Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population.

The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations.

Addressing adolescent substance use in an urban pediatric federally qualified health center.

OBJECTIVE: Screening, brief intervention, and referral to treatment (SBIRT) is a systematic approach to identification and intervention for individuals at risk for substance use disorders. Prior research indicates that SBIRT is underutilized in pediatric primary care. Yet few studies have examined procedures for identifying and addressing substance use in clinics that serve publicly insured adolescents (i.e., federally qualified health centers [FQHC]). This descriptive, multi-method study assessed adolescent substance use frequency and provider perspectives to inform SBIRT implementation in an urban pediatric FQHC in California. METHODS: A medical record review assessed substance use frequency and correlates among publicly insured adolescents aged 12-17 years who completed a well-child visit in pediatric primary care between 2014 and 2017 (N = 2252). Data on substance use (i.e., alcohol, illicit drugs, and tobacco) were from a health assessment tool mandated by Medicaid. Semi-structured interviews with 12 providers (i.e., pediatricians, nurse practitioners, behavioral health clinicians) elicited information about the current clinic workflow for adolescent substance use and barriers and facilitators to SBIRT implementation. RESULTS: Of 1588 adolescents who completed the assessment (70.5%), 6.8% reported current substance use. Self-reported use was highest among non-Hispanic Black (15.2%) adolescents and those with co-occurring depressive symptoms (14.4%). Provider-reported challenges to implementing SBIRT included a lack of space for confidential screening and a lack of referral options. Providers favored implementing technology-based tools such as tablets for adolescent pre-visit screening and electronic medical record-based decision support to facilitate brief intervention and treatment referrals. CONCLUSIONS: This study fills a substantial research gap by examining factors that impede and support SBIRT implementation in pediatric FQHC settings. Successful SBIRT implementation in these settings could significantly reduce the unmet need for substance use treatment among uninsured and publicly insured adolescents. Pediatric primary care and urgent care providers perceived SBIRT to be feasible, and health information and digital technologies may facilitate the integration of SBIRT into clinic workflows. Ensuring confidentiality for screening and expanding referral options for adolescents in need of community-based addiction treatment are also critical to increasing SBIRT uptake.

Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.

Teaching Death Disclosure: A Mixed-Method Comparison of Resident Self-Assessment and Standardized Patient Assessment.

OBJECTIVE: To characterize how pediatric resident self-evaluation compares to standardized patient evaluations in simulated child death disclosure scenarios. METHODS: This was a prospective, observational, mixed-methods study in which 18 second-year pediatric residents delivered the news of a death of a child to a trained standardized patient (SP) couple. The SPs evaluated residents via a quantitative global rating (1-3 scale) and via qualitative comments. Following the training, the residents completed self-assessments consisting of a global rating, qualitative comments, and their confidence related to 5 death disclosure skills. RESULTS: Agreement between SPs and resident ratings was poor; resident scores were compared to each of their 2 SP evaluators yielding Kappa coefficients of -0.23 (95% confidence interval = -0.60 to -0.07) and -0.30 (95% confidence interval = -0.70 to -0.04). Residents uniformly rated themselves as less capable in their communication skills than SPs did. Residents reported significant increases in their confidence in discussing autopsy and organ donation. Major themes determined from the qualitative comments from SPs included nonverbal communication, verbal communication, attunement to parents, and management of next steps. Residents' comments mirrored these themes with the exception of the absence of nonverbal communication. CONCLUSIONS: Pediatric residents underestimated their abilities in a self-assessment of their performance in a SP death disclosure scenario, demonstrating the importance of external feedback, particularly from SPs themselves. Based on SP feedback, future death disclosure trainings should emphasize nonverbal communication skills and specific behaviors that convey effective attunement to families.

Plan-Do-Study-Act Cycles Applied to a Longitudinal Research Protocol in a Family Medicine Residency.

BACKGROUND AND OBJECTIVES: Barriers to research in family medicine are common. Resident studies are at risk of remaining incomplete. This report describes a process improvement (PI) to optimize survey data collection in a longitudinal research protocol led by family medicine residents. The protocol subject to the process improvement sought to evaluate maternal outcomes in group prenatal care vs traditional care. In the months preceding the PI, the resident researchers noted many surveys were not completed in their intended timeframe or were missing, threatening study validity. We describe a practical case example of the use of a PI tool to resident-led research. METHODS: The residents applied three plan-do-study-act (PDSA) cycles over 8 months. Throughout the cycles, we solicited barriers and proposed solutions from the research team. Process measures included percentage of surveys completed within 2 weeks of the deadline ("on-time" response rate), and percentage of surveys completed overall. RESULTS: A secure, shared survey tracker was created and optimized during three PDSA cycles to calculate and track survey deadlines automatically upon enrollment in the study. Automated colored flags appeared for due or overdue surveys. On-time response rates did not improve. Overall response rates did improve meaningfully from 57% (19 of 33 eligible) to 84% (16 of 19 eligible). CONCLUSIONS: The PDSA cycles improved survey response rates in this research protocol. This intervention incurred no cost, was easily implemented, and was impactful. Other research teams can apply this PI tool to barriers in their research processes with minimal risk and cost.

Texts for Talking: Evaluation of a Mobile Health Program Addressing Speech and Language Delay.

