Genomic sequencing research in pediatric cancer care: Decision making, attitudes, and perceived utility among adolescents and young adults and their parents.

PURPOSE: Professional guidelines recommend engaging adolescents and young adults (AYAs) in medical decision making (DM), including whether to undergo genomic sequencing (GS). We explored DM around GS and attitudes after return of GS results among a diverse group of AYAs with cancer and their parents. METHODS: We surveyed AYAs with cancer (n = 75) and their parents (n = 52) 6 months after receiving GS results through the Texas KidsCanSeq study. We analyzed AYAs' DM role in GS research enrollment and their satisfaction with that role. We compared AYAs' and parents' self-reported understanding of, attitudes toward, and perceived utility of the AYA's GS results. RESULTS: Most AYAs reported equally sharing DM with their parents (55%) or leading DM (36%) about GS research. Compared with their cancer care DM role, 56% of AYAs reported the same level of involvement in GS research DM, whereas 32% were more involved, and 13% were less involved (P = .011). AYAs were satisfied (99%) with their DM role regarding GS study participation. AYAs and parents had similar self-reported understanding of, attitudes toward, and perceived utility of the GS results. CONCLUSION: Our results support engaging AYAs in DM about GS research and provide insights into AYAs' DM preferences and positive attitudes toward GS.

Parents' decision-making regarding whether to receive adult-onset only genetic findings for their children: Findings from the BabySeq Project.

PURPOSE: Most professional guidelines recommend against genetic screening for adult-onset only (AO) conditions until adulthood, yet others argue that there may be benefit to disclosing such results. We explored parents' decision-making on this issue in the BabySeq Project, a clinical trial of newborn genomic sequencing. METHODS: We conducted interviews with parents (N = 24) who were given the option to receive actionable AO results for their children. Interviews explored parents' motivations to receive and reasons to decline AO genetic disease risk information, their decision-making process, and their suggestions for supporting parents in making this decision. RESULTS: Parents noted several motivations to receive and reasons to decline AO results. Most commonly, parents cited early intervention/surveillance (n = 11), implications for family health (n = 7), and the ability to prepare (n = 6) as motivations to receive these results. The most common reasons to decline were protection of the child's future autonomy (n = 4), negative effect on parenting (n = 3), and anxiety about future disease (n = 3). Parents identified a number of ways to support parents in making this decision. CONCLUSION: Results show considerations to better support parental decision-making that aligns with their values when offering AO genetic information because it is more commonly integrated into pediatric clinical care.

Educating military primary health-care providers in genomic medicine: lessons learned from the MilSeq Project.

PURPOSE: With few trained genetics professionals, the Military Health System is ill-equipped to manage the rapid expansion of genomic medicine. The MilSeq Project introduces an alternative service delivery model (ASDM) in which primary health-care providers (HCPs) provide post-test counseling (PTC) to healthy Airmen who have undergone exome sequencing. We describe HCP performance after a prerequisite educational intervention (EI). METHODS: After a brief EI and pre-/posteducation surveys, HCPs were eligible to provide PTC with a genetic counselor available for consult. PTC was recorded, transcribed, and reviewed. Opportunities for improvement were organized into four error adjustment categories: (1) knowledge limitation, (2) minor, (3) moderate, and (4) critical. Thematic analysis was also performed. RESULTS: Pre-/posteducation survey responses revealed statistically significant improvements in all domains. Minor error adjustments were most represented (n = 93), followed by knowledge limitation (n = 39) and moderate (n = 19). No critical errors were identified, and 17 transcripts required no adjustment. Thematic analysis revealed four themes that would benefit from more focused education: (1) family-centered care, (2) conveying risk, (3) disease knowledge, and (4) assay knowledge. CONCLUSION: HCPs demonstrated competence in basic PTC after a brief EI. This ASDM may be a viable interim response to the shortage of genetics professionals in some systems.

Airmen and health-care providers' attitudes toward the use of genomic sequencing in the US Air Force: findings from the MilSeq Project.

