Conceptualization of utility in translational clinical genomics research.

Prior to integration into clinical care, a novel medical innovation is typically assessed in terms of its balance of benefits and risks, often referred to as utility. Members of multidisciplinary research teams may conceptualize and assess utility in different ways, which has implications within the translational genomics community and for the evidence base upon which clinical guidelines groups and healthcare payers make decisions. Ambiguity in the conceptualization of utility in translational genomics research can lead to communication challenges within research teams and to study designs that do not meet stakeholder needs. We seek to address the ambiguity challenge by describing the conceptual understanding of utility and use of the term by scholars in the fields of philosophy, medicine, and the social sciences of decision psychology and health economics. We illustrate applications of each field's orientation to translational genomics research by using examples from the Clinical Sequencing Evidence-Generating Research (CSER) consortium, and we provide recommendations for increasing clarity and cohesion in future research. Given that different understandings of utility will align to a greater or lesser degree with important stakeholders' views, more precise use of the term can help researchers to better integrate multidisciplinary investigations and communicate with stakeholders.

Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for pediatric diagnostic testing.

PURPOSE: Measuring the effects of genomic sequencing (GS) on patients and families is critical for translational research. We aimed to develop and validate an instrument to assess parents' perceived utility of pediatric diagnostic GS. METHODS: Informed by a 5-domain conceptual model, the study comprised 5 steps: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Parents of pediatric patients who had received results of clinically indicated GS participated in structured cognitive interviews and 2 rounds of surveys. After eliminating items based on theory and quantitative performance, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments. RESULTS: We derived the 21-item Pediatric Diagnostic version of the GENEtic Utility (GENE-U) scale, which has a 2-factor structure that includes an Informational Utility subscale (16 items, α = 0.91) and an Emotional Utility subscale (5 items, α = 0.71). Scores can be summed to calculate a Total scale score (α = 0.87). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS, and the Emotional Utility subscale was moderately associated with psychosocial impact and depression and anxiety. CONCLUSION: The pediatric diagnostic GENE-U scale demonstrated good psychometric performance in this initial evaluation and could be a useful tool for translational genomics researchers, warranting additional validation.

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.

Attitudes, Knowledge, and Risk Perceptions of Patients who Received Elective Genomic Testing as a Clinical Service.

BACKGROUND: Elective genomic testing (EGT) is increasingly available clinically. Limited real world evidence exists about attitudes and knowledge of EGT recipients. METHODS: After web-based education, patients who enrolled in an EGT program at a rural nonprofit healthcare system completed a survey that assessed attitudes, knowledge, and risk perceptions. RESULTS: From August 2020 to April 2022, 5,920 patients completed the survey and received testing. Patients most frequently cited interest in learning their personal disease risks as their primary motivation. Patients most often expected results to guide medication management (74.0%), prevent future disease (70.4%), and provide information about risks to offspring (65.4%). Patients were "very concerned" most frequently about the privacy of genetic information (19.8%) and how well testing predicted disease risks (18.0%). On average, patients answered 6.7 of 11 knowledge items correctly (61.3%). They more often rated their risks for colon and breast cancers as lower rather than higher than the average person, but more often rated their risk for a heart attack as higher rather than lower than the average person (all p<0.001). CONCLUSION: Patients pursued EGT because of the utility expectations, but often misunderstood the test's capabilities.

Measuring health-related quality of life in children with suspected genetic conditions: validation of the PedsQL proxy-report versions.