Speech and language delays are common developmental disorders that can lead to long-term academic and psychosocial impairments. Affected families often benefit from instruction in cultivating a language-rich home environment. This study investigated the feasibility of utilizing text messaging to deliver developmental education to families. Parents of children aged 11 to 36 months with concerning language development were enrolled in a 3-month text messaging program. Pre-program and post-program telephone surveys were completed. All enrolled parents were of low socioeconomic status, and 48% were monolingual Spanish speakers. A total of 27 parents (87%) completed the program and follow-up survey. After program completion, parents reported increased awareness of language-promoting activities and local child development resources (P = .002; P = .005). Parents also reported increased engagement in language-promoting activities (P = .004). The marginal program cost was 37 cents per participant. Findings from this pilot study indicate that text messaging is a feasible, engaging, and inexpensive platform for delivering developmental education to families.

Addressing Adolescent Substance Use: Teaching Screening, Brief Intervention, and Referral to Treatment (SBIRT) and Motivational Interviewing (MI) to Residents.

BACKGROUND: The American Academy of Pediatrics Committee on Substance Use recommends screening, brief intervention, and referral to treatment (SBIRT) at every adolescent preventive and all appropriate urgent visits. We designed an SBIRT curriculum as part of the adolescent block of a pediatric residency that combined online modules with an in-person workshop, faculty feedback on resident interactions with patients, and resident self-reflection on their motivational interviewing (MI) skills. METHODS: To evaluate the curriculum, we measured resident satisfaction and self-reported confidence in using SBIRT and MI with teens using a retrospective pre/post questionnaire. We used qualitative analysis to evaluate the written comments from faculty observations of patient-trainee interactions and comments from resident self-reflection(s) on patient interactions. RESULTS: Thirty-two residents completed the curriculum. Residents reported high satisfaction with the training. Comparing retrospective pre/post scores on the survey of resident self-reported confidence, measures increased significantly in all domains, including for both alcohol and other drug use. Regarding self-reported MI, skillfulness also increased significantly. Analysis of specific faculty feedback to residents revealed subthemes such as normalizing confidentiality and focusing more on the patient's perspectives on substance use. Resident reflections on their own abilities with SBIRT/MI focused on using the ruler tool and on adapting the MI style of shared decision-making. CONCLUSIONS: A curriculum that combines online training, small-group practice, clinical observations, and self-reflection is valued by residents and can increase resident self-reported confidence in using SBIRT and MI in adolescent encounters. Future studies should examine to what extent confidence predicts performance using standardized measures of MI skillfulness in patient encounters.

Institutional review board practices regarding assent in pediatric research.

OBJECTIVE: To assess how Institutional Review Boards (IRBs) implement the assent requirement for research with children. METHODS: Telephone interviews were conducted with 188 chairpersons of IRBs from a range of institutions nationwide. Respondents were queried on 4 topics: 1) which children are considered capable of assent, 2) which information investigators must provide pediatric research subjects, 3) whether IRBs favor the enrollment of children who are capable of assent, and 4) how chairpersons view payment for children's research participation. RESULTS: Half of IRBs have a method that they require investigators to follow when determining which children are capable of assent, most commonly an age cutoff. Half of IRBs do not have a method, and the majority rely on investigators' clinical judgment. IRBs largely follow the adult research regulations when determining which information should be provided to an assenting child. A total of 58% of IRBs would enroll a child who is incapable of assent in a nonbeneficial study, even if children who are capable of assent could be enrolled instead. Almost half (46%) of chairpersons believe that it sometimes or always acceptable to offer incentive payments to children, and more than one third (35%) thought it acceptable to offer payment to the parents. CONCLUSION: When possible, IRBs follow the federal regulations for research with adults when implementing the assent requirement. For considerations that do not have analogs in the adult regulations, IRB practices vary widely. These data suggest that IRBs need guidance on how to implement the assent requirement in a way that provides appropriate protections for pediatric research subjects.

How do institutional review boards apply the federal risk and benefit standards for pediatric research?

CONTEXT: Federal regulations allow children in the United States to be enrolled in clinical research only when the institutional review board (IRB) determines that the risks are minimal or a minor increase over minimal, or that the research offers a prospect of direct benefit. Despite this reliance on IRBs, no data exist on how IRBs apply the risk and benefit categories for pediatric research. OBJECTIVE: To determine how IRB chairpersons apply the federal risk and benefit categories for pediatric research. DESIGN, SETTING, AND PARTICIPANTS: Telephone survey, conducted between May and August 2002 of 188 randomly selected chairpersons of IRBs in the Unites States. The survey consisted of 21 questions to assess the application of federal risk standards to research procedures, whether certain interventions offer a prospect of direct benefit to participating children, and the extent to which IRBs use the federal definition of minimal risk when categorizing the risks of research procedures in children. MAIN OUTCOME MEASURES: Responses regarding categorization of the risk level and direct benefits of pediatric research procedures. RESULTS: A single blood draw was the only procedure categorized as minimal risk by a majority (152 or 81%) of the 188 respondents. An electromyogram was categorized as minimal or a minor increase over minimal risk by 100 (53%) and as more than a minor increase over minimal risk by 77 (41%). Allergy skin testing was categorized as minimal risk by 43 IRB chairpersons (23%), a minor increase over minimal risk by 81 (43%), and more than a minor increase over minimal risk by 51 (27%). Regarding benefits, 113 chairpersons (60%) considered added psychological counseling to be a direct benefit, while participant payment was considered a direct benefit by 10% (n = 19). CONCLUSIONS: Application of the federal risk and benefit categories for pediatric research by IRB chairpersons is variable and sometimes contradicted by the available data on risks and the regulations themselves. To protect children from excessive risks while allowing appropriate research, IRB chairpersons need guidance on applying the federal risk and benefit categories and also need data on the risks children face in daily life and during routine physical or psychological tests.