PURPOSE: The use of genomic sequencing (GS) in military settings poses unique considerations, including the potential for GS to impact service members' careers. The MilSeq Project investigated the use of GS in clinical care of active duty Airmen in the United States Air Force (USAF). METHODS: We assessed perceived risks, benefits, and attitudes toward use of GS in the USAF among patient participants (n = 93) and health-care provider participants (HCPs) (n = 12) prior to receiving or disclosing GS results. RESULTS: Participants agreed that there are health benefits associated with GS (90% patients, 75% HCPs), though more HCPs (75%) than patients (40%) agreed that there are risks (p = 0.048). The majority of both groups (67% HCPs, 77% patients) agreed that they trust the USAF with genetic information, but far fewer agreed that genetic information should be used to make decisions about deployment (5% patients, 17% HCPs) or duty assignments (3% patients, 17% HCPs). Despite their hesitancy, patients were supportive of the USAF testing for nondisease traits that could impact their duty performance. Eighty-seven percent of patients did not think their GS results would influence their career. CONCLUSION: Results suggest favorable attitudes toward the use of GS in the USAF when not used for deployment or assignment decisions.

Workflow Improvement of Electronic Health Record Usage in a Tertiary Pediatric Burns Clinic.

BACKGROUND: As a high patient-throughput clinic, the Royal Children's Hospital's multidisciplinary burns clinic's efficiency of clinic workflow and streamlined patient assessment is crucial. The clinic has been using a customized "burns assessment tool" (BAT) as part of its integrated electronic health record (EHR) since 2016. OBJECTIVES: The aim was to assess the usage patterns of the BAT at baseline, followed by re-evaluation following interventions to improve efficiency and utilization of the BAT. METHODS: This study was a prospective observational time-motion quality improvement study. Observations of 19 clinicians in the pediatric burns clinic by five trained observers using a validated time-motion capture tool (TimeCaT 3.9) to map clinician workflow, with specific reference to time spent on a list of predetermined tasks, were conducted. Baseline data were collected for 7 weeks followed by three cycles of interventions and observations over 5 months. RESULTS: At baseline, the median time for a patient visit was 24.56 minutes (range: 2.78-73.72 minutes, interquartile range: 14.17-27 minutes), with most of the time spent on documentation (34.6%) and patient contact tasks (26.0%). In each of the study cycles, the median time spent on documentation within the EHR was significantly reduced compared with baseline (cycle 1 29.8%, p = 0.08; cycle 2 20.4%, p ≤ 0.01; cycle 3 27.32%, p = 0.04). The time spent on patient contact increased when comparing baseline to data of cycles 1, 2, and 3 (25.96 vs. 33.27% of visit, p = 0.04). There was no significant change in absolute time spent on the BAT during the study. CONCLUSION: The study findings of clear, significant, and sustained improvement in documentation efficiency and the corresponding increase in patient contact time after interventions were introduced reinforce the importance of integration of an EHR with clinical workflow.

Views of Adolescents and Young Adults with Cancer and Their Oncologists Toward Patients' Participation in Genomic Research.

Purpose: With increased use of genomic testing in cancer research and clinical care, it is important to understand the perspectives and decision-making preferences of adolescents and young adults (AYAs) with cancer and their treating oncologists. Methods: We conducted an interview substudy of the BASIC3 Study, which enrolled newly diagnosed cancer patients <18 years of age with assent. Of 32 young adults (YAs) with cancer who reached the age of majority (AOM; 18 years) while on study, 12 were successfully approached and all consented to study continuation at AOM. Of those, seven completed an interview. Patients' oncologists, who enrolled and participated in return of clinical genomic results, were also interviewed (n = 12). Interviews were transcribed, deidentified, and analyzed using thematic analysis. Results: YAs cited the possibility of helping others and advancing science as major reasons for their assent to initial study enrollment and their willingness to consent at AOM. YAs thought obtaining informed consent from research participants for study continuation at AOM was a good idea in case they changed their minds or wanted to make their own decisions, and to keep them aware of study activities. There was diversity in what YAs understood and learned from genomic testing: some recalled specific findings, while some remembered minimal information about their results. Oncologists varied in their assessment of adolescents' engagement with the study and understanding of their results. Conclusion: Given the different ways AYAs engage with genomic information, careful assessment of AYAs' diverse communication and decision-making preferences is needed to tailor interactions accordingly.

Researchers' Ethical Concerns About Using Adaptive Deep Brain Stimulation for Enhancement.