PURPOSE: Measuring health-related quality of life (HRQoL) of children with suspected genetic conditions is important for understanding the effect of interventions such as genomic sequencing (GS). The Pediatric Quality of Life Inventory (PedsQL) is a widely used generic measure of HRQoL in pediatric patients, but its psychometric properties have not yet been evaluated in children undergoing diagnostic GS. METHODS: In this cross-sectional study, we surveyed caregivers at the time of their child's enrollment into GS research studies as part of the Clinical Sequencing Evidence Generating Research (CSER) consortium. To evaluate structural validity of the PedsQL 4.0 Generic Core Scales and PedsQL Infant Scales parent proxy-report versions, we performed a confirmatory factor analysis of the hypothesized factor structure. To evaluate convergent validity, we examined correlations between caregivers' reports of their child's health, assessed using the EQ VAS, and PedsQL scores by child age. We conducted linear regression analyses to examine whether age moderated the association between caregiver-reported child health and PedsQL scores. We assessed reliability using Cronbach's alpha. RESULTS: We analyzed data for 766 patients across all PedsQL age group versions (1-12 months through 13-18 years). Model fit failed to meet criteria for good fit, even after modification. Neither age group (categorical) nor age (continuous) significantly moderated associations between PedsQL scores and caregiver-reported child health. Cronbach's alphas indicated satisfactory internal consistency for most PedsQL scales. CONCLUSION: The PedsQL Generic Core Scales and Infant Scales may be appropriate to measure HRQoL in pediatric patients with suspected genetic conditions across a wide age range. While we found evidence of acceptable internal consistency and preliminary convergent validity in this sample, there were some potential problems with structural validity and reliability that require further attention.

Cascade testing after exome sequencing: Retrospective analysis of linked family data at 2 US laboratories.

PURPOSE: Cascade testing, the process of testing a proband's at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after a positive exome sequencing (ES) result in a population of probands with diverse clinical indications. METHODS: We retrospectively reviewed administrative data from 2 US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives' cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and relatives categorized on the basis of cascade testing completion. RESULTS: Among the 3723 positive ES results across both laboratories, 426 relatives of 282 probands completed cascade testing (uptake = 7.6%). An average of 1.5 relatives (SD = 0.9) were tested per proband. Of the 426 relatives tested, 200 had a variant of interest detected (variant detection yield = 47.0%). CONCLUSION: In our real-world data analysis, a small proportion of probands with a positive ES result subsequently had relatives complete cascade testing at the same laboratory. However, approximately half of the tested relatives received a clinically significant result that could have implications for clinical management or reproductive planning. Additional research on ways to increase cascade testing uptake is warranted.

Access to clinically indicated genetic tests for pediatric patients with Medicaid: Evidence from outpatient genetics clinics in Texas.

PURPOSE: Little is known about how Medicaid coverage policies affect access to genetic tests for pediatric patients. Building upon and extending a previous analysis of prior authorization requests (PARs), we describe expected coverage of genetic tests submitted to Texas Medicaid and the PAR and diagnostic outcomes of those tests. METHODS: We retrospectively reviewed genetic tests ordered at 3 pediatric outpatient genetics clinics in Texas. We compared Current Procedural Terminology (CPT) codes with the Texas Medicaid fee-for-service schedule (FFSS) to determine whether tests were expected to be covered by Medicaid. We assessed completion and diagnostic yield of commonly ordered tests. RESULTS: Among the 3388 total tests submitted to Texas Medicaid, 68.9% (n = 2336) used at least 1 CPT code that was not on the FFSS and 80.7% (n = 2735) received a favorable PAR outcome. Of the tests with a CPT code not on the FFSS, 60.0% (n = 1400) received a favorable PAR outcome and were completed and 20.5% (n = 287) were diagnostic. The diagnostic yield of all tests with a favorable PAR outcome that were completed was 18.7% (n = 380/2029). CONCLUSION: Most PARs submitted to Texas Medicaid used a CPT code for which reimbursement from Texas Medicaid was not guaranteed. The frequency with which clinically indicated genetic tests were not listed on the Texas Medicaid FFSS suggests misalignment between genetic testing needs and coverage policies. Our findings can inform updates to Medicaid policies to reduce coverage uncertainty and expand access to genetic tests with high diagnostic utility.

Clinically Indicated Genomic Sequencing of Children in Foster Care: Legal and Ethical Issues.

There are approximately 400 000 children in foster care in the US, approximately one-half of whom have chronic health problems and approximately 10% of whom have complex healthcare needs. Given the increasing relevance of genomic sequencing to guide clinical care for children with rare, chronic, and undiagnosed conditions, it may be an important component of diagnostic evaluation for children in foster care. Clinically indicated genomic sequencing may provide information that has health implications for children in foster care, as well as for their biological parents and other relatives. Whether and how genomic sequencing results impact legal decision making and family court outcomes is not yet well-understood. We describe scenarios that highlight legal, ethical, and policy issues surrounding genomic sequencing for children in foster care using 3 cases adapted from real-world events. Together, these cases highlight important yet underexplored issues that arise when genomic information has legal relevance in family court and ethical implications for child and family well-being. As genomic sequencing becomes more routine for the general pediatric population, additional research is needed to better understand its impacts on children and other stakeholders within the foster care system.

