an outcomes survey. The most commonly reported motivation for seeking testing through AGHI was contribution to genetic research (64%). Participants with positive results reported a higher median number of planned actions (median = 5) due to AGHI results as compared to negative results (median = 3). Interviews were conducted with survey participants with positive screening results. As determined by certified genetic counselors, 50% of interviewees took appropriate medical action based on their result. There were no negative or harmful actions taken. These findings indicate population genomic screening of an unselected adult population is feasible, is not harmful, and may have positive outcomes on participants now and in the future; however, further research is needed in order to assess clinical utility.

Does genetic testing offer utility as a supplement to traditional family health history intake for inherited disease risk?

CONTENT: This study examines the potential utility of genetic testing as a supplement to family health history to screen for increased risk of inherited disease. Medical conditions are often misreported or misunderstood, especially those related to different forms of cardiac disease (arrhythmias vs. structural heart disease vs. coronary artery disease), female organ cancers (uterine vs. ovarian vs. cervical), and type of cancer (differentiating primary cancer from metastases to other organs). While these nuances appear subtle, they can dramatically alter medical management. For example, different types of cardiac failure (structural, arrhythmia, and coronary artery disease) have inherited forms that are managed with vastly different approaches. METHODS: Using a dataset of over 6,200 individuals who underwent genetic screening, we compared the ability of genetic testing and traditional family health history to identify increased risk of inherited disease. A further, in-depth qualitative study of individuals for whom risk identified through each method was discordant, explored whether this discordance could be addressed through changes in family health history intake. FINDINGS: Of 90 individuals for whom genetic testing indicated significant increased risk for inherited disease, two-thirds (66%) had no corroborating family health history. Specifically, we identify cardiomyopathy, arrhythmia, and malignant hyperthermia as conditions for which discordance between genetic testing and traditional family health history was greatest, and familial hypercholesterolaemia, Lynch syndrome, and hereditary breast and ovarian cancer as conditions for which greater concordance existed. CONCLUSION: We conclude that genetic testing offers utility as a supplement to traditional family health history intake over certain conditions.

Parent perspectives on disclosing a pediatric neurofibromatosis type 1 diagnosis.

Neurofibromatosis 1 (NF1) is a common genetic disorder typically diagnosed in childhood and characterized by cutaneous findings, nerve sheath tumors, skeletal abnormalities, malignancies, and developmental differences. Due to its variability, NF1 is an unpredictable condition that parents have concerns about discussing with their children. While there are publications addressing the disclosure of genetic conditions in general, no NF1-specific disclosure literature exists. To fill this gap, this mixed methods study sought to evaluate the concerns, barriers, failures, or successes parents or guardians have experienced when they have or have not chosen to tell their child(ren) about an NF1 diagnosis. Parents of children between ages 0 and 17 with a diagnosis of NF1 completed a survey and some parents were selected for an interview invitation. A total of 258 surveys were completed, and 20 parents were interviewed. Interview transcripts were categorized into disclosure and non-disclosure groups. Themes were organized into five categories based on interview questions: disclosure concerns, factors affecting disclosure/non-disclosure, approaches to disclosure, desired resources, and recommendations for disclosure. Sentiment analysis was performed on responses about the disclosure discussion itself. Results indicated that most parents (70.5%) disclosed the NF1 diagnosis to their child and overall felt it was a positive experience. Almost one-third of parents (29.5%) had not disclosed the diagnosis. A strong significance was identified between disclosure and severe presentation of NF1 (p = 0.0008). Parents in both groups shared similar concerns about discussing the diagnosis and multiple factors influenced the disclosure decision. Most parents approached disclosure as a process and emphasized the need to be honest and supportive of their child. Parents highlighted the need for more educational resources for children and guidance on how to disclose. These findings indicate that additional resources and support for parents would facilitate disclosure and the involvement of genetic counselors in the process would be beneficial.

Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls.

PURPOSE: To evaluate the effectiveness and specificity of population-based genomic screening in Alabama. METHODS: The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results. RESULTS: Among 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Variants detected within African American individuals were significantly enriched for FPs, likely due to a higher rate of nontargeted alternative alleles close to array-targeted P/LP variants. CONCLUSION: In AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.

A state-based approach to genomics for rare disease and population screening.

PURPOSE: The Alabama Genomic Health Initiative (AGHI) is a state-funded effort to provide genomic testing. AGHI engages two distinct cohorts across the state of Alabama. One cohort includes children and adults with undiagnosed rare disease; a second includes an unselected adult population. Here we describe findings from the first 176 rare disease and 5369 population cohort AGHI participants. METHODS: AGHI participants enroll in one of two arms of a research protocol that provides access to genomic testing results and biobank participation. Rare disease cohort participants receive genome sequencing to identify primary and secondary findings. Population cohort participants receive genotyping to identify pathogenic and likely pathogenic variants for actionable conditions. RESULTS: Within the rare disease cohort, genome sequencing identified likely pathogenic or pathogenic variation in 20% of affected individuals. Within the population cohort, 1.5% of individuals received a positive genotyping result. The rate of genotyping results corroborated by reported personal or family history varied by gene. CONCLUSIONS: AGHI demonstrates the ability to provide useful health information in two contexts: rare undiagnosed disease and population screening. This utility should motivate continued exploration of ways in which emerging genomic technologies might benefit broad populations.

Recruiting diversity where it exists: The Alabama Genomic Health Initiative.

Lack of diversity among genomic research participants results in disparities in benefits from genetic testing. To address this, the Alabama Genomic Health Initiative employed community engagement strategies to recruit diverse populations where they lived. In this paper, we describe our engagement techniques and recruitment strategies, which resulted in significant improvement in representation of African American participants. While African American participation has not reached the representation of this community as a percentage of Alabama's overall population (26%-27%), we have achieved an overall representation exceeding 20% for African Americans. We believe this demonstrates the value of engagement and recruitment where diverse populations reside.

Enhancing Neurofibromatosis Clinical Trial Outcome Measures Through Patient Engagement: Lessons From REiNS.

OBJECTIVE: As part of an evaluation of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration patient representative program, we surveyed REiNS members to (1) identify facilitators and barriers to involving patient representatives and (2) understand whether and how involving patient representatives affected recommendations for clinical trial outcomes. METHODS: We administered an anonymous online survey to all REiNS members. Facilitators and barriers to patient representative involvement were solicited using a modified free listing technique; responses were inductively grouped into higher-order categories and ranked based on saliency score (Smith s). Open-ended questions assessed patient representative expectations for engagement, perceived benefits/costs of patient engagement, and patient representative contributions; responses were analyzed using conventional content analysis. RESULTS: A total of 63/172 (37%) members responded, including 18/30 (60%) patient representatives. Providing sufficient opportunities to meaningfully engage in research tasks and cultivating a respectful, inclusive atmosphere were key facilitators to patient representatives' satisfaction and ability to make an impact. Respondents perceived that patient representatives directly (through their input on research tasks) and indirectly (through effects on other stakeholders' knowledge and communication style) improved the organization's research, leading to selection of more meaningful, relevant, and feasible clinical trial outcome measures. Ongoing challenges to patient engagement include difficulty scheduling meetings and concerns about the level of scientific knowledge patient representatives needed to effectively engage. CONCLUSIONS: Involving patient representatives in REiNS improved perceived quality of neurofibromatosis clinical trial outcome measures. Negotiating sufficient opportunities to engage, fostering an inclusive atmosphere, and navigating time pressures are key to effective patient engagement.