The capacity of next-generation closed-loop or adaptive deep brain stimulation devices (aDBS) to read (measure neural activity) and write (stimulate brain regions or circuits) shows great potential to effectively manage movement, seizure, and psychiatric disorders, and also raises the possibility of using aDBS to electively (non-therapeutically) modulate mood, cognition, and prosociality. What separates aDBS from most neurotechnologies (e.g. transcranial stimulation) currently used for enhancement is that aDBS remains an invasive, surgically-implanted technology with a risk-benefit ratio significantly different when applied to diseased versus non-diseased individuals. Despite a large discourse about the ethics of enhancement, no empirical studies yet examine perspectives on enhancement from within the aDBS research community. We interviewed 23 aDBS researchers about their attitudes toward expanding aDBS use for enhancement. A thematic content analysis revealed that researchers share ethical concerns related to (1) safety and security; (2) enhancement as unnecessary, unnatural or aberrant; and (3) fairness, equality, and distributive justice. Most (70%) researchers felt that enhancement applications for DBS will eventually be technically feasible and that attempts to develop such applications for DBS are already happening (particularly for military purposes). However, researchers unanimously (100%) felt that DBS ideally should not be considered for enhancement until researchers better understand brain target localization and functioning. While many researchers acknowledged controversies highlighted by scholars and ethicists, such as potential impacts on personhood, authenticity, autonomy and privacy, their ethical concerns reflect considerations of both gravity and perceived near-term likelihood.

Pediatric Oncologists' Experiences Returning and Incorporating Genomic Sequencing Results into Cancer Care.

Pediatric oncologists' perspectives around returning and incorporating tumor and germline genomic sequencing (GS) results into cancer care are not well-described. To inform optimization of cancer genomics communication, we assessed oncologists' experiences with return of genomic results (ROR), including their preparation/readiness for ROR, collaboration with genetic counselors (GCs) during ROR, and perceived challenges. The BASIC3 study paired pediatric oncologists with GCs to return results to patients' families. We thematically analyzed 24 interviews with 12 oncologists at two post-ROR time points. Oncologists found pre-ROR meetings with GCs and geneticists essential to interpreting patients' reports and communicating results to families. Most oncologists took a collaborative ROR approach where they discussed tumor findings and GCs discussed germline findings. Oncologists perceived many roles for GCs during ROR, including answering families' questions and describing information in lay language. Challenges identified included conveying uncertain information in accessible language, limits of oncologists' genetics expertise, and navigating families' emotional responses. Oncologists emphasized how GCs' and geneticists' support was essential to ROR, especially for germline findings. GS can be successfully integrated into cancer care, but to account for the GC shortage, alternative ROR models and access to genetics resources will be needed to better support families and avoid burdening oncologists.

Examining access to care in clinical genomic research and medicine: Experiences from the CSER Consortium.

INTRODUCTION: Ensuring equitable access to health care is a widely agreed-upon goal in medicine, yet access to care is a multidimensional concept that is difficult to measure. Although frameworks exist to evaluate access to care generally, the concept of "access to genomic medicine" is largely unexplored and a clear framework for studying and addressing major dimensions is lacking. METHODS: Comprised of seven clinical genomic research projects, the Clinical Sequencing Evidence-Generating Research consortium (CSER) presented opportunities to examine access to genomic medicine across diverse contexts. CSER emphasized engaging historically underrepresented and/or underserved populations. We used descriptive analysis of CSER participant survey data and qualitative case studies to explore anticipated and encountered access barriers and interventions to address them. RESULTS: CSER's enrolled population was largely lower income and racially and ethnically diverse, with many Spanish-preferring individuals. In surveys, less than a fifth (18.7%) of participants reported experiencing barriers to care. However, CSER project case studies revealed a more nuanced picture that highlighted the blurred boundary between access to genomic research and clinical care. Drawing on insights from CSER, we build on an existing framework to characterize the concept and dimensions of access to genomic medicine along with associated measures and improvement strategies. CONCLUSIONS: Our findings support adopting a broad conceptualization of access to care encompassing multiple dimensions, using mixed methods to study access issues, and investing in innovative improvement strategies. This conceptualization may inform clinical translation of other cutting-edge technologies and contribute to the promotion of equitable, effective, and efficient access to genomic medicine.