US private payers' perspectives on insurance coverage for genome sequencing versus exome sequencing: A study by the Clinical Sequencing Evidence-Generating Research Consortium (CSER).

PURPOSE: There is limited payer coverage for genome sequencing (GS) relative to exome sequencing (ES) in the U.S. Our objective was to assess payers' considerations for coverage of GS versus coverage of ES and requirements payers have for coverage of GS. The study was conducted by the NIH-funded Clinical Sequencing Evidence-Generating Research Consortium (CSER). METHODS: We conducted semi-structured interviews with representatives of private payer organizations (payers, N = 12) on considerations and evidentiary and other needs for coverage of GS and ES. Data were analyzed using thematic analysis. RESULTS: We described four categories of findings and solutions: demonstrated merits of GS versus ES, enhanced methods for evidence generation, consistent laboratory processes/sequencing methods, and enhanced implementation/care delivery. Payers see advantages to GS vs. ES and are open to broader GS coverage but need more proof of these advantages to consider them in coverage decision-making. Next steps include establishing evidence of benefits in specific clinical scenarios, developing quality standards, ensuring transparency of laboratory methods, developing clinical centers of excellence, and incorporating the role of genetic professionals. CONCLUSION: By comparing coverage considerations for GS and ES, we identified a path forward for coverage of GS. Future research should explicitly address payers' conditions for coverage.

Cost-effectiveness frameworks for comparing genome and exome sequencing versus conventional diagnostic pathways: A scoping review and recommended methods.

PURPOSE: Methodological challenges have limited economic evaluations of genome sequencing (GS) and exome sequencing (ES). Our objective was to develop conceptual frameworks for model-based cost-effectiveness analyses (CEAs) of diagnostic GS/ES. METHODS: We conducted a scoping review of economic analyses to develop and iterate with experts a set of conceptual CEA frameworks for GS/ES for prenatal testing, early diagnosis in pediatrics, diagnosis of delayed-onset disorders in pediatrics, genetic testing in cancer, screening of newborns, and general population screening. RESULTS: Reflecting on 57 studies meeting inclusion criteria, we recommend the following considerations for each clinical scenario. For prenatal testing, performing comparative analyses of costs of ES strategies and postpartum care, as well as genetic diagnoses and pregnancy outcomes. For early diagnosis in pediatrics, modeling quality-adjusted life years (QALYs) and costs over ≥20 years for rapid turnaround GS/ES. For hereditary cancer syndrome testing, modeling cumulative costs and QALYs for the individual tested and first/second/third-degree relatives. For tumor profiling, not restricting to treatment uptake or response and including QALYs and costs of downstream outcomes. For screening, modeling lifetime costs and QALYs and considering consequences of low penetrance and GS/ES reanalysis. CONCLUSION: Our frameworks can guide the design of model-based CEAs and ultimately foster robust evidence for the economic value of GS/ES.

Sex Education on TikTok: A Content Analysis of Themes.

Leading medical and public health societies endorse comprehensive sex education, but only 20 states and Washington, D.C., currently require information about contraception when sex education is taught, and even fewer require the inclusion of topics such as gender diversity or consent. At the same time, social media use, especially the video-sharing app TikTok, is increasing among teens. TikTok, therefore, offers a novel opportunity to make up for shortcomings in sex education and convey sexual health information to adolescents. To describe the availability and content of sexual education on TikTok, we conducted a content analysis of themes for 100 sex education-focused videos. We found that female anatomy was the most frequently addressed topic. Sexual pleasure was the second most common theme, within which discussions of the female orgasm and arousal constituted the most common subtheme. Other common themes include contraception and sexual health. These sought-after topics may be incongruent with those presented in standard school- or home-based sex education or interactions with health care providers, and this disconnect suggests opportunities for health care providers and educators to initiate conversations or offer resources on these themes as part of routine interaction. We conclude with recommendations for future research to consider the factual accuracy of sex education on TikTok and determine how exposure to this content affects adolescents' understanding of the risks and benefits of intercourse, sexual practices, age- and gender-based sexual norms, and other health behaviors.

