Maya C. del Rosario

Purpose: It is essential that studies of genomic sequencing (GS) in newborns and children include individuals from under-represented racial and ethnic groups (URG) to ensure future applications are equitably implemented. We conducted interviews with parents from URG to better understand their perspectives on GS research, develop strategies to reduce barriers to enrollment, and facilitate research participation. Methods: Semi-structured interviews with 50 parents from URG. Results: Nearly all parents (44) said they would be interested in participating in an infant GS study. Parents were interested in participating in GS research for reasons including clinical utility, personal utility, and/or family health benefits. Deterrents to enrollment cited by parents were discomfort with enrollment procedures (e.g., not wanting a heel stick), limited emotional bandwidth, unfavorable perceptions of the study, and concerns about potential results. Most parents (35 of 40) said they would want to receive all types of genetic results, including actionable and non-actionable, as well as childhood- and adult-onset. Conclusion: Our findings demonstrate that parents from URG are interested in participating in GS research. Based upon these findings, we provide recommendations for designing GS studies that are responsive to their concerns.

The electronic MEdical Records and GEnomics (eMERGE) consortium will return risk reports pertaining to specific diseases, a key component of which will be polygenic risk scores (PRS), to 25,000 participants, including 5000 children. Understanding comprehension and the perceived value of these PRS-based reports among parents will be critical for effective return of results in children. To address this issue, we conducted semi-structured interviews with 40 African American and Hispanic parents at The Children’s Hospital of Philadelphia and Boston Children’s Hospital. Each participant received a hypothetical risk report identifying their child as high risk for either type 2 diabetes or asthma. Participants were assessed on their comprehension of absolute versus relative risk framing, likelihood of following risk-reduction recommendations, perceived value of the information, psychosocial impact, education/support needed, and suggestions to improve the PRS-based report to make it more accessible. Results demonstrated high perceived value in receiving PRS-based reports but also draws attention to important shortfalls in comprehension due to factors including the health of the child, family history, and how the risk was framed. This study provides an insight into implementing the return of genomic risk scores in a pediatric setting.

Genomic sequencing is a powerful diagnostic tool in critically ill infants, but performing exome or genome sequencing (ES/GS) in the context of a research study is different from implementing these tests clinically. We investigated the integration of rapid ES into routine clinical care after a pilot research study in a Level IV Neonatal Intensive Care Unit (NICU). We performed a retrospective cohort analysis of infants admitted with suspected genetic disorders to the NICU from December 1, 2018 to March 31, 2021 and compared results to those obtained from a previous research study cohort (March 1, 2017 to November 30, 2018). Clinical rapid ES was performed in 80/230 infants (35%) with a suspected genetic disorder and identified a genetic diagnosis in 22/80 infants (28%). The majority of diagnoses acutely impacted clinical management (14/22 (64%)). Compared to the previous research study, clinically integrated rapid ES had a significantly lower diagnostic yield and increased time from NICU admission and genetics consult to ES report, but identified four genetic diagnoses that may have been missed by the research study selection criteria. Compared to other genetic tests, rapid ES had similar or higher diagnostic yield and similar or decreased time to result. Overall, rapid ES was utilized in the NICU after the pilot research study, often as the first-tier sequencing test, and could identify the majority of disease-causing variants, shorten the diagnostic odyssey, and impact clinical care. Based on our experience, we have identified strategies to optimize the clinical implementation of rapid ES in the NICU.

Background Identifying a precise genetic diagnosis can improve outcomes for individuals with rare disease, though the resources required to do so may impede access and exacerbate healthcare disparities leading to inequitable care. Our objective was therefore to determine the effect of multiple sociodemographic factors on the yield of the diagnostic evaluation for genetics outpatients. Methods This is a retrospective cohort study from 2017 to 2019 of outpatient genetics referrals at a pediatric academic tertiary care center. Exposures included: primary language, insurance type, and neighborhood resources (via the Childhood Opportunity Index, COI). The primary outcome was identification of a genetic diagnosis within 2 years of the initial clinic visit. Results COI quintile was not significantly associated with the odds of diagnosis but was significantly associated with clinic attendance, with lower neighborhood resources leading to incomplete referrals. Limited English proficiency was associated with a higher odds of diagnosis, though at an older age. Public insurance was associated with increased access to genetic testing. Conclusions Lower neighborhood resources are negatively associated with clinic attendance. Our findings further suggest delays in care and a referral bias for more severe phenotypes among families with limited English proficiency. Improved access to clinical genetics is needed to improve diagnostic equity. Impact The resources required to identify a genetic diagnosis may impede access and exacerbate healthcare disparities leading to inequitable care. In an analysis of pediatric outpatient genetics referrals, we observed a significant association between neighborhood resources and clinic attendance but not diagnostic yield for those attending, and a higher diagnostic yield for families with limited English proficiency, suggesting referral bias for more severe phenotypes. Thus, the primary barrier to finding a genetic diagnosis was initiation of care, not the ensuing diagnostic odyssey. Further research efforts should be directed at increasing access to clinical genetics evaluations for children with rare disease.