Researcher Perspectives on Ethical Considerations in Adaptive Deep Brain Stimulation Trials.

Interest and investment in closed-loop or adaptive deep brain stimulation (aDBS) systems have quickly expanded due to this neurotechnology's potential to more safely and effectively treat refractory movement and psychiatric disorders compared to conventional DBS. A large neuroethics literature outlines potential ethical concerns about conventional DBS and aDBS systems. Few studies, however, have examined stakeholder perspectives about ethical issues in aDBS research and other next-generation DBS devices. To help fill this gap, we conducted semi-structured interviews with researchers involved in aDBS trials (n = 23) to gain insight into the most pressing ethical questions in aDBS research and any concerns about specific features of aDBS devices, including devices' ability to measure brain activity, automatically adjust stimulation, and store neural data. Using thematic content analysis, we identified 8 central themes in researcher responses. The need to measure and store neural data for aDBS raised concerns among researchers about data privacy and security issues (noted by 91% of researchers), including the avoidance of unintended or unwanted third-party access to data. Researchers reflected on the risks and safety (83%) of aDBS due to the experimental nature of automatically modulating then observing stimulation effects outside a controlled clinical setting and in relation to need for surgical battery changes. Researchers also stressed the importance of ensuring informed consent and adequate patient understanding (74%). Concerns related to automaticity and device programming (65%) were discussed, including current uncertainties about biomarker validity. Additionally, researchers discussed the potential impacts of automatic stimulation on patients' autonomy and control over stimulation (57%). Lastly, researchers discussed concerns related to patient selection (defining criteria for candidacy) (39%), challenges of ensuring post-trial access to care and device maintenance (39%), and potential effects on personality and identity (30%). To help address researcher concerns, we discuss the need to minimize cybersecurity vulnerabilities, advance biomarker validity, promote the balance of device control between patients and clinicians, and enhance ongoing informed consent. The findings from this study will help inform policies that will maximize the benefits and minimize potential harms of aDBS and other next-generation DBS devices.

Researcher Perspectives on Data Sharing in Deep Brain Stimulation.

The expansion of research on deep brain stimulation (DBS) and adaptive DBS (aDBS) raises important neuroethics and policy questions related to data sharing. However, there has been little empirical research on the perspectives of experts developing these technologies. We conducted semi-structured, open-ended interviews with aDBS researchers regarding their data sharing practices and their perspectives on ethical and policy issues related to sharing. Researchers expressed support for and a commitment to sharing, with most saying that they were either sharing their data or would share in the future and that doing so was important for advancing the field. However, those who are sharing reported a variety of sharing partners, suggesting heterogeneity in sharing practices and lack of the broad sharing that would reflect principles of open science. Researchers described several concerns and barriers related to sharing, including privacy and confidentiality, the usability of shared data by others, ownership and control of data (including potential commercialization), and limited resources for sharing. They also suggested potential solutions to these challenges, including additional safeguards to address privacy issues, standardization and transparency in analysis to address issues of data usability, professional norms and heightened cooperation to address issues of ownership and control, and streamlining of data transmission to address resource limitations. Researchers also offered a range of views on the sensitivity of neural activity data (NAD) and data related to mental health in the context of sharing. These findings are an important input to deliberations by researchers, policymakers, neuroethicists, and other stakeholders as they navigate ethics and policy questions related to aDBS research.

What is a Medical Information Commons?

A 2011 National Academies of Sciences report called for an "Information Commons" and a "Knowledge Network" to revolutionize biomedical research and clinical care. We interviewed 41 expert stakeholders to examine governance, access, data collection, and privacy in the context of a medical information commons. Stakeholders' attitudes about MICs align with the NAS vision of an Information Commons; however, differences of opinion regarding clinical use and access warrant further research to explore policy and technological solutions.

Perceived Benefits, Risks, and Utility of Newborn Genomic Sequencing in the BabySeq Project.