Outcomes of prior authorization requests for genetic testing in outpatient pediatric genetics clinics.

PURPOSE: Genetic testing is an important diagnostic tool in pediatric genetics clinics, yet many patients face barriers to testing. We describe the outcomes of prior authorization requests (PARs) for genetic tests, one indicator of patient access to clinically recommended testing, in pediatric genetics clinics. METHODS: We retrospectively reviewed PARs for genetic tests (n = 4,535) recommended for patients <18 years of age (n = 2,798) by pediatric medical geneticists at two children's hospitals in Texas, 2017-2018. We described PAR outcomes, accompanying diagnostic codes, and diagnostic yield. RESULTS: The majority (79.9%) of PARs received a favorable outcome. PARs submitted to public payers were more likely to receive a favorable outcome compared with private payers (85.5% vs. 70.3%, respectively; p < 0.001). No diagnostic codes were associated with higher likelihood of PAR approval for exome sequencing. Among the 2,685 tests approved and completed, 522 (19.4%) resulted in a diagnosis. CONCLUSION: Though there was a high PAR approval rate, our findings suggest that insurance coverage remains one barrier to genetic testing. When completed, genetic testing had a high yield in our sample. Further evidence of clinical utility and development of clinical practice guidelines may inform payer medical policy development and improve access to testing in the future.

Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted. METHODS: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record. RESULTS: Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort. CONCLUSION: Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.

Using the Delphi method to identify clinicians' perceived importance of pediatric exome sequencing results.

PURPOSE: Information obtained from clinical exome sequencing (ES) may impact clinical care or other aspects of a patient's life. Little is known about clinicians' perceptions regarding either the value of ES results or which among various outcomes are most relevant to determine value. This study aims to assess clinicians' opinions of the importance of ES results for medical decision making and identify a set of outcomes to be measured in future ES evaluations. METHODS: Expert opinion regarding the value of remarkable (diagnostic/positive) and unremarkable (nondiagnostic/negative) ES results was elicited via the Delphi method, consisting of two survey rounds and a teleconference. Participants had expertise in caring for clinically diverse infants and children with suspected underlying genetic etiologies. Descriptive statistics and (dis)agreement were calculated for each survey item. RESULTS: Remarkable ES results were considered important for 17 outcome domains. Unremarkable ES results were also perceived as important in terms of psychological impact and ability to inform follow-up diagnostic test decisions. CONCLUSION: Clinicians regard remarkable ES results as more important in many ways than findings from other diagnostic modalities. Unremarkable ES results were not considered unimportant for decision making, but rather uncertain in most outcome domains.

Exome sequencing compared with standard genetic tests for critically ill infants with suspected genetic conditions.

PURPOSE: As exome sequencing (ES) is increasingly used as a diagnostic tool, we aimed to compare ES with status quo genetic diagnostic workup for infants with suspected genetic disorders in terms of identifying diagnoses, survival, and cost of care. METHODS: We studied newborns and infants admitted to intensive care with a suspected genetic etiology within the first year of life at a US quaternary-referral children's hospital over 5 years. In this propensity-matched cohort study using electronic medical record data, we compared patients who received ES as part of a diagnostic workup (ES cohort, n = 368) with clinically similar patients who did not receive ES (No-ES cohort, n = 368). RESULTS: Diagnostic yield (27.4% ES, 25.8% No-ES; p = 0.62) and 1-year survival (80.2% ES, 84.8% No-ES; p = 0.10) were no different between cohorts. ES cohort patients had higher cost of admission, diagnostic investigation, and genetic testing (all p < 0.01). CONCLUSION: ES did not differ from status quo genetic testing collectively in terms of diagnostic yield or patient survival; however, it had high yield as a single test, led to complementary classes of diagnoses, and was associated with higher costs. Further work is needed to define the most efficient use of diagnostic ES for critically ill newborns and infants.

