The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The "BabySeq Project" is a randomized trial that explores the medical, behavioral, and economic ...impacts of integrating genomic sequencing into the care of healthy and sick newborns.
Families of newborns are enrolled from Boston Children's Hospital and Brigham and Women's Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns.
The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns.
The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015.
Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader ...and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants’ known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant’s known clinical or family history, and the interpretation of results can substantially benefit from parental testing.
Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value.
To describe the effect on clinical care and outcomes of adding WGS to ...standardized family history assessment in primary care.
Pilot randomized trial. (ClinicalTrials.gov: NCT01736566).
Academic primary care practices.
9 primary care physicians (PCPs) and 100 generally healthy patients recruited at ages 40 to 65 years.
Patients were randomly assigned to receive a family history report alone (FH group) or in combination with an interpreted WGS report (FH + WGS group), which included monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits. Each patient met with his or her PCP to discuss the report.
Clinical outcomes and health care use through 6 months were obtained from medical records and audio-recorded discussions between PCPs and patients. Patients' health behavior changes were surveyed 6 months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results.
Mean age was 55 years; 58% of patients were female. Eleven FH + WGS patients (22% 95% CI, 12% to 36%) had new MDR results. Only 2 (4% CI, 0.01% to 15%) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). Primary care physicians recommended new clinical actions for 16% (CI, 8% to 30%) of FH patients and 34% (CI, 22% to 49%) of FH + WGS patients. Thirty percent (CI, 17% to 45%) and 41% (CI, 27% to 56%) of FH and FH + WGS patients, respectively, reported making a health behavior change after 6 months. Geneticists rated PCP management of 8 MDR results (73% CI, 39% to 99%) as appropriate and 2 results (18% CI, 3% to 52%) as inappropriate.
Limited sample size and ancestral and socioeconomic diversity.
Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Nongeneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value.
National Institutes of Health.
The development of massively parallel sequencing (or next-generation sequencing) has facilitated a rapid implementation of genomic sequencing in clinical medicine. Genomic sequencing (GS) is now an ...essential tool for evaluating rare disorders, identifying therapeutic targets in neoplasms, and screening for prenatal aneuploidy. Emerging applications, such as GS for preconception carrier screening and predisposition screening in healthy individuals, are being explored in research settings and utilized by members of the public eager to incorporate genomic information into their health management. The rapid pace of adoption has created challenges for all stakeholders in clinical GS, from standardizing variant interpretation approaches in clinical molecular laboratories to ensuring that nongeneticist clinicians are prepared for new types of clinical information. Clinical GS faces a pivotal moment, as the vast potential of new quantities and types of data enable further clinical innovation and complicated implementation questions continue to be resolved.
Clinical sequencing emerging in health care may result in secondary findings (SFs).
Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing ...Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions.
The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care.
Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.
Newborn genomic sequencing (nGS) has great potential to improve pediatric care. Parental interest and concerns about genomics are relatively unexplored. Understanding why parents decline research ...consent for nGS may reveal implementation barriers.
We evaluated parental interest in a randomized trial of nGS in well-baby and intensive care unit nursery settings. Interested families attended an informational enrollment session (ES) with a genetic counselor prior to consenting. Reason(s) for declining participation and sociodemographic associations were analyzed.
Of 3860 eligible approached families, 10% attended ES, 67% of whom enrolled. Of 1760 families queried for decline reasons, 58% were uninterested in research. Among 499 families considering research, principal reasons for decline prior to ES included burdensome study logistics (48%), feeling overwhelmed postpartum (17%), and lack of interest/discomfort with genetic testing (17%). Decliners after ES more often cited concerns about privacy/insurability (41%) and uncertain/unfavorable results (23%).
Low interest in research and study logistics were major initial barriers to postpartum enrollment and are likely generic to many postpartum research efforts. Concerns over privacy and result implications were most commonly cited in decliners after ES. Understanding parental concerns around research nGS may inform future integration of nGS into newborn screening, predictive testing, and pediatric diagnostics.
Medication-related harm represents a significant issue for patient safety and quality of care. One strategy to avoid preventable adverse drug events is to utilize patient-specific factors such as ...pharmacogenomics (PGx) to individualize therapy.
We measured the number of patients enrolled in a health-system biobank with actionable PGx results who received relevant medications and assessed the incidence of adverse drug events (ADEs) that might have been prevented had the PGx results been used to inform prescribing.
Patients with actionable PGx results in the following four genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines were identified: HLA-A*31:01, HLA-B*15:02, TPMT, and VKORC1. The patients who received interacting medications (carbamazepine, oxcarbazepine, thiopurines, or warfarin) were identified, and electronic health records were reviewed to determine the incidence of potentially preventable ADEs.
Of 36,424 patients with PGx results, 2327 (6.4%) were HLA-A*31:01 positive; 3543 (9.7%) were HLA-B*15:02 positive; 2893 (7.9%) were TPMT intermediate metabolizers; and 4249 (11.7%) were homozygous for the VKORC1 c.1639 G>A variant. Among patients positive for one of the HLA variants who received carbamazepine or oxcarbazepine (n = 92), four (4.3%) experienced a rash that warranted drug discontinuation. Among the TPMT intermediate metabolizers who received a thiopurine (n = 56), 11 (19.6%) experienced severe myelosuppression that warranted drug discontinuation. Among patients homozygous for the VKORC1 c.1639 G>A variant who received warfarin (n = 379), 85 (22.4%) experienced active bleeding and/or international normalized ratio (INR) > 5 that warranted drug discontinuation or dose reduction.
Patients with actionable PGx results from a health-system biobank who received relevant medications experienced predictable ADEs. These ADEs may have been prevented if the patients' PGx results were available in the electronic health record with clinical decision support prior to prescribing.
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