BACKGROUND AND OBJECTIVES: There is interest in applying genomic sequencing (GS) to newborns' clinical care. Here we explore parents' and clinicians' attitudes toward and perceptions of the risks, benefits, and utility of newborn GS compared with newborn screening (NBS) prior to receiving study results. METHODS: The BabySeq Project is a randomized controlled trial used to explore the impact of integrating GS into the clinical care of newborns. Parents (n = 493) of enrolled infants (n = 309) and clinicians (n = 144) completed a baseline survey at enrollment. We examined between-group differences in perceived utility and attitudes toward NBS and GS. Open-ended responses about risks and benefits of each technology were categorized by theme. RESULTS: The majority of parents (71%) and clinicians (51%) agreed that there are health benefits of GS, although parents and clinicians agreed more that there are risks associated with GS (35%, 70%) than with NBS (19%, 39%; all P < .05). Parents perceived more benefit and less risk of GS than did clinicians. Clinicians endorsed concerns about privacy and discrimination related to genomic information more strongly than did parents, and parents anticipated benefits of GS that clinicians did not. CONCLUSIONS: Parents and clinicians are less confident in GS than NBS, but parents perceive a more favorable risk/benefit ratio of GS than do clinicians. Clinicians should be aware that parents' optimism may stem from their perceived benefits beyond clinical utility.

Autoantibodies to oxidized low-density lipoprotein in patients with type 2 diabetes mellitus.

BACKGROUND: Oxidation of low-density lipoprotein (LDL) is a crucial step in atherogenesis. There is an urgent need for direct measures of in vivo oxidative stress. Autoantibodies against oxidized low-density lipoprotein (Ab against Ox-LDL) are a direct measure of oxidative stress and predict cardiovascular disease. Our aim was to evaluate an ELISA for Ab against Ox-LDL in Type 2 diabetes, a condition with increased oxidative stress. METHODS: Ab against Ox-LDL were measured by ELISA and expressed as a ratio of Ox-LDL to native LDL (N-LDL). Samples were obtained from 45 Type 2 diabetic patients and 25 matched controls before and after supplementation with alpha tocopherol (AT, 1200 IU/day). RESULTS: The assay had good precision. While there was no interference with bilirubin and hemolysis, triglycerides 500 mg/dl increased antibody titer, which was abrogated by airfuging. Compared to controls, significantly increased titers of Ab against Ox-LDL were found in diabetics (diabetes mellitus Type 2) with macrovascular disease (DM2-MV), but not without macrovascular disease (DM2) (DM2: 1.32+/-0.33; DM2-MV: 1.48+/-0.44 vs. controls, 1.21+/-0.28; p<0.05). AT supplementation significantly decreased titers of Ab against Ox-LDL in both diabetic groups (p<0.01). CONCLUSION: This assay may serve as a future test for the assessment of cardiovascular risk especially in patients with increased oxidative stress.

Hyperhomocysteinemia measured by immunoassay: a valid measure of coronary artery atherosclerosis.

CONTEXT: Homocysteine is emerging as a novel marker of atherothrombosis. Its role as an independent risk factor for cardiovascular disease is generally accepted. There is scanty data correlating homocysteine levels measured by immunoassay with cardiovascular disease. We previously validated a fluorescence polarization immunoassay for measuring homocysteine, which compared favorably with high performance liquid chromatography. OBJECTIVE: To determine if homocysteine levels measured by immunoassay correlate with extent of atherosclerotic burden, as represented by degree of coronary artery stenosis determined by coronary angiography. DESIGN: Fasting plasma samples were obtained from patients undergoing coronary angiography (N = 165). Homocysteine levels were measured by immunoassay and coronary artery stenosis was determined by coronary angiography. RESULTS: Median coronary artery stenosis for the 3 homocysteine subgroups, less than 1.35, 1.35 to 6.75, and greater than 6.75 mg/L (<10, 10-15, and >15 micromol/L), was 75%, 90%, and 99%, respectively (P = .01 for trend). Also, folate and vitamin B12 levels decreased with increasing homocysteine levels (P = .01 and .04, respectively, for trend). Spearman's correlation showed a significant association between homocysteine level and coronary artery stenosis (r = 0.20; P = .009). When men and women were examined separately, the correlation was significant only for women (r = 0.30; P = .01). CONCLUSION: Homocysteine levels, as measured by immunoassay, show a positive correlation with cardiovascular disease in women. Thus, this is a valid measure of atherosclerotic burden and, therefore, a reliable addition to the established laboratory repertoire for the assessment of cardiovascular disease.