Clinical Application of Genome and Exome Sequencing as a Diagnostic Tool for Pediatric Patients: a Scoping Review of the Literature.

PURPOSE: Availability of clinical genomic sequencing (CGS) has generated questions about the value of genome and exome sequencing as a diagnostic tool. Analysis of reported CGS application can inform uptake and direct further research. This scoping literature review aims to synthesize evidence on the clinical and economic impact of CGS. METHODS: PubMed, Embase, and Cochrane were searched for peer-reviewed articles published between 2009 and 2017 on diagnostic CGS for infant and pediatric patients. Articles were classified according to sample size and whether economic evaluation was a primary research objective. Data on patient characteristics, clinical setting, and outcomes were extracted and narratively synthesized. RESULTS: Of 171 included articles, 131 were case reports, 40 were aggregate analyses, and 4 had a primary economic evaluation aim. Diagnostic yield was the only consistently reported outcome. Median diagnostic yield in aggregate analyses was 33.2% but varied by broad clinical categories and test type. CONCLUSION: Reported CGS use has rapidly increased and spans diverse clinical settings and patient phenotypes. Economic evaluations support the cost-saving potential of diagnostic CGS. Multidisciplinary implementation research, including more robust outcome measurement and economic evaluation, is needed to demonstrate clinical utility and cost-effectiveness of CGS.

Multidimensional and Longitudinal Impact of a Genetic Diagnosis for Critically Ill Infants.

Background and Objectives: Many genetic conditions present in the neonatal intensive care unit (NICU), where a diagnostic evaluation is pursued. However, understanding of the impact of a genetic diagnosis on clinical outcomes and health-related quality of life for these infants remains incomplete. We therefore evaluated parent-reported outcomes complemented by clinical outcomes measures over one year for a cohort of infants in the NICU undergoing genetic evaluation. Methods: Prospective cohort study evaluating outcomes after genetics consultation in a level IV NICU via parent-report and electronic medical records (EMR) review. Eligible infants were genetically undiagnosed at enrollment. Parent surveys were administered at baseline and three, six-, and 12-months following enrollment and assessed genetic testing utility as well as parent-reported infant health-related quality of life using the Infant Toddler Quality of Life Questionnaire. Results: 110 infant-parent pairs were enrolled. Infants had a median age at enrollment of 15 days (interquartile range 8-37.75). At baseline, 74% (81/110) of parents endorsed high importance of finding a genetic diagnosis, but perceived importance significantly decreased over time. Over the study period, 38 infants received a molecular diagnosis per parent report, though this was discordant with EMR review. Identification of a diagnosis did not significantly impact health-related quality of life across most domains, which was lower overall than population norms. Conclusions: A genetic diagnosis is highly desired by parents in the NICU, though waning interest over time for undiagnosed families may reflect parental emotional adaptation and acceptance. Additional supports are needed to improve perceived quality of life.

The motivation and process for developing a consortium-wide time and motion study to estimate resource implications of innovations in the use of genome sequencing to inform patient care.

Costs of implementing genomic testing innovations extend beyond the cost of sequencing, affecting personnel and infrastructure for which little data are available. We developed a time and motion (T&M) study within the Clinical Sequencing Evidence-Generating Research (CSER) consortium to address this gap, and herein describe challenges of conducting T&M studies within a research consortium and the approaches we developed to overcome them. CSER investigators created a subgroup to carry out the T&M study (authors). We describe logistical and administrative challenges associated with resource use data collection across heterogeneous projects conducted in real-world clinical settings, and our solutions for completing this study and harmonizing data across projects. We delineate processes for feasible data collection on workflow, personnel, and resources required to deliver genetic testing innovations in each CSER project. A critical early step involved developing detailed project-specific process flow diagrams of innovation implementation in projects' clinical settings. Analyzing diagrams across sites, we identified common process-step themes, used to organize project-specific data collection and cross-project analysis. Given the heterogeneity of innovations, study design, and workflows, which affect resources required to deliver genetic testing innovations, flexibility was necessary to harmonize data collection. Despite its challenges, this heterogeneity provides rich insights about variation in clinical processes and resource implications for implementing genetic testing innovations.